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Feline leukaemia virus (FeLV)

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  • Disciplina: Malattie infettive
  • Specie: Gatto

Feline leukaemia virus (FeLV), family Retroviridae, genus Alpharetrovirus, is responsible for  one of the most important infectious diseases of the cat. Indeed, FeLV is among the leading causes of death of domestic cats, especially in those living in close contact with each other (the virus does not survive long in the environment). The FeLV genome contains three genes: the envelope gene (env), which codes for a surface glycoprotein (gp70) and a transmembrane protein (p15E); the polymerase gene (pol), which codes for reverse transcriptase, protease and integrase; and the gene for the group-specific antigens (gag), which codes for the proteins of the viral nucleus, including protein p27. There are four subtypes of the virus, A, B, C and T, which are differentiated based on the type of host cell; of these, only subtype B can be transmitted among cats. The other subtypes develop as a result of recombination with an endogenous sequence of feline DNA.

 

TRANSMISSION

FeLV is extremely labile and can be destroyed in a few minutes by atmospheric conditions; consequently the most common route of infection is contact with infected body fluids, especially saliva, but also nasal secretions, urine, faeces and maternal milk. Transmission can, therefore, take place through normal social contact or grooming, as well as through bite wounds, and is more likely in environments in which the cat density is high. In pregnant queens with viraemia, the usual outcome is intrauterine or neonatal death, whereas in the presence of a latent infection the virus is normally not transmitted to the foetuses; only rarely will a few kittens result positive. In such cases the transmission may take place because the latent virus can survive in a single mammary gland and become reactivated. The infection is most commonly diagnosed in cats between 1 and 6 years of age. Kittens under 5 months of age are particularly vulnerable to becoming persistently infected. Adult cats are more resistant to the infection.

 

PATHOGENESIS

Following oronasal contagion the virus initially replicates within the tonsils and local lymphoid tissues before spreading to lymphocytes and to the lymphoid system and finally to the bone marrow, the epithelium of the intestinal and respiratory mucosae and the salivary glands (viraemic stage). This process lasts 2-4 weeks. If the virus localises to the bone marrow, a latent infection may be established. At times the viraemia may develop a few months after a constant exposure to the virus. The mechanism which regulates the development and maintenance of viraemia is linked to the more or less correct functioning of the immune system. Viral factors which have an impact on the development of  viraemia are the dose and virulence of the viral strain, the age of the host and the route of infection.

Once infected with FeLV there are four possible outcomes:

  1. the cat may develop persistent viraemia; this takes place in about 33% of cats exposed to the virus; most of these subjects develop the clinical signs of  infection-related diseases, which will be the cause of death of the animals within 3-5 years.
  2. In the remaining 66% of cats, after an initial transient viraemia, evolution into a persistent viraemia does not occur, perhaps because of a rapid and effective humoral immune response which neutralises the virus. The infection in transiently infected cats usually resolves within 4-6 weeks after viral penetration (extinction of the infection);
  3. about 33% of  cats with a transient viraemia are not capable of eliminating all the infected cells within 4-6 weeks and develop a latent infection. In such cases the virus remains “hidden” within the bone marrow and may be “re-expressed” (with the development of a new viraemic phase) following specific stimuli or steroid treatment. Latent FeLV infections in cats are usually extinguished within 3 years. Cats with a transient viraemia do not develop FeLV-related diseases and the virus cannot be detected in the blood.
  4. Some cats (5%) may develop a (localized)  focal form of the infection. In this case the virus is sequestered within some tissues, such as the gastrointestinal tract, spleen and bone marrow, where it can continue to replicate. An infection localized within the mammary gland tissues may  be transmitted to kittens during nursing.

 

EPIDEMIOLOGY

FeLV infection is distributed throughout the world. Its prevalence is influenced by the density of the feline population, with a major role played also by environmental and geographic conditions. In some areas of Europe, Canada and the USA the prevalence may vary greatly between cats living alone in a domestic setting (about 1-2%) and free-roaming or community cats (13-20%), as shown in greater detail in Table 1. Thanks to the use of vaccination programmes and the more extensive use of tests, the importance of FeLV has gradually decreased over the last 25 years.

 Table 1: Prevalence of  FIV and FeLV

 

CLINICAL SIGNS

The most common clinical signs of persistent FeLV viraemia are immunosuppression, anaemia and lymphoma. Less common manifestations are immune-mediated diseases, chronic enteritis, reproductive disorders and peripheral neuropathies. Most cats with a persistent viraemia die within 2-3 years.

