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Overview of Rhodococcosis

By Márcio Garcio Ribeiro, DVM, PhD, São Paulo State University - UNESP

Rhodococcosis is a pyogranulomatous disease of domestic animals, wildlife, and people. It is caused by Rhodococcus equi (formerly Corynebacterium equi), the pathogenicity of which has been mainly attributed to the presence of virulence-associated antigens and plasmids.

Etiology:

Rhodococcus spp belong to the aerobic actinomycetes in the order Actinomycetales, which is taxonomically related to the genera Mycobacterium, Corynebacterium, and Nocardia. R equi is a facultative intracellular opportunistic pathogen. In Gram smears, the bacteria appear as gram-positive rods, cocci, or rod-shaped (pleomorphic) organisms.

The virulence of R equi is intimately associated with its ability to survive and multiply inside macrophages, mainly the presence of a large plasmid that contains genes encoding a number of proteins associated with virulence (Vap). Seven genes have been classically associated with R equi virulence, the most important being the VapA plasmid because of its probable regulatory action over other genes. This gene regulation of R equi is a complex mechanism, influenced by various factors, including iron and magnesium availability, as well as environmental conditions such as temperature and pH.

Epidemiology:

R equi has been isolated from a wide variety of species, including horses, cattle, swine, sheep, goats, dogs, cats, camelids, birds, and wild animals.

R equi is distributed worldwide. It is widespread in surface soil, particularly in feces of foals and other herbivores, and in their environment. R equi may survive up to 12 mo in soil and can multiply in a wide temperature range (15°–40°C) and neutral pH (6.5–7.3).

Inhalation of soil dust particles is considered the main route of infection for domestic animals. Contaminated water and food is a less frequent route of infection, except for swine. Infected sputum may be swallowed by foals with pneumonia, causing ulcerative colitis and mesenteric lymphadenitis. Foals showing clinical and subclinical disease may spread R equi via aerosol.

Risk factors associated with a higher prevalence of disease in horses include large numbers of foals and mares, transient equine population, high foal density, foals born to mares that shed high numbers of the microorganism in the feces, and inadequate transfer of maternal antibodies. Poor animal management, housing, seasonal effect on foals’ birth, and environmental conditions (eg, dry, dusty, windy) have also been reported as predisposing conditions.

VapA plasmid is usually found in foal and bovine rhodococcosis cases, indicating a major risk of infection to companion animals by contact with livestock or their environment.

Pathogenesis:

The outcome of exposure to R equi is strongly influenced by the virulence, infective dose, and age and immune response of the host. Virtually all foals are exposed to R equi shortly after birth, although most do not develop clinical signs. Adult horses are commonly resistant to the clinical disease, because they have developed effective immune responses against R equi.

R equi may invade the animal via the respiratory or digestive tracts or the skin. It then spreads through hemolymphatic vessels, reaching different tissues and organs and developing pyogenic reactions in the liver, spleen, kidneys, bones, brain, and lymph nodes.

The basis of pathogenicity is attributed to the ability of the organism to survive and multiply inside macrophages, subsequently destroying these phagocytic cells. Other factors that contribute to the pathogenesis include the iron acquisition mechanism and the presence of phospholipase C and cholesterol oxidase (so called “equi factors”). In nonequine species, immunosuppressive conditions of the host may enable avirulent or less virulent strains to persist inside phagocytes.

Passive humoral immunity generated by ingestion of mare colostrum contributes to the control of R equi infection in foals. However, humoral response by itself does not confer complete protection. Consistent evidence supports the essential role of cellular immune response in control of R equi infections.

Clinical Findings:

Suppurative bronchopneumonia and ulcerative colitis in foals, lymphadenitis in cattle and swine, and cutaneous or organ abscesses are the major clinical manifestations of rhodococcosis in domestic animals. R equi infections are frequently found only in foals and swine, whereas they are rare or uncommon in small ruminants, companion animals, birds, and wildlife.

