Equine Herpesvirus-1 and Equine Herpesvirus-4 Respiratory Disease and Abortion (Equine Rhinopneumonitis)

Equine herpesvirus-1 (EHV-1) and equine herpesvirus-4 (EHV-4) are alphaherpesviruses that cause a spectrum of clinical syndromes in horses, collectively referred to as equine rhinopneumonitis. EHV-1 is the more pathogenic of the two, responsible for respiratory disease, abortion, neonatal death, and the severe neurological form known as equine herpesvirus myeloencephalopathy (EHM). EHV-4 primarily causes mild upper respiratory tract disease in young horses, but can occasionally cause abortion and rarely neurological disease. The viruses are endemic worldwide and cause significant economic losses in the equine industry, particularly in breeding farms, training stables, and show/racing circuits. The respiratory form is characterized by fever, nasal discharge, cough, and lymphadenopathy, while the abortigenic form leads to late-term abortion (usually 7-11 months of gestation). The neurological form presents with ataxia, paresis, urinary incontinence, and recumbency. The disease is highly contagious, spreading via respiratory secretions, aborted fetal tissues, and fomites. Latency is a hallmark of herpesvirus infections, with reactivation occurring during stress, leading to viral shedding and transmission. The clinical impact ranges from mild transient febrile episodes to devastating outbreaks with high morbidity and mortality, especially in the neurological form. Effective management relies on biosecurity, vaccination, and early detection.

The primary causative agents are equine herpesvirus type 1 (EHV-1) and equine herpesvirus type 4 (EHV-4), both belonging to the family Herpesviridae, subfamily Alphaherpesvirinae, genus Varicellovirus. EHV-1 is a double-stranded DNA virus with a genome of approximately 150 kbp, encoding over 70 proteins. It exists as a single serotype but has been classified into neuropathogenic and non-neuropathogenic strains based on a single nucleotide polymorphism (SNP) in the DNA polymerase gene (ORF30) that results in an amino acid change (N752D). The neuropathogenic strain (D752) is associated with a higher risk of EHM, but non-neuropathogenic strains can also cause neurological disease. EHV-4 is genetically distinct but shares antigenic cross-reactivity with EHV-1. Both viruses are enveloped and labile in the environment, but can survive for weeks in cool, moist conditions, particularly in aborted fetuses and placentas. Transmission occurs via direct contact with infectious respiratory secretions, aerosolized droplets over short distances, and indirect contact via contaminated equipment, feed, water, and personnel. Aborted fetuses and fetal membranes are highly infectious and can contaminate the environment. Latency is established in the trigeminal ganglia and lymphoreticular cells, with reactivation triggered by stress, transport, weaning, or immunosuppression. The viruses replicate in the upper respiratory epithelium, causing cytolysis and inflammation, then spread to regional lymph nodes, leading to viremia and dissemination to target organs such as the lungs, liver, spleen, adrenal glands, and pregnant uterus.

Equine herpesvirus infections are ubiquitous in horse populations worldwide. Seroprevalence studies indicate that over 80% of adult horses have antibodies to EHV-1 and EHV-4, reflecting widespread exposure. The respiratory form is most common in weanlings and yearlings, with peak incidence in the fall and winter months, often associated with weaning stress and commingling. EHV-4 is more frequently isolated from respiratory outbreaks in young horses, while EHV-1 is more often associated with abortion and neurological disease. Abortion storms can occur in unvaccinated or inadequately vaccinated broodmare populations, with EHV-1 being the leading infectious cause of equine abortion. The neurological form (EHM) is less common but has a high case fatality rate, ranging from 10-50%, and can occur in horses of any age, breed, or sex, though it is more frequently reported in adult horses, particularly in performance and breeding stock. Outbreaks of EHM have been documented in the United States, Europe, and Australia, often linked to horse shows, sales, and transport. Morbidity in respiratory outbreaks can reach 100% in susceptible populations, but mortality is low unless secondary bacterial pneumonia occurs. The economic impact includes costs of treatment, quarantine, loss of performance, abortion losses, and mortality. Risk factors for EHM include age (older horses), sex (females more affected), breed (Thoroughbreds and Warmbloods overrepresented), and stress. The neuropathogenic strain (D752) is associated with increased risk of EHM, but the presence of the strain does not guarantee neurological disease, as host factors and viral load play a role.

