Approaches to managing and treating equine herpesvirus

Equine herpesvirus (EHV) has been in the news this year. A filly arrived at The National Stud with neurological signs and was positive for EHV1, and several British breeding farms reported EHV1-related abortion and neonatal illness. Internationally, this year has seen reports of EHV1 from France, Belgium, Italy, Ireland and the US. Meanwhile, problems sourcing EHV1,4 vaccine have caused anxiety in the Thoroughbred community.

EHVs form a group within the herpesviridae family. EHV1 and EHV4 are a-herpesviruses. They are closely related, but genetically and antigenically distinct, and cause different clinical problems. EHV4 is very widespread, particularly in young horses, and causes respiratory disease. Although this interrupts training, it is usually troublesome, rather than life threatening. EHV4 can be spread when young horses mingle – for example, at sales complexes. A survey conducted in South Africa showed 14% of 2-year-old Thoroughbreds arriving at an auction were shedding EHV4 and 93% showed serological evidence of prior exposure to EHV4¹.

EHV1 is more serious, as it is associated with abortion, stillbirth, neonatal illness and neurological signs. Virulence markers, identified by molecular characterisation of EHV1 from viruses recovered in outbreaks during a 30-year period in the US and Europe, introduced the concept of neuropathic and non-neuropathic strains^2. However, it is important to recognise although the odds of having neurological disease are greatly increased with the ORF30 G(2254) genotype, the opposite allele (ORF30 A[2254]) can also be associated with neurological signs³. Therefore, strain differences account, in part, for why some EHV1-infected horses develop neurological signs and others do not. Differences in pathogenicity may relate to strain differences in magnitude and duration of viraemia, and the affected animals’ vaccination status, age and other, as yet unclear, factors play a role in leading to clinical disease.

EHV infection

A key feature of EHVs is they can become latent (or dormant) and an astoundingly large number of horses carry latent virus. Infection begins when the horse breathes in virus, usually from close contact with an infected animal. Once it enters the nasal passages, EHV1 and EHV4 can travel up from the nasal lining into the trigeminal nerve, which links the nasal passages and the brain, where the virus can survive for the rest of the horse’s life. EHV can also become latent within lymphoid tissue.

A study in US Thoroughbred racehorses found latent EHV1 in 25% and latent EHV4 in 83%⁴, and it is likely latent virus is equally prevalent in British horses⁵. Clinical signs occur when the virus becomes reactivated and spreads to the bloodstream to create viraemia. At that point, the original host may develop clinical signs, or it may become infectious to others. Frustratingly, we do not know exactly how virus is reactivated, but we do know stressful events – such as other illnesses, transport and other stressors – can be trigger factors.

The possibility of EHV1 infection must be considered with various clinical scenarios. The respiratory form can be mild – particularly in older animals. But in naïve animals, signs will typically last around two to three weeks, leading to fever, nasal and ocular discharge, and lymphadenopathy. It is also important to consider EHV1 does not always occur in isolation, and coinfection with Rhodococcus equi has been reported in a two-month-old foal with severe bronchointerstitial pneumonia⁶. EHV1 is also associated with chorioretinopathy⁷.

On stud farms, EHV1 is associated with late-term abortion and stillbirth. Some foals may be alive at birth, but show signs of lethargy and respiratory dysfunction. A high index of suspicion is required⁷ because it is easy to assume these signs relate to bacterial infection (neonatal sepsis) – a common cause of morbidity and mortality in this age group. Every sick foal should be considered a possible EHV1 case. One clue EHV1 might be involved is an extremely low white blood cell count, and EHV1-affected foals often have a diffuse pneumonia, which can be visualised with ultrasound and/or radiography, rather than the more localised ventral pattern typically seen with bacterial pneumonia.

With the neurological form of EHV1 (or EHV myeloencephalopathy), several horses in a group may show fever, with a smaller proportion showing neurological signs. The neurological signs typically develop 6 to 10 days after the fever and usually without respiratory signs. Classically affected horses show ascending, symmetrical paralysis – that is, left and right are affected equally and the hind end is most severely affected, with weakness of the hindlimbs and urinary incontinence. In some horses, the signs are mild and temporary, while others progress to recumbency. Some cases develop central signs, such as depression, head tilt, vestibular ataxia and cranial nerve defects⁷.

Because the consequences of missing EHV1 infection can be so devastating, it is essential all potential cases are investigated until EHV1 is ruled out. This is relatively straightforward for abortions and stillbirths, where all material can be submitted to a laboratory for further testing. Where animals succumb to undiagnosed neurological disease, it is often tempting to feel a postmortem is not required, but this approach risks missing the case that begins an outbreak and, although moving an adult horse to a suitable autopsy facility can be difficult and expensive, no place for shortcuts exists with this disease.

For premortem diagnosis in sick foals and neurological cases, nasopharyngeal swabs are tested with PCR, and these swabs, together with buffy coat from heparinised blood, can be submitted for virus isolation. The amount of EHV1 DNA found in nasal swabs varies markedly and is not associated with disease severity or age. It is not possible to rely on the severity of clinical signs to predict the duration of EHV1 shedding. Some horses shed virus for up to nine days⁸ after the onset of signs, but because neurological signs occur after viraemia, it is also possible PCR will be negative in some neurological EHV1 cases (Figure 2).

Various serological tests have been developed, and the complement fixation test, available at the AHT, measures the IgM response – a high complement fixation titre in a single serum sample suggests acute infection and a four-fold rising antibody at 14 to 28 days provides unequivocal evidence of EHV-1 infection⁹.

