Equine strangles: diagnosis, treatment, and options for prevention (Proceedings)

Summary

Strangles is a result of bacterial infection with Streptococcus equi subspecies equi (referred to as S. equi). The disease has been in the equine population for centuries and was first reported in 1251 (Sweeney et al, 2005i). The infection is highly contagious in horse populations and can become endemic on farms with previous outbreaks of the disease. Diagnosis of the disease has often been made based on clinical examination, however, confirmation via culture and/or PCR is recommended. Routine abscessation of lymph nodes localized to the submandibular region and the head generally requires supportive care with anti-inflammatory drugs and drainage when possible. Treatment of S. equi infection with antimicrobials is generally reserved for complicated cases. Complications from S. equi infection include metastatic infection, purpura hemorrhagica, myositis, and rarely glomerulonephritis, myocarditis, or agalactia (Sweeney et al, 1987a;Divers et al, 1992a). Control of outbreaks can be attainable through strict management and identification of exposed and infected horses in conjunction with implementation of barrier control, isolation, and disinfection procedures. Vaccination is generally not recommended during outbreaks, but remains a valuable tool for possible disease prevention and mitigation of clinical signs. Serology with the SeM-specific ELISA is useful to detect recent infections and determine the need for vaccination.

Etiology and pathogenesis

Streptococcus equi subsp equi is a gram-positive beta-hemolytic bacterium of the Lancefield Group C, which results in the purulent lymphadenitis and pharyngitis recognized as equine strangles. Studies indicate that S. equi is a clone derived from the more genetically diverse S. zooepidemicus (Timoney et al, 1997a). However, S. equi is not a normal inhabitant of the equine upper respiratory tract. The bacterium enters the horse through inhalation into the nose or ingestion into the mouth. S. equi attaches to cells in the crypt of the lingual and palatine tonsils and to the follicular-associated epithelium of the pharyngeal and tubal tonsils. The bacterium gains access to the local lymphatics and lymph nodes where extracellular replication occurs within hours of attachment (Timoney, 1993). Multiple virulence factors contribute to the pathogenicity of S. equi which include the antiphagocytic SeM protein, the hyaluronic acid capsule, Mac protein, and other undetermined factors and/or cytotoxins (Muhktar & Timoney, 1988;Sweeney et al, 2005h). The SeM protein, also known as fibrinogen-binding protein, is a 58-kd cell wall antigen that prevents activation of the alternative complement pathway by limiting deposition of C3b on the bacterium's surface. SeM also disrupts neutrophil killing of the bacterium and binds fibrinogen (Timoney et al, 1997b). The hyaluronic acid capsule aids in repelling phagocytes due to its negative charge. These factors favor conditions for abscess formation due to the accumulation of large numbers of extracellular bacteria surrounded by degenerating neutrophils.

Infection with S. equi occurs primarily but not exclusively in young horses from 1 to 5 years of age. Transmission of the bacterium occurs via direct contact with nasal or lymph node discharge from infected horses or from exposure to contaminated fomites such as halters, brushes or clothing. New additions to a farm are a potential source of exposure to naïve herds. The incubation period ranges from 2 to 6 days prior to the onset of clinical signs. Nasal shedding occurs from infected horses 2 to 3 days after the onset of fever and typically continues for 2-3 weeks in most cases. Shedding may persist for months to years in rare cases, especially when guttural pouch infection is present (Newton et al, 1997b). A recovered horse may be a potential source of infection for at least 6 weeks after clinical signs have resolved (Sweeney et al, 2005g). Periodic subclinical carrier horses present a challenge for identification and prevention of further herd outbreaks. The carrier state develops in up to 10% of infected horses, and may result in chronic empyema of the guttural pouch.

