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Epidemiology of Rhodococcus equi foal pneumonia and control of disease on endemic farms (Proceedings)
Rhodococcus equi, formerly called Corynebacterium equi, is the etiology of one of the most severe and devastating forms of pneumonia in foals.
Rhodococcus equi, formerly called Corynebacterium equi, is the etiology of one of the most severe and devastating forms of pneumonia in foals. R.. equi is a Gram-positive, soil-borne, facultative, pleomorphic coccobacillus, and has been recognized as a pulmonary pathogen of foals for over 80 years, causing significant morbidity and mortality in foals, typically between the ages of 3 to 20 weeks of age. Pneumonia caused by R.. equi results in animal distress and economic losses to the equine breeding industry. Prevalence is high on some equine breeding farms. Case fatality rates can be high as well. Diagnosis is challenging, particularly during the early stages of infection. Treatment is generally prolonged, expensive, associated with adverse effects, and not always successful. Breeding farms reputed to have endemic pneumonia attributable to R.. equi are likely to lose clients.
Foals affected with pneumonia caused by R.. equi develop pyogranulomatous lesions in the lungs and mediastinal lymph nodes. Clinical signs include fever, cough, lethargy, tachypnea, and progressive respiratory distress. Although pneumonia is the most common manifestation of infection, R..equi can invade other organs and cause extrapulmonary disorders, such as osteomyelitis, abdominal lymphadenitis, and enterocolitis.(Chaffin 1997) Also, immune-mediated disorders, such as uveitis and polysynovitis, can result from R.equi infections.
Although R.equi can be cultured from the feces of foals and older horses, and may be a normal commensal of the GI tract, it does not cause disease in horses > 6 months of age, unless they are severely immunocompromised. There are only a handful of case reports of adult horses with R.equi infections, and some involved horses with documented immunosuppression. Similarly, in humans, the disease occurs typically in immunocompromised patients (ie, infected with the HIV virus or immunocompromised by chemotherapeutic or other immunosuppressive agents).
Age of foals at time of infection
Clinical signs of R.equi–induced pneumonia do not typically become apparent until foals are 30 to 100 days old; however, there is a growing body of evidence that most affected foals become infected early during the neonatal period. Foals < 2 weeks old are more susceptible to experimental infection with R.equi, compared with the susceptibility of older foals. (Martens, 1989). Epidemiologic data, using Sartwell's model, are consistent with the hypothesis that most foals with naturally developing disease become infected near the time of birth (Horowitz 2001). Researchers recognize controversy over the age when foals become infected, and it has been suggested that although many foals become infected very early in life, it has been proposed that infection is not limited to this time period (Hooper-McGrevy 2001).
The reasons for increased susceptibility of neonatal foals remain unknown. Foals from farms with endemic R.equi infections that subsequently develop pneumonia caused by R.equi have lower CD4+ T-lymphocyte concentrations at 2 and 4 weeks of age than do unaffected foals.(Chaffin 2004). Also, they have lower CD4+:CD8+ T-lymphocyte ratios during the first 2 weeks after birth than do foals that do not subsequently develop R .equi–induced pneumonia (Chaffin 2004). As foals increase in age, the immunophenotypic differences between affected and unaffected foals become smaller in magnitude until they are no longer apparent.
Also, foals are born with an inherent inability to mount a Thelper-1–based cell-mediated immune response and to generate ?-interferon (Breathnatch 2006, Boyd 2003). Newborn foals exhibit a marked inability to express the IFN-gamma gene and produce IFN-gamma protein. This deficiency occurs in both circulating and pulmonary lymphocytes. However, IFN-gamma gene expression and protein production increases steadily throughout the first 6 months of life (Breathnatch 2006).
These mechanisms represent critical components of the host protective immune response against R.equi infections. Analysis of these findings suggests that affected foals probably have relatively ineffective or immature immune responses to R.equi during the early neonatal period and are thereby less prepared to develop an adequate antimicrobial defense against R.equi infections.