The clinical scenarios which follow FeLV infection depend on various factors, such as the viral strain, the dose and duration of the exposure, the immune status and the age of the cat at the time of infection: it has been shown that sensitivity to the infection is inversely proportional to the age of the animal. The exact mechanism underlying the development of the various clinical manifestations in cats with a persistent viraemia is still not well known. It is, however, clear that the clinical evolution is determined by a combination of viral and host-related factors; other variables may be the immunosuppressive properties of the virus itself and the presence of various subtypes, which may be responsible for the differences in the clinical pictures of the patients (FeLV-B is mostly associated with tumours while FeLV-C is mostly linked to the presence of non-regenerative forms of anaemia). The manifestations typically related to FeLV  infection usually develop with 3 years of the beginning of the infection and are extremely variable and often difficult to define, but lead to the death of about 70% of the patients. The manifestations mainly include disorders related to immunosuppression, anaemia,  lymphoid malignancies, but also dermatitis and immune-mediated disorders.

Lymphoma and FeLV

FeLV-positive cats have a 60-fold higher risk of developing lymphomas compared to FeLV-negative cats. Lymphomas seem to develop in about 25% of infected cats, tending to occur in young animals about 2-4 years old;  the most frequently diagnosed forms are mediastinal (thymic or, more frequently, lymph node) lymphoma (Figs. 1 and 2) and multicentric lymphoma. Although less common, renal, spinal and atypical (cutaneous, ocular) lymphomas may also be observed in FeLV-positive animals. The form that is least frequently associated with FeLV infection is gastrointestinal tract lymphoma. Based on these data it is clear that any cat that develops a lymphoma MUST undergo a test for FeLV; the test is also useful for determining the prognosis of the disease.

Immunosuppression
FeLV-induced immunosuppression is more complex and severe than the immunosuppression  caused by Feline immunodeficiency virus (FIV). There are reports of thymic atrophy, lymphocytopenia, neutropenia (greater during the acute phase of the infection), partial reduction of CD4+ lymphocytes and, more severe, a loss of CD8+ lymphocytes.

Independently of whether or not the cat shows infection-related clinical signs, all FeLV-viraemic cats are immunosuppressed. This may favour infections caused by other agents to which the cat should normally be resistant, such as Salmonella spp. Furthermore, some other infectious diseases may be exacerbated, such as those by poxvirus, Mycoplasma haemofelis, Cryptococcus spp. andToxoplasma gondii (this last is usually rare in cats with a functioning immune system).

Anaemia
Anaemia is one of the most important and evident clinical signs (Figs. 3 and 4) and is caused by the primary viral infection (often by FeLV-C subtype strains) of totipotent  haematopoietic cells (stem cells) and stromal cells, which form the supportive structure for haematopietic cells. A severe non-regenerative anaemia is the  most common form, often associated with a marked depletion and  block of maturation of erythroid precursurs within the bone marrow. A haemolytic regenerative anaemia in FeLV-positive cats is rarer, and usually occurs in the presence of co-infection by Mycoplasma haemofelis or M. haemominutum. It is also worth recalling that about one-third of cats with immune-mediated haemolytic anaemia are FeLV-positive. Other cytopenias, in particular thrombocytopenia and neutropenia, can also be present in anaemic subjects, most likely caused by FeLV-induced immune-mediated mechanisms and by bone marrow suppression.

A full-blown bone marrow aplasia is not frequent in FeLV-positive cats; however, there are some reports showing that when such aplasia is present in young subjects, in most cases the patient is also FeLV-positive.

Other diseases
Many immune-mediated diseases may be the consequence of a FeLV infection, including, as already mentioned, haemolytic anaemia, but also glomerulonephritis (rare) and polyarthritides. A benign, peripheral lymphadenopathy is commonly diagnosed in FeLV-infected cats, and it often appears during the first stages of the viraemia. Sometimes it can be so severe as to be mistaken for a multicentric lymphoma. A particular form of chronic enteritis, with degeneration of the intestinal epithelial cells and necrosis of the crypts, has been diagnosed in conjunction with the infection, as have inflammatory and degenerative liver diseases. Reported reproductive system manifestations (rare) include cases of foetal reabsorption, neonatal death and  “fading kitten syndrome”. Neurological expressions, apart from those related to the development of a lymphoma in the central nervous system, mostly consist in the appearance of a peripheral neuropathy, which can be manifested as anisocoria, mydriasis, Horner’s syndrome, urinary incontinence (mostly nocturnal), anomalous vocalizations, hyperaesthesia, paresis and paralysis.

 

LABORATORY ALTERATIONS

The most important laboratory alteration is undoubtedly anaemia, associated or not with other cytopenias. The only biochemical alteration that can be directly correlated to a FeLV-positive status is hyperproteinaemia with  polyclonal gammopathy, which is not, however, specific to FeLV.

