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clinician’s update
™
Feline Infectious
Disease Protection
INTRODUCTION
The 2013–2014 National Pet Owner Survey
reported 37.3% of US households own a
total of 95.6 million cats.1 Unfortunately,
while cats make up more than half of the pet
population, they comprise only 39% of the
veterinary patient base.2 Owner misconceptions that indoor cats do not get sick and
that cats do not need veterinary care as they
age are two factors contributing to this discrepancy in care.2
Compounding this are concerns that have
been raised about vaccines and vaccine safety over recent years, leading some cat owners to be less inclined to want to vaccinate
their cats, especially if the cat spends all or
most of its time indoors. Restricting a cat to
the home does not, however, eliminate its
risk for infectious disease. The American
Association of Feline Practitioners (AAFP)
has formulated protective objectives that
include vaccinating the greatest number of
cats in the population at risk, vaccinating
against only those infectious diseases for
which a cat is at risk, vaccinating only when
potential benefits outweigh potential risks,
and vaccinating appropriately for public
health protection.3 Toward this end, the
AAFP has developed a list of core vaccines
recommended for all cats, noncore vaccines
for cats in specific risk groups, and vaccines
not generally recommended (see AAFP
Vaccine Categories).
In the following special report, recognized
experts in feline medicine discuss some of
the most pressing concerns of small animal practitioners with the most up-to-date
evidence-based medicine available today.
REFERENCES
1. 2013/2014 National Pet Owner Survey. Greenwich,
CT: American Pet Products Association, 2013.
(americanpetproducts.org)
2. Bayer Veterinary Care Usage Study, 2011. Available
at: http://www.ncvei.org/articles/FINAL_BAYER_
VETERINARY_CARE_USAGE_STUDY.pdf
3. The 2006 American Association of
Feline Practitioners Feline Vaccine
Advisory Report. AAFP Feline Vaccine
Advisory Panel. JAVMA 229:1405-1441,
2006.
INSIDE:
• What you need to know
about FeLV and FIV
• Risk assessment and
creating a vaccine protocol
• The latest on feline
injection-site sarcoma
AAFP Vaccine Categories
Core:
• Feline panleukopenia virus
(FPV)
• Feline herpesvirus-1 (FHV-1)
• Feline calicivirus (FCV)
• Rabies virus
Noncore:
• Feline leukemia virus (FeLV)
• Feline immunodeficiency
virus (FIV)
• Chlamydophila felis
• Bordetella bronchiseptica
Generally Not
Recommended:
• Feline infectious peritonitis
(FIP) virus
• Feline Giardia
Spending all or most of its time indoors does not
eliminate a cat's risk for infectious disease.
clinician’s update™ • 1
Feline Retroviruses
Carrie R. White, DVM, DACVIM
VCA Family Animal Hospital
Pearl City, Hawaii
FELINE LEUKEMIA VIRUS
Acute infection with
FeLV may follow 1
of 2 main courses.
Prevalence & Pathogenesis
FeLV is found worldwide. While some slight
geographic and local variations exist, overall
infection rates are relatively similar and
range from 1% to 8% in healthy cats and up
to 21% in sick cats.1-5 Kittens (especially <4
months old) are at increased risk for infection; resistance develops with age. However,
adult cats may still be at risk. A recent study
revealed 67% of adult cats developed
persistent FeLV infection after challenge.5
FeLV-negative cats living with FeLV-infected cats are at increased risk for contracting
the virus. Males and females are infected
with FeLV with equal frequency; however,
outdoor cats are more likely to be infected.
Cats with abscesses are another high-risk
population for FeLV.1
Following infection, FeLV replicates in many
tissues, including bone marrow, respiratory
epithelium, and salivary glands. Social
behaviors (eg, grooming and sharing food
bowls) are effective means of transmission.
While virus may enter other body fluids and
Diagnosis of FeLV
Diagnostic Test
Sample
Detects
Interpretation
ELISA
Plasma or
serum, tears,
saliva
Free soluble
p27 antigen
Recommended screening test;
can have false negative
IFA
Blood smears,
bone marrow
Cell-associated Confirmatory test; positive
p27 antigen
indicates progressive infection
(cytoplasm)
PCR
Blood, bone
marrow,
lymph nodes,
saliva, other
tissues
Viral RNA,
proviral DNA
2 • clinician’s update™
Most sensitive test; may be
only way to detect regressive
infection; lab dependent
secretions, transmission via urine and feces is
less likely. Iatrogenic transmission, via contaminated fomites and blood transfusions,
can occur. Vertical transmission is possible
transplacentally or through the milk.
New research suggests most
regressor cats actually remain
infected for life.
Acute infection with FeLV may follow 1 of 2
main courses. An effective immune response
can eliminate antigenemia after a few weeks
(prior to bone marrow involvement); this is
called a regressive infection. Historically, it
was believed these patients had cleared the
virus; however, new research suggests most
actually remain infected for life. While these
cats have no serologic evidence of infection,
the virus persists in circulation, and provirus
can be detected by PCR. They are unlikely to
develop FeLV-associated diseases or shed
virus in saliva but could be infectious to
other cats via blood transfusion or organ
transplantation. Rarely, regressor cats may
have a recurrence of viremia, resulting in
clinical disease.
