Equine herpes I virus and equine neurologic disease (Proceedings)

Equine herpes virus-1 (EHV-1) is, for multiple reasons, a problematic infectious disease in the horse. EHV-1 may cause several different clinical syndromes, some of which result in epidemics of disease following the arrival of an infected horse on the premise. The virus can also be maintained in carrier animals, which may then result in either self-disease and/or spread at some later point in time. Spread of the virus is mostly horse to horse as its persistence in the environment is relatively short. Transmission is typically via infected nasal secretions, although fetal membranes and placental fluid from the aborted fetus are also highly infective. After direct contact, the virus first colonizes the nasal mucosa and then replicates in regional lymph nodes by 1-3 days. This is followed by viremia for 3-14 days (depending upon the strain). From day 2 or 3 post-infection to day 7, there should be high virus load in nasal secretions. Following the acute disease, horses may "silently" harbor the virus as a latent infection in peripheral nerves or lymphoid tissue and reactivation may occur following an environmental stressor or very high doses of steroids resulting in clinical disease (e.g., abortion) in the carrier, or environmental spread. A lot of our inability to predict outbreaks of EHV-1 disease is a result of a lack of understanding of the latently infected horse. How many are there? What causes the recrudescence?

Clinical diseases include: (1) upper respiratory disease with fever, nasal discharge and lymphadenopathy, often in weanling foals, (2) rarely pulmonary disease with severe pulmonary vasculitis thrombosis, (3) abortion with both placental and fetal infection in most cases, but only placental infection in other cases, (4) outbreaks of neurologic disease associated in many situations with a mutation in the polymerase gene, high levels of viremia and CNS vasculitis, and (5) neonatal sepsis, involving multiple organs (liver, lung, and even gut), and severe neutropenia. Healthy carrier foals acquiring the infection transplacentally is unproven.

A few general comments can be made regarding:

• outbreaks of respiratory disease – mostly in naïve populations.

• outbreaks of abortions – outbreaks in late pregnant mares most often caused by introduction of a shedding horse or reactivation in a resident horse into a relatively susceptible population. Isolated cases may be reactivation within the pregnant mare without appreciable nasal shedding.

• Neurologic disease – outbreaks are the rule with fever, posterior ataxia, and dysuria all common. Edema of limbs and nasal discharge may also be seen.

Further Information/Questions on Neurologic Disease resulting from EHV-1 infection (to be discussed):

• Is there a seasonal incidence? Cases are rarely reported in late summer or early fall.

• There appears to be an age predilection. Adult horses > 4 years are the great majority of cases. There are rare reports in yearling and young adults.

• Outbreaks are most common at boarding stables, show facilities, and seemingly less common at racetracks.

• Is there a sex predisposition? One report suggests it is most common in nonpregnant, competition horses. Kendrick, in his early experimental studies, suggested it was more easily produced in pregnant mares.

• Does tissue factor (TF) activity along with level of viremia play a major role in the CNS pathology? TF is likely highest in the endothelial cells of CNS and placenta!

• Does prior vaccination increase or decrease the risk of developing EHV-1 neurologic disease? Might the ratio of subset of IgGs play a role in protection or predict protection?

• Should we perform nasal swabs for PCR and genotyping on all horses with fever of unknown origin? What do we do with positive cases?

• How contagious are horses with CNS signs? How do we prevent outbreaks at referral hospitals and show centers, etc.? How do we manage horses at a facility that has the virus?

• Do infected mules show clinical disease? Could they possibly allow mutation of the virus?

• How do we evaluate protective humoral and cell-mediated immunity? Which vaccines are most likely to produce the best effect of secretory and circulatory antibody along with interferon and cytotoxic lymphocyte activity?

• What is the future of EHV-1 vaccination? Currently modified live vaccine? (MLV) given intramuscularly can stimulate high titers of serum virus neutralization antibody, which reduces the amount and duration of same strain virus shedding and primes the mucosal compartment. Do these vaccines protect against the "neurologic strain"? Killed vaccines have not shown the same response. What is on the horizon for genetically engineered EHV-1 vaccines and how effective might they be?

• What is the role of immune modulators given concurrent with vaccination? What are the indicators for Valacyclovir 25 mg/kg PO q 8-12h (:>$300/day) in EHV-1 outbreaks?

