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Feline Herpesvirus Infection: Virus
Feline Herpesvirus Infection: Virus
Virus
Epidemiology
The domestic cat is the main host of FHV, but it has been isolated also from
other felids, including cheetahs and lions, and antibodies have been detected
in pumas. There is no evidence of human infection.
Latent chronic infection is the typical outcome of an acute infection, and intermittent
reactivation gives rise to viral shedding in oronasal and conjunctival secretions.
Except in catteries, contamination of the environment is not important for virus
transmission. Virus shedding by acutely infected cats as well as by latently infected
cats experiencing reactivation are the two main sources of infection (Gaskell and
Transplacental infection has not been seen in the field. Latently infected queens
may transmit FHV to their offspring because parturition and lactation are stressful
events leading to viral reactivation and shedding. Kittens may therefore acquire
FHV infection at an early age, before vaccination. The outcome of the infection
depends on MDA: when high levels are present, kittens are protected against
disease, experience a subclinical infection that leads to virus latency, whereas in
the absence of sufficient MDA, clinical manifestations may follow (Gaskell and
Povey, 1982).
In healthy small populations, the prevalence of viral shedding may be less than
1%, whereas in large populations, especially with clinical signs present, up to 20%
of the cats may shed (Coutts et al., 1994; Binns et al., 2000; Helps et al., 2005). In
shelters, the risk is higher: with 4% of shedders entering the shelter, after one
week, 50% of the cats may excrete the virus (Pedersen et al., 2004). The low
initial prevalence is likely to reflect the intermittent nature of viral shedding during
latency.
Pathogenesis
The virus enters via the nasal, oral or conjunctival routes. It causes a lytic infection
of the nasal epithelium with spread to the conjunctival sac, pharynx, trachea,
bronchi and bronchioles. Lesions are characterised by multifocal necrosis of
epithelium, with neutrophile granulocyte infiltration and inflammation. A transient
viraemia associated with blood mononuclear cells is observed after natural infection
in young cats (Westermeyer et al., 2009). This has been observed exceptionally
also in neonates (Gaskell et al., 2007).
Viral excretion starts as soon as 24 hours after infection and lasts for 1 to 3 weeks.
Acute disease resolves within 10 to 14 days. Some animals may develop chronic
lesions in the upper respiratory tract and ocular tissues.
Upon infection, the virus spreads along the sensory nerves and reaches neurons,
particularly in the trigeminal ganglia, which are the main sites of latency. Almost
all cats experiencing primary infection become lifelong latent carriers. There are
no direct diagnostic methods to identify latency, because the virus persists as
Some adult cats show acute lesions at the time of viral reactivation;
disease ensuing reactivation is referred to as recrudescence.
Conjunctivitis may be associated with corneal ulcers, which may develop into
chronic sequestra. Stromal keratitis is a secondary, immune-mediated reaction
due to the presence of virus in the epithelium or stroma. Damage to the nasal
turbinates during acute disease is thought to be a predisposing factor for chronic
rhinitis (Gaskell et al., 2007).
Immunity
During their first weeks of life, kittens are protected against infectious disease by
MDA, but in FHV infection, antibody levels are generally low. They may persist for
10 weeks (Johnson and Povey, 1985), but may have vanished already at 6
weeks of age (in about 25% of kittens; Dawson et al., 2001).
Natural FHV infection does not result in a comprehensive immunity; in general, the
immune response protects against disease but not against infection, and after re-
infection, mild clinical signs have been observed only 150 days after primary
infection (Gaskell and Povey, 1979). VNA titres after natural infection are often
Since FHV is a pathogen of the respiratory tract, mucosal cellular and humoral
responses are important. Studies with intranasal vaccines have shown clinical
benefits as early as 2-6 days after vaccination (Slater and York, 1976; Weigler et
al., 1997b; Lappin et al., 2006).