 

DIAGNOSTIC TESTS

It is always important to assess the retroviral status of a cat because the consequences of the infection are nearly always fatal. An accurate diagnosis is, therefore, important for both infected and non-infected subjects. Some guidelines have been prepared in order to understand the criteria to be followed when testing an apparently healthy or a sick cat.

There are essentially two types of tests for diagnosing FeLV infections: those that assess the cell-associated viraemia (immunofluorescence) and those that detect the serum-associated viraemia (p27 ELISA, immunochromatography). The immunofluorescent assay (IFA) is carried out only in specialised laboratories while the ELISA is commonly performed in most laboratories and even in veterinary clinics. The ELISA is about 100 times more sensitive than the IFA and only rarely gives false negative results;  it also allows an earlier diagnosis. When these assays are used in a veterinary clinic it is extremely important to avoid technical mistakes and the instructions of the test’s manufacturer must be followed carefully; most of these tests are carried out on whole blood or serum. The specificity and sensitivity of these tests is often close to 95%, although some differences have been reported (Hartmann et al., 2007; Pinches et al., 2007a EBM grade I) (Table 2).

Interpretation of FIV/FeLV tests

FeLV: the tests more commonly used to diagnose FeLV infections are ELISA and immunochromatography

  • a doubtful positive test in an healthy cat must be confirmed, preferably by using a provirus-polymerase chain reaction (DNA PCR) test;
  • a positive test in a cat with clinical signs suggestive of FeLV infection is probably correct;
  • a cat positive in serum or plasma FeLV tests is viraemic, and can remain viraemic for at least 2-6 weeks or, in rare cases, for even longer. Consequently every cat with a positive test  must be retested after a few weeks or months;
  • a cat which eliminates the infection becomes negative in virus isolation, ELISA, immunochromatography, IFA and RNA PCR tests, although it can result positive in a DNA PCR test [Gomes-Keller et al., 2006a]; these cats must be considered as having a latent infection, and clinical signs of FeLV will be rare;
  • a persistently infected cat is positive in rapid tests and RNA PCR analysis;
  • a small number of cats (2-3%) which have eliminated the virus still remain positive in ELISA or immunochromatography.
  • these cats have residual foci of infection outside the bone marrow, from which the soluble p27 is released into the circulation; these cats are a potential source of infection [Lutz et al., 1980c]

Table 2. Interpretation of the results of tests for feline retrovirus.

 

Discrepancies between tests. Discrepancies between the results of an ELISA and indirect immunofluorescence (IIF)  may also be present in other cases; however, the reason for such discrepancies lies mainly in the different targets of the two tests. Both assays detect the presence of the virus in the blood,  but the former detects the free virus in the serum, while the second detects virus within leucocytes/platelets: a positive ELISA therefore identifies both persistent and transient viraemia, while a positive result by IIF (which detects the cell-associated antigen) signifies persistent viraemia of blood or bone marrow origin.

In latent infections, and in the so-called “atypical infections”, the reduced antigenaemia, which is often intermittent, and the occasional elimination of the virus are detected exclusively by an ELISA. This assay often gives different results for the same cat: a conversion of a positive to negative result 1 month after a first positive test means that the animal has been able to counteract the diffusion of the virus. It has also been demonstrated that positive results of immune-enzymatic tests can include some false-positive results, caused by the presence of anti-mouse antibodies – found in a very limited number of cat sera- which interfere with the correct interpretation of the test as they bind non-specifically to the murine monoclonal antibodies used in the commercial kits.

It must be underlined that the positive predictive value of the test (the probability that a positive result really indicates an infected subject) is lower than the negative predictive value (the probability that a negative result really indicates a non-infected subject). This means that for each cat a careful assessment of the results of the serological tests is necessary, bearing in mind the existing limitations of each single test. From a diagnostic point of view specific additional problems arise when dealing with extremely young patients.

Molecular biology diagnostic techniques
One of the limiting factors of  ELISA and IIF assays is their poor sensitivity in detecting low levels of circulating antigens and  latent FeLV. In such cases PCR  may be used, which has been successfully employed in the diagnosis of infections caused by other retroviruses such as  human immunodeficiency virus (HIV) and feline immunodeficiency virus (FIV).

A PCR assay is capable of detecting both the proviral DNA and the viral RNA of FeLV in both blood and tissues. In a study carried out by Miyazawa and Jarrett  positivity by viral isolation and the IIF test was then confirmed with the PCR technique, with positive results also for the so-called “discordant” cases -  i.e., cats that are antigen-positive but not viraemic, positive for protein p27 in the ELISA but negative by viral isolation tests and IIF – suggesting a possible use of PCR in the assessment of “discordant” cases.

