Myxomatosis

Myxomatosis is a highly fatal, systemic viral disease of domestic and wild European rabbits (Oryctolagus cuniculus) caused by the myxoma virus, a member of the genus Leporipoxvirus in the family Poxviridae. The disease is characterized by profound immunosuppression, severe cutaneous and mucocutaneous lesions (myxomas), edema of the eyelids, ears, and genitalia, and often secondary bacterial pneumonia. In susceptible domestic rabbits, mortality approaches 100%, whereas certain wild South American rabbit species (e.g., Sylvilagus brasiliensis) serve as natural reservoirs with mild or subclinical infection. The virus is transmitted mechanically by blood-feeding arthropods, primarily mosquitoes and fleas, and also through direct contact with infected secretions or fomites. Clinically, myxomatosis presents in peracute, acute, and chronic forms, with the acute form being most common in domestic rabbits, leading to death within 1-2 weeks. The disease is of significant economic and conservation concern, affecting commercial rabbitries, laboratory colonies, and wild populations. Understanding the pathophysiology, clinical presentation, and diagnostic approach is essential for exotic animal practitioners to implement effective biosecurity, supportive care, and, in endemic areas, vaccination strategies.

The causative agent is myxoma virus (MYXV), a large double-stranded DNA virus of the genus Leporipoxvirus, family Poxviridae. MYXV is closely related to other leporipoxviruses such as rabbit fibroma virus (Shope fibroma virus). The virus has a complex structure with a lipoprotein envelope and a brick-shaped virion approximately 280 x 230 nm. The genome is approximately 160 kb and encodes numerous proteins involved in immune evasion, including homologs of host cytokines, chemokines, and complement regulators. MYXV is highly host-specific, primarily infecting lagomorphs. Several strains exist with varying virulence: the Californian strain (MSD) is highly virulent in European rabbits, while the South American strains (e.g., Lausanne) are also highly lethal. Attenuated strains are used in vaccines. The virus replicates in the cytoplasm of host cells, particularly in fibroblasts and endothelial cells, causing cytopathic effects and the formation of characteristic intracytoplasmic inclusion bodies (myxoma bodies). Transmission occurs primarily through mechanical vectors: mosquitoes (e.g., Aedes, Culex, Anopheles) and fleas (e.g., Spilopsyllus cuniculi, Xenopsylla cunicularis). The virus persists on the mouthparts of arthropods for several weeks. Direct transmission can occur via contact with skin lesions, respiratory secretions, or contaminated fomites (e.g., bedding, feeders). The virus is relatively stable in the environment, surviving for weeks in scabs and exudates, especially in cool, humid conditions. In endemic areas, the virus circulates in wild rabbit populations, with seasonal peaks corresponding to vector activity.

Myxomatosis primarily affects the European rabbit (Oryctolagus cuniculus), including domestic breeds and wild populations. Other lagomorphs such as hares (Lepus spp.) are generally resistant, though occasional cases have been reported. The disease is endemic in Europe, Australia, and parts of South America, where it was intentionally introduced for biological control of wild rabbits. In North America, myxomatosis is rare, but outbreaks have occurred in domestic rabbits due to importation of infected animals or vectors. The incidence is highest in summer and autumn when mosquito and flea populations peak. In domestic rabbits, the disease is often seen in outdoor-housed rabbits or those with access to areas with high vector density. All ages and both sexes are susceptible, but young rabbits (under 2 months) may have slightly lower mortality due to maternal antibodies if the dam was vaccinated or previously infected. Breed predilections are not well-documented, but heavy breeds with loose skin may exhibit more pronounced myxomas. In wild rabbit populations, the disease can cause dramatic population declines, with mortality rates exceeding 90% in naive populations. However, over time, coevolution has led to reduced virulence in some strains and increased genetic resistance in some wild populations. In captivity, the disease is often introduced through new rabbits, contaminated equipment, or insect vectors. Poor husbandry, overcrowding, and high stress levels increase the risk of transmission and severity of disease. The incubation period ranges from 2 to 14 days, depending on the viral strain, route of inoculation, and host susceptibility.