Clinical signs

Strangles acquired its name because affected horses were sometimes suffocated from large, infected lymph nodes that obstructed their upper airway or trachea. The hallmark clinical signs of infection are fever, mucopurulent nasal discharge, and lymphadenopathy of the submandibular and/or retropharyngeal lymph nodes with subsequent abscessation. Lymph nodes usually rupture and drain 7 to 10 days after the initial onset of clinical signs. Purulent nasal discharge is typically present, although it may initially be serous. Mucopurulent ocular discharge may also occur, and the nasal and ocular mucosal membranes are often hyperemic. Depression, pharyngitis and rhinitis are frequently seen. Anorexia and dysphagia may occur secondary to pharyngitis and/or lymph node compression of the throat. Swelling may become so severe that respiratory distress ensues and tracheostomy may be required. Peripheral lymph node abscessation is occasionally disseminated. Coughing is not a significant clinical sign in many cases, although some horses will develop a soft moist cough that worsens with disease progression. The average clinical course of the disease is about 3 weeks. Disease severity appears dependent on challenge load and duration, and inocula of less than 106 CFU are not consistently effective in causing disease because such low numbers are efficiently removed via mucociliary clearance (Sweeney et al, 2005f).

Guttural pouch empyema can result from retropharyngeal lymph nodes that abscess and rupture into the guttural pouches or from bacterial entrance through the pharynx. Purulent secretions that persist in the guttural pouch may form hard, inspissated chondroids. Chondroid formation can present a treatment challenge, and removal is typically performed endoscopically with a basket or via a surgical approach to the guttural pouch. Undiagnosed guttural pouch empyema or chrondroids can result in persistent shedding of S. equi into the environment.

Complications of infection

Fortunately, although strangles' morbidity is high, the mortality rate for uncomplicated infections remains relatively low. Complications are reported to occur in approximately 20% of strangles cases (Sweeney et al, 1987b;Sweeney et al, 2005e). The occurrence of complications will increase the likelihood of death from 8% to 40% of cases (Sweeney et al, 1987c). Metastatic spread of infection (also known as bastard strangles) with internal abscessation, purpura hemorrhagica, myositis from muscle infarction, rhabdomyolysis, glomerulonephritis, myodarditis, agalactia in periparturient mares, and septicemia with spread to the lungs, joints or central nervous system are all possible complications associated with S. equi infection (Yelle, 1987;Sweeney et al, 1987d;Divers et al, 1992b;Spoormakers et al, 2003;Pusterla et al, 2003b;Sponseller et al, 2005b;Sweeney et al, 2005d;Finno et al, 2006;Pusterla et al, 2007a). Horses that develop complicated infection typically require antimicrobial and additional supportive therapies.

Metastatic spread of S. equi can infect the thorax, brain, mesentery, liver, spleen, or kidneys. Although metastatic infection is classically associated with a poor prognosis, one study that evaluated horses with abdominal abscesses achieved a long term survival rate of 40% (Pusterla et al, 2007b). Diagnostic evaluation to determine the presence of metastatic infection may include rectal examination, abdominocentesis, abdominal and/or thoracic ultrasound, radiographs, and/or transtracheal aspiration. The horse's clinical signs will typically dictate the appropriate modalities for disease investigation. Long-term administration of antimicrobials is necessary for treatment of internal abscesses; the mean duration in the study by Pusterla et al was 72 days. There is not strong evidence to support the belief that antimicrobial use early in the course of disease contributes to metastatic infection with S. equi (Ramey, 2007).

Purpura hemorrhagica is an aseptic vasculitis characterized primarily by edema of the limbs and petechial or ecchymotic hemorrhage. The clinical signs of purpura can vary from a mild, transient reaction to a severe or even fatal disease (Pusterla et al, 2003a). The edema may become severe enough to cause serum seepage and/or sloughing of the skin. In addition to the limbs, the edema may affect the head or trunk. In some cases, the vasculitis may result in colic, respiratory difficulty, and muscle pain from its affect on the gastrointestinal tract, muscle, and respiratory system. Colic and muscle stiffness may be the primary clinical signs in horses with muscle infarctions due to purpura hemorrhagica (Kaese et al, 2005b). Early recognition of muscle swelling, abdominal pain, neutrophilia, hypoalbuminemia and high creatine kinase levels may improve the outcome for horses with infarctive purpura; however 4 of the 5 horses in the study by Kaese et al were euthanized (Kaese et al, 2005a). In addition to muscle infarctions, rhabdomyolysis and immune-mediated myositis have also been described in horses following exposure to S. equi (Sponseller et al, 2005a;Lewis et al, 2007).

