Eric C. Ledbetter, DVM, DACVO
1. Epidemiology and basic pathophysiology
2. Historical canine herpesvirus-1 diseases
a. Fetal dogs
b. Neonatal dogs
c. Mature dogs
3. Canine herpesvirus-1 ocular disease in mature dogs
a. Clinical signs
1) Epidemiology and Basic Pathophysiology
Canine herpesvirus-1 (CHV-1) is a varicellovirus of the subfamily Alphaherpesvirinae with a host range restricted to domestic and wild canids. Canine herpesvirus-1 is among the most prevalent infectious diseases of domestic dogs and has a worldwide distribution. Canine herpesvirus-1 infections are endemic in dogs in all countries where studies have been performed (e.g., Australia, Belgium, Czech Republic, England, Finland, France, Germany, Iran, Japan, Netherlands, Norway, Slovakia, South Africa, Turkey, United States, etc.). In reports of CHV-1 seroprevalence, 20–95% of dogs are infected depending on the specific study and canine population evaluated.
Canine herpesvirus-1 is closely related to several other herpesviruses of animal and human importance, including herpes simplex virus-1, herpes simplex virus-2, varicella zoster virus, feline herpesvirus-1, and bovine herpesvirus-1. These alphaherpesviruses share several biological features: 1) the pattern and severity of disease associated with infection is host age-dependent (i.e., typically severe disseminated disease in the young and localized recurrent mucosal disease in mature individuals); 2) life-long latent infection is established in neurons of sensory ganglia during initial exposure in individuals surviving primary infection; and 3) latent viral infections reactivate in some hosts and result in viral shedding and recurrent disease, typically localized to the anatomic site of initial exposure.
Within the host dog, CHV-1 exists in three distinct viral states: 1) primary infection, 2) latent infection, and 3) recurrent infection. Primary infection is a rapid, cytolytic infection of epithelial cells in the naïve host. Clinical signs of primary infections are contingent upon the route of viral inoculation, age of the host, and the host's immune status. Typically, the host immune response controls and eliminates the active infection, although neonates and immunosuppressed dogs may develop systemic infections. During primary infection, CHV-1 is conveyed in sensory nerves by retrograde axonal transport to regional sensory ganglia where it establishes latency.
Latency is a period without clinical disease, viral replication, or recoverable infectious virus; however, virus can be induced to reactivate. The only abundant viral gene product that is transcribed during latency is the latency-associated transcripts or latency-related transcripts. Recurrent infection occurs when CHV-1 reactivates and descends sensory nerve axons to reach peripheral epithelial tissues (virus returns to the site of primary infection). Viral reactivation results in varying degrees of recurrent disease and viral shedding; however, the severity and tissues involved are variable between individuals and episodes.
2) Historical CHV-1 Diseases
Canine herpesvirus-1 was first identified in the 1960s as an etiology of neonatal dog mortality. In puppies < 2 weeks of age born to seronegative bitches, CHV-1 infection is associated with systemic viral dissemination and several clinical diseases. A cell-associated viremia results in visceral hemorrhagic necrosis, meningoencephalitis, and typically death. Transplacental transmission of CHV-1 to fetal pups in utero may also produce fetal death and resorption, premature or stillborn pups, and birth of infected pups. Ocular disease associated with fetal and neonatal CHV-1 infection is the result of panuveitis and direct intraocular viral infection. In the uncommon scenario where a dog survives neonatal CHV-1 infection, blindness, cataracts, optic nerve atrophy, retinal degeneration, and retinal dysplasia are potential residual sequelae.
Infection of dogs > 2 weeks of age was previously thought to be subclinical in the majority of dogs (except for impacts on fertility and reproduction), although CHV-1 infection may be associated with genital mucositis and respiratory tract disease in some dogs. Ocular disease in mature dogs associated with CHV-1 infection was identified relatively recently.
3) CHV-1 Ocular Disease in Mature Dogs
In contrast to fetal and neonatal dogs, ocular lesions associated with CHV-1 infection in mature dogs are typically restricted to the ocular surface. Canine herpesvirus-1 infection may produce a variety of corneal, conjunctival, and eyelid lesions. In immunocompetent dogs, these lesions are frequently mild and self-limiting; however, they are a source of discomfort and their recurrent nature may be frustrating to clients. Nonspecific clinical signs associated with CHV-1 ocular infection in mature dogs include blepharospasm, photophobia, and ocular discharge. Blepharospasm and ocular pain are often disproportionally severe compared to that expected from the extent of ocular lesions. Ocular discharge is initially restricted to epiphora, but becomes mucoid, mucopurulent, or serosanguineous with infection progression.
