Diagnosis

Diagnosis of FHV-1 represents one of the greatest challenges in the management of chronic herpetic diseases. Diagnostic tests either detect the virus (or some part of it) or the host response to the virus. However, at least 3 problems confound the diagnostic value of these tests: 1) virus can be detected in up to ½ of normal cats; 2) HSV-1 (and possibly FHV-1) can be stimulated to reactivate by irritation of the peripheral sensory neurons. Therefore, virus detected at a peripheral site in a diseased animal may be there as a result rather than cause of disease; 3) no test differentiates vaccine from wild-type virus.

Therefore, there are at least 4 possible explanations when virus is detected in a cat with disease:

1.  Its presence is coincidental (i.e., unrelated to the primary disease process)

2.  Its presence is a consequence of the primary disease process

3.  It is the cause of the primary disease process

4.  It is vaccine virus

Perhaps one of the best ways to diagnose FHV-1 is to maintain a strong clinical suspicion of its involvement in any cat with surface ocular disease and to be well aware of its classical clinical features, but to be questioning of its role in that disease process whenever it is detected using any currently available diagnostic assays.

Therefore, defining "diagnostic" clinical signs is important. The only pathognomonic clinical sign of herpetic infection is dendritic corneal lesions. However, these are unreliably and transiently present, and are sometimes detectable only with rose bengal stain. Despite this, clinical suspicion of herpetic disease in cats should be high because the vast majority of feline keratoconjunctivitis is due to FHV-1 or Chlamydophila felis (previously Chlamydia psittaci). Feline calicivirus is an unlikely and minor primary conjunctival pathogen and is not a recognized corneal pathogen (Table).

Treatment

Therapy for cats infected with FHV-1 can be considered in one of 4 categories: supportive therapy, antiviral therapy, experimental therapies, and contraindicated therapies. For brevity, I have emphasized the latter 3 categories here.

Antiviral Agents

FHV-1 is variably susceptible to commercially available antiviral ophthalmic medications developed for human herpesviruses; however safety and efficacy of these compounds is not predictable. For these reasons, careful in vitro investigation of efficacy against FHV-1, followed by safety and pharmacokinetic trials, subsequent placebo-controlled efficacy studies in experimental animals, and finally judicious clinical trials in client-owned animals should always precede widespread clinical use and anecdotal reporting.

Important general concepts:

 Antiviral agents tend to be more toxic than antibacterial drugs. This rarely limits topical application of these drugs but may severely limit their systemic use.

 Antiviral agents are virostatic and require relatively frequent dosing.

 No antiviral drug is antibacterial.

Relative In vitro efficacy against FHV-1 of commercially available antiviral drugs (Lower IC₅₀ = more effective).

Idoxuridine (IDU) is a nonspecific inhibitor of DNA synthesis. Therefore, host cells and viruses are similarly affected, systemic therapy is not possible, and corneal toxicity can occur. It has been used as an ophthalmic 0.1% solution or 0.5% ointment, which is reasonably well tolerated by most cats and seems efficacious in many. It should be topically applied 5-6 times daily.

Vidarabine (VDB) also is non-selective in its effect and associated with notable host toxicity if administered systemically. Because it affects a viral replication step different from that targeted by idoxuridine, vidarabine may be effective in patients whose disease seems resistant to idoxuridine. As a 3% ophthalmic ointment, vidarabine often appears to be better tolerated than many of the antiviral solutions. It should be topically applied 5-6 times daily.

Trifluridine (TFU) is too toxic to be administered systemically but topically administered trifluridine is considered one of the most effective drugs for treating HSV-1 keratitis; in part due to its superior corneal epithelial penetration. As a 1% ophthalmic solution, it should be topically applied 5-6 times daily. However, its clinical efficacy is somewhat unpredictable, it is expensive, and frequently irritating.

Acyclovir (ACV) is an acyclic nucleoside analogue that requires 3 phosphorylation steps for activation; the first of which is catalyzed by viral thymidine kinase. This permits them to be systemically administered. The second and third phosphorylation steps must be performed by host enzymes, which may not be present or effective in cats. In addition to relatively low antiviral potency against FHV-1, acyclovir has poor bioavailability and is potentially toxic when systemically administered to cats. Oral administration of 50 mg/kg acyclovir to cats was associated with peak plasma concentrations that are only about one third the IC₅₀ for FHV-1. Signs of toxicity are referable to bone marrow suppression; therefore a CBC should be monitored in patients receiving acyclovir systemically.

Valacyclovir is a prodrug of acyclovir that, in humans and cats, is more efficiently absorbed from the gastrointestinal tract compared with acyclovir and is converted to acyclovir by a hepatic hydrolase. Plasma concentrations of acyclovir that surpass the IC₅₀ for FHV-1 can be achieved after oral administration of this drug. However, in cats experimentally infected with FHV-1, valacyclovir induced fatal hepatic and renal necrosis, along with bone marrow suppression, and did not reduce viral shedding or clinical disease severity. Therefore, despite its superior pharmacokinetics, valacyclovir should not be used in FHV-1-infected cats.

Penciclovir (PCV) is another acyclic nucleoside analogue with potent antiviral activity against a number of human herpesviruses and FHV-1. It is available as a dermatologic cream for humans that should not be applied to the eye. Although there are some data regarding administration of famciclovir to cats (which is converted to penciclovir), in vivo studies of penciclovir's safety or efficacy in cats are lacking and at this time, its use in cats cannot be recommended.