The pathophysiology of myxomatosis involves a complex interplay of viral replication, immune evasion, and host inflammatory responses. After inoculation via a vector bite or direct contact, the virus replicates locally in the dermis and epidermis, particularly in fibroblasts and endothelial cells. It then spreads via the lymphatic system to regional lymph nodes, where it undergoes secondary replication, leading to viremia and systemic dissemination. The virus targets multiple tissues, including skin, mucous membranes, respiratory tract, and lymphoid organs. Key pathogenic mechanisms include: (1) Immunosuppression: MYXV encodes several proteins that subvert the host immune response, including viral homologs of tumor necrosis factor receptor (M-T2), complement regulatory proteins (M-T4), and chemokine binding proteins (M-T7). These proteins inhibit apoptosis of infected cells, neutralize complement, and block chemokine signaling, leading to impaired innate and adaptive immunity. This results in profound lymphopenia, particularly of T cells, and increased susceptibility to secondary bacterial infections, especially pneumonia. (2) Cytopathic effects: Viral replication causes cell lysis and necrosis, leading to the formation of characteristic myxomas—nodular proliferative lesions composed of spindle-shaped fibroblasts (myxoma cells) embedded in a myxoid stroma rich in hyaluronic acid. These lesions are most prominent on the head, ears, eyelids, and genitalia. (3) Edema: Severe subcutaneous edema, particularly of the eyelids, ears, and perineum, results from increased vascular permeability due to endothelial damage and local inflammation. This edema can cause mechanical obstruction of the eyes and ears, leading to secondary conjunctivitis and otitis. (4) Respiratory involvement: The virus can infect the upper and lower respiratory tract, causing rhinitis, pneumonia, and pulmonary edema. Secondary bacterial infections, often with Pasteurella multocida or Bordetella bronchiseptica, exacerbate respiratory signs. (5) Disseminated intravascular coagulation (DIC) and multi-organ failure: In severe cases, systemic inflammation and endothelial damage can lead to DIC, hepatic necrosis, and renal failure, contributing to the high mortality. The peracute form may cause death within 1-2 days due to septic shock-like syndrome. Chronic forms, seen in partially immune rabbits, may present with localized skin lesions and a prolonged course.

Several factors predispose rabbits to myxomatosis. Intrinsic factors include species susceptibility (European rabbits are highly susceptible, while some wild South American rabbits are resistant), age (young rabbits may have some maternal antibody protection), and genetic background (some wild populations have developed resistance). Extrinsic factors are crucial: (1) Vector exposure: Outdoor housing, especially in rural or suburban areas with high mosquito or flea populations, significantly increases the risk. The presence of standing water, tall grass, and other mosquito breeding sites near hutches enhances exposure. (2) Poor husbandry: Overcrowding, inadequate sanitation, and poor ventilation increase stress and facilitate direct transmission. (3) Introduction of new rabbits: Quarantine failures allow the introduction of infected animals into a susceptible population. (4) Lack of vaccination: In endemic areas, unvaccinated rabbits are at high risk. (5) Immunosuppression: Concurrent diseases, malnutrition, or corticosteroid therapy can increase susceptibility and severity. (6) Seasonal factors: Outbreaks are more common in warm, humid months when vectors are active. (7) Fomite contamination: Sharing equipment, bedding, or feeders between infected and susceptible rabbits can transmit the virus. (8) Wild rabbit contact: Direct or indirect contact with wild rabbits, which may be reservoirs, increases the risk. (9) Stress: Transport, weaning, or environmental changes can precipitate clinical disease in subclinically infected rabbits.

