Rhodococcus equi is a soil saprophytic, Gram-positive, intracellular bacteria and one of the most common causes of pneumonia in foals worldwide. The bacteria are ubiquitous and can be cultured from the environment of virtually all horse farms. However, the prevalence of clinical disease varies from endemic on some farms to sporadic or unseen on others.
Bronchopneumonia is the most common clinical manifestation of R.equi in foals aged between 1 and 6 months. Disease in adult horses has been described, although this is limited to cases with severe underlying immunodeficiency. Similarly, R.equi infection has also been reported in immunodeficient humans, for example those with HIV or those undergoing chemotherapy for cancer. In addition to pneumonia, R.equi can also result in infections in other body systems, for example bone infection, ocular disease, diarrhoea and abdominal abscesses. On farms where the disease is endemic, costs associated with treatment and foal losses can be substantial. This article provides an update on the epidemiology, diagnosis and treatment of R.equi, in addition to current strategies for the prevention of disease.
Epidemiology
R.equi is commonly found in the faeces of adult horses and is therefore impossible to eliminate from the environment of mares and foals. Despite the widespread presence of R.equi in the environment, disease prevalence not only varies from region to region and farm to farm, but also from year to year. The reasons for this variation of disease incidence are not well understood.
The major route of infection is by inhalation of a dust aerosol into the foal's respiratory tract. Factors contributing to aerosolisation of R.equi, such as dry climate and the density of mares and foals in paddock, are associated with higher airborne concentration of R.equi and to higher infection rates (Muscatello et al, 2006). In contrast, soil concentrations of R.equi and poor hygiene and management practices are not reported to play a role (Cohen et al, 2005, 2008). Such studies have provided an insight into factors contributing to the incidence of disease, although it is clear that other factors have yet to be identified.
Clinical disease in foals typically develops from around 1 month of age, but some evidece suggests that exposure to infection happens shortly after birth, likely as a result of natural exposure to a naïve or immature immune system (Cohen et al, 2013). The disease then develops very slowly over weeks or months, and foals can have well established pathology by the time clinical signs are evident. While it is likely that all foals are exposed to R.equi, only some develop clinical signs. At present, there is limited evidence regarding foal risk factors, although those suggested include differences in pathogen exposure, innate and adaptive immune responses and genetic differences (McQueen et al, 2015). Further studies are needed to better understand these factors and how they impact the outcome of R.equi infection.
The virulence of the individual strain of bacteria is known to play an important role in the development of clinical disease. The vapA gene is a key factor in intracellular survival in equine alveolar macrophages and is central to the development of disease. However, vapA expression alone is not sufficient to allow intracellular growth and it has recently been discovered that additional plasmid encoded genes (virR and virS) also play a role (Coulson et al, 2015).
Diagnosis
Bronchopneumonia is the most common clinical manifestation of R.equi in foals aged 1–6 months old (Giguère et al, 2011). Common presenting signs include fever, cough, increased respiratory rate and effort, and abnormal tracheal and lung sounds on auscultation. Mucopurulent nasal discharge may be apparent in some cases but this is not a consistent finding. Progression of clinical disease is insidious and disease may be extensive before clinical signs are evident. In addition to pneumonia, foals may also present with extrapulmonary signs of infection. The presenting clinical signs depend on the body system involved, but can include diarrhoea, lameness, joint swelling or uveitis. In some cases, ill thrift and poor weight gain may be all that is apparent. Where R.equi infection is suspected, close monitoring of extrapulmonary sites should be performed. In some cases, multiple sites may be involved and the presence of an extrapulmonary disorder is associated with a poorer outcome (Reuss et al, 2009).
Diagnosis is not made with one single diagnostic test alone, but instead based on clinical presentation, findings on diagnostic imaging and laboratory testing. Definitive diagnosis of pneumonia caused by R.equi should be based on confirmation of the infectious agent (either by bacterial culture or polymerase chain reaction detection of the vapA gene) from a tracheobronchial aspirate obtained from a foal with evidence of clinical disease. Clinical disease may be demonstrated by one or more of the following:
- Clinical signs of lower respiratory tract disease
- Cytological evidence of septic airway inflammation
- Radiographic or ultrasonographic evidence of bronchopneumonia (Giguère et al, 2011).
Ideally, bacterial culture should be performed alongside polymerase chain reaction testing, as this will allow identification of other bacterial pathogens and provide information on sensitivity.
Clinical findings alone are not pathognomonic, therefore the above diagnostic criteria are recommended to establish a definitive diagnosis. Other causes of infectious pneumonia, for example Streptococcus zooepidemicus, can present in the same way and incorrect diagnostic approaches may lead to inappropriate treatment, particularly on non-endemic farms. It is also worth noting that foals can be positive for R.equi on tracheobronchial aspirate samples as a result of subclinical infection or inhalation of the pathogen that does not lead to clinical disease, highlighting the importance of interpreting these findings alongside other diagnostic criteria. However, on farms with confirmed endemic R.equi, it is common practice to make a presumptive diagnosis based on clinical signs and ultrasound alone. Furthermore, in foals presenting with signs of respiratory distress, performing more invasive diagnostics such as an endoscopy and tracheobronchial aspirate may be contraindicated, so a presumptive diagnosis is often used in these situations.