The pathogenesis of purpura hemorrhagica is not completely understood but it appears to be secondary to immune complex deposition within blood vessel walls. It can occur following vaccination for S. equi or from re-exposure to the organism in natural infection, but may also be due to other organisms. In a study of 53 horses with purpura, 17 were exposed to or infected with S. equi and 5 had been vaccinated with the S. equi M protein; the remaining 31 cases were associated with other organisms or had no known etiology (Pusterla et al, 2003c). A pre-existing high serum antibody titer to S. equi antigens may predispose horses to the development of purpura (Sweeney et al, 2005c). Hence, vaccination is contraindicated for horses with antibody levels of > 1:1,600. Diagnosis of purpura can be confirmed by a leukocytoclastic vasculitis on skin biopsy, isolation of the organism, or increased antibody levels (>1:12,800). Treatment typically consists of corticosteroids, supportive care, and frequently antimicrobials such as penicillin. Dexamethasone at 0.1-0.2 mg/kg is typically used for initial therapy and then tapered. Hydrotherapy and bandaging can be beneficial adjunctive therapies for edema and serum exudation from the skin. In the study of 53 horses with purpura, the majority required treatment for more than 7 days (Pusterla et al, 2003d).

Diagnosis

Clinical signs of strangles are highly suggestive of the diagnosis. However, definitive diagnosis is made by culture of the bacteria from a nasal swab, aspirate of an abscessed lymph node, or a nasal-pharyngeal wash. Culture remains the gold standard diagnostic modality for S. equi. When compared to culture for the diagnosis of strangles, polymerase chain reaction (PCR) is considered to be two to three times more sensitive (Timoney & Artiushin, 1997a;Newton et al, 2000;Gronbaek et al, 2006a). The PCR detects the DNA sequence of SeM, the antiphagocytic protein of the bacteria (Sweeney et al, 2005b). Although an allele of this gene is found on some strains of S. zooepidemicus, the sequence is of low homology and PCR of S. zooepidemicus is unlikely to yield a false positive result. Additionally, there is no evidence that an SeM-like protein is expressed by S. zooepidemicus (Sweeney et al, 2005a). PCR cannot differentiate between live and dead bacteria, so is ideally used in conjunction with culture for confirmation of strangles. However, if consecutive PCRs are negative when screening for infection or subclinical carrier status, the horse is unlikely to have strangles. Nasal washes are also considered superior to swabs for diagnosis because a larger surface area within the nares is sampled (Timoney & Artiushin, 1997b). The real challenge is diagnosing horses that are asymptomatic carriers. Anywhere from 4-50% of the horses on farms with recurring strangles are carriers of the infection, although it is estimated that the carrier state develops in up to 10% of affected horses and results in chronic empyema of the guttural pouch (Sweeney et al, 2005j). Endoscopy is an excellent adjunctive tool for diagnosis of asymptomatic carriers, and can facilitate obtaining samples via guttural pouch lavage. Most horses will begin shedding the bacteria from their nasal passages a couple of days after the onset of fever. Bacterial shedding occurs intermittently for several weeks. Some horses may continue to shed the bacteria for months to even years, serving a continual source of new infections on the farm.

A recent study that used a nested PCR assay suggests that S. equi DNA can be detected longer in convalescent horses, and that horses in the group without disease may also be infected (Gronbaek et al, 2006b). Further work is required to confirm how long such animals can be detected by PCR analysis and, most importantly, what proportion is actually harboring viable S. equi (Prescott & Timoney, 2007).

Serology can be a useful diagnostic test to determine recent (but not necessarily current) S. equi infection, determine the need for vaccination, and to aid in the diagnosis of metastatic infection and purpura hemorrhagica. An SeM-specific antibody ELISA is commercially available through IDEXX. The ELISA cannot distinguish between the response to vaccination and natural infection. Serum titers peak about 5 weeks after exposure and remain high for at least six months, while the response to commercial vaccines peaks at about 2 weeks and also remains high for 6 months (Sheoran et al, 1997). Interpretation of results should consider that there may be considerable variation in the response of individual horses. Horses with a titer of greater than 1:1,600 should never be vaccinated (Sweeney et al, 2005k).