Clinical signs
FHV infection typically causes acute upper respiratory and ocular disease, which
is particularly severe in young kittens. Viral replication causes the erosion and
ulceration of mucosal surfaces, resulting in rhinitis, conjunctivitis, and
occasionally corneal ulcerative disease; dendritic ulcers are considered a
pathognomonic manifestation (Maggs, 2005). FHV is the most important cause of
corneal ulceration (Hartley, 2010).
Typical clinical signs start with salivation, sneezing and coughing, followed by
pyrexia, depression and anorexia, serous or sero-sanguineous ocular and/or
nasal discharge, and conjunctival hyperaemia (Gaskell et al., 2006). Secondary
bacterial infection is common, in which case secretions become purulent.
Occasionally, primary pneumonia and a viraemic state are seen, with severe
generalized signs and a fatal outcome (Gaskell et al., 2006).
After reactivation and recrudescence, cats may show acute cytolytic disease as
described above. Others may present with chronic ocular immune-mediated
disease in response to the presence of FHV antigen. Experimental infections
resulting in stromal keratitis with corneal oedema, inflammatory cell infiltrates,
vascularisation and eventually blindness suggest this pathogenetic mechanism
(Nasisse et al., 1989; Maggs, 2005).
Corneal sequestra and eosinophilic keratitis have been linked to the presence of
FHV in the cornea and/or blood. However, a definite causal association cannot be
made since some affected cats are FHV-negative (Nasisse et al., 1998; Cullen et
al., 2005). Viral DNA has been detected in the aqueous humour of a larger
proportion of cats suffering from uveitis as compared to healthy cats, suggesting
that FHV may play a role in the inflammation (Maggs et al., 1999b).
FHV infection often occurs in combination with feline calicivirus and/or Chlamydia
felis, Bordetella bronchiseptica, Mycoplasma spp. Other microorganisms, including
Staphylococcus spp. and Escherichia coli may lead to secondary infection of the
respiratory tract, causing a multi-agent respiratory syndrome (Gaskell et al., 2006).
Diagnosis
The PCR variants currently used to detect FHV DNA in conjunctival, corneal or
oropharyngeal swabs, corneal scrapings, aqueous humour, corneal sequestra,
blood or biopsy specimens include conventional PCR, nested PCR and real-time
PCR (Hara et al., 1996; Nasisse and Weigler, 1997; Stiles et al., 1997a, 1997b;
Weigler et al., 1997a; Maggs et al., 1999a; Sykes et al., 2001; Vögtlin et al., 2002;
Helps et al., 2003; Marsilio et al., 2004). Most PCR primers are based on the
highly conserved thymidine kinase gene.
Molecular diagnostic methods are more sensitive than virus isolation or indirect
immunofluorescence (Reubel et al., 1993; Stiles et al., 1997b; Weigler et al.,
1997a; Burgesser et al., 1999; EBM grade I).
Because of the minute amounts of viral nucleic acid detectable by PCR, positive
test results should be interpreted with caution – they may not prove any
association with the disease. The sensitivity of PCR depends on the test format
(Maggs and Clarke, 2005); the system should include a control to measure feline
DNA, to estimate the quantity of material on the swab, and to check for inhibitory
substances. Due to its high sensitivity, PCR may also detect viral DNA in scrapings
of the cornea and/or tonsils suggesting non-productive infection (Reubel et al.,
1993; Stiles et al., 1997a; Maggs et al., 1999b). Consequently, its diagnostic value
for clinical infection may be poor, depending on the test sensitivity, the samples
analysed (biopsies and corneal scrapings yield positive results more frequently
than conjunctival samples) and the population tested (e.g. shelter cats are more
likely to test positive than household cats).
Additionally, PCR tests can detect FHV DNA in modified-live virus vaccines
(Maggs and Clarke, 2005); it is unknown if vaccinal strains are detected in
recently vaccinated animals and for how long after vaccination.