Virulence of the organism
There are virulent and avirulent strains of R.equi. Virulent strains of R.equi characterized by their ability to survive and replicate within macrophages. This ability is associated with the presence of a large plasmid of approximately 80 to 90 kilobases. A number of different strains carry the virulence plasmid and these strains appear to be geographically widespread. The virulence plasmid contains a 27.5 kilobase pathogenicity island that encodes for at least 7 related virulence-associated proteins. Virulent isolates containing virulence-associated protein antigen (VapA) genes and have been isolated from the lungs of diseased foals. The virulence plasmid is required to produce disease in foals. Strains lacking these plasmids are considered as avirulent or intermediately virulent in foals and are not associated with disease in foals.
The epidemiologic aspects of pneumonia in foals caused by this bacterium are not completely characterized. R.equi is a soil inhabitant found in the fecal matter of grazing animals (Barton 1984). The bacteria are ingested by grazing animals, survive and multiply in the GI tact, and then are excreted back into the environment in feces. Growth of R.equi in the environment is influenced by concentration of horse feces, soil pH and ambient temperature. Neutral to moderately alkaline soil at 30C with horse feces appear to by the optimal environment for the organism. R.equi thrives on the volatile fatty acids present in horse feces (Hughes 1987). R.equi present on most, if not all, equine farms as part of the microbiologic environment of the farm.
Pneumonia in foals caused by R.equi is endemic (high prevalence) on some farms and develops intermittently on others, but is not found on most farms. There is marked variability from farm to farm in the prevalence of R.equi (Chaffin 2003). Also, on endemic farms, there is marked year-to-year variability in foals with pneumonia attributable to R.equi (Chaffin 2003). Generally, the proportion of foals with pneumonia attributable to R.equi at endemic farms is approximately 5% to 20%, but proportions > 20% are not unusual. The reasons for this variation among and within farms remain unknown.
The following are morbidity rates from 64 breeding farms in Texas (Chaffin 2003). A total of 113 foals on 32 affected farms developed R.equi pneumonia. Median number of affected foals on the 32 affected farms was 1.5 foals (range, 1 to 15 foals). Median percentage of foals on affected farms that developed R.equi pneumonia was 6.6% (range, 1.3 to 100%). Of the 32 affected farms, 12 (37.5%) had < 5% of foals affected, 8 (25.0%) had 5 to 10% of foals affected, 4 (12.5%) had 11 to 20% of foals affected, 7 (21.9%) had 21 to 50% of foals affected, and 1 (3.1%) had 100% of foals affected.
Molecular epidemiologic data indicate that recurrence of the problem at a farm does not appear to be attributable to a particular genotypic strain of R.equi at that farm, and various genotypes may be isolated from affected foals or their environment at a particular farm (Cohen 2003, Morton 2001).
Pneumonia caused by R.equi in foals appears to be a disease of particular importance to larger breeding farms that use management practices determined to be desirable for improving health (ie, farms that are considered well managed). Breeding farm characteristics associated with R.equi pneumonia were reported for 64 breeding farms in Texas (Chaffin 2003). Breeding farms with large acreage, a large number of mares and foals, high foal density, and a population of transient mares and foals are at high risk for foals developing pneumonia caused by R.equi.
Acreage of the farm was significantly associated with R.equi pneumonia. Large farms (farms that used ≥ 60 acres in the husbandry of horses) were approximately 3 times as likely to have foals that developed R.equi pneumonia, compared with smaller farms. The risk of having affected foals increased with acreage, indicating that the greater the acreage, the greater the risk. In the multivariate analyses, farms with > 200 acres were considerably more likely to have foals that developed R.equi pneumonia (Chaffin 2003).
There were numerous variables regarding the number and density of horses and foals that represented increased risk for development of R.equi pneumonia in foals. Farms with > 160 horses and farms with > 17 foals were at higher risk of R.equi foal pneumonia. The density of total horses on the farm was not associated with increased risk for development of R.equi pneumonia in foals, but the density of foals on the farm was associated with increased risk.
Farms with foal densities > 0.25 foals/acre were approximately 10 times as likely to have affected foals as were farms with ≤ 0.25 foals/acre. On farms with a high density of breeding horses and where R.equi pneumonia is endemic, reduction of foal density should be considered to help minimize the impact of this disease (Chaffin 2003).
Rhodococcus equi pneumonia does not appear to be associated with poor farm management or a lack of attention to preventative health practices (Chaffin 2003). One study suggested that housing foals in stalls with dirt floors may increase the risk for development of R.equi pneumonia (Chaffin 2003), but a subsequent study found that concrete floors in foaling stalls were associated with increased risk (Cohen 2005). It is currently unclear what effect the type of floors in foaling stalls has on the prevalence of R.equi.