In horses, R equi is a commensal intestinal organism; it can actively multiply in the intestines of foals up to ~3 mo old and can also be isolated from the feces of adult horses. Suppurative bronchopneumonia is the primary clinical sign in foals. Foals are affected between 2 wk and 6 mo of age, although foals 1–3 mo old are most commonly affected, possibly because of the decline in maternal antibodies at ~6 wk of age. On endemic farms, it is estimated that 5%–40% of foals may develop clinical signs, and up to 50% of cases may be fatal. Foals >6 mo old appear to be refractory to development of clinical signs. (Also see Rhodococcus equi Pneumonia in Foals.)

Initially, foals show nonspecific signs, including fever, lack of appetite, and reluctance to move and suckle. Most foals with lung infections show respiratory distress, with tachycardia, tachypnea, and a strong inspiratory effort manifested by abdominal movement and nostril flaring. On auscultation, inspiratory and expiratory wheezes and crackles are possibly audible, predominantly in the cranioventral region. Decreased airway sounds suggest consolidation, extensive abscess formation, or occasional pleural effusion. Mucous membranes may be pale or cyanotic. Weight loss, cough, and serous to mucopurulent nasal secretion are not consistent signs. Typically, the disease is insidious in foals because of the ability of horses to compensate for respiratory lesions, making early diagnosis difficult.

Abdominal R equi infections in foals are clinically manifest by diarrhea, ulcerative colitis, mesenteric lymphadenitis, abdominal abscesses, typhlitis, and peritonitis. Foals rarely develop intestinal signs without pulmonary signs, but intestinal lesions are found in ~30%–50% of foals with pulmonary rhodococcosis. Colic, diarrhea, and weight loss are the major clinical signs of the intestinal form.

Immune-mediated polysynovitis affects ~20%–30% of foals, caused by immune complex deposition in joints. Any joint may be involved, although the tibiotarsal and stifle joints are most commonly affected. Synovial fluid aspiration reveals nonseptic mononuclear pleocytosis, without isolation of R equi. Septic arthritis of foals is another joint lesion caused by R equi. Different from immune-mediated polysynovitis, the septic lesion is usually combined with lameness signs.

A variety of other R equi infections are sporadically seen in horses, including cellulitis, ulceration, subcutaneous abscesses, lymphangitis, lymphadenitis, renal abscesses, pleuritis, hepatitis, and hepatoencephalopathy. Ocular signs, such as hypopyon and immune-mediated uveitis, may be seen. Osteomyelitis causing ataxia, decubitus, and limb paralysis is uncommon. Rarely, R equi is associated with abortion, placentitis, and infertility in mares, and it has been occasionally isolated from equine semen.

Clinical manifestations in adult horses are uncommon. The disease probably affects immunocompromised horses, or animals coinfected with immunosuppressive agents, infected by plasmid strains expressing VapA. The predominant clinical signs in adult horses are similar to those in foals, with suppurative bronchopneumonia, pleuritis, enteritis, lymphadenitis, and osteomyelitis.

In swine, R equi infections are basically restricted to the lymphatic tract. Usually, pyogranulomatous cervical lymphadenitis is seen, although mesenteric, bronchial, and other lymph nodes may be involved. R equi has also been isolated from apparently normal lymph nodes. Occasionally, pneumonia may be seen. Gross lesions in lymph nodes caused by R equi observed in slaughterhouses resemble those caused by Mycobacterium spp, a major cause of swine lymphadenitis (see Tuberculosis in Pigs).

Rhodococcosis is rare in dogs and cats, although it is more commonly reported in cats than in dogs. The most common routes of infection in dogs and cats are traumatic percutaneous introduction of microorganisms, primary contamination of wounds, or secondary to scratches in cat fights. Most cats present with cutaneous lesions on one extremity, along with localized swelling, ulcers, and fistulas with purulent drainage. The lesions are commonly painful, and usually no systemic signs are seen. Regional lymph nodes may be enlarged. Respiratory and visceral involvement represents the systemic or disseminated form of disease. Pyothorax is usually caused by dissemination of the organism from mediastinal lymph nodes. These animals present with fever, anorexia, dyspnea, and weight loss. In visceral infections, there is abdominal distention with palpable fluid, splenomegaly, hepatomegaly, and mesenteric lymphadenomegaly. Underlying conditions, including immunosuppressive viral infections, should be investigated in cats with rhodococcosis.

