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Feline Herpesvirus (Feline viral rhinotracheitis)

Last updated October 30, 2012

Feline herpesvirus type1 (FHV-1) is the causative agent of feline viral rhinotracheitis, an infective and contagious disease characterised by respiratory symptomology and often complicated by the simultaneous presence of other pathogens associated with the respiratory diseases complex in the cat (URTD: Upper Respiratory Tract Disease) such as feline Calicivirus (FCV), Chlamydophila felis and Bordetella bronchiseptica.

 

PROPERTIES OF THE VIRUS


FHV-1 is a virus with worldwide distribution belonging to the Herpesviridae family, α-herpesvirinae subfamily, Varicellovirus genus, with morphological characteristics common to its family of belonging. The virus has an icosahedral symmetry, an approximate diameter of 150-200 nm and a glycoprotein envelope, beneath which there is a protein shell known as a matrix or internal membrane which surrounds the capsid. The DNA of the strains isolated to date in various countries has shown a certain homogeneity, although differences exist from the pathogenetic perspective. Under natural conditions, domestic cats and some wild felines are susceptible to the infection, among which the leopard, the tiger, the bobcat (Lynx rifus) and the cheetah. The virus is found to be sensitive to the action of lipid solvents; it is rapidly inactivated at 56°C, while it resists for long periods of time when exposed to temperatures of refrigeration and freezing. A characteristic of Herpesvirus type 1 is its low genetic variability, for which reason it is rare to come across recombinations of its genome.

 

TRANSMISSION OF THE VIRUS


The infection can be transmitted both horizontally, i.e. by contact between healthy cats and infected animals, and vertically during pregnancy. In addition, kittens can contract the infection from their mother after birth or between two and twelve weeks of life, when colostrum immunity wears off. FHV-1 penetrates the body through the oral, nasal and conjunctival route and, as it is only able to replicate at temperatures equal to or below 37° C, its effects are limited to so-called “cold” surfaces, such as the conjunctiva, nasal turbinates, rhinopharynx and, experimentally, the vulvovaginal mucosa; the extension of the infection to the lower respiratory tract and lungs is therefore unusual. Shedding of the virus can be evidenced in oropharyngeal and nasal swabs starting from 24 hours post-infection and can persist in the replication site for a period varying from one to three weeks.

 

PATHOGENESIS


The virus is shed into the external environment by ocular, nasal and pharyngeal secretions of cats in the acute phase of the illness or by carriers. A particularly important characteristic of herpetic infections is the phenomenon of latency, i.e. the capacity of viral DNA to remain localised in inert form in the nucleus of the host cells in the form of episome or extrachromosomalplasmid.

In clinically healed animals, FHV-1 is able to become latent in the trigeminal ganglia, optic nerves, optic chiasm, olfactory bulb, lacrimal glands, cornea and nasal turbinates. The presence of the virus during the latent infection phase cannot be demonstrated by conventional virological techniques, and requires specific methodologies such as, for example, molecular biology techniques aimed at genomic identification of FHV-1 starting with samples taken in the anatomical sites of latency. Unlike what is observed in the infection caused by FCV, where the carrier state is characterised by the persistence and then continuous shedding of the virus into the external environment, in the case of FHV-1 viral excretion is intermittent and is present only during phases when the virus comes out of latency (is reactivated). Like other alpha herpesviruses, virtually every infected cat can become a carrier, with episodes of reactivation of viral secretion.

Stressful conditions such as treatments with corticosteroids, pregnancy and lactation, transportation for mating or shows, or the concomitant presence of immunosuppressive diseases or of other pathogens associated with URTD may result in reactivation and consequent shedding of the virus into the external environment. Experimentally, spontaneous virus shedding in a carrier cat is 1%; corticosteroid treatment may induce excretion in 70% of cats and lactation in 40%. Virus secretion during suckling is the ideal mechanism for infecting kittens as soon as there is a reduction of maternally derived antibodies (MDA).

Episodes of stress do not induce shedding immediately: a latency phase of 4-11 days precedes excretion of the infectious virus, which continues for approximately 2-10 days. In some cases, the patient may also show some mild clinical signs. The exact mechanism of reactivation is unclear: it is interesting to note that cats studied for their stress-induced reactivation had a primary disease that was significantly more severe than those which do not reactivate the infection, and they also exhibit a significantly greater degree of stress.