In a subsequent study (Cohen 2005) of 138 farms from the USA, affected farms were determined significantly more likely to have raised Thoroughbreds, housed ≥ 15 foals, used concrete floors in foaling stalls, and tested foals for passive transfer of immunity than unaffected farms. These data further supported the findings that farms with large acreage and a large number of mares and foals have greater odds of being affected by R.equi pneumonia. The finding that Thoroughbred breed was significant associated with increased risk is still unclear, but perhaps reflects other characteristics of those farms on which Thoroughbred foals are raised. Rhodococcus equi pneumonia was associated with an environment that was subjectively determined by participating veterinarians to be moderately to severely dusty. Desirable management factors commonly used on farms were not effective for controlling or preventing development of R.equi pneumonia.
It has been said that R.equi infections are associated with affluent equine breeding farms. Although the disease appears to be most common at larger breeding farms that use practices deemed desirable for management of optimum foal health (Chaffin 2003, Cohen 2005) these criteria do not reliably differentiate farms with foals that have pneumonia attributable to R.equi from farms with unaffected foals.
The bacterium lives in the superficial layer of the surface soil. Martens (2002) compared geochemical factors (pH, salinity, nitrate, phosphorus, potassium, calcium, magnesium, sodium, sulfur, zinc, iron, manganese and copper) of surface soils of 24 farms with R.equi affected foals and 21 farms without affected foals. Significant differences in geochemical factors were not detected between the farms, suggesting that these factors do not affect risk of foals becoming infected with R.equi pneumonia.
However, extremely alkaline (pH > 9) and acidic (pH < 5) environments retard growth of R.equi (Hughes 1987). The organism is acid-tolerant and virulence plasmid gene expression is regulated by pH (Ren 2003). Soil pH may play a role in virulent R.equi survival outside the host. A positive relationship between acidic soil pH and the proportion of virulent R.equi in the soil has recently been demonstrated (Muscatello 2006). Studies are underway to examine the capacity of pH modification to reduce the burden of virulent R.equi in the soil (Muscatello, unpublished).
Most foals are exposed to R.equi, based upon serologic studies that demonstrate a high prevalence of foals having antibodies against R.equi. Furthermore, studies have demonstrated that the soil and fecal samples have a high prevalence of R.equi, including virulent organisms.
R.equi bacteria have been isolated from the soil of many horse farms (Makrai 2006; Takai 2001; Cohen 2008). Virulent R.equi has been isolated on farms where R.equi pneumonia was considered endemic as well as on farms with no history of R.equi disease. It has been suggested that the prevalence of R.equi within the soil and the concentration of virulent R.equi in soil affects the prevalence of R.equi pneumonia on the farm. However, more recent studies have revealed that soil concentrations of total R.equi and virulent R.equi are not associated with prevalence of pneumonia attributable to R.equi.
Cohen et al (2008), in a study of soil samples obtained from 37 breeding farms in central Kentucky, demonstrated that virulent R.equi were commonly recovered from soil samples, regardless of the incidence of R.equi pneumonia in the foal population at the farm. Soil samples from all farms yielded both virulent and avirulent R.equi for all sample collection points. There were no significant differences at any sample collection point among affected, previously affected, and unaffected farms in soil concentrations of total R.equi or virulent R.equi or in the proportion of virulent organisms in soil samples. These data demonstrate that differences in soil concentrations of virulent R.equi or the proportion of virulent isolates in the soil do not appear to predict or correlate with the incidence of foals with pneumonia attributable to R.equi at breeding farms in central Kentucky.
The results from the Kentucky study are consistent with another report (Muscatello, 2006) in which soil concentrations of virulent R.equi were not significantly correlated with prevalence of pneumonia caused by R.equi among foals at Thoroughbred breeding farms in Australia.
Recent studies (Muscatello 2006) highlight the significance of airborne virulent R.equi concentrations on the prevalence of R.equi pneumonia in foals. Airborne concentrations of virulent R.equi were correlated with prevalence of pneumonia in foals caused by this bacterium. The prevalence of R.equi pneumonia on farms with a mean airborne concentration of virulent R.equi of ≥1 CFU/1,000 liters was significantly greater than on farms with airborne concentrations of virulent R.equi of ≤1 CFU/1,000 liters. Similarly, the prevalence of disease due to R.equi on farms on which ≥35% of airborne R.equi were virulent was significantly greater than on farms on which a lower proportion of airborne R.equi were virulent.