A positive PCR result may indicate low level shedding or viral latency and does not
mean that the virus is responsible for the observed clinical signs, although it
indicates the possibility of recurring signs in the future. However, when quantitative
In cats undergoing primary FHV infection, the virus can be detected by isolation
from conjunctival, nasal or pharyngeal swabs or scrapings, or from post-mortem
lung samples. In chronic infections, VI may be difficult.
Asymptomatic FHV carriers can be detected by VI, but both the positive and
negative predictive value of VI is low (Gaskell and Povey, 1977; Maggs et al.,
1999b). Samples must be collected before application of fluorescein or Rose
Bengal stain, which inhibit viral replication in cell culture (Brooks et al., 1994;
Storey et al., 2002). Also, clinical specimens must be sent quickly to the
laboratory, and refrigerated during shipping. For these logistic reasons and
despite its good sensitivity in acute disease, VI is not routinely used for FHV
infection diagnosis.
Serology
Moreover, antibody detection does not allow differentiation between infected and
vaccinated animals, neutralizing antibodies are undetectable until 20 to 30 days
after a primary infection, and titres may be low, both in animals with acute and
chronic disease. Consequently serology is of limited value in the diagnosis of feline
herpesvirus infection (Nasisse and Weigler, 1997; Maggs et al., 1999b; Maggs,
2005).
Disease management
Supportive treatment
The restoration of fluids, electrolytes and the acid-base balance (e.g. replacement
of losses of potassium and bicarbonate due to salivation and reduced food intake),
preferably by intravenous administration, is required in cats with severe clinical
signs. Food intake is extremely important. Many sick cats do not eat because of
their loss of smell due to nasal congestion, or because of ulcers in the oral cavity.
Food may be blended to cause less pain when eating, should be highly palatable,
and may be warmed up to increase the smell. Appetite stimulants (e.g.
cyproheptadine) may be used. If the cat has not eaten for three days, placement of
a nasal or oesophageal feeding tube is indicated.
Severely affected cats need intensive nursing care and appropriate supportive
therapy. Nasal discharge should be cleaned away several times a day using
physiologic saline solution, and local ointment applied. Drugs with mucolytic
effects (e.g. bromhexine) may be helpful. Eye drops or ointment can be
administered several times a day. Nebulisation of saline can be used to take care
of dehydration of the airways.
placement of a feeding to ensure sufficient necessary if the cat has not been 4
tube and enteral nutrition food intake eating for three days
Systemic treatment
Fluid therapy to control dehydration necessary in cats with severe clinical signs 4
and restore electrolyte
and acid base imbalance
Antibiotics to control secondary broad-spectrum antibiotics with good 4
bacterial infections penetration in the respiratory tract are
recommended for cats with severe
disease
Non-steroidal anti- to decrease fever recommended if cat is severely depressed 4
inflammatory drugs
Antiviral therapy
Table 4. Antiviral drugs recommended for topical and systemic treatment of acute
FHV
ocular disease. The drugs are listed in decreasing order of preference.
Topical treatment
Drug Type of drug Route of Efficacy Efficacy Controlled Comments EBM
administration in vitro in vivo study in level
vivo?
Trifluridine Nucleoside Topical Excellent n.d. no Topical treatment of 3
analogue Use every hour choice in ocular FHV
for 1st day and manifestations. Some
every 4 hours cats averse to topical
thereafter application. Toxic if
(Maggs, 2 001) given systemically
(Maggs,
2001)
Cidofovir Nucleoside 0.5% solution yes yes yes Topical treatment for 3
analogue applied topically ocular FHV; potent
drug with only two
daily applications
(Fontenelle et al.,
2008; Maggs, 2010)
Aciclovir Nucleoside Topical and oral Poor some yes Least in vitro effect of 3
analogue (high all herpes antivirals
doses (van der Meulen et
may be al., 2006; Williams et
needed al., 2004), moderate
to in vivo effect
overcom (Williams et al.,
e viral 2005). Synergy in
resistance combination with
) human IFN−α
(Weiss, 1989). Toxic
systematically
(Maggs,
2001; Maggs, 2010)
Systemic treatments
Famciclovir Nucleosid Oral, 90 mg/kg tid for Yes (for yes yes Tested in conventional 3
e 21 days penciclovir, and SPF cats
analogue as experimental
(prodrug) famciclovir is challenge, against
a prodrug primary infection (Malik
of et al., 2009; Thomasy
penciclovir) et al., 2011)