 

IMMUNITY


Immunity acquired through colostrum
Maternally derived antibodies protect kittens from the disease during their initial weeks of life but, in the case of infection from FHV, antibody levels are usually low. Maternal derived antibodies (MDA) can persist in general for approximately 10 weeks, but some research shows that approximately 25% of cats may become MDA-negative from as young as 6 weeks of age.

Active immunity
Natural infection from FHV does not result in solid immunity as is the case with other diseases. Generally, the immune response protects against the disease, but not against the infection, and mild clinical signs may be observed in the case of reinfection. Virus neutralising antibody (VNA) titres are usually low and slowly decrease until becoming absent 40 days after infection. However, as for other alpha herpesviruses, cell-mediated immunity plays an extremely important role in protecting the animal, so that vaccinated cats, even in the absence of detectable antibodies, are not necessarily susceptible to the disease. As this is a pathogen of the respiratory tract, cellular mucosal and humoural immunity also play a significant role. Although there is a correlation between Ac-FHV and protection against the clinical signs, no validated tests exist that are able to indicate the level of protection in a single individual.

 

CLINICAL SIGNS


The symptomology associated with FHV-1 infection can manifest itself with various clinical pictures; the incubation period is usually of 2-6 days, but it can be longer. In the majority of cases an acute viral rhinotracheitis is present, affecting animals aged between six and twelve weeks, with the onset of respiratory symptoms characterised by sneezing, nasal and ocular serous discharge, fever and anorexia. The sneezing of transparent, serous droplets is typical of the initial phases, but also of chronic stages not complicated by bacteria. These manifestations are followed by the onset of conjunctivitis, which is initially serous and often evolves into amucopurulent form. Not uncommon in very young animals are corneal ulcers (pathognomonic) and episodes of keratitis of variable severity complicated by secondary invasion of bacteria and often characterised by further lesions such as symblepharon (adhesion of the conjunctiva to itself or to the injured cornea) (Fig. 1) and permanent prolapse of the third eyelid. During the resolution stages of the conjunctival form, ulcers and crusty skin lesions often appear; they are particularly evident in the medial canthus of the eye, at the side of the nostrils (Fig. 2) and on the ear pinnae.  Less frequently observed are skin and oral ulcers (much less frequently than with calicivirus infection), dermatitis and neurological signs. In the chronic stages of the infection or in asymptomatic carriers, the presence of the virus can give rise to rare but sometimes very severe clinical conditions, such as skin diseases (herpetic dermatitis) or, in pregnant cats, abortion. In the latter case, experimental studies have ruled out a direct action of the virus on the placenta; it is more likely that abortion is a result of the poor general health status caused by the infection.

In the majority of affected animals, the clinical signs of rhinotracheitis disappear within 2-3 weeks; however, the process of reactivation and exacerbation as well as of inflammation of the nasal turbinates can induce an acute cytolytic disease and permanent damage, predisposing the cat to the development, in the adult age, of rhinitis, sinusitis and chronic bacterial conjunctivitis. In the adult cat, infection from FHV-1 is associated with an ocular syndrome known as herpetic keratitis. The role of FHV-1 in other ocular diseases such as corneal sequestrum, eosinophilic keratitis, uveitis and keratoconjunctivitis has not yet been fully clarified. Experimental studies suggest that stromal keratitis with corneal oedema, inflammatory cell infiltration, neovascularisation and possible blepharospasm are the result of an immune-mediated chronic ocular disease.

Herpetic Dermatitis. Dermatitides induced by FHV-1 are mainly localised facially (Fig. 3) and are characterised by erosions, ulcers and crusts associated with variable degrees of erythema, exudation and tumefaction. Lesions may also be present on the plantar pads (Fig. 4) and the trunk. Many cases may initially be confused with lesions from CGE/eosinophilic ulcers. Occasionally, skin lesions may be combined with conjunctivitis or keratitis and potentially with gingivitis/stomatitis/faucitis.

