Version May 2024
INTRODUCTION — Rhodococcus equi has been recognized as an animal pathogen since its original isolation as Corynebacterium equi in 1923 from foals with pneumonia. Foals less than six months old are uniquely susceptible to the development of a chronic suppurative bronchopneumonia that can lead to lung and bronchial lymph node abscesses, sometimes called "rattles" [1]. Ulcerative colitis and mesenteric adenitis may also occur, usually associated with pulmonary infection. In swine, R. equi is commonly isolated from the lymph nodes of animals with submaxillary adenitis. The organism can rarely cause pulmonary and extrapulmonary abscesses, wound infections, and lymphadenitis in other animals, primarily rooting and grazing mammals. However, when hosts other than foals and swine develop R. equi infections, they are frequently immunocompromised [2].
The first case of human infection was reported in 1967 [3]; only 12 additional cases were reported in the next 15 years [4]. While still rare, R. equi has been isolated increasingly, especially as an opportunistic pathogen. Most human infections have been associated with immune system dysfunction, and a dramatic increase occurred in the setting of human immunodeficiency virus (HIV) infection [5-14]. In addition, improved laboratory identification of infections has led to increasing recognition of R. equi as a pathogen in both immunocompromised and normal hosts.
The microbiology, pathogenesis, and epidemiology of R. equi infections will be reviewed here. The clinical manifestations, diagnosis, treatment, and prevention of these infections are discussed separately. (See "Clinical features, diagnosis, therapy, and prevention of Rhodococcus equi infections".)
MICROBIOLOGY — R. equi was originally named Corynebacterium equi in 1923 based upon its morphologic appearance. Subsequently, the cell wall composition and biochemical reactions were found to be more closely related to Nocardia and mycobacteria than corynebacteria; in 1980, the organism was reclassified in the genus Rhodococcus. (See "Nocardia infections: Clinical microbiology and pathogenesis" and "Tuberculosis: Natural history, microbiology, and pathogenesis".)
While there are more than a dozen Rhodococcus species, R. equi is the one most often described in human disease, with rare cases reported with other species such as Rhodococcus rhodochrous, Rhodococcus fascians, Rhodococcus erythropolis, and Rhodococcus defluvii [15].
Part of the phylogenetic group of nocardioform actinomycetes, within the genus Actinobacteria, Rhodococcus is characterized in part by rod-to-coccus growth cycle variation and the presence of tuberculostearic acid and cell wall mycolic acids [2]. Little is known about the pathogenic potential of rhodococci other than R. equi. Some have been isolated from granulomatous lesions in humans [2], but reports of disease are rare.
R. equi is easily cultivated on ordinary nonselective media when incubated aerobically at 37°C. Large, smooth, irregular, highly mucoid colonies develop by 48 hours. Although named for its production of red pigment, cultures less than four days old rarely appear pigmented. After four to seven days of incubation, colonies usually develop a delicate salmon pink color, although they may also be nonpigmented or slightly yellow (picture 1).
Pleomorphism characterizes this gram-positive organism. On solid media and in clinical specimens, it typically appears coccoid, but in liquid media, particularly in young cultures, it forms long rods or short filaments, at times with rudimentary branching [2]. The organisms can be acid fast with the Ziehl-Neelsen stain, but this is not a constant feature and is related to the age of the culture and the growth media. Growth on Lowenstein-Jensen agar, one medium used to isolate mycobacteria, may promote acid-fastness.
R. equi is non-carbohydrate fermenting (distinguishing it from pathogenic corynebacteria), gelatinase-negative, catalase positive, usually urease positive, and oxidase negative. So-called equi factors are elaborated that interact with the products of other organisms, including the beta toxin of Staphylococcus aureus, to produce hemolysis. Lipase and phosphatase are produced, but not DNase, elastase, or protease [16]. At least 27 different polysaccharide capsular serotypes have been identified, but no relationship between serotype and virulence has been reported [17].
In the modern microbiology laboratory, a commercially available panel of biochemical tests (API [RAPID] CORYNE) can be employed to easily identify R. equi. This panel should be applied to isolates with the typical colony characteristics and Gram stain morphology or R. equi. It is crucial for the laboratory to perform these tests in order to recognize the pathogenic potential of such isolates, and not to discount them automatically as contaminants [18].
Matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry identification has also been found to be a rapid and accurate system for identification of Rhodococcus. In one study, the correlation between API and MALDI-TOF results was 91 percent (10/11), with MALDI-TOF identifying one isolate as Dietzia maris (a closely related pathogen that is even more rare in humans), which was confirmed by 16S rRNA gene sequencing [19]. Another group found that 8 of 15 clinical isolates presumptively identified as R. equi by API (RAPID) CORYNE actually belonged to the genus Dietzia when 16S rRNA gene sequencing was used [20], although others found that 16S rRNA gene sequencing is not always able to differentiate all Rhodococcus species [21].
ANIMAL/ENVIRONMENTAL RESERVOIRS — R. equi is a soil organism carried in the gut of many herbivores and widespread in their environment, throughout much of the world. In one report, it was isolated from 54 percent of soil sites examined in Australia, including 18 of 19 horse farms [22]. Most isolates were from areas where animals had grazed. R. equi was isolated from gut contents or dung of all herbivores examined that grazed in those areas, but from none that were penned and unable to graze. On horse farms, progressive environmental contamination with R. equi has been related to the length of time that animals were present. The highest numbers of organisms have been found in the surface soil on horse farms with endemic disease. The number of organisms isolated from the air increased with warmer temperatures and was highest on dry and windy days. The simple nutrient growth requirements of R. equi are met completely by horse manure. Thus, the organism appears to thrive in the interaction between grazing herbivores and their environment.
Reports of disease in animals other than horses, such as cats and dogs, are rare and often extrapulmonary. A small series in dogs suggested that R. equi was more common in immunocompromised animals and reported a range of clinical disease from cutaneous to ophthalmologic to disseminated [23].
TRANSMISSION — Exposure to soil contaminated with herbivore manure is likely the major route of acquisition for both animal and human infection. Contact with farm animals or manure has been reported in 32 to 50 percent of cases [9,12]. Considering that this epidemiologic information is not often sought or reported, the true percentage may be even higher.
The presentation of R. equi infections either as pneumonia or as disease associated with the gastrointestinal tract without pulmonary involvement suggests that humans and animals can acquire infection by either inhalation or ingestion of contaminated material. Airborne dust particles are the likely vehicle for human lung infections [24], which are the most common site of infection in humans. Human and animal infection can also be acquired by traumatic inoculation or superinfection of wounds. (See "Clinical features, diagnosis, therapy, and prevention of Rhodococcus equi infections", section on 'Clinical features'.)
A survey of Australian farms found that the prevalence of R. equi pneumonia in foals was associated with the airborne burden of virulent R. equi, both the concentration as well as the proportion of R. equi bacteria that were virulent; however, it was not associated with the burden of virulent R. equi in the soil [25]. Thus, reducing the exposure of susceptible foals to airborne virulent R. equi might be the best way to reduce the rate of R. equi pneumonia. In a study of 30 horse breeding farms in central Kentucky, there were higher airborne rates of virulent Rhodococcus in stalls versus paddocks and in the winter versus summer months [26]; these findings may be helpful to inform infection control measures.
PATHOGENESIS — Induction of R. equi infection has been studied primarily in the foal, its major natural host, and in murine models. Many of the findings in animals may be applicable to the pathogenesis of human infection.
Virulence — The pathogenic potential of R. equi results from its ability to persist in and destroy macrophages [2]. The organism appears to evade killing by interfering with phagosome-lysosome fusion; induction of nonspecific lysosome degranulation may be the means by which infected macrophages and surrounding tissues are destroyed [27].
Variation in the virulence of R. equi isolates has been demonstrated in experimentally infected mice and foals; clinical isolates are usually more pathogenic than environmental isolates [28]. However, assays of extracellular enzyme production by clinical and environmental isolates reveal no clear differences [16]. The ability of different serotypes to resist clearance from the lung and spleen and to evade phagocytosis and intracellular killing by peritoneal macrophages is associated with virulence in murine models [29,30].