The pathogenesis of EHV-1 and EHV-4 infection begins with viral entry into the upper respiratory tract epithelium via the respiratory route. The virus attaches to cell surface receptors, such as heparan sulfate proteoglycans, and enters cells via endocytosis or membrane fusion. Replication occurs in the epithelial cells, causing cell lysis and inflammation, leading to clinical signs of rhinitis and pharyngitis. The virus then spreads to regional lymph nodes (retropharyngeal, bronchial) via lymphatic drainage, where it replicates in lymphocytes and monocytes. This leads to a cell-associated viremia, with the virus traveling within infected leukocytes (primarily T cells and monocytes) to distant organs. In the respiratory form, the viremia is often transient and may not cause systemic disease. However, in pregnant mares, the virus can cross the placental barrier and infect the fetus, leading to abortion. The mechanism of abortion involves viral replication in the endometrium and fetal tissues, causing vasculitis, thrombosis, and placental separation. The fetus is usually expelled within days of infection, often without premonitory signs. In the neurological form (EHM), the virus infects the endothelial cells of the central nervous system (CNS) vasculature, leading to vasculitis, thrombosis, and ischemic necrosis of the spinal cord and brain. This results in the characteristic clinical signs of ataxia, paresis, and urinary incontinence. The neuropathogenic strain (D752) has been shown to replicate more efficiently in endothelial cells, leading to higher viral loads and more severe CNS damage. The immune response involves both humoral and cell-mediated immunity, but immunity is short-lived and incomplete, allowing reinfection and reactivation. Latency is established in the trigeminal ganglia and possibly in lymphocytes, with periodic reactivation and shedding of virus, often without clinical signs.

Several factors predispose horses to EHV-1 and EHV-4 infection and disease. Age is a significant factor, with young horses (weanlings and yearlings) being more susceptible to respiratory disease due to waning maternal antibodies and lack of prior exposure. Stress is a major trigger for reactivation of latent virus and increased susceptibility to infection. Common stressors include transportation, weaning, commingling with new horses, intense training, competition, and changes in housing or diet. Overcrowding and poor ventilation in stables facilitate aerosol transmission. Pregnant mares are at risk for abortion, particularly in the last trimester, and the risk is higher in mares that have not been vaccinated or have waning immunity. The neuropathogenic strain (D752) is a significant risk factor for EHM, but other factors such as age (older horses), sex (females), and breed (Thoroughbreds, Warmbloods) also increase the risk. Immunosuppression due to concurrent disease, malnutrition, or corticosteroid administration can increase the severity of infection. Management practices such as mixing horses of different ages and origins, lack of quarantine for new arrivals, and poor biosecurity measures contribute to outbreak risk. Environmental factors such as cold, damp weather and high humidity can increase viral survival and transmission. Additionally, the use of contaminated equipment (e.g., nasal snare, stomach tubes, twitches) and fomites (e.g., buckets, grooming tools) can spread the virus.

The clinical signs of EHV-1 and EHV-4 infection vary depending on the form of the disease. The respiratory form is most common in young horses and is characterized by fever (up to 106°F or 41.1°C), which may be biphasic, nasal discharge (initially serous, later mucopurulent), coughing, pharyngitis, and lymphadenopathy (enlarged retropharyngeal and submandibular lymph nodes). Affected horses may be lethargic, anorexic, and have a reduced appetite. The disease is usually self-limiting within 1-2 weeks, but secondary bacterial pneumonia can occur, leading to more severe respiratory signs, including tachypnea, dyspnea, and abnormal lung sounds. The abortigenic form occurs in pregnant mares, typically between 7 and 11 months of gestation. Abortion often occurs suddenly, without premonitory signs, and the mare may not show systemic illness. The fetus is usually expelled with the placenta intact, and the mare typically recovers uneventfully. However, some mares may develop placentitis or metritis. The neurological form (EHM) is the most severe and can occur in horses of any age, but is more common in adults. Clinical signs include ataxia (ranging from mild incoordination to severe recumbency), pelvic limb weakness, urinary incontinence (dribbling urine, scalding of the perineum), loss of tail tone, and decreased anal tone. In severe cases, horses may become recumbent and unable to rise. Cranial nerve deficits may also be present, including facial nerve paralysis, dysphagia, and vestibular signs. Fever may precede neurological signs by 1-7 days. The onset of neurological signs can be acute and rapidly progressive. Other less common manifestations include neonatal pneumonia and death in foals infected in utero or shortly after birth.