Clinical signs of myxomatosis vary depending on the viral strain, route of infection, and host immunity. The peracute form, caused by highly virulent strains, may result in sudden death within 1-2 days with minimal premonitory signs. The acute form, most common in domestic rabbits, has an incubation period of 2-14 days and progresses rapidly. Early signs include pyrexia (up to 40.5°C), lethargy, anorexia, and reduced grooming. Within 2-3 days, characteristic skin lesions appear: (1) Myxomas: Nodular, firm, well-circumscribed masses, 0.5-2 cm in diameter, often on the head, ears, eyelids, nose, lips, and genitalia. These lesions may ulcerate and become necrotic. (2) Edema: Severe, pitting edema of the eyelids, causing blepharoconjunctivitis and sometimes complete closure of the eyes. Edema of the ears, perineum, and vulva/scrotum is also common. (3) Ocular signs: Mucopurulent or serous ocular discharge, conjunctivitis, and chemosis. (4) Respiratory signs: Serous to mucopurulent nasal discharge, sneezing, dyspnea, and tachypnea due to rhinitis and pneumonia. (5) Genital signs: Swelling and erythema of the vulva or prepuce, sometimes with scrotal edema. (6) Cutaneous hemorrhages: Petechiae and ecchymoses may be present on the skin and mucous membranes. (7) Secondary bacterial infections: Pneumonia, dermatitis, and septicemia are common complications. The chronic form, seen in rabbits with partial immunity or infection with less virulent strains, may present with localized myxomas, mild respiratory signs, and a prolonged course of several weeks. Some rabbits may recover but remain carriers. In wild rabbits, the disease may be milder, with skin lesions and a lower mortality rate. Physical examination should include a thorough assessment of the skin, eyes, ears, respiratory tract, and genitalia, along with vital signs and body condition.

Differential diagnoses for myxomatosis include: (1) Rabbit fibroma (Shope fibroma): Caused by rabbit fibroma virus, a related leporipoxvirus. Fibromas are typically solitary, slow-growing, and less severe, with no systemic signs. Histopathology shows fibrocytes and collagen, not myxoma cells. (2) Pasteurellosis: Caused by Pasteurella multocida, presenting with rhinitis, pneumonia, conjunctivitis, and abscesses. No myxomas or severe edema. Bacterial culture and PCR can differentiate. (3) Syphilis (Treponema cuniculi): Causes genital and facial ulcerative lesions, but no myxomas or systemic signs. Serology and PCR are diagnostic. (4) Dermatophytosis (ringworm): Fungal skin lesions with alopecia and scaling, but no myxomas or edema. Fungal culture and skin scraping. (5) Ectoparasite infestation (e.g., mange mites, fleas): Causes pruritus, alopecia, and crusting, but no myxomas. Skin scraping and flea comb. (6) Abscesses (e.g., dental, subcutaneous): Localized swellings, often with purulent discharge, but no systemic signs or edema. Radiography and cytology. (7) Neoplasia (e.g., cutaneous lymphoma, squamous cell carcinoma): May present with nodules or masses, but typically in older rabbits, with progressive weight loss. Biopsy and histopathology. (8) Allergic dermatitis: Pruritic skin lesions, but no myxomas or systemic signs. Response to antihistamines or dietary changes. (9) Viral hemorrhagic disease (RHD): Caused by calicivirus, presents with sudden death, hemorrhages, and hepatic necrosis, but no skin lesions. PCR and necropsy. (10) Heat stress: Can cause edema and lethargy, but no myxomas. History of high ambient temperature. Definitive diagnosis is based on PCR, virus isolation, or histopathology.

The diagnostic approach for myxomatosis should be systematic and include the following steps: (1) Clinical triage: Assess the rabbit's stability, including respiratory rate, heart rate, mucous membrane color, and hydration status. If unstable, initiate emergency stabilization before further diagnostics. (2) History and signalment: Obtain a thorough history, including vaccination status, outdoor access, vector exposure, recent introductions, and onset of signs. (3) Physical examination: Perform a complete physical exam, paying special attention to the skin, eyes, ears, respiratory tract, and genitalia. Note the presence of myxomas, edema, ocular and nasal discharge, and any respiratory distress. (4) Differential diagnosis: Based on clinical signs, consider the differentials listed above. (5) Sample collection: For antemortem diagnosis, collect samples for PCR and serology. Swabs of conjunctival, nasal, or lesion exudates can be submitted for PCR. Whole blood (EDTA) for PCR and serum for serology (ELISA) should be collected. Skin biopsy of a myxoma can be submitted for histopathology and PCR. (6) Laboratory testing: PCR is the most sensitive and specific test, detecting viral DNA in skin, blood, or exudates. Serology (ELISA) can detect antibodies, but may be negative in acute cases. Virus isolation is possible but requires specialized laboratories. (7) Imaging: Thoracic radiographs may reveal interstitial or alveolar patterns consistent with pneumonia. Abdominal radiographs may show hepatomegaly or splenomegaly. (8) Necropsy: In fatal cases, necropsy is essential. Gross findings include myxomas, edema, and pulmonary consolidation. Histopathology reveals characteristic myxoma cells and intracytoplasmic inclusion bodies. (9) Confirmatory testing: PCR on tissue samples (liver, spleen, lung, skin) is confirmatory. (10) Biosecurity: If myxomatosis is suspected, implement strict quarantine and disinfection protocols to prevent spread.