Treatment

Antimicrobial therapy remains controversial for the treatment of strangles. Uncomplicated cases of submandibular lymph node abscessation do not require antimicrobial therapy in the authors' opinion. Complicated cases and those requiring tracheostomy for management of respiratory distress generally do require antimicrobial and other supportive therapies. There is some evidence that treatment with antimicrobials at the first sign of fever and in horses with no lymph node enlargement may prevent infection. However, early antimicrobial treatment will also prevent these cases from developing immunity to the infection, and subsequently makes them susceptible to reinfection sooner.

In horses with uncomplicated lymphadenopathy, treatment should be aimed at encouraging maturation and rupture of effected lymph nodes. Antimicrobial therapy is not necessary and may prolong the course of the disease. To encourage maturation of abscesses, topical poultice application and hot packing is recommended by some authors (Sweeney et al, 2005l). Once abscesses mature and an area of thinning forms on the ventral surface, they can be lanced to promote drainage. Care should be taken in transcutaneous drainage of retropharyngeal abscesses due to the proximity of large vessels. Ultrasonographic examination is recommended to determine the exact depth of the abscess. After lancing, abscesses can be flushed frequently with a dilute povidone-iodine solution to aid in healing (Sweeney et al, 2005m). Guttural pouch empyema following rupture of the retropharyngeal lymph nodes should be treated with copious lavage, as accumulation of purulent material in the guttural pouches promotes chondroid formation, making resolution of disease and carrier status more difficult. Depending on the amount and character of guttural pouch empyema, lavage can be performed transendoscopically using a pressure bag or fluid pump, indwelling catheter, or with a small bore stomach tube (Adkins et al, 1997b;Judy et al, 1999a;Sweeney et al, 2005n). Although sterile saline is ideal, the author has also used non-sterile saline made with tap water and salt (4 ounces of salt in 18 liters of water). During lavage, it is essential that the horse be adequately sedated to keep the head lowered and decrease the risk of aspiration. Frequent re-evaluation of the guttural pouches endoscopically allows determination of ongoing drainage from the retropharyngeal lymph nodes and the need for further lavage.

Retropharyngeal abscessation causing respiratory distress may require placement of a temporary tracheostomy. Though antimicrobial therapy has been recommended in these cases to prevent lower airway infection, the author has successfully treated horses with S. equi with a tracheostomy without antimicrobials with no complications. Antimicrobial therapy has been recommended by some authors (Sweeney et al, 2005o) once drainage from abscesses has been established, as it may promote a more rapid recovery. However, it is important to keep in mind that it is often difficult to determine when all effected lymph nodes have matured and are draining.

Horses that develop chondroids become significantly more challenging to treat. Complete removal of all chondroids is essential to eliminate carrier status (Verheyen et al, 2000a). Non-surgical approaches to chondroid removal include copious lavage, suction, and use of an endoscopically guided memory-helical polyp retrieval basket (Seahorn & Schumacher, 1991;Adkins et al, 1997a;Judy et al, 1999b;Sweeney et al, 2005p). In cases with significant chondroid accumulation, surgical approaches to the guttural pouch may be required (Schaaf et al, 2006a). Techniques have been described for surgical approaches to the guttural pouch under general anesthesia (Schaaf et al, 2006b) and standing (Gehlen & Ohnesorge, 2005;Perkins et al, 2006). Complete removal of chondroids may not be accomplished intra-operatively and it is vital to examine the guttural pouches endoscopically after surgery as continued lavage may be necessary.