 

 

 

 

 

DIAGNOSIS


The diagnosis of viral rhinotracheitis cannot be made solely on the basis of the symptomatology, as no clinical signs exist that allow us to differentiate FHV-1 from other pathogens associated with URTDs, although the presence of severe clinical signs and corneal lesions may be considered indicative. Specific laboratory tests, aimed at identifying the pathogenic agent, are therefore necessary to confirm the infection: viral isolation on cells, indirect immunofluorescence (IFI) and PCR methodologies. Viral isolation from conjunctival and oropharyngeal swabs is easily performed; however, some false negative results are possible, as a result, for example, of the presence of a small amount of virus in the sample or the presence of antibodies in the extracellular liquids which inhibit its replication. IFI from conjunctival and oropharyngeal smears is a sensitive method in the acute phases of the infection, but it is not very reliable in chronic infections. An indirect diagnosis based on the identification of anti-FHV-1 antibodies is not very reliable due to the ubiquitous nature of the virus, the possible absence of circulating antibodies when the virus is in the latency phase and because of the routine use of vaccines. The technique which is currently preferred, having an increased sensitivity and being of rapid execution, is PCR, which is commonly used to trace the FHV-DNA using conjunctival, corneal, oropharyngeal, corneal sequestrum and blood samples. The use of quantitative real-time PCR to measure the concentration of the virus can provide some useful additional information: the presence of high viral shedding in nasal or conjunctival secretions is suggestive of active replication and hence of the contribution of FHV to the clinical signs. A low number of DNA copies in corneal scrapings is often indicative of the presence of a latent infection.

 

FHV-1 DIAGNOSIS

  • The serum antibody titre is not useful in diagnosing FHV-1 infections.
  • Viral isolation is a sensitive method in acute forms but is not diagnostic in the chronic forms except at times when there is a return of clinical signs.
  • Diagnosis through identification of viral DNA with PCR is superior to other diagnostic methods but may present false negative results. PCR may be performed on samples taken from the conjunctival sulcus or from conjunctival scrapings.

 

DIFFERENTIAL DIAGNOSIS


 

TREATMENT


Supportive Care
In cats with severe respiratory clinical signs, with sialorrhea or loss of appetite, it is often necessary to restore fluids and electrolytes, preferably intravenously (fluid therapy). As very young animals are often affected, it is extremely important to ensure that they are nourished; many cats do not eat due to their respiratory difficulties or the presence of lingual ulcers. It may be useful to use nasal decongestants, saline drops, or even low-dose corticosteroids, preferably by aerosol. Food should be very appetising and slightly heated. If the kitten cannot be fed, forced feeding through a tube should be considered. A broad spectrum antibiotic with good penetration in the respiratory system is recommended, in order to prevent often disastrous concomitant bacterial infections.

Antiviral agents (Table 1)
No specific antiviral agents are available for veterinary use; many nucleoside analogues developed for humans have been studied also against FHV-1. Aciclovir and other analogues have been used in cats but have proven to be too toxic at therapeutic levels for oral administration. The use  of systemic antiviral drugs such as acyclovir is therefore not recommended, as they can compromise marrow and renal function.

The current treatment for herpetic keratitis is based on the use of ophthalmic antiviral drugs, generally used for treating herpetic infections in humans, such as 1% trifluridine and 0.1% or 0.5% idoxuridine which, compared to the former, is less irritating, cheaper and easy to prepare. Trifluridine has proven to be particularly effective in the treatment of ulcerative herpetic keratitis (1 drop every 2-3 hours for the first 24 hours and at 6-hour intervals on subsequent days).

In kittens with severe acute symptomatology, feline omega interferon (FeIFNΩ) may be used, administered subcutaneously (s.c.) (1 MU/kg per day for 5 days or every other day) or orally (50,000-100,000 units per day). Several in vitro and in vivo studies have shown that FHV-1 is susceptible to this molecule, particularly if used during the acute phases of the illness. It is likely that such treatment could limit the development of forms of viral latency.

The same drug may be used topically in cases of conjunctivitis by diluting 500,000 IU FeIFNΩ in 1 ml of artificial tears and administering 1 drop/eye 3 times a day for 5-30 days. Some veterinarians have started to use it also in cases of keratitis from FHV-1, but to date there are no controlled trials on its effectiveness.

Similarly, Interferon alpha-2B may be used as an adjuvant therapy both orally (30 IU per day) and topically (30-50 U/ml diluted in artificial tears, applied 3-5 times per day, but for some months).