In ruminants, lymphadenitis (mesenteric, submaxillary, and bronchial), pneumonia, pyometra, ulcerative lymphangitis, and occasionally mastitis have been reported in cattle and buffalo. Pneumonia is the most common clinical picture in goats. Sporadic abortion and organ abscesses have been reported in sheep and goats.

Diagnosis:

Periodic clinical examinations, WBC counts, serum fibrinogen levels, serologic tests, and diagnostic imaging have been proposed as measures for early diagnosis, mainly because of the insidious and precocious characteristic of foal rhodococcosis. Weekly physical examination, including thoracic auscultation, is an effective clinical practice for early diagnosis. Monthly or more frequent monitoring of increased WBC counts (>13,000 cells/µL), serum fibrinogen concentration (>400 mg/dL), and thoracic ultrasonography are also valuable procedures for early diagnosis. Efficacy of periodic immunodiffusion testing in predicting individual cases in affected foals is controversial.

Supportive clinical and epidemiologic findings are important in presumptive diagnosis, but diagnosis by isolation, microbiologic culture, and phenotypic characterization of R equi is considered the “gold standard.” Tracheobronchial lavage, skin, synovial and peritoneal fluid, organs, and abscesses are the main clinical specimens used. On staining, the presence of gram-positive pleomorphic organisms supports a presumptive diagnosis, although this preliminary identification of the organism should be carefully evaluated, because few bacteria may be present in some clinical samples. Tracheobronchial lavage is the main clinical specimen for isolation of R equi in foals. However, the organism may occasionally be isolated from the trachea of foals without signs of pneumonia. Nasal swabs of foals are not indicated as evidence of rhodococcosis because of contamination with local microflora. Likewise, the presence of R equi in the nasal region is not predictive of pulmonary infection.

R equi is naturally isolated from feces of most livestock species, especially foals. Despite the fact that foals often swallow sputum containing R equi, <20% of foals confirmed with pulmonary rhodococcosis show positive fecal isolation of bacterium.

R equi can be isolated from feces, soil, or other contaminated samples. Potentially contaminated material, including feces, soil, and sand of parks and yards, should be submitted to selective culture media.

Neutrophilic leukocytosis, hyperfibrinogenemia, and hyperglobulinemia are the most consistent hematologic findings in foals with rhodococcosis. Thrombocytosis and monocytosis are variable findings. Serum amyloid A (SAA), an acute-phase protein, has been proposed as an inflammatory marker of rhodococcosis because of increased SAA levels in foals with R equi infections. Abdominal and thoracic effusions are usually exudates and reveal increased protein levels and nucleated cell counts.

Thoracic, abdominal, and joint radiography have also been used in diagnosis. Initial pneumonia is characterized by a mild to moderate, diffuse bronchointerstitial pattern, revealing small nodules and possibly cavitary masses, which can be multiple and large in severe cases. Occasionally, mediastinal lymphadenomegaly is seen. Thoracic ultrasonography is valuable to evaluate mainly peripheral lung lesions.

Serologic assays (eg, agar-gel immunodiffusion, ELISA, synergistic hemolysis inhibition) have been proposed for use in diagnosis, particularly of horses. However, titer results have varied greatly, probably because of differences in antigen preparation, interference of maternal antibodies, and continuous exposure to R equi in the environment. In addition, these tests have failed to differentiate between healthy and sick foals and, therefore, are inappropriate for diagnosis of individual cases.

Detection of R equi-specific DNA by PCR is also available for rapid and reliable diagnosis. However, because R equi can be found in the trachea of foals without pulmonary signs, PCR may be positive in healthy animals. Thus, epidemiologic aspects, clinical signs, hematologic tests, imaging findings, microbiologic culture, and/or molecular assays must all be considered in making a diagnosis.