PCR has also been used successfully to study the viral genome starting from oral and ocular tissues and from FelV-induced tumours. This technique is extremely important for that minority of patients, usually adults, which are not viraemic but which develop tumours following FeLV infection with subsequent elimination of the virus or its sequestration in some districts of the body.

Use of PCR in the diagnosis of FeLV

  • PCR to detect the provirus (DNA PCR)
  • PCR to detect RNA (RNA PCR)

 

THERAPEUTIC APPROACH

To date there are relatively few effective therapeutic protocols aimed directly at eliminating FeLV infection. It is important to remember that the diseases present in FeLV-positive cats are often secondary disorders, caused by immunosuppression and not by the direct effect of the viral infection. When dealing with diseases caused by a retrovirus the correct approach should, therefore, be to maintain an optimal state of health of the animal in order to avoid the possibility of it contracting other diseases that could aggravate the underlying condition. If the cat is sick, an accurate diagnosis of the existing problem is crucial, as prompt, precise identification of secondary diseases is essential in order to implement the most appropriate therapeutic intervention.

If a FeLV-positive cat lives in a community or in a group the first rule is to separate this animal from non-infected cats. To avoid the spread of the disease the cat should also be confined in a secluded environment; each infected cat, whether male or female, must be sterilized to avoid the risk of transmission. One additional advantage resulting from isolation is that this prevents the cat from contracting other infections, which could worsen the clinical status of the patient. Something to remember is that good nutrition and optimal hygiene are essential to maintain the good health of FeLV-positive patients. A programme of periodic controls should always be implemented in order to prevent the transmission of gastrointestinal, pulmonary and ecto-parasites. Contact with food which may potentially transmit bacterial or parasitic (Toxoplasma) infections should be avoided, as the risk of disease in immunocompromised patients is extremely high. During control examinations special attention should be paid to the respiratory tract, lymph nodes and the oral cavity, so as to identify lymphatic alterations (persistent lymphoadenopathies, the development of lymphomas [4]), or the development of faucitis/stomatitis as soon as possible. The weight of the cat should also be monitored carefully, as weight loss is one of the first clinical signs of a deteriorating condition in a cat. A FeLV-positive cat must, therefore, be evaluated regularly, by periodically performing a full blood count, biochemistry panel and urinalysis. In view of the high prevalence of virus-correlated haematological disorders in FeLV-infected cats a complete blood count should be carried out at least every 6 months.

To date there are relatively few effective therapeutic protocols aimed at eliminating FeLV infection. It is worth recalling that the diseases present in FeLV-positive cats are often secondary disorders caused by immunosuppression and not by a direct effect of the viral infection.

It should also be remembered that many cats infected by FeLV, like those infected by FIV respond to specific therapies just as well as healthy cats, although more aggressive or prolonged therapy may sometimes be necessary.

Specific treatments
Various drugs and protocols have been used to treat FeLV. It has often been suggested that  “immunomodulatory agents” be used in order to restore the function of the immune system of FeLV-infected subjects, and to help the patient to maintain the viraemia under control and to reduce the incidence of correlated diseases. Antiretroviral drugs, on the other hand, should play a role in containing the infection. The immunomodulatory agents  include Acemannan,  Propionibacterium acnes (ImmunoRegulin), human interferon-alpha at low doses, Staphylococcus A (SpA) and  PIND-ORF (Baypamune). There are many doubts concerning the efficacy of these therapies, mainly because of the lack of published placebo-controlled clinical trials. The efficacy of antiviral agents has yet to be confirmed; there are many publications suggesting the efficacy of some of these drugs, while the results of others are more questionable. In fact only a few controlled studies show some positive effects. The drugs which can be used are: AZT/zidovudine (Retrovir) (5-15 mg/kg s.c. b.i.d.); high doses of human interferon-alpha (10,000-1,000,000 U/kg/die s.c.) and high doses of  recombinant feline interferon-omega (Virbagen Omega, Virbac) (1 million U/kg/die s.c. for 5 days starting on days 0, 14, and 60).

 

PREVENTION

The European Advisory Board on Cat Diseases (ABCD) considers FeLV vaccination as a “non-core” vaccination, meaning “non-essential”. In many circumstances, however, the FeLV vaccine should be considered as an essential component of a good prevention programme against infectious diseases of the cat. The plan for prophylactic vaccination should, however, be customised for each single patient, based on the real risk of exposure, which varies with the age and state of health of the cat, degree of environmental exposure and the geographical prevalence of the disease.

 

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