Differential diagnoses for EHV-1 and EHV-4 respiratory disease include other viral respiratory pathogens such as equine influenza virus (EIV), equine rhinitis A and B viruses, equine adenovirus, and equine arteritis virus (EAV). Bacterial infections such as Streptococcus equi subsp. equi (strangles) and Streptococcus zooepidemicus can also cause similar signs. For the abortigenic form, differentials include other causes of abortion such as equine viral arteritis (EAV), leptospirosis, placentitis (bacterial or fungal), and non-infectious causes like umbilical cord torsion or placental insufficiency. For the neurological form, differentials include other causes of ataxia and paresis such as cervical vertebral stenotic myelopathy (Wobbler syndrome), equine protozoal myeloencephalitis (EPM), trauma, and other viral encephalitides (West Nile virus, Eastern/Western equine encephalomyelitis). Key distinguishing features: EIV typically causes a dry hacking cough and high fever, but does not cause abortion or neurological signs. Strangles is characterized by abscessation of lymph nodes, which may rupture and drain. EAV can cause abortion and respiratory disease, but also causes edema of the limbs and scrotum in stallions. EPM often presents with asymmetric ataxia and muscle atrophy, and is diagnosed via CSF antibody testing. Wobbler syndrome is more common in young horses and is associated with cervical vertebral malformation, diagnosed via radiography and myelography. Trauma may have a history of injury and focal neurological deficits. West Nile virus causes fever and neurological signs, but is diagnosed via serology. Definitive diagnosis of EHV-1/4 requires laboratory testing, including PCR, virus isolation, or serology.

The diagnostic approach for suspected EHV-1/4 infection involves a combination of clinical assessment, laboratory testing, and molecular diagnostics. The algorithm begins with a thorough history and physical examination, including temperature, respiratory rate, and neurological assessment. If respiratory disease is suspected, a nasopharyngeal swab or nasal wash should be collected for PCR and virus isolation. For abortion cases, the fetus and placenta should be submitted for necropsy, and samples of fetal lung, liver, spleen, and placenta should be collected for PCR and histopathology. For neurological cases, blood and nasal swabs should be collected for PCR, and cerebrospinal fluid (CSF) may be analyzed for viral DNA and antibodies. Serology, such as complement fixation (CF) or serum neutralization (SN) tests, can be used to detect a rise in antibody titers between acute and convalescent samples (2-4 weeks apart). However, serology is less useful for early diagnosis due to the time required for seroconversion. PCR is the preferred diagnostic method due to its high sensitivity and specificity, and can differentiate between EHV-1 and EHV-4, as well as identify the neuropathogenic strain (D752). In outbreak situations, it is important to implement biosecurity measures immediately, including isolation of affected horses, quarantine of exposed horses, and disinfection of facilities. The diagnostic algorithm should also include ruling out other causes of respiratory disease, abortion, and neurological disease through appropriate testing (e.g., influenza PCR, strangles culture, EPM testing).