Lesions:

Suppurative abscesses with necrotic areas and regional lymphadenitis are the major gross lesions seen at necropsy. Typically, pulmonary lesions reveal multiple firm nodules, atelectasis, congestion, and cavitary lesions. Multiple miliary lesions may be seen as well. Multifocal enteritis, typhlitis, mesenteric lymphadenitis, and Peyer’s patches reaction are seen in cases of intestinal involvement. Abdominal dissemination is characterized by peritonitis and organ abscesses. Septic arthritis, hypopyon, and vertebral osteomyelitis are signs indicative of hematogenous dissemination. Abortion, placentitis, and fetal infection are uncommon.

Histologically, the tissue and organ lesions are characterized as pyogranulomatous lesions containing foci of necrosis. The lesions reveal numerous gram-positive pleomorphic organisms phagocytized by macrophages, multinucleate giant cells, and fewer neutrophils. Moderate infiltrate of plasma cells and lymphocytes are also found.

The primary pathogens that should be differentiated from R equi as causal agents of foal respiratory diseases are Salmonella spp, Streptococcus equi, influenza virus, herpesvirus, and migrating stages of Parascaris equorum. Differential diagnosis of R equi causing intestinal manifestations should be performed with Clostridium spp, Salmonella spp, Escherichia coli, Strongyloides westeri, rotavirus, and coronavirus. Septic arthritis caused by R equi should be differentiated, especially from Salmonella spp and Streptococcus equi. Swine lymphadenitis caused by Mycobacterium spp should be differentiated from R equi because of similar appearance of lymph nodes at the slaughterhouse.

Treatment:

Treatment involves appropriate antimicrobial therapy, surgical drainage, debridement, and supportive care.

R equi is typically refractory to conventional antimicrobial therapy. Successful therapy varies dramatically between animal species, probably because of the intracellular location of the pathogen, development of pyogranulomatous lesions, and antimicrobial resistance patterns of the isolates. Antimicrobial susceptibility profile of animal and human strains usually shows in vitro sensitivity to rifampin, erythromycin, aminoglycosides (lincomycin, gentamicin), and imipenem. However, lipid-soluble drugs are the antimicrobials of choice because of the need for adequate tissue and cellular penetration, particularly into macrophages.

Since 1980, the standard effective chemotherapy protocol for foals is based on administration of rifampin (5 mg/kg, PO, bid, or 10 mg/kg/day, PO) and erythromycin (25 mg/kg, PO, tid, or 37.5 mg/kg, PO, bid). These drugs have a synergic effect, and their combined use decreases resistance rates. Throughout the past decade, the macrolides clarithromycin (7.5 mg/kg, PO, bid) and azithromycin (10 mg/kg/day, PO) have been investigated as treatment alternatives because of their bioavailability, stability, and higher concentration in the cells than erythromycin. The combination of rifampin and clarithromycin has shown better efficacy than rifampin-erythromycin or azithromycin-rifampin.

The duration of treatment is variable, although 4–8 wk is frequently recommended. Therapy may be extended in complicated cases in foals. However, after a longer course of therapy, some foals may develop antibiotic-associated colitis. Recent resistance of R equi isolates to rifampin and erythromycin have been described, especially with use of these drugs as monotherapy.

Azithromycin has been used as an alternative to erythromycin in foals with adverse signs after the use of erythromycin, including respiratory distress and diarrhea. However, there is a paucity of information regarding prolonged use (≥4 wk) and adverse effects of this drug.

In companion animals, combined therapy using rifampin (10 mg/kg/day, PO) and clarithromycin (7.5–12.5 mg/kg, PO, bid) for 2–5 wk may be recommended. Combined treatment using lincomycin (20 mg/kg, PO, bid, for 7–10 days) and gentamicin (5–8 mg/kg/day, SC, IM, or IV, for 5 days) has been effective in some cats, although longterm therapy or a second course of antimicrobials may be necessary. Erythromycin (15 mg/kg, PO, bid, for 14 days) may be combined with rifampin or other drugs in treatment of dogs and cats.