The second main outcome is progressive
infection, which results from an ineffective
immune response. In this case, there is
extensive virus replication, first in the lymphoid, mucosal, and glandular epithelial tissues, followed by the bone marrow. Cats in
this group remain persistently viremic and
antigenemic, thus positive by all testing
methods (ELISA, IFA, PCR), and are infectious to other cats. Many go on to develop
FeLV-associated diseases, often within the
first few years following infection.
Two very rare stages of FeLV infections also
exist: abortive infections, characterized by
the absence of virus, antigen, and provirus
Pathogenesis: Stages of FeLV Viremia
Remember that infection is not the same as clinical illness; FeLV- and FIV-infected cats can live
for many years with appropriate management, including twice yearly veterinary examinations.
FeLV Exposure
Ineffective Immune Response
Effective Immune Response
Progressive
Infection
Regressive
Infection
Extensive virus
replication in lymphoid
tissues, bone marrow
Persistent viremia,
antigenemia
FeLV-associated
diseases
Abortive
Exposure
Focal
Infection
Virus localized
in tissues
FeLV antigen, virus
detectable in blood for
2–3 weeks after exposure
Cats maintain proviral
DNA but are not
antigenemic long term
Unlikely to develop
FeLV-associated disease
Rare recurrence of
viremia, clinical disease
clinician’s update™ • 3
FeLV Diagnostic Algorithm
ELISA
Negative
Retest if <12 weeks old
or if recently exposed.
Consider PCR to rule out
regressive or early
infection
The AAFP now
recommends
vaccinating all
kittens against
FeLV, regardless of
risk for infection.
Positive
IFA or PCR
Retest in
6–8 weeks
Positive
Negative
Progressive
Infection
Retest in
60 days
(ELISA, IFA)
after initial infection, and focal infections,
which are restricted to tissues such as the
spleen, lymph nodes, small intestine, or
mammary gland.
Clinical Signs
FeLV infection can cause variable clinical
signs. In a study of over 8,000 FeLV positive cats, the most common presenting
signs were various infections,6 followed by
anemia, lymphoma, leukopenia or thrombocytopenia, and leukemia or myeloproliferative disorders. FeLV infection can
also cause various malignancies, most
commonly lymphoma and leukemia; however, other tumors have been reported as
well. Hematopoietic disorders, particularly
cytopenias, can occur as a result of bone
marrow suppression. Approximately 10%
A negative FeLV test result is more
reliable than a positive result; it is
important to consider the history
and clinical signs when interpreting
all results.
4 • clinician’s update™
of FeLV-associated anemias are regenerative, most often resulting from immunemediated hemolytic anemia or concurrent
mycoplasma infection, but most are nonregenerative, resulting from myelosuppression, myelodestruction, myeloproliferative
disease, neoplasia, or chronic inflammatory
disease. Immunosuppression resulting from
FeLV infection accounts for a large portion
of the morbidity and mortality of infected
cats, due either to lymphopenia or abnormal
lymphocyte function. Other disorders, such
as glomerulonephritis and reproductive disorders, have also been reported.
Diagnosis
Available diagnostic tests for FeLV have a high
negative predictive value (99% to 100%), but
a lower positive predictive value (91% to
100%). Thus, a negative result is more reliable than a positive result; it is important to
consider the history and clinical signs when
interpreting all results.
The ELISA test, which detects free soluble
FeLV–p27 antigen in plasma or serum, is
the recommended screening test. Cats
become ELISA positive in the first phase of
viremia, which is within the first weeks following infection; experimentally, most test
positive within 28 days. The ELISA test is
very sensitive but can yield false positive
results. Additionally, regressor cats or cats
with acute infection can test negative.
Immunofluorescent antibody testing (IFA)
detects cell-associated p27 antigen in blood
cells, primarily neutrophils and platelets.
Cats become positive only after bone marrow infection, which occurs after at least 3
weeks of viremia. A positive IFA result indicates bone marrow infection, thus progressive infection. Negative IFA results can be
seen either with regressive infection or initial stages of viremia. PCR can be used to
detect the FeLV virus and is currently being
offered by several commercial laboratories.
Technical errors, which can result from a
lack of standardization of current reagents
and testing protocols, can significantly
decrease the sensitivity and specificity of
this test. PCR is most useful in patients with
suspected regressive infection, as this is the
only method that will confirm the presence
of DNA without the presence of antigen.
cycline is warranted. While erythropoietin
concentrations are often elevated in cats
with FeLV-related anemia, treatment with
human recombinant erythropoietin has
anecdotally been helpful in some cases.
Cats with lymphoma and FeLV should be
treated with chemotherapy; however, FeLV
infection is a negative prognostic indicator.
Prevention
The AAFP now recommends vaccinating all
kittens against FeLV, regardless of risk for
infection. Most veterinarians administer
FeLV vaccines on an annual basis, which
aligns with the administration recommendations for the leading vaccine on the market. Of the commercially available vaccines,
the Fel-O-Vax (bi-vetmedica.com) and
Fevaxyn FeLV (merck-animal-health.com)
demonstrated up to 100% preventable fractions.7 One recent paper showed the risk for
FeLV in unvaccinated cats to be greater than
8 times higher than in vaccinated cats, lending clinical support for vaccination.8
Vaccination against FeLV does not interfere
with testing, as the available diagnostic tests
are for antigen.