Ultrasound is the most commonly used technique to evaluate R.equi pneumonia in foals. It is non-invasive and relatively fast to perform. Findings include comet tails (indicating fluid or cellular infiltration of the pleural surface) and focal areas of consolidation or abscessation. This technique is sensitive enough for the detection of peripheral lung abscesses or consolidation, although deeper lesions may be missed.
In foals presenting with clinical signs, blood evaluation is usually performed and will typically demonstrate evidence of infection, such as increased fibrinogen, serum amyloid A and white blood cell count. Although these are useful to the overall evaluation of the foal, these are not considered to be sensitive or specific enough to R.equi and are therefore not useful as a single diagnostic tool. Similarly, studies evaluating the performance of serological tests have demonstrated poor sensitivity and specificity for the diagnosis of R.equi pneumonia (Martens et al, 2002; Giguère et al, 2003; Phumoonna et al, 2006).
Treatment
A variety of antimicrobials have been shown to be effective against R.equi in vivo. However, owing to the intracellular nature of the pathogen, not all are effective in vitro. A combination of rifampicin and a macrolide (clarithromycin or azithromycin) has been shown to be effective in foals infected with susceptible strains and has thus been the treatment of choice for many years (Giguère et al, 2011). While they are effective, these drugs do carry the risk of side effects. The most common side effects of macrolides are diarrhea and hyperthermia, with this being especially apparent in older foals in warmer climates or seasons (Stieler et al, 2016; Wetzig et al, 2020). It has been suggested that mares of foals being treated with these oral antimicrobials may be at risk of developing diarrhoea (Baverud et al, 1998). Although these cases are infrequent, diarrhoea can be severe and in some cases even fatal. This appears to be less of a problem with the newer generation macrolides, but measures to prevent accidental ingestion by the mares should be taken.
Monotherapy of longer acting macrolides has been evaluated in foals because of the convenience of less frequent dosing, which may improve owner compliance. Tulathromycin was not found to be more effective than a placebo in one study (Venner et al, 2013a). Another study evaluated the combination of tulathromycin and rifampicin and reported that this was associated with less treatment failures than the combination of azithromycin and rifampin (Arnold-Lehna et al, 2019). The use of a once weekly intramuscular injection of gamithromycin for the treatment of R.equi has also been evaluated (Berghaus et al, 2012). This was found to maintain bronchoalveolar lavage cell concentrations above the minimum inhibitory concentration of R.equi for 7 days and was non-inferior to azithromycin-rifampin for the treatment of mild to moderate bronchopneumonia (Hildebrand et al, 2015). Although treatment was effective, a high percentage of foals were reported to show side effects, including colic and moderate to severe lameness that resolved over a 72-hour period (Hildebrand et al, 2015). Investigations into alternative drug choices continue, although treatment with rifampicin and a macrolide remains the current recommendation.
Widespread use of antimicrobials has led to the emergence of resistant R.equi strains that are no longer susceptible to these commonly used medications (Giguère et al, 2010; Burton et al, 2013; Erol et al, 2020). The appearance of these resistant strains of R.equi has highlighted the need to critically review the way in which the current antimicrobials are used (Bordin et al, 2022). In particular, the need for widespread treatment of foals that are not suffering from severe forms of disease has been questioned. Over recent years, treatment strategies have been redefined, with the aim of reducing the number of foals that are treated. It is widely accepted that around 70–80% of foals that develop subclinical pneumonia (for example, pulmonary lesions on ultrasound but no clinical signs) recover without treatment (Chaffin et al, 2012; Venner et al, 2012, 2013b; Wetzig et al, 2020).
In addition to antimicrobial therapy, supportive care such as non-steroidal anti-inflammatory medications and gastroprotectants may also be required in foals with R.equi. Efforts should also be made to avoid stress and control temperature, ensuring foals are kept in a cool, shaded area. In more severe cases, hospitalisation and oxygen therapy may be required.
Prevention
Owing to the potential for widespread disease on endemic farms, and the associated costs, there has been growing interest into how to reduce the incidence of disease. The most widely used strategy is the administration of hyperimmune plasma in the first few days of life. Studies have reported conflicting evidence regarding the efficacy of R.equi hyperimmune plasma (Muller and Madigan, 1992; Hurley and Begg, 1995; Higuchi et al, 1999; Hooper-McGrevy et al, 2001; Giguère et al, 2002; Perkins et al, 2002; Caston et al, 2006; Erganis et al, 2014; Bordin et al, 2014, Sanz et al, 2016). Although the reasons for this variability are unclear, effectiveness is likely to be determined by several factors, including the presence of specific antibodies, the timing of antibody administration relative to disease, and the amount of antibodies delivered (Bordin et al, 2022). Despite the fact that protection is incomplete, plasma administration provides the mainstay of prevention on most farms with a history of disease. Plasma transfusions are usually performed shortly after birth to provide protection at the age when foals are most susceptible to R.equi, with some veterinarians performing a second transfusion at 3–4 weeks of age, corresponding to the earliest age of onset of disease for most foals and the point at which maternal antibodies begin to wane. Results of two retrospective studies reported that foals transfused with 2 litres of R.equi hyperimmune plasma shortly after birth were significantly less likely to develop R.equi pneumonia than foals transfused with 1 litre of plasma (Kahn et al, 2019; Flores-Ahlschwede et al, 2021). However, there remains a need for well-designed clinical trials to determine the best protocols regarding the timing and volume of transfusions.