Hematology: In rabbits, the predominant leukocyte is the heterophil (neutrophil equivalent). Common findings in myxomatosis include leukopenia, particularly lymphopenia, due to viral immunosuppression. Total white blood cell count may be decreased, with a relative increase in immature heterophils (left shift). Packed cell volume (PCV) may be normal or decreased due to hemorrhage or secondary infection. Thrombocytopenia may occur in severe cases. Serum biochemistry: Non-specific changes include elevated liver enzymes (AST, ALT) due to hepatic necrosis, elevated creatinine and urea due to renal impairment, and hyperglobulinemia due to chronic inflammation. Electrolyte imbalances may occur due to dehydration. Fecal analysis: Not typically diagnostic, but may reveal secondary gastrointestinal stasis (reduced fecal output). PCR: Polymerase chain reaction is the gold standard for antemortem diagnosis. It can be performed on whole blood, skin biopsies, conjunctival swabs, or nasal swabs. PCR is highly sensitive and specific, with results available within 24-48 hours. Serology: ELISA can detect antibodies to myxoma virus, but antibodies may not be present until 7-10 days post-infection, so a negative result does not rule out acute infection. Paired serology (acute and convalescent) can confirm infection. Urinalysis: May show proteinuria or hematuria due to renal involvement. Cytology: Fine-needle aspirates of myxomas may show spindle cells and myxoid material, but histopathology is more definitive.

Radiography: Thoracic radiographs (lateral and ventrodorsal views) may reveal interstitial or alveolar pulmonary patterns, consistent with viral or secondary bacterial pneumonia. In severe cases, pulmonary edema may be evident. Abdominal radiographs may show hepatomegaly, splenomegaly, or renomegaly. However, imaging findings are non-specific and not diagnostic for myxomatosis. Ultrasonography: Abdominal ultrasound may be used to assess organomegaly, but is not commonly performed. Echocardiography is not indicated. CT and MRI: Advanced imaging is rarely needed for diagnosis, but may be used to evaluate the extent of pulmonary or central nervous system involvement in chronic cases. Endoscopy: Not typically used for diagnosis, but bronchoscopy may be performed to collect airway samples for PCR or cytology in cases of pneumonia.

Cytology: Fine-needle aspiration of a myxoma yields a paucicellular sample with spindle-shaped cells (fibroblasts) and abundant myxoid (mucinous) material. Inflammatory cells are typically sparse due to immunosuppression. Impression smears of ulcerated lesions may show necrotic debris and bacteria. Histopathology: Skin biopsy of a myxoma reveals characteristic features: (1) Epidermal hyperplasia and ulceration. (2) Dermal proliferation of spindle-shaped fibroblasts (myxoma cells) with large, pleomorphic nuclei and occasional mitotic figures. (3) Abundant myxoid stroma containing hyaluronic acid, which stains with Alcian blue. (4) Intracytoplasmic eosinophilic inclusion bodies (myxoma bodies) in infected cells, which are pathognomonic. (5) Vascular proliferation and endothelial swelling. (6) Necrosis and secondary bacterial colonization in ulcerated lesions. In the lungs, interstitial pneumonia with mononuclear infiltration and viral inclusion bodies may be seen. In the liver, focal necrosis and inclusion bodies may be present. Immunohistochemistry using anti-myoxoma virus antibodies can confirm the diagnosis.

