Clinical Presentations

Feline herpesvirus is a ubiquitous virus that varies very little worldwide with respect to their clinical virulence. And yet, we see a huge range of clinical signs in cats infected with this virus. There are probably a large number of reasons for this; however, principle among these is likely the host’s response to this virus. FHV-1-naïve kittens infected in the first few weeks of life against a backdrop waning maternal immunity almost inevitably get severe upper respiratory and ocular disease with high morbidity but rare mortality. By contrast, adult cats can undergo viral reactivation with viral shedding and can infect in-contact cats; all without demonstrating clinical signs themselves. These two scenarios represent just the two extremes of infection; within your clinic you see cats with a huge diversity of clinical signs in between. For this reason, I like to consider clinical signs associated with FHV-1 under one of three broad categories: primary infection, recrudescent infections, and FHV-1-associated syndromes.

Primary Herpetic Disease

Primary ocular FHV-1 infection is characterized by blepharospasm, conjunctival hyperemia, serous ocular discharge that becomes purulent by day 5–7 of infection, mild to moderate conjunctival swelling, and often conjunctival ulcers. Corneal involvement is not reliable; however, some cats develop corneal ulcers which are transiently dendritic at the very earliest phase only. These dendrites quickly coalesce to become geographic ulcers. The ocular signs are seen in association with typical signs of upper respiratory infection. The uncomplicated clinical course is typically 10–14 days; however, it is critical to realize that almost all cats become latently infected within ganglia for life. Reactivation from latency is likely in at least 50% of cats, sometimes with viral shedding.

Recrudescent FHV-1 Syndromes

Despite the frequency with which latently infected cats undergo viral reactivation at the ganglia and viral shedding at peripheral epithelial sites, recrudescent disease occurs in a minority of these. Further, disease severity and tissue involvement can range very widely between individuals and even between episodes in the same cat. Recrudescent conjunctivitis is usually milder than in acute infections, but can become chronic and “smoldering”. Although recrudescent conjunctivitis is usually nonulcerative, substantial conjunctival thickening and hyperemia can occur secondary to inflammatory cell infiltration. Corneal involvement is relatively frequent in recrudescent disease compared to primary infection and may involve the corneal epithelium or stroma. With epithelial involvement, dendritic and later geographic corneal ulceration may be seen just as in primary infections. Corneal stromal disease is typically immunopathological (i.e., immune-mediated, but not necessarily autoimmune) in origin and includes stromal neovascularization, edema, stromal cell infiltration, and ultimately fibrosis usually under an intact epithelium. Consensus has not been reached regarding the antigens responsible for the subepithelial immunological response within cornea and/or conjunctiva. Some believe the process is driven by viral antigens, while others are suspicious that altered self-antigens are the focus of the immunological response.

FHV-1-Associated Disease Syndromes

The following diseases have been associated with detection of FHV-1 in affected tissues; however, the causative role of the virus in each syndrome has been variably proven.

Symblepharon

There is little question that symblepharon can be a sequela to severe primary FHV-1 infection. It is commonly seen in young animals, and presumably occurs as a result of widespread ulceration with exposure of the conjunctival substantia propria and sometimes also the corneal stroma. FHV-1 is almost certainly the predominant cause of symblepharon formation in cats and other infectious agents are unlikely to cause symblepharon formation.

Corneal Sequestration

Experimentally, FHV-1 inoculation (in cats receiving corticosteroids) can result in corneal sequestration. However, the prevalence of detectable FHV-1 in samples collected from cats with sequestra has varied widely in the clinical setting and the link between FHV-1 and sequestra has not been shown to be causative. It seems likely that sequestration is a non-specific response to stromal exposure or damage and that FHV-1 is just one possible cause of this disease. This is borne out in a study by Nasisse et al. who reported identification of FHV-1 DNA in 86 of 156 (55%) of sequestra analyzed (compared with only 6% of clinically normal corneas). A lower prevalence of FHV-1 DNA was found in corneas of Persian and Himalayan cats with sequestration, suggesting that other non-viral causes of sequestration are more likely to be operative in these breeds.

Eosinophilic Keratitis

Prior clinical studies have suggested a link between FHV-1 infection and eosinophilic keratitis. PCR testing of corneal scrapings from cats with cytology-confirmed eosinophilic keratitis has revealed 76% (45/59) of cases to be FHV-1 positive. However, PCR performed on tears collected onto a STT was negative in 10 cats with cytologically proven eosinophilic keratitis. As with corneal sequestra, the role of the virus in the initiation or exacerbation of this disease has not been determined; however, anecdotally some patients with this syndrome improve with antiviral therapy alone.