Codes of practice

The UK is fortunate that breeders and racehorse trainers have developed codes of practice for dealing with disease outbreaks for a variety of infectious diseases, including EHV1. The breeding world is served by the Horserace Betting Levy Board (HBLB) codes, while trainers follow the National Trainers Federation (NTF) codes. These codes are available separately via their websites and, this year, these two documents are available in one smartphone app, EquiBioSafe. The app has been funded by the HBLB and was released with the intention of providing another, easily accessible source of information for those managing Thoroughbreds.

As an immediate measure, the movement of horses on and off the premises must cease. The first step in managing an outbreak, or potential outbreak, is to separate the positive cases from others. Horses with active nasal EHV1 shedding should be isolated in an airspace that is separate from other horses by strictly enforced biosecurity and isolation procedures. Serial testing with PCR may be a useful adjunct to determine when the risk of transmission has been minimised¹⁰. Horses should be segregated into smaller subgroups – the smaller the better – and each group managed as a discrete unit. Ideally, separate staff teams attend to separate groups and the HBLB and NTF codes, and EquiBioSafe, provide considerable detail of biosecurity and disinfection protocols.

The aim is to document the horse population is free from disease and no longer a threat to others, and this is based on segregate, collect, test and observe steps. A three-tier approach to outbreak management has been defined by Sonia Gonalez-Medina and Richard Newton¹¹:

• Gold tier involves collection and comprehensive testing of all animals by PCR, virus isolation and serology in the initial phase. Segregated groups are created based on the laboratory data and the comprehensive testing increases the likelihood of a specific virus being characterised. That information may not necessarily benefit the farm immediately, but is of considerable value for epidemiological research.
  • If clinical signs are observed in a group within three to four weeks, comprehensive testing is repeated on all animals, positives are isolated and tests are repeated after two to three weeks. This cycle may have to be repeated if further positives are present and the premises can be considered EVH1-free when all results are negative.
  • If no clinical signs are observed after three to four weeks, serology is paired with the initial test results and the animals are considered EHV1-free if all results are negative.
• Silver tier proposes initial collecting and testing by nasopharyngeal (NP) swab PCR and serology only. Segregated groups are created based on the laboratory data.
  • If clinical signs are observed in a group within the next three to four weeks, PCR, virus isolation and serology is performed from all horses in the affected group, positives are isolated and further cycles of full testing are performed until all results are negative.
  • If no clinical signs are observed after three to four weeks, serology is paired with the initial test results and the animals are considered EHV1-free if all results are negative.
• Bronze tier has merit where finances are limited. Samples are collected at the beginning of an outbreak and frozen, but not immediately tested. Segregated groups are created without specific knowledge of each individual’s disease status and, therefore, subclinical cases may inadvertently be left dispersed throughout the subgroups. If this is the case, ultimately it will take longer to declare freedom from infection and costs may be as high, or even higher.
  • If clinical signs are observed in a group within the next three to four weeks, a full set of samples is collected from the group, and these, plus all frozen samples, are tested. Positives are isolated and further cycles of full testing are performed until all results are negative.
  • If no clinical signs are observed after three to four weeks, a second set of NP swabs and sera are collected and paired serology is performed using the recent, plus frozen, samples. Negative results confirm freedom from disease; however, positive serological responses in animals with no clinical signs indicate subclinical infection and warrant isolation of positives, continued observation and further cycles of testing until all results are negative.

Sick foals and neurological cases

Mares that have aborted rarely require anything but routine post-foaling management. In sick foals and neurological cases, supportive care is tailored to the individual’s specific problems. The antiviral drug valaciclovir (VCV) is often used, but has not been definitively proven to improve outcomes. VCV is metabolised to its active form, aciclovir, and two treatment protocols have been reported. The first suggested a loading dose of 27mg/kg VCV every 8h for 2 days, followed by a maintenance dose of 18mg/kg every 12h, would maintain effective serum aciclovir concentrations¹².

Alternatively, VCV is given 3 times daily, at a dosage of 40mg/kg¹³. However, in an experimental study, VCV had no effect on clinical signs, viral shedding and viraemia of EHV1-infected ponies. It has been suggested, because EHV1 viraemia is associated with activation of coagulation, and because EHV1 entry in cells is blocked by heparin, the anticoagulant heparin (25,000IU SC twice daily for 3 days) might be beneficial in limiting the prevalence of neurological signs during an EHV1 outbreak¹⁴.

The prognosis for neonates with EHV1 is very poor, while the prognosis for neurological cases is variable. Horses with mild signs generally recover fully and often quite quickly. More severely affected horses can recover with intensive nursing, but prolonged recumbency is likely to require considerable effort. Perhaps counter-intuitively, a report suggested no relationship existed between the severity of signs at presentation and survival, but some survivors had higher viral loads in nasal secretions and blood¹⁵.

This year, the inactivated herpesvirus vaccine with both EHV1 and EHV4 activity has been unavailable until recently. This vaccine is marketed for the reduction of respiratory disease and abortion, but it is important to note abortion can still occur in vaccinated animals. Alternative products are available for the prevention of EHV1-related disease and are, therefore, suitable for broodmares, but not ideal for youngstock or racehorses. Most farms begin foals’ EHV vaccines at around six months and prefer to stagger vaccines rather than vaccinate against multiple organisms simultaneously.

However, a study from the US has shown 90-day-old foals are capable of equivalent responses to those vaccinated against EHV1,4, influenza, tetanus (and other pathogens not relevant in UK) simultaneously¹⁶. In racehorses, EHV1,4 vaccines are given with the aim of reducing the prevalence and severity of respiratory disease within the group, and it is often suggested that influenza and EHV1,4 vaccines should be given separately; however, research has shown concurrent vaccination against influenza and EHV1,4 increased the response to influenza and did not compromise the humoral response to EHV1,4¹⁷.