REFERENCES
Based on AAFP guidelines, any sick cats
should be tested for FeLV, regardless of previous test results, age, or vaccine status. All
cats should be tested prior to adoption,
especially those entering households with
uninfected cats, as should be currently
owned cats prior to admission of a new,
uninfected cat. Any cat recently exposed to
an infected cat, or cats with exposure to the
outdoors, should be tested. All cats with
unknown FeLV status and those that will
be blood or tissue donors should be tested.
Management
It is important to treat secondary diseases
in cats with FeLV, as these patients are
often immunosuppressed. Blood transfusions are an important part of therapy for
those with anemia. If the anemia is regenerative and there is evidence of immunemediated destruction, immunosuppression is indicated. If mycoplasma infection
is suspected, antibiotic therapy with doxy-
1. Seroprevalence of feline leukemia virus and feline
immunodeficiency virus infection among cats in
North America and risk factors for seropositivity.
Levy JK, Scot HM, Lachtara JL, Crawford PC. JAVMA
228:371-376, 2006.
2. Seroprevalence of Bartonella henselae, Toxoplasma
gondii, FIV and FeLV infections in domestic cats in
Japan. Maruyama S, Kabeya H, Nakao R, et al.
Microbiol Immunol 47:147-53, 2003.
3. Seroprevalence of feline leukemia virus and feline
immunodeficiency virus infection among cats in
Canada. Little S, Sears W, Lachtara J, Bienzle D. Can
Vet J 50:644-648, 2009.
4. Prevalence of feline immunodeficiency virus and
feline leukaemia virus among client-owned cats and
risk factors for infection in Germany. Gleich SE,
Krieger S, Hartmann K. J Feline Med Surg 11:985-992,
2009.
5. Efficacy of a canarypox virus-vectored vaccine against
feline leukaemia. Poulet H, Brunet S, Boularand C, et
al. Vet Rec 153:141-145, 2003.
6. Management of healthy feline leukemia virus-positive cats. Cotter SM. JAVMA 199:1470-1473, 1991.
7. Feline leukemia virus immunity induced by whole
inactivated virus vaccination. Torres AN, O’Halloran
KP, Larson LJ, et al. Vet Immunol Immunopathol 134:
122-131, 2010.
8. Seroprevalence of feline leukemia virus and feline
immunodeficiency virus in cats with abscesses or
bite wounds and rate of veterinarian compliance
with current guidelines for retrovirus testing.
Goldcamp CE, Levy JK, Edinboro CH, Lachtara JL.
JAVMA 232:1152-1158, 2008.
Based on AAFP
guidelines, any sick
cat should be tested
for FeLV, regardless of
previous test results,
age, or vaccine status.
It is important to
treat secondary
diseases in cats with
FeLV, as these
patients are often
immunosuppressed.
clinician’s update™ • 5
FELINE IMMUNODEFICIENCY
VIRUS
Prevalence & Pathogenesis
Feline immunodeficiency virus (FIV)
prevalence varies significantly worldwide,
with rates reported at 4.3%, 28.9%, 47%,
and 2.5% in Canada, Japan, the UK, and
the United States, respectively.1-4 The
prevalence of FIV is significantly higher in
male cats than in females, and it most
commonly affects adults. As with FeLV,
cats presenting to a veterinary clinic with a
wound or abscess are also more likely to
test positive for FIV.4
Kittens up to
12 weeks of age
may test positive
due to presence
of maternal
antibodies.
In the acute phases of infection the virus
exists in salivary epithelium, lymphocytes,
plasma, and serum. Experimentally, FIV is
easily transmitted by all parenteral routes.
However, in natural settings, FIV transmission occurs primarily by bite or fight
wounds. Vertical transmission is also possible, and some kittens will acquire infection in utero or via nursing.
Pathogenesis of FIV is influenced by a
number of factors, including age at time of
infection (young animals develop clinical
signs faster), properties of the FIV isolate,
amount of virus involved with infection,
and route of infection. The hallmark of FIV
pathogenesis is progressive disruption of
normal immune function.
Diagnosis of FIV
Diagnostic Test
Sample
Detects
Interpretation
Serum
FIV-specific
antibodies
(p24)
Very sensitive and specific;
vaccine interferes; false
negative in acute phase,
in end-stage disease
Serum,
plasma
Antibodies
Confirmatory test; vaccine
interferes
IFA
Serum,
plasma
Antibodies
Confirmatory test; vaccine
interferes
PCR
Tissue
Viral DNA
Very sensitive and specific;
variable results between labs;
genomic variability of virus
problematic
ELISA
Western blot
6 • clinician’s update™
Clinical Signs
Clinical signs of FIV infection are nonspecific. In the acute phase, cats may show
fever, lethargy, acute gastrointestinal signs,
stomatitis, dermatitis, conjunctivitis, or
respiratory signs. In experimentally infected cats, enlarged lymph nodes are present
in the acute phase. This phase may last
from several days to a few weeks, after
which cats will appear clinically healthy.
The duration of this asymptomatic phase
is variable; FIV production continues in
cells and tissues and cats are still prone to
complications, thus it is not a true latent
period.