Dermatitis

Periodically, FHV-1 has been identified as a cause of dermatological lesions, particularly those surrounding the eyes and involving nasal skin of domestic and wild felidae. This is not surprising when one considers the marked epithelial tropism of this virus and the reliability with which HSV-1 causes dermal lesions. We have recently examined the diagnostic utility of FHV-1 PCR for this disease. FHV-1 DNA was detected in all 9 biopsy specimens from 5 cats with herpetic dermatitis but in 1 of 17 biopsy specimens from the 14 cats with non-herpetic dermatitis, and was not detected in any of the 21 biopsy specimens from the 8 cats without dermatitis. This is in sharp contrast to the use of this technique in ocular tissues where the extent of viral shedding in normal animals dramatically reduces the sensitivity of a positive test in affected animals. When results of histologic examination were used as the gold standard in this study of cats with dermatitis, sensitivity and specificity of the PCR assay were 100% and 95%, respectively. We concluded that FHV-1 DNA can be detected in the skin of cats with herpetic dermatitis, that the virus may play a causative role in the disease, and that this PCR assay may be useful in confirming a diagnosis of herpetic dermatitis.

Diagnosing Cats with Keratoconjunctivitis

One of my least favorite questions is “What is the best laboratory test for cats with corneal or conjunctival disease?” In reality there is not one. Explaining this position requires an understanding of an essential fact about feline herpesvirus (FHV-1)—clinically normal cats (and lots of them) can shed FHV-1 at their ocular surface. Because PCR is more sensitive than IFA or VI, this assay exacerbates this problem. In fact, in some humane shelter-based populations, about half of all normal cats are shedding FHV-1 DNA as determined by PCR. Therefore, in some circumstances, the number of false positive test results we can expect is extraordinarily high and we may be better to flip a coin than to run that PCR assay! Given the predictably high rate of false positive (particularly with serology and PCR) and negative test results (particularly with VI and IFA), I now no longer conduct laboratory tests for FHV-1 or Chlamydia felis (previously Chlamydia psittaci and, before that, Chlamydophila felis) in individual cats with keratoconjunctivitis. Rather, I resort to good old fashioned clinical acumen. My diagnostic “tests” now are (i) the history and clinical exam findings followed by (ii) response to therapy. This requires acceptance of a couple of critical facts: first I have to be willing to be wrong when making an educated guess regarding the etiological diagnosis and, second, I have to use the absolute best therapeutic trial and demand excellent owner compliance in executing that trial.

Diagnosing Keratoconjunctivitis Using Clinical Signs as Your Guide

Using clinical signs of surface ocular disease as a “diagnostic assay” requires a philosophical approach that I liken to adding pebbles to one of two sides of an old-fashioned scale or balance. I start with the paradigm that feline keratoconjunctivitis is infectious till proven otherwise and that by far and away the most commonly implicated infectious organisms are FHV-1 and Chlamydia felis. I then consider the clinical signs outlined in the table. Using each feature as a discerning feature I aim to place one of my “diagnostic pebbles” on the herpetic or chlamydial sides of the balance, thereby making a clinical judgment at the end of the examination as to which of these 2 organisms is more likely to be the cause of the disease seen.

Note that both agents cause some of the signs and that it is a weighted assessment. This introduces a notable element of subjectivity into the assessment. I unashamedly tell clients this and explain that I still believe that this is better than wasting their money on a laboratory test. I also use this time to introduce the concept that the clients themselves will form the critical next step in the diagnostic process—”response to therapy”. We will discuss this more fully in the next session.

Antiviral Therapy

If we are to use response to therapy as a “diagnostic test”, then we must choose the optimum therapeutic approach possible for each cat. Although a large variety of antiviral agents exists for oral or topical treatment of cats infected with feline herpesvirus type 1 (FHV-1), some general comments regarding these agents are possible:

• No antiviral agent has been developed for FHV-1; although many have been tested for efficacy against this virus. Agents highly effective against closely-related human herpesviruses are not necessarily or predictably effective against FHV-1 and all should be tested in vitro before they are administered to cats.
• No antiviral agent has been developed for cats; although some have been tested for safety in this species. Agents with a reasonable safety profile in humans are not always or predictably non-toxic when administered to cats and all require safety and efficacy testing in vivo.
• Many antiviral agents require host metabolism before achieving their active form. These agents are not reliably or predictably metabolized by cats and pharmacokinetic studies in cats are required.
• Antiviral agents tend to be more toxic than do antibacterial agents since viruses are obligate intracellular organisms and co-opt or have close analogues of the host’s cellular “machinery”. This limits many antiviral agents to topical (ophthalmic) rather than systemic use.
• All antiviral agents currently used for cats infected with FHV-1 are virostatic. Therefore, they typically require frequent administration to be effective.

The following antiviral agents have been studied to varying degrees for their efficacy against FHV-1, their pharmacokinetics in cats, and/or their safety and efficacy in treating cats infected with FHV-1.

Trifluridine (TFU or trifluorothymidine) is too toxic to be administered systemically but topically administered trifluridine is considered one of the most effective drugs for treating HSV-1 keratitis. This is in part due to its superior corneal epithelial penetration. It is also one of the more potent antiviral drugs for FHV-1. It is commercially available in the USA as a 1% ophthalmic solution that should be applied to the affected eye 5–6 times daily. Unfortunately, it is expensive and is often not well tolerated by cats, presumably due to a stinging reaction reported in humans.

Idoxuridine (IDU) is a nonspecific inhibitor of DNA synthesis, affecting any process requiring thymidine. Therefore, host cells 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. This drug is reasonably well tolerated by most cats and seems efficacious in many. It is no longer commercially available in the USA but can be obtained from a compounding pharmacist. It should be applied to the affected eye 5–6 times daily.