Variables that were significantly associated with the airborne concentrations of virulent R.equi were the date that air samples were obtained, location within the farm, pasture height and soil moisture.(Muscatello 2006) Airborne virulent R.equi burdens were highest from the middle of the foaling season throughout the later stages of foaling season. Warm ambient temperature and low pasture height were associated with elevated airborne concentrations, as was dry soil. Dry soil was also associated with elevated proportions of airborne R.equi bacteria that were virulent. These results support the use of farm management practices that increase soil moisture and promote good pasture cover on paddocks. These practices may reduce the level of exposure to aerosolized R.equi.
Another potentially important finding of the Australia study (Muscatello 2006) was that holding pens and travel lanes were associated with higher concentrations of airborne virulent R.equi. These pens and lanes had low soil moisture and poor grass cover. Theoretically, foals that spend greater time in these areas would be expected to have increased exposure to higher levels of airborne virulent R.equi, which in turn may increase the relative risk of foals contracting R.equi pneumonia. The high airborne concentrations of virulent R.equi in the lanes and holding pens make these areas dangerous places to allow foals to congregate for any extended period of time. However, it is unclear whether the increased airborne concentrations of R.equi were a cause or effect of infected foals.
Muscatello (2006) concluded that environmental management strategies focusing on reduction of the level of aerosol exposure to susceptible foals through the use of selective irrigation in dry areas such as holding pens and lanes, avoidance of areas with soils with a low water-holding capacity, and maintenance of good pasture cover where foals between the ages of 4 and 12 weeks are kept are likely to substantially reduce the impact of R.equi pneumonia on the horse-breeding industry. Studies demonstrating the effectiveness of these strategies are lacking.
Isolation of R.equi from the air has been reported to increase on dry, windy days (Takai 1986).
Studies in Northern Europe suggest that the indoor stall environment has higher airborne concentrations of R.equi than does the outdoor environment (Muscatello 2006).
Fecal excretion of both virulent and avirulent R.equi is associated with contamination of the soil environment on equine farms (Takai 1997). Most mature horses shed 100 to 1000 R.equi per garm of feces with virulent strains constituting < 10% of the fecal R.equi population. Foals shed much higher concentrations of R.equi, between 1000 and 10,000 R.equi per gram with virulent strains constituting 10-40% of the fecal population ( Takai 1994; Grimm 2007). Between 3 and 12 weeks of age, foal's fecal excretion of R.equi reaches it peak (Takai 1994). In foals with R.equi pneumonia, fecal concentrations can be as high as 108 R.equi per garm of feces., with as much as 80% of the bacteria being virulent.
A study of fecal-borne R.equi by Grimm (2007) demonstrates the widespread presence of virulent R.equi in the feces of dams. Grimm (2007) studied 171 mares and their foals from a farm in Kentucky to determine whether mares are an important source of R.equi for their foals. Fecal samples were collected at 4 time points in the peri-partum period. R.equi–associated pneumonia developed in 53 of 171 (31%) foals. Fecal shedding of virulent R.equi was detected in at least 1 time point for every mare (100%); bacteriologic culture results were positive for 62 of 171 (36%) mares at all time points. However, compared with dams of unaffected foals, fecal concentrations of total or virulent R.equi in dams of foals with R.equi–associated pneumonia were not significantly different. These data indicate that dams of foals with R.equi–associated pneumonia did not shed more R.equi in feces than dams of unaffected foals; therefore, R.equi infection in foals was not associated with comparatively greater fecal shedding by their dams. However, detection of virulent R.equi in the feces of all mares during at least 1 time point suggests that mares can be an important source of R.equi for the surrounding environment. Foals exposed to this contaminated environment are thus likely to be exposed to virulent R.equi from birth.
It has been suggested that genetic factors may play a role in susceptibility to R.equi infections, however, further research is needed to better clarify this hypothesis.
Control of R.equi at endemic equine breeding farms
Control of R.equi pneumonia at equine breeding farms that have a high prevalence of disease is challenging. Control programs should be tailored to each farm, based upon the prevalence of disease at that farm and the resources and concerns of that farm and it's veterinarian(s). Efforts should focus on early detection of affected foals, treatment of affected foals, and prevention of new cases.