In later stages of disease, clinical signs
often reflect opportunistic infections, neoplasia, myelosuppression, and neurologic
disease. Ocular abnormalities, including
uveitis, glaucoma, and retinal hemorrhages, may be observed. Chronic renal insufficiency has been reported in FIV-positive
patients, potentially due to immune complex deposition. Neoplasia has been associated with FIV infection, and FIV-positive
cats are more likely to develop lymphoma
or leukemia compared to noninfected cats.5
Stomatitis is a common finding during any
stage of infection. The cause is unknown;
however, histopathology suggests either an
immune response to chronic antigenic
stimulation or immune dysregulation.
Diagnosis
Clinical screening is performed by detecting
circulating antibodies against the virus, most
commonly using the ELISA test, which
detects FIV-specific antibodies and is very
sensitive. Kittens up to 12 weeks of age may
test positive due to the presence of maternal
antibodies. For this reason it is advised to
retest cats at 6 months of age, at which time
they should test negative unless truly infected. Additionally, cats in the acute phase of
infection may test negative; thus, cats with a
recent history of exposure should be retested
in 8 weeks.
Confirmatory tests for FIV include western
blot, IFA, and PCR. The ELISA, western
blot, and IFA tests can all yield false positive
Diagnosis of FIV
A positive retroviral test should always be confirmed—preferably using a different method
than was used for the initial screening test.
–
Cat is likely
not infected
Retest in 60 days if
recently exposed
ELISA
<6
months
+
Consider age
of cat
Western blot
or PCR
Likely maternal
antibody
Retest when
>6 months
>6
months
+
Likely
infected
–
Likely not
infected; retest
in 6 months
to confirm
clinician’s update™ • 7
results in FIV vaccinated cats. PCR detects
viral DNA; therefore, vaccinated cats should
not test positive. An ELISA test that detects
antibodies against formalin-treated FIV
whole virus and untreated transmembrane
peptide exists, which can differentiate uninfected from infected cats, regardless of vaccination status. Developed in Japan, this test
is not currently available in the US. One
study demonstrated this discriminant
ELISA was very effective at detecting positively infected cats, regardless of vaccination
status, with very high sensitivity (97.1%)
and specificity (100%) rates.6 While PCR is
very sensitive and specific, false positive and
negative results are possible. Additionally,
the marked variability of the viral genome
raises concerns about the ability of PCR to
detect all FIV variants. Methods for this test
are not yet standardized; results from different laboratories have shown widely variable
results, with misdiagnosis of both uninfected and infected cats.7
FIV prevention
includes minimizing
risk of transmission
and vaccination.
Management
It is important to keep cats with FIV indoors.
These patients should visit the veterinarian
at least twice yearly, for a physical examination, basic blood analysis, and a urinalysis.
When underlying infections are present, cultures should be considered to determine the
most appropriate antibiotic therapy. It is recommended that intact animals be spayed or
neutered.
While the immune deficiency often associated with this disease can affect response
to vaccines, it is important to protect these
patients against diseases for which vaccines
exist. It is generally recommended that killed
vaccines be used to eliminate the potential of
cats developing illness from modified live
vaccines.
Prevention
FIV prevention includes minimizing risk of
transmission and vaccination. Vaccination
can cause false positive results using the
ELISA test for at least 1 year.8
8 • clinician’s update™
The risk versus benefit of vaccination for
each individual cat should be strongly
considered. The difficulty in yielding false
positive results in vaccinated cats may be
mitigated by microchip implantation at
the time of vaccination, as well as future
improvements in diagnostic testing for
FIV.
REFERENCES
1. Seroprevalence of feline leukemia virus and feline
immunodeficiency virus infection among cats in
Canada. Little S, Sears W, Lachtara J, Bienzle D. Can
Vet J 50:644-648, 2009.
2. Feline immunodeficiency virus in cats of Japan.
Ishida T, Washizu T, Toriyabe K, et al. JAVMA 194:221225, 1989.
3. Phylogeographic patterns of feline immunodeficiency virus genetic diversity in the domestic cat.
Carpenter MA, Brown EW, MacDonald DW,
O’Brien SJ. Virology 251:234-243, 1998.
4. Seroprevalence of feline leukemia virus and feline
immunodeficiency virus infection among cats in
North America and risk factors for seropositivity.
Levy JK, Scot HM, Lachtara JL, Crawford PC.
JAVMA 228:371-376, 2006.
5. Feline immunodeficiency virus and feline
leukemia virus infections and their relationships
to lymphoid malignancies in cats: A retrospective
study (1968-1988). Shelton GH, Grant CK, Cotter
SM, et al. J Acquir Immune Defic Syndr 3:623-630,
1990.
6. Differentiation of feline immunodeficiency virus
vaccination, infection, or vaccination and infection in cats. Levy JK, Crawford PC, Kusuhara H, et
al. J Vet Intern Med 22:330-334, 2008.
7. Accuracy of polymerase chain reaction assays for
diagnosis of feline immunodeficiency virus infection in cats. Crawford PC, Slater MR, Levy JK.
JAVMA 226:1503-1509, 2005.
8. Effect of vaccination against feline immunodeficiency virus on results of serologic testing in cats
JAVMA 225:1558-1561, 2004.