Vaccination ultimately represents the ideal prevention strategy for controlling R.equi pneumonia on farms. Despite intensive investigation, no effective vaccine is yet available, but researchers are making promising steps towards the development of a vaccine to protect foals against R.equi. A major challenge is that during the first weeks of life, when they are most susceptible to infection with R.equi, foals have deficits in both innate and adaptive immune responses that limit effective responses to a vaccine (Sanz et al, 2013). Better understanding of the foals' immune system and the responses required for protection will be essential for developing an effective R.equi vaccine for foals (Bordin et al, 2022).
Screening
The lack of highly effective measures of prevention, in addition to the challenges of early diagnosis, has led to the implementation of screening methods on many horses farms with endemic R.equi. The insidious nature of R.equi means that pathology is generally extensive by the time clinical signs are detected, and advanced disease is associated with poorer prognosis (Giguere and Prescott, 1997). Therefore, the rationale for screening is that earlier detection can reduce mortality and shorten the duration of treatment (Slovis et al, 2005; McCracken and Slovis, 2009).
Various strategies have been suggested, but serial clinical examinations, blood work and ultrasound examinations form the basis of most screening programmes. The widespread implementation of screening has led to the detection of subclinical forms of disease, and has consequently led to the unnecessary treatment of many foals that would likely have resolved spontaneously. The overtreatment of foals with widespread use of antimicrobials has contributed to emerging resistance to macrolides and rifampicin. To date, strong evidence that the use of thoracic screening decreases the prevalence of severe R. equi pneumonia and deaths from R. equi infection is lacking.
It is now well established that most foals with subclinical disease will recover without treatment (Venner et al, 2009, Chaffin et al, 2012; Venner et al, 2013b; Huber et al, 2018; Arnold-Lehna et al, 2020; Wetzig et al, 2020). It has recently been reported that antimicrobial use could be reduced without increasing mortality by increasing the threshold of pulmonary lesion scores from thoracic ultrasound (for example, only treating foals with larger lesions) (Arnold-Lehna et al, 2020). This retrospective study compared management of an initial group, in which the decision to treat was based on the presence of clinical signs and/or sonographic evidence of pulmonary consolidation exceeding 1cm in diameter, to a second group, in which the decision to treat was based on the presence of clinical signs, in addition to a minimum abscess score of 8cm (this minimum abscess score increased over time to >15cm based on the results of concurrent studies) (Arnold-Lehna et al, 2020). The study concluded that selective treatment of foals with more extensive pulmonary lesions significantly decreased antimicrobial usage, without increasing the mortality rate. Strategies such as this are required to help reduce antimicrobial use and decrease the pressure of antimicrobial resistance, without compromising foal health.
Conclusions
R.equi remains an important cause of pneumonia in foals around the world and has a significant impact on the horse breeding industry worldwide. There is a great need to better understand the factors underlying why some foals or farms are more affected than others, and to identify management practices that can reduce the incidence of disease. It is now widely accepted that many foals will recover without the need for antimicrobial therapy and the treatment of subclinical cases should be avoided, although close monitoring is required to ensure deterioration does not occur. Strategies are required to help identify the foals that require treatment, in order to reduce antimicrobial use without impacting foal health. Currently, highly effective methods for the prevention of R.equi are lacking. Administration of hyperimmune plasma is the mainstay of prevention on most farms, but this does not prevent disease in all cases. Promising steps are being made towards the development of a vaccine to prevent R.equi, which is much needed by the global breeding industry.
KEY POINTS
- R.equi is one of the most common causes of pneumonia in foals and is ubiquitous on horse farms worldwide, although disease prevalence varies greatly between farms and individual foals.
- Although some risk factors have been identified, the reasons for this variation of disease remain poorly understood.
- A combination of rifampicin and a macrolide (clarithromycin or azithromycin) is the treatment of choice in most foals, but widespread use has led to the emergence of resistant R.equi strains that are no longer susceptible to these medications.
- Screening is commonly used on endemic farms to identify foals with subclinical disease. It is now widely accepted that many foals will recover without the need for antimicrobial therapy, therefore more targeted treatment strategies are required.
- Administration of hyperimmune plasma is the mainstay of prevention on most farms, but highly effective methods of prevention are lacking.