Early detection of affected foals
Early recognition of R.equi pneumonia in foals (prior to development of clinical signs) and appropriate treatment likely reduces economic losses and mortality, and likely limits the costs associated with long-term treatment of severely affected animals. Suggested approaches for early identification of R.equi-infected foals on farms with enzootic infections include daily or twice daily rectal temperatures and observation of clinical signs, weekly physical examinations, periodic determination of WBC concentration, measurement of plasma fibrinogen concentration, serologic surveillance and other immunologic assays, thoracic ultrasonography, and thoracic radiography.
Higuchi (1998) suggested that physical examination of foals at 30 and 45 days of age was useful for early detection of affected foals at endemic farms. Prescott (1989) reported that complete physical examination with auscultation of the lungs performed twice weekly was successful in promoting early diagnosis and preventing death caused by R.equi pneumonia. However, this may be expensive and time-consuming.
Although it was quite popular in the 1990s at endemic farms, serologic surveillance is probably of minimal value for early detection of R.equi pneumonia in an individual foal. The presence of antibodies indicates either exposure or maternal transfer of antibodies, but not necessarily active infection.
Recent studies have demonstrated that serology was not useful for differentiating affected foals from unaffected foals. Martens (2002) reported a nested, case-control study of serologic testing in 26 affected foals and a group of unaffected foals. An agar gel immunodiffusion assay, synergistic hemolysis inhibition assay, and 3 ELISA assays were performed. None of the serologic assays differentiated affected from unaffected foals, either at the time of onset of clinical signs, or at any time period prior to onset of clinical signs.
Giguere (2003) examined the performance of four ELISA assays and an agar gel immunodiffusion test for diagnosis of R.equi pneumonia in foals. Antibody concentrations of foals with culture-confirmed R.equi pneumonia (n = 41) were compared to those of age-matched pasturemates that remained clinically healthy during the entire breeding season (n = 24). The results suggested that the serological assays do not differentiate between diseased and clinically healthy foals.
Hematology is one effective mechanism for early detection of affected foals. Serial monitoring of the WBC and fibrinogen concentration of foals is beneficial for early identification of foals with R.equi infections. Giguere (2003) evaluated WBC concentration, and plasma fibrinogen concentration for early identification of R.equi-infected foals. In a prospective study of 100 unaffected and 42 affected foals from a farm with enzootic R.equi infection, Giguere measured WBC and fibrinogen at 4 week intervals starting at 3-5 weeks of age. He found that the diagnostic performance of WBC concentration was significantly higher than that of fibrinogen concentration. Sensitivity and specificity of measurement of WBC concentration at a cutoff of 13,000 cells/μL were 95.2 and 61.2%, respectively. At a cutoff value of 15,000 cells/μL, sensitivity was 78.6% and specificity was 90.8%. Fibrinogen (using 400 as a cutoff) was 90.5% sensitive, but only 51% specific. Giguere concluded that both fibrinogen and WBC were useful for early identification of affected foals, but monitoring WBC concentration was significantly better than measurement of fibrinogen.
One must recognize that WBC and fibrinogen concentrations are nonspecific indicators of infection or inflammation. Thus, they would be of value for early identification of R.equi-infected foals only on farms where the prevalence of the disease is high. Measurement of WBC or fibrinogen concentrations on a farm with a low prevalence of disease would result in poor positive predictive values regardless of the cutoff used (Giguere 2003).
Surveillance with Serum Amyloid A concentrations
Serum amyloid A (SAA) is an acute-phase protein. In one limited study, foals with R.equi pneumonia had increased concentrations of SAA, and SAA decreased to normal following treatment sooner than WBC and fibrinogen.
Cohen (2005) reported a study aimed at determining whether serum amyloid A (SAA) concentrations differentiate foals affected with R.equi pneumonia from unaffected foals, either prior to the onset of disease or at the time of onset of clinical signs. Serum samples were obtained from 212 foals 7–14 days and 196 foals 21–28 days of age, and from affected foals and age-matched controls at the time of onset of signs of pneumonia. There were no significant differences between SAA concentrations of foals with R.equi and clinically unaffected foals during the 2 periods of examination or at the time of onset of clinical signs of R.equi pneumonia. The authors concluded that concentrations of SAA are variable among foals with R.equi pneumonia and cannot be used reliably either as an ancillary diagnostic tool or to screen for early detection of disease during the first month of life.