Primary and recurrent ocular CHV-1 infection may be subclinical or associated with various combinations of blepharitis, conjunctivitis, keratitis, and corneal ulceration. Clinical lesions during primary ocular CHV-1 infection are typically bilateral; however, the severity and specific manifestations of CHV-1 infection are not always symmetrical between eyes of individual dogs. In most cases, primary ocular CHV-1 infection resolves spontaneously and without permanent ocular lesions; however, recovered dogs are at risk for developing recurrent ocular disease associated with reactivation of latent CHV-1 in the future. Recurrent CHV-1 ocular disease may present as either unilateral or bilateral lesions. Recurrent CHV-1 ocular infection may occur in dogs with no identifiable risk factors; however, one or more sources of immunocompromise are present in most dogs including immunomodulating systemic conditions and immunosuppressive therapeutics.
Blepharitis is occasionally present with ocular CHV-1 infection. Canine herpesvirus-1-associated blepharitis appears as focal or generalized eyelid erythema, edema, exudates, and crusting. Regions of alopecia may be present. Conjunctivitis is the most frequently reported ocular lesion associated with both primary and recurrent CHV-1 infection. Canine herpesvirus-1 conjunctivitis presents with conjunctival hyperemia, chemosis, and ocular discharge. Ulceration of the conjunctival epithelium may occur and appears as flat, irregular, pale or pink regions on the conjunctival surface surrounded by regions of hyperemia. Conjunctival ulcerations are more readily detected with application of sodium fluorescein, rose bengal, or lissamine green stains. Although the clinical features of CHV-1 conjunctivitis are often indistinguishable from other etiologies, conjunctival petechiae are frequent in dogs with CHV-1 infection. Although not specific to CHV-1 infection, conjunctival petechiae are an uncommon finding with most other etiologies of conjunctivitis and are suggestive of CHV-1.
Ulcerative keratitis and nonulcerative keratitis are frequent lesions associated with both primary and recurrent ocular CHV-1 infection. A variety of clinical manifestations are observed in the cornea with CHV-1 infection and these may represent a continuum along the progression of active corneal epithelial infection. Punctate keratitis is the earliest detectable CHV-1 corneal ulceration and appears clinically as a fine stippling of epithelial loss. This subtle lesion may be overlooked when examination is performed without magnification, but application of corneal stains (especially rose bengal or lissamine green) facilitate detection. As punctate ulcerations progress, they form the classic alphaherpesvirus corneal lesion of dendritic corneal ulcers. Dendritic corneal ulcerations are strongly suggestive of CHV-1 infection in the dog. These linear, branching ulcers stain brightly with sodium fluorescein, rose bengal, and lissamine green. Coalescence of dendritic ulcers may result in the formation of geographic corneal ulcers. These appear as larger, irregular-shaped areas of corneal epithelial loss. In dogs with CHV-1 ulcerative keratitis, corneal ulcers are commonly in discrete groups or linear arrangements on the surface of the cornea. Unless complicated by opportunistic bacterial infection, CHV-1 corneal ulcers remain superficial and corneal stromal loss is not appreciable. Nonulcerative keratitis is a less frequent lesion observed with CHV-1 ocular infection. Nonulcerative keratitis appears clinically as a circumferential ring of cornea stromal vascularization with epithelial and subepithelial leukocyte infiltrates in the peripheral cornea. Nonulcerative keratitis may represent a resolution stage of active corneal epithelial disease.
Diagnosis of CHV-1 keratitis is achieved by virus isolation or PCR assay analysis of corneal or conjunctival samples. In contrast to some other alphaherpesviruses associated with ocular disease in domestic animals, subclinical ocular shedding of CHV-1 occurs uncommonly in mature dogs and viral detection in dogs with compatible clinical signs is strongly suggestive of an etiologic role for the virus. A robust serologic response is often detected in dogs with primary or recurrent CHV-1 ocular infection; however, this diagnostic approach requires acute and convalescent serum samples to be collected.
In addition to nonspecific treatments to prevent secondary bacterial infection (topical ocular antimicrobials) and improve comfort (topical ocular atropine), topical ophthalmic antiviral therapy is reported for CHV-1 ocular infections. These antivirals have included 0.1% idoxuridine and 1% trifluridine ophthalmic solutions. Both antivirals are administered 6–8 times daily for the first 48 hours and then 4 times daily until resolution of clinical signs of active infection. When possible, ophthalmic and systemic immunosuppressive medication administration should be discontinued. After resolution of the ocular disease, dogs remain at risk for recurrent episodes of infection associated with reactivation of latent CHV-1.