Feline IFN-ω Interferon Systemic yes n.d. yes Safe and licensed for 4
1 MU/kg SC sid or eod use in cats.
n.d. = not determined; eod = every other day; sid = once daily; bid = twice
daily; tid = three times daily.
The drugs listed may not be readily available or licensed for cats.
The amino acid l-lysine has been proposed for systemic treatment, to be
administered as a bolus, separate from food. No side effects have been published,
but reports on efficacy are conflicting (Maggs, 2001, 2010; Stiles et al., 2002;
Maggs et al., 2003, 2007; Rees and Lubinski, 2008; Drazenovich et al., 2009;
Gould, 2011). Cave et al. (2014) investigated the effects of physiologic
concentrations of l-lysine on the in vitro replication of FHV at L-arginine levels
sufficient to maintain cell growth. FHV was not inhibited at any l-lysine
concentration studied. The in vivo efficacy of the measure on primary and recurrent
FHV infection is unknown.
Other drugs have been proposed for the treatment of FHV ocular infections,
including bromovinyldeoxyuridine, HPMA, ribavirin, valacyclovir, vidarabine,
foscarnet and lactoferrin. However, the efficacy of these drugs has not
been proven.
Most current FHV vaccines are combined with FCV, either as bivalent
products (only in some countries) or with additional antigens. Both modified
live and inactivated parenteral vaccines are available. Subunit FHV vaccines
and modified intranasal vaccines have been or still are available elsewhere,
but no longer in Europe.
For routine vaccination, there is no reason to prefer any FHV vaccine above
another, since all are based on a single serotype. Modified live vaccines
might retain some pathogenic potential and may rarely induce disease, e.g.
when accidentally aerosolised or spilt on the skin and taken up during
grooming.
Maternal antibodies interfere with the response to vaccination until 8 weeks of age
on average (Poulet, 2007); the primary course of vaccination is therefore usually
started at around nine weeks of age, although some products are licensed for
earlier use. Kittens should receive a second vaccination two to four weeks later, with
the second given around twelve weeks of age. This protocol has been developed to
ensure optimal protection. For longer intervals, no information is available.
Booster vaccinations
Experimental studies and serological surveys in the field have clearly shown that
immunity against FHV lasts longer than one year (Lappin et al., 2002, Mouzin et
al., 2004; EBM grade II). However, there is a significant proportion of cats for which
this might not be true. While most cats in the field either have antibody against FCV
and FPV, or show an anamnestic response after the booster, only around 30%
have titres against FHV, and around 20% fail to react to booster vaccinations
(Lappin et al., 2002; Mouzin et al., 2004). In experimental vaccine efficacy studies,
protection clearly decreases with time.
Cats that have recovered from disease caused by FHV may not enjoy lifelong
protection against further episodes. Furthermore, in most clinical cases, the
causative agent will not have been identified and the cat may contract infection
with other respiratory pathogens. To be on the safe side, vaccination of
recovered cats is generally recommended.
Multi-cat households
FHV infection is common in multi-cat households. Depending on the management,
ABCD recommendations will refer either to shelters or to breeding catteries.
Shelters
FHV infections can pose a problem in cat shelters. Management to prevent and
limit the spread of infection is as important as vaccination. In shelters where
incoming cats are mixed with resident ones, high infection rates are frequent. To
control this situation, newcomers should be quarantined for the first three weeks,
and kept individually – unless known to be from the same household. Shelter
design and management measures should be aimed at avoiding cross infections.