Surveillance with thoracic ultrasonography
Slovis (AAEP, 2005) has demonstrated the effectiveness of using ultrasound to screen foals for early detection of R.equi in foals at endemic farms. Thoracic ultrasonography was started at 30 days of age and repeated at 2-wk intervals until the foal was weaned (16–20 wk). All pulmonary lesions were graded on a scale from 0 to 10. All foals with a graded pulmonary lesion were placed on antibiotic treatment that consisted of azithromycin (10 mg/kg, q 24 h, PO for 7 days and then every other day) and rifampin (5 mg/kg, q 12 h, PO). Treatments were continued until ultrasonographic resolution was determined. The implementation of thoracic ultrasonography on the endemic farms was highly sensitive, because no foals that were diagnosed as a grade 0 developed clinical disease. The farms that implemented thoracic ultrasonography had no mortalities and a marked reduction of clinical disease associated with R.equi. The authors concluded that thoracic ultrasonography is a practical, quick, accurate, and useful diagnostic modality when screening for R.equi.
Slovis (2005) described a grading system for pulmonary consolidation and abscessation as defined below:
Grade 0: No evidence of pulmonary consolidation. Pleural irregularities appear as vertical hyperechoic lines and are described as reverberation artifacts.
• Grade 1: Lesions are <1 cm in diameter/depth
• Grade 2: Lesions are 1.0–2.0 cm in size.
• Grade 3: Lesions are 2.0–3.0 cm in size.
• Grade 4: Lesions are 3.0–4.0 cm in size.
• Grade 5: Lesions are 4.0–5.0 cm in size.
• Grade 6: Lesions are 5.0–6.0 cm in size.
• Grade 7: Lesions are 6.0–7.0 cm in size.
• Grade 8: Lesions are 7.0–9.0 cm in size. If pleural effusion is present, the lesion is assigned
• this grade regardless if lesser grades of consolidation or abcessation are present.
• Grade 9: Lesions are 9.0–11.0 cm in size.
• Grade 10: The entire lung is affected.
Cortez (2008) reported the results from a Thoroughbred farm in Argentina where ultrasound was used to detect pulmonary lesions. One hundred foals were monitored by thoracic ultrasonography at ages 1–5 months. This strategy allowed reducing the number of foal deaths almost totally. The authors concluded that ultrasonography was very efficient in detection of early cases of pneumonia.
Ultrasound offers several advantages as a screening tool over radiography. The entire chest can be scanned in just a few minutes, and when the periphery of the lung is affected, it is more sensitive than radiography. Ultrasound screening has highlighted the magnitude of subclinical disease at endemic farms. Foals with no clinical signs and ultrasound abnormalities consisting of only "comet-tails" generally do not require therapy. However, foals with focal areas of consolidation > 1 cm in diameter or in depth and foals with clinical signs of respiratory disease are usually treated. Follow-up examinations permit a more objective assessment of response to therapy.
Surveillance with thoracic radiography
Radiography has the advantage over ultrasonography that both central and peripheral lesions can be detected. However, numerous disadvantages exist, including the requirement for more personnel, radiation exposure of personnel, costs for special equipment. Also, early in the disease process, radiographic lesions can be very subtle and less typical of those seen in more advanced cases of R.equi pneumonia.
Although they are considered the gold standard for identifying R.equi in foals with clinically-apparent respiratory disease, culture and.or PCR amplification of tracheobronchial aspirates should not be used as screening tests on healthy foals for early detection of R.equi. Ardans (1986) reported a study on a farm with enzootic R.equi pneumonia. Bacteriologic culture results from tracheobronchial aspirates were positive for R.equi in 77 of 216 (35%) foals that did not show signs of respiratory tract disease.
Treatment of affected foals
Affected foals should be treated as soon as they are identified. For further information about treatment of affected foals, see the accompanying proceedings on "Diagnosis and Treatment of Rhodococcus equi Foal Pneumonia."