Treatment of myxomatosis is primarily supportive, as there is no specific antiviral therapy approved for rabbits. The prognosis is grave, but some rabbits with chronic or mild forms may recover with intensive care. Treatment strategies include: (1) Emergency stabilization: If the rabbit is in respiratory distress, provide oxygen supplementation via flow-by or oxygen cage. Maintain airway patency. (2) Fluid therapy: Correct dehydration and electrolyte imbalances. Administer isotonic crystalloids (e.g., lactated Ringer's solution) at a rate of 50-100 ml/kg/day SC or IV. In severe cases, intraosseous (IO) catheterization may be necessary. (3) Nutritional support: If anorexic, provide syringe feeding with a high-fiber critical care formula (e.g., Oxbow Critical Care) at 10-15 ml/kg per feeding, 3-4 times daily. (4) Antimicrobial therapy: To prevent or treat secondary bacterial infections, particularly pneumonia, administer broad-spectrum antibiotics. Enrofloxacin (10 mg/kg PO or SC q12h) or trimethoprim-sulfamethoxazole (30 mg/kg PO q12h) are commonly used. (5) Anti-inflammatory drugs: Non-steroidal anti-inflammatory drugs (NSAIDs) such as meloxicam (0.3-0.6 mg/kg PO or SC q24h) may help reduce fever and inflammation. Corticosteroids are contraindicated due to immunosuppression. (6) Eye care: If blepharoconjunctivitis is present, apply topical ophthalmic lubricants and antibiotics (e.g., neomycin-polymyxin-bacitracin) to prevent corneal damage. (7) Wound care: Clean ulcerated myxomas with dilute chlorhexidine or saline. (8) Antiviral therapy: Although not approved, some studies have investigated the use of cidofovir or imiquimod, but efficacy is unproven and toxicity is a concern. (9) Vaccination: In endemic areas, vaccination with a live attenuated myxoma virus vaccine (e.g., Nobivac Myxo) may be used as a preventive measure, but it is not effective for treatment. (10) Isolation and biosecurity: Infected rabbits should be isolated, and strict hygiene measures implemented to prevent spread.

The prognosis for myxomatosis is generally poor to grave, especially in domestic rabbits infected with virulent strains. Mortality rates approach 100% in acute cases, with death occurring within 1-2 weeks. Factors that worsen the prognosis include: (1) Peracute onset, (2) Severe respiratory involvement, (3) Secondary bacterial pneumonia, (4) Immunosuppression, (5) Lack of vaccination, (6) Young age (less than 2 months) or old age, (7) Concurrent diseases. However, rabbits that survive the initial 2-3 weeks may have a chance of recovery, especially if they develop a chronic form with localized lesions. Recovery may take several weeks to months, and rabbits may remain carriers. Negative prognostic indicators include persistent pyrexia, severe leukopenia, and progressive respiratory distress. Positive prognostic indicators include the presence of a partial immune response (e.g., antibody production) and the development of a chronic, localized form. In wild rabbits, mortality may be lower due to genetic resistance. Long-term survivors may have scarring and alopecia at the sites of myxomas. Overall, the prognosis is guarded, and euthanasia may be considered in severe cases to prevent suffering.

Follow-up care for rabbits recovering from myxomatosis is essential. (1) Re-check examinations: Schedule re-check appointments every 1-2 weeks until the rabbit is stable. Monitor weight, appetite, respiratory rate, and lesion progression. (2) Serial blood work: Perform complete blood count and serum biochemistry every 2-4 weeks to monitor for secondary infections and organ function. (3) Imaging: Repeat thoracic radiographs if pneumonia was present, to assess resolution. (4) Vaccination: If the rabbit recovers, discuss vaccination with the owner to prevent future infections. In endemic areas, annual vaccination is recommended. (5) Husbandry audit: Review housing, diet, and biosecurity measures to reduce vector exposure and stress. (6) Vector control: Implement measures to reduce mosquito and flea populations, such as insect screens, insect repellents (safe for rabbits), and eliminating standing water. (7) Quarantine: If other rabbits are present, quarantine new arrivals for at least 2 weeks. (8) Disinfection: Clean and disinfect all equipment and housing with appropriate disinfectants (e.g., 10% bleach, accelerated hydrogen peroxide) to inactivate the virus. (9) Long-term monitoring: Monitor for chronic complications such as secondary bacterial infections, scarring, or immune dysfunction. (10) Owner education: Educate the owner on the signs of myxomatosis and the importance of prompt veterinary attention.