Developing a Feline Vaccine
Protocol: Core and Noncore
Gary D. Norsworthy, DVM, DABVP (Feline)
Alamo Feline Health Center
San Antonio, Texas
Dozens of small animal vaccine protocols
are in use in the United States. Some are
used based on expert recommendations,
others after personal research. This document details the results of the investigative
process that I undertook in developing a
vaccine protocol for my feline practice.
RISK ASSESSMENT
Prior to 1985, cats were vaccinated against
feline panleukopenia virus, feline herpesvirus-1 (FHV-1), feline calicivirus (FCV),
and rabies. Every cat presented for vaccination received all 4 antigens, 3 of which were
combined into a single vaccine known as
FVRCP. The concept of risk assessment
began in 1985 with the introduction of the
feline leukemia virus (FeLV) vaccine. Some
veterinarians administered it to every cat;
others, like me, limited it to cats with risk of
exposure. The concept of risk exposure was
popularized when the American Association
of Feline Practitioners (AAFP) made its first
vaccine recommendations. It is an idea that
should be embraced by all veterinarians who
vaccinate cats. Giving every available vaccine
to every cat should be unthinkable.
CORE VACCINES
There is little debate among veterinarians
regarding what constitutes a feline core
vaccine; FVRCP and rabies vaccines are as
universally accepted now as they were 30
years ago. With 60% of practitioners still
not adopting the AAFP recommended
intervals,1 debate remains regarding the
frequency of administering these vaccines;
however, there is little debate on whether
or not to use them.
Still, many of my clients with indoor-only
cats no longer vaccinate their cats with
FVRCP, claiming they never leave the house.
The lifestyle of an indoor-only cat may
reduce potential exposure; however, it
does not remove it. When clients tell me
this, I remind them that their cats do leave
the house when they take them to a veterinary hospital. Few have given thought to
the potential exposure that occurs when
sitting in a veterinary waiting room or
being hospitalized with other cats. This is
an important talking point that we, as veterinarians, need to convey to clients.
Rabies vaccination is also debated. Most
states, including mine (Texas), have mandated cats be vaccinated against rabies. I wholeheartedly endorse that mandate for public
health reasons and comply with it for both
my personal cats and my hospital cats.
However, this recommendation is more difficult to explain for resistant owners of
indoor-only cats. While it is unlikely indooronly cats will be exposed to rabies, the law
must be enforced, and we need to be agents
of education on this point.
Giving every
vaccine to every
cat should be
unthinkable.
NONCORE VACCINES
Noncore vaccinations include those against
feline leukemia virus (FeLV) and feline
immunodeficiency virus (FIV). Each is used
only when real risk for exposure exists.
When starting a kitten vaccine series, we
ask clients if the cat will be going outdoors
unsupervised. If not, we limit our recommendations to core vaccines. However, we
The lifestyle of an indoor-only cat
may reduce potential exposure;
however, it does not remove it.
clinician’s update™ • 9
advise clients that if the cat’s lifestyle
changes, other vaccines will be needed.
This approach works well for very motivated clients. Answers from casual cat
clients may not be as reliable so we tend to
be more aggressive in recommending our
noncore vaccines.
In general, exposure risk for FeLV and FIV
is the same. Both are found in saliva and
can be transmitted by bite wounds. Social
contact (sharing food and water bowls, cogrooming) can readily transmit FeLV and,
to a lesser degree, FIV.2 Therefore, the 2
main at-risk groups are: 1) cats that go
outdoors unsupervised, and 2) cats living
in direct contact with infected cats.
FeLV PREVENTION
It is my very strong
opinion that no cat at
risk for FeLV exposure
should be denied
FeLV vaccine.
FeLV vaccine has been used in the US
since 1985. At that time, FeLV-infected
cats might be seen on a weekly, if not
daily, basis. While virus testing was
available as of 1973, we remained
frustrated at the infection rate within our
patient populations. The introduction of
Leukocell by Norden Laboratories was
The efficacy and safety of the FeLV
vaccine were very good, and
allowed veterinarians to quickly
reduce the incidence of this deadly
infection.
one of the greatest events in the history of
feline medicine. Its efficacy and safety
were very good, allowing veterinarians to
quickly reduce the incidence of this
deadly infection. Veterinary graduates of
the past 15 years have a difficult time
understanding the positive change this
vaccine has made in feline health.
In the early 1990s, recognition of feline
injection-site sarcomas (FISS), at the time
incompletely referred to as vaccine-associated sarcomas, dampened enthusiasm of
some toward FeLV vaccination. However,
as time and research have progressed,
informed practitioners realize it is not the
agent (vaccine or other injectable products) that is the cause of these tumors.
Rather, it is a genetic predisposition of the
individual cat that permits them to occur.
Hopefully, as this concept becomes better
accepted, reluctance to give FeLV vaccine
will dissipate. It is my very strong opinion
that no cat at risk for FeLV exposure
should be denied FeLV vaccine.
FIV PREVENTION
Figure 1: An 8-year-old cat was diagnosed with lymphoplasmacytic stomatitis gingivitis
and treated medically for several months. When response to medical therapy failed, all
of the premolars and molars were extracted. However, the expected response did not
occur. Many FIV-infected cats do not respond to treatment as well as uninfected cats.