Famciclovir (FCV) is a prodrug of penciclovir; however metabolism of famciclovir to penciclovir in humans is complex and requires di-deacetylation, predominantly in the blood, and subsequent oxidation to penciclovir by aldehyde oxidase in the liver. Unfortunately, hepatic aldehyde oxidase activity is nearly absent in cats. This has necessitated cautious extrapolation to cats of data generated in humans. In a recent study of famciclovir pharmacokinetics in normal cats given 9-18 mg/kg q 8-12 hours, peak plasma penciclovir concentrations achieved were approximately 1/5th the concentration required for in vitro activity against feline herpesvirus-1. In a subsequent study cats given 90 mg/kg TID achieved plasma concentrations that were surprisingly low (approximately 2/3 of IC₅₀). Taken together, data from these two studies suggest that the pharmacokinetics of famciclovir in cats are extremely complex and require more work. However, in a masked, prospective, placebo-controlled study of efficacy, experimentally infected cats receiving 90 mg/kg famciclovir TID had significantly reduced clinical signs and serum FHV-1 titers than did placebo-treated cats. No clinically important adverse physical, hematologic or biochemical changes were associated with famciclovir administration. Despite this, there are reports that suggest famciclovir is effective in some cats with suspected herpetic disease at lower doses and dose frequency. Further studies of the pharmacokinetics, safety and efficacy of famciclovir and penciclovir are required before dose rates and frequency can be recommended.

Cidofovir (CDV) is a cytosine analogue that requires 2 host-mediated phosphorylation steps but does not require virally-mediated phosphorylation. Its safety arises from its relatively high affinity for viral DNA polymerase compared with human DNA polymerase. Its metabolites also appear to have a particularly long tissue half-life suggesting less frequent application may be possible. It is available in injectable form in the United States that has been compounded for topical application as a 0.5% solution. In a recent study, twice daily topical application to cats experimentally infected with FHV-1 was associated with reduced viral shedding and clinical disease. There are occasional reports of its experimental topical use in humans being associated with stenosis of the nasolacrimal drainage system components and, as yet, it is not commercially available as an ophthalmic agent in humans. Therefore, although its in vitro and short-term in vivo efficacy against FHV-1 are proven, at this stage there are insufficient data to support its long term safety as a topical agent in cats.

Experimental Agents

Lysine. Some in vitro and in vivo data are available to support use of lysine. In the presence of diminished arginine concentrations, in vitro replication of FHV-1 was suppressed by approximately 80% when the lysine concentration in the culture medium was doubled. This effect was negated at higher arginine concentrations, which suggests a similar mechanism of arginine antagonism to that described for HSV-1. Administration of 500 mg lysine PO BID to cats (beginning 6 hours prior to experimental inoculation with FHV-1) was associated with less severe conjunctivitis than cats receiving placebo. However, viral shedding did not differ between groups. Oral lysine supplementation (400 mg PO SID) reduced viral reactivation and/or shedding in latently infected cats. Despite significant elevations in plasma lysine concentration, no change in plasma arginine concentration or any ill effects attributable to lysine administration were observed in either study.

Because daily bolus administration of lysine is often impractical, we studied the safety and efficacy of dietary lysine supplementation. Cats fed a diet supplemented with up to 8.6% (dry matter) lysine showed no signs of toxicity, had normal plasma arginine concentrations, and had normal food intake. Mean plasma lysine concentration of these cats was increased to levels similar to that achieved with bolus administration. Subsequently, cats with enzootic upper respiratory tract disease were fed a diet containing 5.1% lysine for 52 days following rehousing intended to cause viral reactivation. Ironically, food (and therefore lysine) intake decreased coincident with peak disease and viral presence, cats did not receive lysine at the time they needed it most, and disease and viral shedding were worse in cats fed the supplemented ration than in cats fed the basal diet. This has been subsequently proven in a shelter population.

λ-carrageenan (a red seaweed extract) was ineffective in experimentally infected cats when 1 drop of a 250 µg/mL solution was applied before and after infection (n = 6 cats) or after infection only (n = 6 cats).

Leflunomide is an immunosuppressive agent that appears to have some in vitro antiviral effects against many herpesviruses including FHV-1. The proposed method of action is through alteration in outer tegument formation. In vivo studies are required.

Lactoferrin has a very potent antiviral effect against FHV-1 replication in vitro apparently through inhibition of FHV-1 adsorption to the cell surface and/or penetration of the virus into the cell.

The interferons are a group of cytokines that may play important physiological roles in control of viral infections; however in vitro and clinical trials have produced conflicting results. In vitro application of recombinant human IFNα or recombinant feline IFNω significantly reduced FHV-1 titer and/or cytopathic effect; at higher concentrations, IFNω was more effective than IFNα. In a separate in vitro study, acyclovir combined with human recombinant IFNα was associated with a nearly eightfold reduction in the dose of acyclovir required to achieve maximal inhibition of FHV-1. However, no beneficial effects were shown when cats received 10,000 IU recombinant feline IFNω OU q 12 hours and 2,000 IU PO q 24 hours 2 days prior to viral inoculation. Dosing was not continued after inoculation. In a separate study, systemic administration of IFNα (10⁸ IU/kg subcutaneously BID beginning 1 day prior to inoculation) did not prevent disease but did lower clinical scores. An abstract compares 1, 5 or 25 IU IFNα administered PO q 24 hrs to cats undergoing primary experimental FHV-1 infection. In this study IFN was given 24 and 48 hours post inoculation only. Scores for disease severity were significantly lower in cats receiving 5 or 25 units than in control cats.