Antimicrobial therapy is warranted in horses that are severely anorexic, depressed, persistently febrile despite NSAID therapy, dysphagic, or have metastatic abscessation to the abdominal or thoracic lymph nodes. Penicillin is the antimicrobial of choice for S. equi as it is consistently sensitive to this agent (Sweeney et al, 2005q). Many isolates may be sensitive in vitro to TMP-SMZ, there are concerns as to the in vivo activity based on work done with S. equi subsp. zooepidemicus casting doubt on the effectiveness of this drug to treat all strangles infections (Ensink et al, 2003). The length of antimicrobial therapy depends on the clinical signs of the horse, but for horses with unresolved lymphadenopathy, a three week course is often required. Long-term antimicrobial treatment is indicated for treatment of metastatic abscesses (Pusterla et al, 2007c). Topical application of a penicillin gelatin solution into the guttural pouches can achieve high concentrations within the guttural pouch and may be indicated for treating guttural pouch empyema and chronic carriers (Verheyen et al, 2000b;Sweeney et al, 2005r). The recipe for 50 mls of penicillin/gelatin solution as reported in Sweeney et al, 2005 is:

     • Weigh out 2 grams of gelatin (Sigma G-6650 or household grade) and add 40 mL sterile water.

     • Heat or microwave to dissolve the gelatin.

     • Cool gelatin to 45–50°C.

     • Meanwhile add 10 mL sterile water to 10,000,000 units (10 Mega) sodium benzylpenicillin G.

     • Mix penicillin solution with the cooled gelatin to make a total volume of 50 mL.

     • Dispense into syringes and leave overnight at 48C to set.

The gelatin solution can be instilled through an endoscope and is retained in the guttural pouch better than an aqueous solution (Sweeney et al, 2005s).

Adjunctive treatment appropriate in most cases includes NSAIDs (flunixin or phenylbutazone) to control fever and pain associated with lymphadenitis and pharyngitis, adequate nutrition, and maintenance of hydration. Nutrition and hydration are of particular importance in horses with dysphagia.

Outbreak management and prevention

In an outbreak of strangles, movement of all horses on or off the farm should be stopped, and new horses should not be introduced. The temperature of all horses on the farm should be taken twice daily to identify new cases as early as possible. Monitoring the rectal temperature and isolating horses at the first sign of fever is one of the most effective ways to stop the spread of infection, since infected horses can transmit the bacteria to healthy horses 2-3 days after onset of fever once shedding has commenced (Sweeney et al, 2005t). Strangles is also a reportable disease in some states, and the state veterinarian may need to be notified. To determine if strangles is reportable in your state, contact the state veterinarian's office. Most states have a list of reportable diseases posted on the web. These authors' do not believe that strangles is considered a reportable disease in the United Kingdom. Strategies to eradicate and prevent strangles (STEPS) in the UK can be found on line at http://www.equine-strangles.co.uk/.

An isolated area should be set up for horses with fever and/or other clinical signs. Extreme care should be taken not to mix horses with infection and horses exposed to horses with strangles to unexposed horses. Ideally, three groups of horses should be created: 1) infected horses 2) horses that have been exposed to or contacted infected horses and 3) clean horses with no exposure. No nose to nose contact or shared water buckets should occur among the groups. Unexposed horses should be kept in a "clean" area, and ideally should have separate caretakers, cleaning equipment, grooming equipment, water troughs and pasture. People and equipment can act as fomites for disease transmission. Extreme care, handwashing, and disinfection of supplies must be observed by everyone involved. If different individuals cannot care for infected and healthy horses, then healthy horses should always be dealt with first. Dedicated protective clothing such as boots, gowns or coveralls, and gloves should be utilized when dealing with infected horses.

Thorough cleaning and disinfection is critical when dealing with any infectious disease. All water troughs should be thoroughly cleaned and disinfected daily during an outbreak. The label instructions on disinfectants should be read to be sure they are used at the correct dilution and are active against S. equi. All surfaces and stalls should be disinfected following removal of manure and organic material. Manure will inactivate bleach and iodine type solutions. Manure and waste feed from infected horses should be composted in an isolated location, and not spread on the pastures. Pastures that were utilized for sick horses should be rested for a minimum of 4 weeks. There is a lack of field-based proof for prolonged environmental persistence of S. equi, which is sensitive to bacteriocins from environmental bacteria and does not readily survive in the presence of other soil-borne flora (Sweeney et al, 2005u).