The cat was euthanized for humane reasons.
10 • clinician’s update™
FIV was first isolated in 1986. The virus is
primarily transmitted by bite wounds. There
is a long latency period before the onset of
immune suppression and disease. As cats
may have no signs of disease for 5 to 10
years, some practitioners maintain a more
casual attitude regarding its pathogenicity.
However, once immunosuppression occurs,
mild infections, especially upper respiratory
infections and otitis externa, can be very difficult to resolve or may even become lifethreatening. Cats with lymphoplasmacytic
stomatitis gingivitis complex (Figure 1) that
are infected with FIV are much more resistant to treatment and are often euthanized.
The incidence of FIV is consistently shown
to be greater than that of FeLV for 2 reasons. It is more common in adult cats, and
the prolonged latency period makes infected cats a source of infection for scores of
other cats.
The in-house ELISA test for FIV detects
antibodies to the virus as well as those
produced in response to FIV vaccination.
This is most easily solved by microchipping. When a cat is first introduced to a
shelter or a stray is first presented to a veterinary practice, responsible employees of
either institution will scan the cat for a
microchip. If present, the cat’s owner can
be contacted. This should be done prior to
FIV testing. In addition, a PCR test offered
by IDEXX Laboratories reacts positively to
only an FIV infection and can be used
when there is a question regarding the
meaning of a positive ELISA test.
SUMMARY
Vaccine protocols have been controversial
for over 15 years and are likely to remain
so for many years to come. It is incumbent
The prolonged latency period
makes infected cats a source of
infection for scores of other cats.
on each practitioner to study
the literature objectively
when deciding on what protocol is most appropriate for
his or her patient population
(see Additional Reading).
Although high-profile speakers and other experts influence the thoughts of many
practitioners on this subject,
personal research of the peerreviewed literature should be
part of the decision-making
process. You are the one who
must answer to the cat owner when an infection occurs in a cat whose vaccination protocol is suboptimal.
REFERENCES
1. Vets slowly move to 3-year vaccine protocols. Ford
R. Vet Pract News 25:24-25, 2013.
2. Long-term impact on a closed household of pet cats
of natural infection with feline coronavirus, feline
leukaemia virus and feline immunodeficiency
virus. Addie DD, Dennis JM, Toth S, et al. Vet Rec
146:419-424, 2000.
It is incumbent on
each practitioner to
study the literature
objectively when
deciding on what
protocol is most
appropriate for
his or her patient
population.
ADDITIONAL READING
• Resistance to tumors.Tizard I. Veterinary
Immunology, 9th ed—St Louis: Elsevier
Saunders 2013, pp 395-398.
• HIV-1 p24 vaccine protects cats against
feline immunodeficiency virus infection.
Coleman JK, Pu R, Martin M, et al. AIDS
19:1457-1466, 2005.
• Dual-subtype vaccine (Fel-O-Vax FIV®)
protects cats against contact challenge
with heterologous subtype B FIV infected
cats. Kusuhara H, Hohdatsu T, Okumura M, et
al. Vet Microbiol 108:155-165, 2005.
• Immunogenicity of an anti-clade B feline
immunodeficiency fixed-cell virus vaccine
in field cats. Matteucci D, Poli A, Mazzetti P,
et. al. J Virol 74:10911-10919, 2000.
• Dual-subtype FIV vaccine protects cats
against in vivo swarms of both homologous
and heterologous subtype FIV isolates. Pu
R, Coleman J, Omori M, et al. AIDS
15:1225-1237, 2001.
• Dual-subtype FIV vaccine (Fel-O-Vax FIV®)
protection against a heterologous subtype
B FIV isolate. Pu R, Coleman J, Coisman J, et
al. J Feline Med Surg 7:65-70, 2005.
• HIV-1 p24 vaccine protects cats against
feline immunodeficiency virus infection.
Coleman JK, Pu R, Martin M, et al. AIDS
19:1457-1466, 2005.
clinician’s update™ • 11
Current Thinking on Feline
Injection-Site Sarcomas
Andrew Sparkes, BVetMed, PhD, DECVIM, MRCVS
Veterinary Director, International Cat Care &
International Society of Feline Medicine
A direct link
between
administration of
vaccines that
caused greater local
inflammatory
reactions and an
increased risk for
subsequent
sarcoma formation
was never
demonstrated.
Feline injection-site sarcomas (FISS) are a
rare occurrence, but can have devastating
consequences for the individual cat when
they do occur. Understandably, FISS cause
considerable concern among veterinarians
and owners alike; addressing the issue properly requires careful consideration of the
known facts. This article briefly reviews historical and contemporary data on FISS to
enable rational conclusions to be drawn in
regard to managing the issue.
HISTORICAL ASPECTS
Awareness that injectables may sometimes
have the ability to trigger sarcoma formation in cats first came to light in the early
1990s when US studies appeared potentially linking the development of fibrosarcomas to injection sites.1 At around the
same time, reports also emerged of very
severe local reactions (necrotizing panniculitis) in some dogs and cats inoculated
with rabies vaccines.2
Aggressive, recurrent fibrosarcoma affecting the hindlimb of a cat—recurrence
despite limb amputation.