Vidarabine (VDB) interferes with DNA polymerase and, like idoxuridine, is non-selective in its effect and so is 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. Where it is not available commercially, it can be obtained from a compounding pharmacist. Like idoxuridine, it should be applied to the affected eye 5–6 times daily.

Acyclovir (ACV) has relatively low antiviral potency against FHV-1, 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 levels of only approximately one third required for this virus. Common signs of toxicity are referable to bone marrow suppression. However, acyclovir is also available as a 3% ophthalmic ointment in some countries. In one study in which a 0.5% ointment was used 5 times daily, the median time to resolution of clinical signs was 10 days. Cats treated only 3 times daily took approximately twice as long to resolve and did so only once therapy was increased to 5 times daily. Taken together, these data suggest that very frequent topical application of acyclovir may produce concentrations at the corneal surface that do exceed the reported concentration required for this virus but are not associated with toxicity. There are also in vitro data suggesting that interferon exerts a synergistic effect with acyclovir that could permit an approximately 8-fold reduction in acyclovir dose. In vivo investigation and validation of these data are needed.

Valacyclovir (VCV) 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. Its safety and efficacy have been studied in cats. 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 never be used in cats.

Ganciclovir (GCV) appears to be at least 10-fold more effective against FHV-1 compared with acyclovir. It is available for systemic (IV or PO) and intravitreal administration in humans, where it is associated with greater toxicity than acyclovir. Toxicity is typically evident as bone marrow suppression. It has been released as a new topical antiviral gel in humans. There are no reports of its safety or efficacy in cats as a systemic or topical agent, although anecdotal reports from Europe (where it is much less expensive) are very promising.

Famciclovir (Famvir® and generic) is a prodrug of penciclovir; however, metabolism of famciclovir to penciclovir in humans is complex; requiring di-deacetylation, in the blood, liver, or small intestine, 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. Indeed data to date suggest that famciclovir and penciclovir pharmacokinetics in the cat are extremely complex and likely nonlinear. For example, an approximately 6-fold increase in dose produced only an approximately 3-fold increase in plasma concentration. However, in a masked, prospective, placebo-controlled study of efficacy, experimentally infected cats receiving 90 mg/kg famciclovir TID had significantly reduced clinical signs, serum globulin concentrations, histologic evidence of conjunctivitis, viral shedding, and serum FHV-1 titers, as well as increased goblet cell density. Importantly, no important adverse clinical, hematologic or biochemical changes were associated with famciclovir administration. More recently, we have shown that 90 mg/kg PO BID produces almost identical plasma and tear concentrations as did the TID dose that was so successful. Do not compound, do not taper the dose when seeing improvement. Rather, treat beyond clinical resolution and then stop.

Cidofovir (CDV) is commercially available only in injectable form in the USA but has been studied as a 0.5% solution applied topically twice daily to cats experimentally infected with FHV-1. Its use in these cats was associated with reduced viral shedding and clinical disease. Its efficacy at only twice daily (despite being virostatic) is believed to be due to the long tissue half- lives of the metabolites of this drug. 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, at this stage there are insufficient data to support its long term safety as a topical agent in cats.

Lysine

The literature regarding lysine has become very interesting recently with some data that at first glance appear contrary to earlier study outcomes which suggested efficacy. This requires a more detailed assessment.

Lysine limits the in vitro replication of many viruses, including FHV-1. The antiviral mechanism is unknown; however, many investigators have demonstrated that concurrent depletion of arginine is essential for lysine supplementation to be effective. This finding suggests that lysine exerts its antiviral effect by antagonism of arginine. Meanwhile, results of 2 early independent in vivo studies have supported the clinical use of L-lysine in cats. Lysine-treated cats undergoing primary herpetic disease had significantly less severe conjunctivitis than cats that received placebo, while latently infected adult cats receiving lysine had reduced viral shedding. In both studies, plasma arginine concentrations remained in the normal range, and no signs of toxicity were observed, despite notably elevated plasma lysine concentrations in treated cats. A subsequent study examined the effects of lysine in 144 shelter cats receiving oral boluses of 250 mg (kittens) or 500 mg (adult cats) of lysine once daily for the duration of their stay. No significant treatment effect was detected on the incidence of infectious upper respiratory disease (IURD), the need for antimicrobial treatment for IURD, or the interval from admission to onset of IURD. A subsequent pair of studies assessed the safety and efficacy of L-lysine incorporated into cat food. Perhaps not unexpectedly, food (and therefore lysine) intake decreased coincident with peak disease and viral presence. As a result, cats did not receive lysine at the very time they needed it most. Surprisingly though, clinical signs and viral shedding in cats fed the supplemented ration were worse than in cats fed the basal diet.

Taking all of this into account, I administer 500 mg lysine per os q 12 hours therapeutically at the time of recrudescent disease and encourage owners of cats that have frequent recurrences to administer this same dose over the long term as a prophylactic measure.

More recently I have strongly recommended that client-owned animals receive lysine as a twice daily bolus; not sprinkled on food.