A significant challenge when dealing with an outbreak of strangles is identifying the horses that are subclinical shedders. These horses can shed the bacteria for weeks, months, or even years, and serve as a continual source of reinfection for a farm (Newton et al, 1997a;Chanter et al, 1998;Sweeney et al, 2005v). Ideally, all horses on an infected farm should be tested for strangles. Use of the bacterial culture and PCR combined identifies carriers with an improved success rate. Nasal pharyngeal swabs or washes can be done to sample the horses for infection. The washes improve the chance of identifying carrier horses. Additionally, all infected horses should be tested 3 consecutive times and be negative all three times before being put back with healthy horses (Sweeney et al, 2005w). Since previously infected horses can shed the bacteria for weeks to months, or even years in rare cases, 3 negative test samples are recommended prior to reintroduction to the healthy herd. For the most accurate diagnosis of carriers and horses without obvious clinical signs, upper airway and guttural pouch endoscopy can be performed. This procedure allows for identification of infections that can develop in the guttural pouch, and subsequent culture of that area.

Vaccination

Vaccination is one method for prevention and control of infection with S. equi. Vaccination is recommended on farms where S. equi has been an endemic problem or for horses expected to be at a high risk of exposure. With strangles, vaccination will likely reduce the severity of disease in the majority of horses that are infected, but will not result in complete disease prevention. Available vaccines in the United States can be administered by intramuscular (Strepguard® Intervet, Strepvax® II Boehringer Ingelheim) and intranasal routes (Pinnacle® I.N., Pfizer). To the authors' knowledge, Equilis StrepE® from Intervet is the only vaccine licensed for use in the EU, and is labeled for subcutaneous administration inside the upper lip. Improper administration of the vaccination can result in poor protection against infection and/or complications at the site of injection. The inactivated vaccines have reduced the severity of clinical signs and reduced the incidence of disease by as much as 50% during outbreaks (Hoffman et al, 1991). The injectable vaccines are associated with increased injection site reactions when compared to other equine immunizations. The intranasal vaccination has stimulated high levels of immunity against experimental infection, and will result in excellent local immunity if properly administered. Slowly developing submandibular abscesses have occurred in a very small percent of cases due to residual vaccinal organism in the modified live product (Kemp-Symonds et al, 2007). Cervical abscesses may also result from intramuscular administration of the modified live product or inadvertent needle contamination when administering other vaccinations; hence, the recommendation that other vaccinations be administered prior to or on a different date than the live strangles vaccination (Sweeney et al, 2005x).

Vaccination is generally not recommended during an outbreak of strangles. If there are horses on the farm with no clinical signs of infection and no known contact with sick horses, vaccination may be considered. Horses that have had the disease within the previous year also do not need to be vaccinated. Once recovered from an active infection, approximately 75% of horses have immunity for 5 years or longer (Hamlen et al, 1994). It is generally recommended that recovered horses have titers checked prior to additional vaccination. Vaccination of horses recently exposed to strangles may result in purpura hemorrhagica. Vaccination is generally only recommended in healthy horses with no fever or nasal discharge. Manufacturer recommendations may vary slightly; however, vaccination with inactivated products may have improved efficacy if a primary series of 3 doses of vaccine followed by booster doses at 6 month intervals. Vaccination with the modified live intranasal product requires a 2 dose series and annual or semi-annual booster for adults. Pregnant mares should be vaccinated 30 days prior to foaling with the inactivated IM vaccine to induce colostral antibody production. Foals should begin their vaccination series between 4-6 months of age when using the inactivated IM vaccine. They will require 3 doses 4-6 weeks apart. Foals vaccinated with the modified attenuated live vaccine should start the series at 6-9 months of age and require 2 doses 3 weeks apart.

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**Reprinted with permission from Infectious Diseases of The Horse, edited by TS. Mair, and RE Hutchison, copyrighted 2009, Equine Veterinary Journal, Ltd.