Surgical drainage of abscesses and debridement are indicated in some cutaneous lesions. Hydration and adequate nutrition are recommended as supportive care. NSAIDs may be used to control fever and in animals with arthritis.

Despite appropriate antimicrobial therapy and supportive care, domestic animals with respiratory distress, tachycardia, severe thoracic imaging abnormalities, and osteomyelitis have a poor prognosis.

Control and Prevention:

Control procedures are recommended to maximize the resistance of foals to infection and to reduce infection pressure in their environment. Adequate transfer of colostral immunoglobulins to foals is essential. Different measures have been proposed to prevent and control animal rhodococcosis, particularly in foals, including decrease in environmental exposure to R equi, passive immunization (hyperimmune plasma), active immunization (vaccination), and early diagnosis of disease.

The exposure of domestic animals, particularly foals, to R equi in the environment is theoretically the main risk factor for transmission. A high number of mares and foals on farms, and high density, leading to higher levels of R equi in manure, appear to be predominant risk factors for equine rhodococcosis. Thus, decreasing the number of mares and foals and reducing foal density have been recommended on farms with endemic rhodococcosis.

Removal of excess manure from livestock paddocks, stalls, and pastures could theoretically decrease growth of R equi, and consequently, the risk of infection. However, high concentrations of pathogenic R equi are usually found in the feces of foals, because they commonly swallow sputum containing virulent strains and excrete the pathogen in their feces. Infected foals should be isolated and their manure removed immediately to help control the disease.

Direct involvement of dust as the major risk factor for livestock rhodococcosis is controversial. Nevertheless, irrigation of paddocks and stalls, as well as growing grass in foal environments that are excessively dusty, may decrease aerosolization.

The use of hyperimmune plasma as an alternative prophylactic measure for equine passive immunization against R equi is based on the protective action of plasma components (immunoglobulin, interferon, complement factors, cytokines, and fibronectin). Hyperimmune plasma decreases the severity of clinical signs in foals, although it does not seem to have a curative effect or to shorten the course of disease. Protocols for administration are variable, but hyperimmune plasma is most effective when used before exposure to R equi. Most commonly, 1 L of hyperimmune plasma (or 20 mL/kg of foal), IV, is used for foals 1–60 days old. The initial dose for foals is variable, given at 1–10 days of age, and followed by a second dose at 30–50 days of age. However, because foals are challenged early (in the first days of life), the first dose is probably the most effective for protection.

Different vaccines have been developed to induce active immunity in foals. Most foals challenged with virulent R equi strains develop a protective and prolonged immune response. However, insufficient neonatal response or relative immunologic immaturity, interference with maternal antibodies, and the intracellular location of R equi limit the active immunization of foals in field conditions.

Killed vaccines have shown ineffective or controversial results in inducing a cellular immune response against R equi.

Infection with R equi strains without VapA and VapB genes does not induce protection of foals, indicating that virulent strains are essential for composition of effective vaccines. Studies in experimental and field conditions using VapA vaccines have shown enhanced clearance of R equi. Administration of oral live VapA vaccines has induced high concentrations of VapA-specific antibodies, despite being considered impractical for vaccination of a large number of animals. Efforts are ongoing to develop vaccines using modern concepts, such as transposons, and recombinant and DNA vaccines containing VapA antigen, which induces humoral and especially cellular immune response.

Zoonotic Risk:

Traditionally, contact with soil or manure, or inhalation of aerosols contaminated by livestock, represents the major routes of transmission of R equi to people. Alternatively, human infection may occur by transcutaneous trauma, ingestion, or wound contamination. Recent evidence supports that consumption of pork products or undercooked pork may be a probable route of infection to people because of contamination of the meat with lymph node content or feces.

R equi has emerged as a pulmonary pathogen among immunocompromised people. Therefore, it is recommended that immunocompromised people avoid contact with livestock and their environment, as well as consumption of undercooked pork products.