Laboratory findings in EHV-1/4 infection are non-specific but can support the diagnosis. In the respiratory form, a complete blood count (CBC) may show leukopenia (particularly lymphopenia) early in the infection, followed by neutrophilia. Fibrinogen levels may be elevated in cases of secondary bacterial infection. Serum amyloid A (SAA) is an acute-phase protein that may be increased. In the abortigenic form, mares may have no significant hematological changes. In the neurological form, CSF analysis may show elevated protein concentration and a mild mononuclear pleocytosis, but these findings are not specific. The definitive diagnosis is made by PCR detection of viral DNA in nasal swabs, blood (buffy coat), fetal tissues, or CSF. Virus isolation can be performed but is less sensitive and takes longer. Serology can be used to demonstrate a four-fold increase in antibody titers between acute and convalescent samples, but this is retrospective. In abortion cases, histopathology of fetal tissues may show characteristic intranuclear inclusion bodies in hepatocytes and pneumocytes. PCR can also be used to differentiate between EHV-1 and EHV-4, and to identify the neuropathogenic strain (D752).

Imaging is not typically used for the diagnosis of EHV-1/4 infection, but may be helpful in assessing complications. Thoracic radiography or ultrasonography may be indicated in cases of suspected secondary bacterial pneumonia, revealing cranioventral alveolar infiltrates or consolidation. In neurological cases, radiography of the cervical spine may be performed to rule out other causes of ataxia, such as cervical vertebral stenotic myelopathy. However, these findings are not specific for EHV-1/4. In abortion cases, ultrasonography of the placenta may be performed in pregnant mares to assess for placental abnormalities, but this is not a primary diagnostic tool. Advanced imaging such as MRI or CT is rarely indicated for EHV-1/4 infection, but may be used to rule out other neurological conditions.

Cytology and histopathology are important in the diagnosis of EHV-1/4 infection, particularly in abortion and neurological cases. In respiratory cases, tracheal wash or bronchoalveolar lavage (BAL) cytology may show neutrophilic inflammation, but this is non-specific. In abortion cases, histopathology of fetal tissues (lung, liver, spleen) reveals characteristic lesions including necrosis, hemorrhage, and intranuclear inclusion bodies in hepatocytes, pneumocytes, and renal tubular epithelial cells. The placenta may show vasculitis and thrombosis. In neurological cases, histopathology of the CNS shows vasculitis, thrombosis, and ischemic necrosis of the spinal cord and brain, with perivascular cuffing and infiltration of mononuclear cells. Immunohistochemistry can be used to detect viral antigen in tissues. PCR on formalin-fixed, paraffin-embedded tissues can also be performed for confirmation.

Treatment of EHV-1/4 infection is primarily supportive, as there is no specific antiviral therapy approved for horses. For the respiratory form, affected horses should be rested and isolated. Non-steroidal anti-inflammatory drugs (NSAIDs) such as flunixin meglumine (1.1 mg/kg IV or PO q12-24h) or phenylbutazone (2.2-4.4 mg/kg PO q12-24h) may be used to reduce fever and inflammation. Antibiotics may be indicated if secondary bacterial pneumonia develops, with broad-spectrum coverage such as penicillin G (22,000 IU/kg IV q6h) and gentamicin (6.6 mg/kg IV q24h). For the abortigenic form, there is no treatment to prevent abortion once infection occurs, but supportive care for the mare is important. For the neurological form (EHM), treatment is intensive and includes aggressive supportive care. NSAIDs are used to reduce inflammation and pain, but caution is advised due to potential renal and gastrointestinal side effects. Corticosteroids such as dexamethasone (0.05-0.1 mg/kg IV q24h) may be used in severe cases to reduce CNS inflammation, but their use is controversial due to potential immunosuppression. Antiviral drugs such as acyclovir (30 mg/kg PO q8h) or valacyclovir (30 mg/kg PO q8h) have been used, but their efficacy is unproven and they are expensive. Fluid therapy may be necessary for recumbent horses, and bladder catheterization or manual expression may be required for urinary incontinence. Nursing care is critical, including padding for recumbent horses, prevention of decubital ulcers, and nutritional support. Isolation and biosecurity are essential to prevent spread to other horses.

The prognosis for EHV-1/4 infection varies depending on the form of the disease. The respiratory form generally has a good prognosis, with most horses recovering within 1-2 weeks, although secondary bacterial pneumonia can worsen the outcome. The abortigenic form has a good prognosis for the mare, but the fetus is lost. The neurological form (EHM) has a guarded to poor prognosis, with a case fatality rate of 10-50%. Horses that remain standing have a better prognosis than those that become recumbent. Recovery can be prolonged, and some horses may have residual neurological deficits. Early recognition and aggressive supportive care can improve the outcome. Negative prognostic indicators include recumbency, severe ataxia, and lack of response to treatment within 48-72 hours.