New cats should be vaccinated as soon as possible when they are healthy and no
contraindications to vaccination have been found. If there is a particularly high risk,
e.g. past or recent FHV infections, modified live vaccines are used, as these
provide earlier protection. In an acute respiratory disease outbreak, identification of
the agent involved – with differentiation between FHV and FCV – can be useful in
deciding on the appropriate preventive measures.
Breeding catteries
FHV infections can be a major problem in breeding catteries, where they most often
appear in young kittens before weaning - typically around 4 to 8 weeks of age,
when maternally derived immunity wanes. The source of infection is often the
queen, who is the virus carrier and whose latent infection has been reactivated in
the course of kittening and lactation.
Infection in such young kittens is often severe, involving the entire litter. Mortality
can be important, and some kittens that have recovered from the acute disease
are left with complications, notably chronic rhinitis. Vaccination of the queen is no
option since it will not prevent her from becoming a carrier. However, if the queen
has a good antibody titre, the kittens will benefit from high levels of MDA
transferred through the colostrum, which provide protection against disease for the
first weeks of life.
Queens should kitten in isolation, and litters should neither mix nor have contacts
with other cats until they have been fully vaccinated. Early vaccination should be
considered for litters from queens that had infected litters previously. The earliest
age for which FHV vaccines are licensed is 6 weeks, but kittens may become
susceptible to infection earlier than this as MDA wanes. Vaccination from around 4
weeks of age may be considered, to be repeated every 2 weeks until the primary
vaccination course is given as usual.
Early weaning into isolation from around 4 weeks of age is an alternative approach
to protecting kittens from maternal infection. There are no reliable tests that will
identify carrier queens and predict which may infect their kittens.
FeLV-positive cats
Chronic disease
References
Dawson S, Willoughby K, Gaskell RM, Woog G, Chalmers WCK (2001). A field trial
to assess the effect of vaccination against feline herpesvirus, feline calicivirus and
feline panleukopenia virus in 6-week-old kittens. J Feline Med Surg 3: 17-22.
Ellis TM (1981). Feline respiratory virus carriers in clinically healthy cats. Aust Vet J
57: 115-118.
Fontenelle JP, Powell CC, Veir JK, Radecki SV, Lappin MR (2008). Effect of topical
ophthalmic application of cidofovir on experimentally induced primary ocular feline
herpesvirus-1 infection in cats. Am J Vet Res 69: 289-293.
Gaskell RM, Povey RC (1982). Transmission of feline viral rhinotracheitis. Vet Rec
111: 359-362.
Hargis AM, Ginn PE (1999). Ulcerative facial and nasal dermatitis and stomatitis
in cats associated with feline herpesvirus-1. Vet Dermatol 10: 267-274.
Johnson LR, Foley JE, De Cockc HE, Clarke HE, Maggs DJ (2005). Assessment of
infectious organisms associated with chronic rhinosinusitis in cats. J Am Vet Med
Assoc 227: 579-585.
Jongh O (2004). A cat with herpetic keratitis (primary stage of infection) treated
with feline omega interferon. In: Karine de Mari (ed.): Veterinary Interferon
Handbook. Carros: Virbac, 138-147.
Lappin MR, Sebring RW, Porter M, Radecki SJ, Veir J (2006). Effects of a single
dose of an intranasal feline herpesvirus 1, calicivirus, and panleukopenia vaccine
on clinical signs and virus shedding after challenge with virulent feline herpesvirus
1. J Feline Med Surg 8: 158-163.
Maggs DJ (2010). Antiviral therapy for feline herpesvirus infections. Vet Clin North
Maggs DJ, Lappin MR, Reif JS, et al (1999b). Evaluation of serologic and viral
detection methods for diagnosing feline herpesvirus-1 infection in cats with acute
respiratory tract or chronic ocular disease. J Am Vet Med Assoc 214: 502-507.