12 • clinician’s update™
Early reports of what was initially termed
vaccine-associated sarcomas (VAS), suggested these occurred more commonly
with the use of adjuvanted vaccines—particularly rabies and FeLV vaccines.3,4 An
apparent rise in the prevalence of this type
of fibrosarcoma also appeared to occur
coincidentally with changes in legislation
that mandated rabies vaccination, adding
further speculation to the role of rabies
vaccine in tumorigenesis.3 Early (though
somewhat limited) epidemiologic studies
appeared to confirm the link between
rabies and FeLV vaccination and an
increased risk for sarcoma formation. The
studies also identified an increased risk
with the injection of multiple vaccines at
the same site.4
By the mid to late 1990s, several studies
and publications on VAS had appeared. A
number of these attempted to quantify the
risk of sarcoma formation; estimates varied
between approximately 2 and 36 cases of
sarcoma for each 10,000 doses of vaccine
administered.5-11 Some, but not all, reports
still suggested a link between rabies and/or
FeLV vaccination, but it became apparent
that other vaccine antigens (eg, feline herpesvirus-1, calicivirus, and feline parvovirus [FVRCP]) might also be linked to
VAS.10
A common assumption was that sarcoma
formation was linked to inflammation
induced by the vaccine at the site of injections. This was based partly on the knowledge that VAS were commonly associated
with a marked inflammatory response3, 12-14
and partly with the knowledge that some
vaccines produced greater inflammation
than others at the site of inoculation.15-17
Nevertheless, a direct link between admin-
istration of vaccines that caused greater
local inflammatory reactions and an
increased risk for subsequent sarcoma formation was never demonstrated.
MORE RECENT STUDIES
In 2002 and 2003, 2 larger epidemiologic
studies from North America were published. One study followed more than
30,000 vaccinated cats for a period of 1 to
3 years, the second was a multicenter casecontrol study evaluating nearly 1,500
cats.18, 19 These were much more substantial studies than had been published previously and suggested that the risk for VAS
may be much lower than previous estimates (in the order of 1 per 30,000 doses of
vaccine) and, further, that VAS were not
associated with any particular manufacturer or brand. In fact, no increased risk
was found even with the use of killed,
adjuvanted, or multidose vaccines in the
case-control study. However, the possibility of injectable products other than vaccines also being associated with the formation of some sarcomas was noted. The
2003 case-control study concluded that the
results did not support the superiority of
any single vaccine brand for preventing
VAS. Further, results were consistent with
the concept that a vaccine alone was insufficient to cause a sarcoma but might, in
some cases, be a contributory factor along
with other factors such as underlying
genetics.
Results of a 2003 case-control
study were consistent with the
concept that a vaccine alone was
insufficient to cause a sarcoma.
The traditional site for vaccination may no longer be appropriate.
A Rational Approach to Feline Injection-Site Sarcoma
• Recognize and communicate with clients that FISS is a rare problem, although serious when it occurs. Sarcomas are seen as a spontaneous disease, but there is evidence that many (if not all) injectable products may have a role in increasing the risk
in some cats. It is likely that vaccines carry a higher risk than other injectables, but
the association with vaccines is not unique.
• Searching for a “perfect” vaccine that is safe, efficacious, and has no ability to be
involved in triggering a sarcoma formation is likely to be futile. All vaccines appear to
carry a risk and FISS are not, as previously thought, particularly associated with
rabies or FeLV vaccines—or even with adjuvanted vaccines.
• At present, we have no way of identifying which population of cats might be more at
risk for developing FISS nor any knowledge of other factors involved that may enable
preventive measures to be taken.
• Reducing the frequency of vaccination and avoiding unnecessary vaccination while
maintaining vaccines’ protective benefits is a sensible and logical approach to helping reduce the prevalence of vaccine-associated adverse events. Both the AAFP and
World Small Animal Veterinary Association (as well as other veterinary organizations)
have recommended a reduced frequency of vaccination in many situations for at
least some vaccine components.30, 31 Altering the site of vaccination according to
AAFP and Vaccine-Associated Feline Sarcoma Task Force guidelines may also help in
managing the problem.30, 32, 33
• As the risk for FISS cannot be prevented (other than by avoiding injecting cats entirely, which would cause vastly more health and welfare problems) and as the risk is
actually very low, a more important priority is to monitor cats carefully after vaccination. Although not subjected to critical scientific appraisal, the so-called “3-2-1 rule”
would seem highly appropriate to emphasize34: any local swelling at the site of vaccination that persists for 3 months after vaccination, and/or is greater than 2 cm in
diameter, and/or is getting larger 1 month after vaccination, should be biopsied and
dealt with according to the histopathologic diagnosis. It would also seem prudent to
apply this rule to the use of all injectable products and not just to single out vaccines.
Client communication and vigilance are vital in this regard.
clinician’s update™ • 13
A further study published in 2007 evaluated
adverse vaccine reactions recorded in cats
vaccinated at Banfield Pet Hospitals in North
America.20 The study looked at adverse reactions that occurred within 30 days of vaccination, then followed the cats for a further
1 to 2 years. The reported adverse reaction
rate was approximately 0.5% (2,560 cases out
of over 469,000 vaccines administered), with
the most common being lethargy and/or
fever (54%), local reactions (25%), vomiting
(10%), facial edema (6%), and pruritus (2%).