Recent studies have assessed the effectiveness of L-lysine (250 mg orally, twice a day) both for treating chronic forms and for reducing viral secretions in carriers. L-lysine is an antagonist of arginine, which has proven to be essential for the replication of human Herpesvirus and FHV-1. Treatment with L-lysine also reduces viral protein synthesis and has some inhibitory effects on the infection. Oral supplementation would reduce the severity of the conjunctivitis and the number of episodes of reactivation of latent infections. Its use is therefore recommended both in the acute form and in cases of possible reactivation from stress. There are indications that dietary supplementation is not effective, and that bolus administration is required.

One drug that has proven to be very effective in chronic cases is famciclovir. Famciclovir is a prodrug of penciclovir, an antiviral analogue of guanosine. It competitively inhibits the viral DNA polymerase of Herpesviruses. In the cat, its use is recommended for treating chronic and acute forms of feline Herpesvirus (FHV-1), whether cutaneous or ocular. The dosages suggested in literature are:

  • Treatment of ocular infections from FHV-1: 62.5 mg/cat per os every 8 hours for 28 days.
  • Treatment of chronic dermatitis from FHV-1: 125 mg/cat per os every 8 hours for 28 days.

 

PREVENTION


In catteries and in all environments with a high density of animals, preventing the spread of respiratory viruses is extremely important, but their elimination is difficult due to the presence of carrier cats. The possibility of contagion is reduced with adequate disinfection, maintaining optimal room temperature with a low degree of relative humidity and with appropriate ventilation; in addition, the carrying out ofdiagnostic tests and of an appropriate quarantine can reduce the possibility of introducing infected animals into the premises. As regards indirect prophylaxis, in general, attenuated vaccines are used, associated with other microorganisms such as FCV and feline panleukopenia virus (FPV) and inoculated subcutaneously. As for the immunisation protocol, it is advisable to provide an initial vaccination at nine weeks of age, followed by a second at twelve weeks and then annual boosters. The immunisation protocol may be modified based upon the epidemiological risks of contracting the infection. In environments with a high density of animals, the timing of immunisation may be anticipated, thus vaccinating between six and twelve weeks of age; in such case, it is advisable to provide boosters at intervals of 3-4 weeks until reaching the twelfth week of age.

Table 1. Antiviral drugs recommended in treating infection from feline Herpesvirus7,8,10-16

Drug

Drug type

Method of administration and dosage

Documented effectiveness

Comments

Trifluridine

Nucleoside analogue

Topical every hour or 2-3 hours for the first day and then every 6 hours for the remaining days

N

Topical treatment chosen in cats with ocular signs of FHV. Some cats may experience local reactions to the drug.

Idoxuridine

Nucleoside analogue

Topical at 0.1% or 0.5%

NA

Topical treatment for ocular FHV.
Toxic when administered systemically

Feline IFN-ω

Antiviral interferon

Systemic: 1 MU/kg s.c. once a day for 5 days or 2.5 MU/kg s.c. or i.v. every 48 hours for 3 administrations. For three times in kittens in the acute phase

Oral: 50,000–100,000 units/day

Topical: treatment of chronic keratoconjunctivitis from FHV-1.

2 drops per eye every 4-6 hours of a solution of 500,000 IU/ml in saline solution (dilute 5 MU in 10 ml of 0.9% NaCl (artificial tears) and use like eye drops

YES

Safe and authorised for use in the cat

No randomised trial data published

Combined with treatment with L-lysine 250 mg per os every 12 hours to inhibit growth and encourage the elimination of the virus

Human IFN alpha

Immunomodulating antiviral  interferon

s.c.at high dose

per os at low dose 35 units/day

YES

Less active than feline interferon.

5–35 units per day seem to help to reduce clinical signs but not environmental shedding. Used long-term with the addition of L-lysine in the case of chronic infections.

L-lysine

Amino acid

Oral

250 mg twice a day or 400 mg once a day

YES

Safe. It reduces the level of viral shedding even in cases of latent infection.

Famciclovir

Antiviral

Treatment for ocular infections from FHV-1

• 62.5 mg/cat per os every 8 hours for 28 days.