Maggs DJ, Sykes JE, Clarke HE, et al (2007). Effects of dietary lysine
supplementation in cats with enzootic upper respiratory disease. J Feline Med
Surg 9: 97-108.
Mouzin DE, Lorenzen MJ, Haworth JD, King VL (2004). Duration of serologic
response to three viral antigens in cats. J Am Vet Med Assoc 224: 61-66.
Nasisse MP, Glover TL, Moore CP, Weigler BJ (1998). Detection of feline
herpesvirus 1 DNA in corneas of cats with eosinophilic keratitis or corneal
Nasisse MP, Guy JS, Davidson MG, Sussman WA, Fairley NM (1989).
Experimental ocular herpesvirus infection in the cat Sites of virus replication,
clinical features and effects of corticosteroid administration. Invest
Ophthalmol Vis Sci 30: 1758-1768.
Nasisse MP, Guy JS, Stevens JB, English RV, Davidson MG (1993). Clinical and
laboratory findings in chronic conjunctivitis in cats: 91 cases (1983-1991). J Am Vet
Med Assoc 203: 834-837.
Nasisse MP, Weigler BJ (1997). The diagnosis of ocular herpes virus infection. Vet
Comp Ophthalmol 7: 44-51.
Pedersen NC, Satop R, Foley JE, Poland AM (2004). Common virus infections in
cats, before and after being placed in shelters, with emphasis on Feline enteric
coronavirus. J Feline Med Surg 6: 83-88.
Poulet H (2007). Alternative early life vaccination programs for companion animals. J
Comp Path 137: S67-S71.
Rees TM, Lubinski JL (2008). Oral supplementation with L-lysine did not prevent
upper respiratory infection in a shelter population of cats. J Feline Med Surg 10:
510-513.
Reubel GH, Ramos RA, Hickman MA, Rimstad E, Hoffmann DE, Pedersen NC
(1993). Detection of active and latent infections using the polymerase chain
reaction. Arch Virol 132: 409-420.
Spatz SJ, Rota PA, Maes RK (1994). Identification of the feline herpesvirus type 1
(FHV-1) genes encoding glycoproteins G, D, I and E: expression of FHV-1
Sykes JE, Allen JL, Studdert VP, Browning GF (2001). Detection of feline
calicivirus, feline herpesvirus 1 and Chlamydia psittaci mucosal swabs by
multiplex RT-PCR/PCR. Vet Microbiol 81: 95-108.
Thiry E (2006). Feline Herpesvirus. In Clinical virology of the dog and cat (Collection
Clinical Virology). Éditions du Point Vétérinaire, Maisons-Alfort (France): 91-97.
Thomasy SM, Lim CC, Reilly CM, Kass PH, Lappin MR, Maggs DG (2011).
Evaluation of orally administered famciclovir in cats experimentally infected with
feline herpesvirus type-1. Am J Vet Res 72: 85-95.
Weigler BJ, Guy JS, Nasisse MP, Hancock SI, Sherry B (1997b). Effect of a live
attenuated intranasal vaccine on latency and shedding of feline herpesvirus 1 in
domestic cats. Arch Virol 142: 2389-2400.
Williams DL, Robinson JC, Lay E, Field H (2005). Efficacy of topical aciclovir for
the treatment of feline herpetic keratitis: results of a prospective clinical trial and
data from in vitro investigations. Vet Rec 157: 254-257.
Lommer MJ, Verstraete FJM (2003). Concurrent oral shedding of feline calicivirus
and feline herpesvirus 1 in cats with chronic gingivostomatitis. Oral Microbiol
immunol 18: 131-134.
Radford AD, Gaskell RM, Dawson S (2004). Feline Viral Upper Respiratory Disease.
In Textbook of Respiratory Disease in Dogs and Cats, LG King (ed.), WB Saunders,
Missouri; 271-278.