None of the cats that developed localized
reactions developed a sarcoma at the injection site during the 1- to 2-year period and
no VAS were identified among the nearly
470,000 cats vaccinated again, in contrast to
the earlier much higher estimates of prevalence.
Along with these data, case reports have
emerged linking the occasional development of subcutaneous sarcomas in cats
with the use of other injectable products,
including glucocorticoids, NSAIDs, cisplatin, lufenuron, nonabsorbable suture
material, and microchips.19, 21-23 Based on
these data and the knowledge from epidemiologic studies, the syndrome was
Fine needle aspirate appearance of fibrosarcoma (stained with Diff-Quik®).
14 • clinician’s update™
subsequently renamed feline injection-site
sarcoma (FISS) rather than VAS to more
accurately reflect the current state of
knowledge and apparent risk associated
with a variety of injectable products.
While studies examining the severity of
postvaccination inflammation at the injection site failed to show a clear direct link
with the risk for sarcoma formation, other
investigators evaluated potential genetic
traits that may increase the risk. Although
no breed-associated risk has been identified,
1 study from the US did suggest that polymorphism in the p53 tumor suppressor
gene was significantly associated with an
increased risk for FISS.24 However, another
more recent study from Germany was
unable to substantiate this finding.25 Further
work is clearly needed in this area.
Most information about FISS has come
from studies and publications in the US.
However, FISS is seen worldwide.26,27
A recent study reviewed cases seen in the
UK in 2007.28 This study estimated the
frequency of FISS to be around 1 per
17,000 to 50,000 cats registered at practices, or 1 per 5,000 to 12,500 vaccination
visits. The authors concluded that the frequency of FISS was very low (and similar
to estimates from the US), that evidence of
a causal relationship between FISS and
vaccination remains weak, and that many
other diseases have a much greater impact
on feline health and remain more important targets for improving feline welfare.
A further US case-control study compared
control cats with those that developed sarcomas in the interscapular region.29 No
significant difference was found in the use
of inactivated and recombinant rabies vaccines, between the use of inactivated and
recombinant FeLV vaccines, or between
use of inactivated and live FVRCP vaccines. Comparing the same data for cats
that developed sarcomas in the hindlimb
regions, there was also no significant difference in the use of inactivated and live
FVRCP vaccines, but there was evidence
of a significantly higher use of inactivated
rather than recombinant rabies vaccines in
the sarcoma group. However, the study
authors noted that all vaccine types
appeared to be associated with some risk
for FISS, and there appeared to be a trend
for a higher risk with the use of modifiedlive FVRCP compared with inactivated
FVRCP. This study also highlighted that,
of all the cats that developed sarcomas at
potential injection sites, only 56% were
reported to have received vaccinations and
13% had received another injectable product. An increased risk for FISS was again
noted with the injection of a variety of glucocorticoid products.
While unequivocally serious and
even devastating when it arises,
FISS is fortunately rare.
WHERE DO THESE STUDIES
LEAVE US NOW?
FISS remains an enigmatic problem. While
unequivocally serious and even devastating
when it arises, it is fortunately rare. Current
and most reliable estimates suggest occurrence with a frequency of around 1 for
every 10,000 to 30,000 vaccines,18-20,28 and it
is clear that vaccines are not the only injections associated with FISS development.
The relatively rare nature of these tumors
means that studying causal and contributory factors to their development is very difficult. The current belief is that vaccines
and a number of other (potentially all)
injectable products may have the ability to
contribute to sarcoma formation, as might
other forms of tissue trauma. It is believed
likely that inflammation at the injection
site and the genetic makeup of the cat may
contribute to the risk of sarcoma development, but these are all putative, rather than
proven, risks; the exact relationship
between any of these and the development
of sarcomas remains elusive.
It appears clear that, in contrast to early
reports, FISS is not linked primarily with
FeLV or rabies vaccination, but in fact all
vaccines appear to carry a risk. Whether
this is because early studies were based on
a limited number of cases or whether it is
because of changes in vaccine formulation
since the initial reports remains unknown.
However, it seems clear that all vaccines
carry some risk of being a contributory
factor in triggering sarcoma formation in
some cats.
As clinicians, the question remains as to
how we can best approach minimizing the
small risk for FISS occurring in our patients.
Until our understanding of the etiopathogenesis of these tumors improves, this
remains challenging. However, from current evidence and the accumulated data
reviewed here, it is possible to develop a
rational and pragmatic approach (see A
Rational Approach to Feline InjectionSite Sarcoma).
Keeping a perspective on the true prevalence of and risks for FISS occurring should
help in formulating rational and informed
approaches to managing the problem.
While the unnecessary use of injectable
products should be avoided, the very low
risk for FISS formation should not preclude
their use, especially when the health benefits (eg, vaccination) clearly vastly outweigh
the very small risk for FISS development.
Further work is clearly needed, however, to
understand how injectable products may
contribute to sarcoma development, which
cats might be at increased risk, and how, if
possible, FISS might ultimately be prevented. In the meantime, vigilance after using
injectable products is perhaps the best way
of minimizing the impact of sarcoma formation, should it arise.
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clinician’s update™ • 15
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16 • clinician’s update™
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