• When, if at all, should steroids be used in EHV-1 CNS disease? I believe there is a time for their use!

• Should horses be slung with severe EHV-1 neurologic disease? What is their prognosis? For horses that need to be slung, recovery to functional use is rare but does occur.

• What is the best way to manage the bladder and rectum atony often seen with EHV-1.

References

Allen, G.P. Antemortem detection of latent infection with neuropathogenic strains of equine herpesvirus-1 in horses. Am J Vet Res 2006;67(8):1401-1405.

Allen, G.P. and Breathnach, C.C. Quantification by real-time PCR of the magnitude and duration of leucocyte-associated viraemia in horses infected with neuropathogenic vs. non-neuropathogenic strains of EHV-1. Equine Vet J 2006;38(3):252-257.

Goodman, L.B., Wagner, B., Flaminio, M.J., Sussman, K.H., Metzger, S.M., Holland, R., and Osterrieder, N. Comparison of the efficacy of inactivated combination and modified-live virus vaccines against challenge infection with neuropathogenic equine herpesvirus type 1 (EHV-1). Vaccine 2006;24(17):3636-3645.

Henninger, R.W., Reed, S.M., Saville, W.J., Allen, G.P., Hass, G.F., Kohn, C.W., and Sofaly, C. Outbreak of neurologic disease caused by equine herpesvirus-1 at a university equestrian center. J Vet Intern Med 2007;21(1):157-165.

Ibrahim, E.S., Kinoh, M., Matsumura, T., Kennedy, M., Allen, G.P., Yamaguchi, T., and Fukushi, H. Genetic relatedness and pathogenicity of equine herpesvirus 1 isolated from onager, zebra and gazelle. Arch Virol 2007;152(2):245-255.

Hussey, S.B., Clark, R., Lunn, K.F., Breathnach, C., Soboll, G., Whalley, J.M., and Lunn, D.P. Detection and quantification of equine herpesvirus-1 viremia and nasal shedding by real-time polymerase chain reaction. J Vet Diagn Invest 2006;18(4):335-342.

Irwin, V.L., Traub-Dargatz, J.L., Newton, J.R., Scase, T.J., Davis-Poynter, N.J., Nugent, J., Creis, L., Leaman, T.R., and Smith, K.C. Investigation and management of an outbreak of abortion related to equine herpesvirus type 1 in unvaccinated ponies. Vet Rec 2007;160(11):378-380.

Kydd, J.H., Townsend, H.G., and Hannant, D. The equine immune response to equine herpesvirus-1: the virus and its vaccines. Vet Immunol Immunopathol 2006;111(1-2):15-30.

Luce, R., Shepherd, M., Paillot, R., Blacklawst, B., Wood, J.L., and Kydd, J.H. Equine herpesvirus-1-specific interferon gamma (IFNgamma) synthesis by peripheral blood mononuclear cells in thoroughbred horses. Equine Vet J 2007;39(3):202-209.

Minke, J.M., Fischer, L., Baudu, P., Guigal, P.M., Sindle, T., Mumford, J.A., and Audonnet, J.C. Use of DNA and recombinant canarypox viral (ALVAC) vectors for equine herpes virus vaccination. Vet Immunol Immunopathol 2006;111(1-2):47-57.

Nugent, J., Birch-Machin, I., Smith, K.C., Mumford, J.A., Swann, Z., Newton, J.R., Bowden, R.J., Allen, G.P., and Davis-Poynter, N. Analysis of equid herpesvirus 1 strain variation reveals a point mutation of the DNA polymerase strongly associated with neuropathogenic versus nonneuropathogenic disease outbreaks. J Virol 2006;80(8):4047-4060.

Paillot, R., Ellis, S.A., Daly, J.M., Audonnet, J.C., Minke, J.M., Davis-Poynter, N., Hannant, D., and Kydd, J.H. Characterisation of CTL and IFN-gamma synthesis in ponies following vaccination with a NYVAC-based construct coding for H1 immediate early gene, followed by challenge infection. Vaccine 2006;24(10):1490-1500.

Pusteria, N., Chaney, K.P., Maes, R., Wise, A.G., Holland, R., and Schott, H.C. 2nd. Investigation of the molecular detection of vaccine-derived equine herpesvirus type 1 in blood and nasal secretions from horses following intramuscular vaccination. J Vet Diagn Invest 2007;19(3):290-293.