Treatment of chronic dermatitis from FHV-1

• 125 mg/cat per os every 8 hours for 28 days.

 

Use in the treatment of chronic ocular forms could give good results according to a recent review

The use of famciclovir was recently reported to be effective in four cats with herpetic dermatitis using different treatment protocols

 

 

 
 
 

References and suggested reading


  1. Etienne Thiry, Diane Addie, Sándor Belák, Corine Boucraut-Baralon, Herman Egberink, Tadeusz Frymus, Tim Gruffydd-Jones, Katrin Hartmann, Margaret J. Hosie, Albert Lloret, Hans Lutz, Fulvio Marsilio, Maria Grazia Pennisi, Alan D. Radford, Uwe Truyen, Marian C. Horzinek. Feline herpesvirus infection. ABCD guidelines on prevention and management. Journal of Feline Medicine & Surgery, Volume 11, Issue 7, July 2009, Pages 547-555.
  2. Gaskell R, Dawson S, Radford A. Feline respiratory disease. In: Greene CE, ed. Infectious disease of the dog and cat. Missouri: WB Saunders, 2006: 145–54.
  3. Gaskell R, Dawson S, Radford A, Thiry E. Feline herpesvirus. Vet Res 2007; 38: 337–54.
  4. Muller GH, Kirk RW, Scott DW, et al. Muller & Kirk's small animal dermatology. 6th ed. Philadelphia: W.B. Saunders, 2001.
  5. Hargis AM, Ginn PE. Feline herpesvirus 1-associated facial and nasal dermatitis and stomatitis in domestic cats. Vet Clin North Am Small Anim Pract 1999;29:1281-90.
  6. 6.  Helps C, Reeves N, Egan K, Howard P, Harbour D.Detection of Chlamydophila felis and feline herpesvirus by multiplex real-time PCR analysis. J Clin Microbiol 41[6]:2734-6 2003
  7. Maggs DJ, Collins BK, Thorne JG, et al. Effects of L-lysine and L-arginine on in vitro replication of feline herpesvirus type-1. Am J Vet Res 2000;61:1474-8.
  8. Maggs DJ. Update on the diagnosis and management of feline herpesvirus-1 infection. In: August JR, ed. Consultations in feline internal medicine. Vol 4. Philadelphia: WB Saunders, 2001: 51–61.
  9. Fitzpatrick TB. Dermatology in general medicine. 5th ed. New York: McGraw-Hill, 1999.
  10. Weiss RC. Synergistic antiviral activities of acyclovir and recombinant human leukocyte (alpha) interferon on feline herpesvirus replication. Am J Vet Res 1989;50:1672-7.
  11. Verneuil M. (2004) – Topical application of feline interferon omega in the treatment of herpetic keratitis in the cat: Preliminary study. Proceedings of ECVO, June 2004, München, Deutschland.
  12. Schmidt-Morand D., Jongh O. (2003) – Kératite Herpétique chez le chat: conduite thérapeutique et résultats. Proceedings of AFVAC congress, November 2003, Nantes, France.
  13. Truyen U. et al. (2002) A study of the antiviral activity of Interferon omega against selected canine and feline viruses. Der Praktische Tierarzt, 10, 2002, 862-865, Germany.
  14. Addie D., Buonavoglia C., Camy G., McCann T., Gunn-Moore D., Hartmann K., Hennet P., Ishida T., Jongh O., Lanore D., De Mari K., Mihaljevic S-Y., Péchereau D., Régnier A., Thiry E., Vinet C. (2004) – Veterinary Interferon Handbook. First Edition.
  15. Jongh O. A cat with herpetic keratitis (primary stage of infection) treated with feline omega interferon. In: de Mari K, ed. Veterinary interferon handbook. Carros: Virbac, 2004: 138–47.
  16. Malik R, Lessels NS, Webb S, et al. Treatment of feline herpesvirus-1 associated disease in cats with famciclovir and related drugs. J Feline Med Surg 2009; 11: 40–8.

Vetpedia is translated by a team of expert scientific translators coordinated by Alberto Scalcerle (InterMed - Italian Association Medical Interpreters - coordinator) and Rachel Stenner (MA (Cantab) MB BS (Lon) - lead translator). 
For further information please contact: alberto.scalcerle@alice.it  www.scalcerle.net

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