Prevention of new cases
Immunoprophylaxis with hyperimmune plasma, obtained from donor horses immunized with various antigens of R.equi, is a common practice at many equine breeding farms. Hyperimmune plasma is commercially available from several plasma companies in the USA. Numerous studies, including experimentally-infected foals and naturally infected foals, have examined the effectiveness of hyperimmune plasma (Martens 1989; Madigan 1991; Becu 1997; Higuchi 1999; Caston 2006; Giguere 2002). However, studies evaluating the efficacy of various products under field conditions have given equivocal results, with only 2 of 5 controlled clinical trials demonstrating a statistically significant reduction in incidence of R.equi.
The mechanism through which hyperimmune plasma helps is not fully understood. The list of possible effector molecules includes antibodies and nonspecific factors such as fibronectin, complement components, collectins, cytokines, and acutephase proteins.
The ideal dosage and ideal time for administration of hyperimmune plasma is not known. The minimal effective dosage is not known. In general, it is suggested that foals should receive hyperimmune plasma IV within the first 3 days of life in order to be most effective. A second dosage at approximately 21-28 days of age is generally recommended at farms with high prevalence rates. Hyperimmune plasma is expected to decrease the incidence of disease , but will not prevent infection in all foals. Hyperimmune plasma has shown no therapeutic benefit in foals that already have well-established, experimentally-induced R.equi infections (Chaffin 1991).
Giguere (2002) reported a randomized trial to determine the efficacy of a commercially available hyperimmune plasma product for the prevention of R.equi in 165 foals. One group of foals received plasma at 950 ml between day 1 and 10 of age and again at 30 to 50 days of age. Another group of foals served as controls. Plasma-treated foals had a cumulative incidence of 19.1% of R.equi, whereas the control foals had an incidence of 30%. This difference was not statistically different, although lack of statistical power may have influenced the results.
Caston (2006) showed that in experimentally-infected foals, pre-treated with hyperimmune plasma had higher VapA titers, lower radiographic scores, lower neutrophil concentrations and a prolonged time till increased respiratory effort.
In another study (Chaffin 2003), the proportion of affected foals (6.25%) that received hyperimmune plasma was less than the proportion of unaffected foals (14.9%) that received hyperimmune plasma; however, this did not represent a significant difference. Limited statistical power in this study may have influenced the inability to show a statistical difference.
Evidence exists that young foals have ineffective immune defenses against R.equi, and are thus more susceptible to infection. Studies are ongoing to develop methodologies for immunomodulation of foals and provide protection against R.equi infections. Thus far, no clinically-applicable methods are available.
Results of clinical trials on azithromycin chemoprophylaxis have shown mixed results. Although the USA study showed beneficial effects, azithromycin prophylaxis, on a widespread basis, is currently not recommended, based largely upon the potential for antimicrobial resistance of R.equi or other pathogens.
A controlled randomized clinical trial of 338 foals born and raised at 10 endemic breeding farms, was reported (Chaffin 2008) to determine the effect of azithromycin chemoprophylaxis on the cumulative incidence of pneumonia caused by R.equi. Foals were randomly assigned to 2 groups. Group 1 foals were controls, and group 2 foals were treated with azithromycin (10 mg/kg, PO, q 48 h) during the first 2 weeks after birth. The proportion of R.equi–affected foals was significantly higher for control foals (20.8%) than for azithromycin-treated foals (5.3%). Azithromycin chemoprophylaxis effectively reduced the cumulative incidence of pneumonia attributable to R.equi among foals at breeding farms with endemic R.equi infections.
Another study (Venner 2007) from Germany evaluated the ability of azithromycin to prevent pulmonary abscesses in foals at a farm with endemic R.equi pneumonia. Forty-five foals served as untreated controls. Twenty-five foals were given azithromycin (10 mg/kg) orally once daily for 4 weeks, starting on day 0 of life. The foals were examined once a week from birth to the age of 5 months. If clinical signs or leucocytosis were noted and pulmonary sonographic findings (diameter >10 mm) were observed, the diagnosis of abscessing pneumonia was made. The prevalence of pulmonary abscesses was similar in the control group (31/45 foals), and in the azithromycin group (15/25 foals), but the foals in the azithromycin group were affected at an older age than were the control foals.