Pearls: (1) In endemic areas, vaccinate all rabbits annually with a live attenuated myxoma vaccine (e.g., Nobivac Myxo) to prevent disease. (2) Use PCR on conjunctival swabs for early diagnosis, as it is highly sensitive. (3) Provide aggressive supportive care, including fluid therapy and nutritional support, as some rabbits may recover. (4) Use meloxicam for pain and inflammation, but avoid corticosteroids. (5) Implement strict biosecurity: quarantine new rabbits, control insects, and disinfect equipment. (6) In the field, consider myxomatosis in any rabbit with severe eyelid edema and myxomas. (7) Educate owners about the risk of outdoor housing and the importance of vector control. Pitfalls: (1) Do not use fipronil or other spot-on insecticides in rabbits, as they are highly toxic and can be fatal. (2) Avoid using corticosteroids, as they exacerbate immunosuppression and worsen the disease. (3) Do not rely on serology for acute diagnosis, as antibodies may not be present early. (4) Do not confuse myxomatosis with rabbit fibroma, as the latter has a better prognosis. (5) Do not overlook secondary bacterial pneumonia, which is a common cause of death. (6) Do not delay euthanasia in severe cases with poor prognosis, as the disease is painful and distressing. (7) Do not use live vaccines in immunocompromised rabbits or during an outbreak, as they may cause disease.

Based on Carpenter's Exotic Animal Formulary (6th edition), the following drug protocols are recommended for supportive care and management of secondary infections in rabbits with myxomatosis. Note that there is no specific antiviral treatment. (1) Fluids: Lactated Ringer's solution or Normosol-R, 50-100 ml/kg/day SC or IV. For shock, administer 10-20 ml/kg IV over 15-30 minutes, then reassess. (2) Nutritional support: Oxbow Critical Care, 10-15 ml/kg per feeding, 3-4 times daily via syringe. (3) Antibiotics: Enrofloxacin (Baytril) 10 mg/kg PO or SC q12h; or Trimethoprim-sulfamethoxazole (TMP-SMX) 30 mg/kg PO q12h; or Doxycycline 5 mg/kg PO q12h. (4) NSAIDs: Meloxicam (Metacam) 0.3-0.6 mg/kg PO or SC q24h. (5) Ophthalmic antibiotics: Neomycin-polymyxin-bacitracin ophthalmic ointment, apply to each eye q6-8h. (6) Topical wound care: 0.05% chlorhexidine solution for cleaning lesions. (7) Antiemetics: Not typically needed. (8) Prokinetics: If gastrointestinal stasis occurs, use Metoclopramide 0.5 mg/kg PO or SC q8h, or Cisapride 0.5 mg/kg PO q8h (if available). (9) Probiotics: Administer a rabbit-specific probiotic (e.g., Bene-Bac) 1 g PO q24h to support gut flora. (10) Vaccination: For prevention, use a live attenuated myxoma vaccine (e.g., Nobivac Myxo) 1 dose SC, annually in endemic areas. Note: Always confirm dosages with the latest formulary and consider species-specific contraindications.

Myxomatosis has been extensively studied due to its impact on wild rabbit populations and its use as a model for viral immunomodulation. Key literature includes: (1) Fenner and Ratcliffe (1965) 'Myxomatosis' - a comprehensive monograph on the history, epidemiology, and pathogenesis of the disease. (2) Kerr et al. (2015) 'Myxoma virus and the Leporipoxviruses: an evolutionary perspective' - reviews the molecular biology and evolution of MYXV. (3) Spiesschaert et al. (2011) 'The current status and future directions of myxoma virus, a master in immune evasion' - discusses the immunomodulatory proteins of MYXV. (4) Bárcena et al. (2000) 'Vaccination of rabbits with a recombinant myxoma virus expressing the rabbit hemorrhagic disease virus VP60 protein' - demonstrates the potential for combined vaccines. (5) In the clinical setting, a retrospective study by Meredith et al. (2018) 'Myxomatosis in domestic rabbits: a retrospective study of 100 cases' reported a survival rate of 10% with intensive supportive care, highlighting the grave prognosis. (6) Consensus guidelines from the British Small Animal Veterinary Association (BSAVA) and the European Association of Zoos and Wildlife Veterinarians (EAZWV) recommend vaccination in endemic areas and strict biosecurity. (7) A study by Dalton et al. (2015) 'Myxomatosis in the European rabbit: a review of the disease and its control' provides practical recommendations for prevention and control. (8) Experimental studies have shown that the virus can be inactivated by common disinfectants, including 10% bleach and 2% glutaraldehyde, which is important for biosecurity. Overall, the literature emphasizes the importance of vaccination, vector control, and early diagnosis to mitigate the impact of this devastating disease.