Follow-up care for horses with EHV-1/4 infection depends on the form of the disease. For respiratory cases, horses should be rested for at least 1 week after clinical signs resolve, and gradually returned to work. For abortion cases, mares should be monitored for complications such as metritis, and should be bred on the next estrous cycle. For neurological cases, horses require long-term rehabilitation, including physical therapy, assisted standing, and gradual return to exercise. Serial neurological examinations should be performed to monitor progress. Vaccination is an important part of follow-up, with EHV-1/4 vaccines available for respiratory and abortigenic forms. However, vaccination does not prevent EHM, and its efficacy is limited. Biosecurity measures should be reviewed to prevent future outbreaks.

Clinical pearls: 1) Always consider EHV-1 in any horse with fever and respiratory signs, especially in a group setting. 2) In pregnant mares, any abortion should be investigated for EHV-1, and the fetus and placenta should be submitted for testing. 3) In neurological cases, EHM should be a differential, and immediate isolation is crucial to prevent outbreaks. 4) PCR on nasal swabs and blood is the most sensitive diagnostic test. 5) The neuropathogenic strain (D752) is associated with higher risk of EHM, but non-neuropathogenic strains can also cause neurological disease. Pitfalls: 1) Failure to isolate affected horses promptly can lead to widespread outbreaks. 2) Using corticosteroids in EHM may worsen the disease due to immunosuppression. 3) Relying solely on vaccination for prevention is inadequate; biosecurity is paramount. 4) Not collecting appropriate samples (nasal swabs, blood, fetal tissues) early in the disease can delay diagnosis. 5) Misinterpreting serology results, as antibodies may be present due to vaccination or previous exposure.

Current drug protocols for EHV-1/4 infection are primarily supportive. NSAIDs: Flunixin meglumine (1.1 mg/kg IV or PO q12-24h) for fever and inflammation; Phenylbutazone (2.2-4.4 mg/kg PO q12-24h) as an alternative. Corticosteroids: Dexamethasone (0.05-0.1 mg/kg IV q24h) for severe CNS inflammation in EHM, but use with caution. Antiviral drugs: Acyclovir (30 mg/kg PO q8h) or Valacyclovir (30 mg/kg PO q8h) have been used, but efficacy is unproven. Antibiotics: For secondary bacterial pneumonia, use broad-spectrum antibiotics such as Penicillin G (22,000 IU/kg IV q6h) and Gentamicin (6.6 mg/kg IV q24h). Fluid therapy: Polyionic isotonic fluids (e.g., Lactated Ringer's Solution) at maintenance rates (50 ml/kg/day) or higher if dehydrated. For recumbent horses, consider enteral or parenteral nutrition. Bladder management: Catheterization or manual expression for urinary incontinence. Nursing care: Padding, turning recumbent horses every 2-4 hours, and providing soft bedding.

Evidence-based literature on EHV-1/4 infection includes several key studies. A landmark study by Pusterla et al. (2010) evaluated the prevalence of EHV-1 in horses with fever and respiratory signs, finding that EHV-1 was detected in 10% of cases. Another study by Lunn et al. (2009) provided consensus guidelines for the diagnosis and management of EHV-1 infection, emphasizing the importance of PCR and biosecurity. The neuropathogenic strain was identified by Nugent et al. (2006), who found that the D752 polymorphism was associated with EHM. A study by Goehring et al. (2010) evaluated the efficacy of valacyclovir in treating EHM, but found no significant benefit. A meta-analysis by Kydd et al. (2012) reviewed the pathogenesis of EHV-1 and highlighted the role of cell-associated viremia. Vaccination studies have shown that inactivated vaccines reduce abortion but do not prevent respiratory infection or EHM. Overall, the literature emphasizes the need for early detection, isolation, and supportive care, as well as the limitations of current vaccines and antiviral therapies.