Strategies designed to exploit the iron dependency of various pathogenic organisms have proven effective in the management of a variety of bacterial diseases. Gallium, a trivalent semi-metal (Ga3+), shares many chemical similarities with Fe3+, which has prompted study of its use to exploit the iron dependency of bacteria. Trivalent gallium (Ga3+), like Fe3+, enters mammalian cells, including macrophages, via both transferrin-dependent and transferrin-independent mechanisms. Gallium competes with Fe3+ for uptake by intracellular bacteria, resulting in bacterial acquisition of Ga3+ instead of Fe3+. The antimicrobial effects of Ga3+ are due to its incorporation into crucial Fe-dependent metabolic and reproductive enzyme systems. Trivalent gallium, unlike Fe3+, is unable to undergo redox cycling, which leads to inactivation of those enzyme systems and bacterial death. Gallium inhibits the growth of Mycobacterium tuberculosis and M. avium (which share many similarities with R.equi), when the bacteria are located extracellularly or within human monocyte-derived macrophages (Oyebode 2000).
Gallium maltolate (GaM) provides high gallium bioavailability following oral administration in people and a variety of laboratory animals, and is not associated with toxicities (Bernstein 2000). Recent studies have demonstrated that gallium effectively inhibits growth of R.equi in vitro, both extracellularly and within macrophages (Harrington 2006; Martens 2008). Also, GaM is readily absorbed when administered orally to mice and effectively reduces tissue burdens of R.equi in experimentally-infected mice Harrington (2006). GaM is safe and readily absorbed by neonatal foals after intragastric administration, and achieves high serum concentrations of gallium (Martens 2007). GaM prepared into a methylcellulose formulation is readily absorbed by neonatal foals, when administered orally.
It is hypothesized that GaM therapy in foals, during the first 2 to 4 weeks of life, will safely provide protection against R.equi. A double-blinded, randomized, controlled, clinical trial is underway in 2008 (Chaffin, unpublished). If this and future studies indicate that gallium is effective in the control of R.equi pneumonia, its use would obviate concerns regarding antimicrobial resistance associated with antimicrobial chemoprophylaxis.
It would be considerably more convenient to control R.equi nfections on endemic farms via active immunization of mares and foals with a protective antigen. Such attempts have thus far proved unrewarding. Currently, there is not an effective vaccine against R.equi.
Decreasing environmental exposure
With most infectious diseases, the outcome of exposure to the etiologic agent is partly determined by the size of the infective challenge. Therefore, practices that minimize exposure to R.equi should affect the incidence of clinical disease. There have been many management practices suggested, but data supporting their efficacy are lacking.
Large numbers of mares and foals kept on bare, dusty manure-containing paddocks may result in heavy environment exposure. As suggested by the Australian studies,(Muscatello 2006), environmental management strategies focused on reducing the level of aerosol exposure through the use of selective irrigation in dry areas such as holding pens and lanes, avoidance of areas with soils with a low water-holding capacity, and maintenance of good pasture cover where foals between the ages of 4 and 12 weeks are kept are likely to substantially reduce the impact of R.equi pneumonia on the horse-breeding industry. In Australia, the use of intensive irrigation of holding pens and lanes was shown to reduce the generation of virulent R.equi aerosols, and reduced the risk of R.equi pneumonia. Avoidance of housing susceptible foals in areas with soil low-water-holding capacity (sandy areas) and maintanence of good pasture cover in paddocks and yards used to house foals have been shown to decrease the risk of inhalation of the organism.
Where foals are routinely stalled, strategies that either reduce the time spent in stalls or methods to improve air hygiene need to be explored to reduce the environmental exposure to the organism. One study suggested that dirt floors in stalls was associated with increased risk, thus use of flooring surface other than dirt may be of benefit.
Since foal density is associated with increased risk of having foals with R.equi (Chaffin 2003; Cohen 2005; Cohen 2008), efforts aimed at reducing the density of foals on endemic farms is likely to have positive benefits. Also, beneficial results are likely to result from efforts to reduce the housing of large herd of foals in yards, pens or paddocks. Such efforts should minimize the high-trafficked, dusty environments with high concentration of fecal-soil derived virulent R.equi in the air that foals breathe.
Because the feces of mares and foals are an important source of virulent R.equi contamination on farms, feces should be regularly removed from stalls, pens, paddocks and composted. (Barton 1991).
Isolation of affected foals may be of some benefit in reducing the infective challenge of virulent R.equi.