The presence of various Rhodococcus virulence-associated plasmid (vap) genes helps determine their pathogenicity. Understanding the role and epidemiology of various vap genes is an emerging topic in R. equi virulence. Strains are classified based on the presence of large plasmid encoding genes for either virulence-associated protein A (VapA, virulent) or B (VapB, intermediately virulent); strains that lack either of these plasmids are classified as avirulent. However, in one series of patients with HIV, virulence plasmids were not detected in over half of isolates [31]. A novel host-adapted linear virulence plasmid (pVAPN) encoding virulence- associated protein N (VapN) has been characterized in bovine isolates [32], companion animals [23], and humans [33]. When 65 R. equi isolates from human infections in different countries collected from 1984 to 2002 were screened for virulence plasmids, of the 37 isolates with plasmids, 43 percent were vapN-positive, 30 percent were vapB-positive, and 16 percent vapA-positive [33].
Histopathology — Defective intracellular processing of R. equi leads to a characteristic histopathologic pattern in clinical specimens, such that the coccobacilli of R. equi stain positive in both Gram and Fite acid-fast preparations.
Granulomatous reaction — The typical appearance is a necrotizing granulomatous reaction dominated by macrophages filled with granular cytoplasm that is periodic acid Schiff (PAS) stain-positive and may contain large numbers of gram-positive coccobacillary forms [10]. Pathologic change elicited by R. equi resembles that of other members of the Corynebacterium-Mycobacterium-Nocardia group, which share lipid-rich cell wall components. The chronic cavitary pneumonia sometimes seen with Rhodococcus may mimic tuberculosis and nocardiosis [34,35].
Malacoplakia — R. equi pulmonary and extrapulmonary infections of humans also have been associated with an unusual chronic granulomatous inflammation called malacoplakia [10,36]. Malacoplakia most commonly involves the genitourinary tract, but many other sites have been reported, particularly in immunocompromised hosts. In addition, pseudotumors can occasionally be seen [37], including mimicking a lung neoplasm in a lung transplant recipient [38]. In a report of five patients with pulmonary nodules clinically suspicious for lung cancer, the histology was compatible with malacoplakia and R. equi was identified in all cases by 16S rRNA gene sequence analysis [39].
Malacoplakia is characterized by aggregates of PAS positive histiocytes containing lamellated iron and calcium inclusions named Michaelis-Gutmann bodies. These structures are believed to result from incomplete intracellular digestion of engulfed bacteria by macrophages. Residual intralysosomal debris acts as a nidus for mineralization and leads to the development of complex lysosomal bodies demonstrable by Prussian blue (iron) and von Kossa (calcium) stains. Although this pathologic response is not pathognomonic of R. equi infection, since it can be observed in infections caused by coliform bacteria and occasionally mycobacteria, the association with R. equi is strong.
Other findings — R. equi infection rarely produces a pathologic appearance that resembles Whipple's disease. (See "Whipple's disease".)
An infection mimicking Whipple's disease has been observed in AIDS patients, most commonly due to Mycobacterium avium complex (MAC), but several cases have also been associated with R. equi lung infection [10]. Analysis of 16S ribosomal RNA sequences has shown that the Whipple's disease bacillus (Tropheryma whipplei) and R. equi are both actinomycetes although only distantly related [40]. Histologic features of Whipple's disease parallel those of R. equi enteritis in foals.
IMMUNE RESPONSE — Some herbivores have asymptomatic carriage of R. equi in their gastrointestinal tracts but do not appear to be susceptible to infection with the organism. Infection in some humans with normal immunologic function may arise from a similar route. Several cases illustrate a potential for the organism to disseminate to regional lymph nodes in immunocompetent individuals and to persist. As examples:
●An asymptomatic woman had mesenteric adenitis with R. equi noted incidentally at laparotomy [41].
●A man with alcohol use disorder developed R. equi peritonitis during an episode of hepatic decompensation; the organism was found in mesenteric nodes [42].
Manifestations of R. equi infection in immunocompromised humans resemble those in foals. Most knowledge about immune responses to R. equi infection comes from animal research. Both humoral and cell-mediated immunity (CMI) appear important [2].
Humoral immunity — Antibodies to R. equi are widespread in the mature horse population. Maternal antibody from colostrum declines to its lowest levels at eight weeks of age in foals; those with low levels are particularly susceptible to naturally-induced R. equi pneumonia [43]. Antibodies can be induced by subcutaneous or intranasal inoculation of the organism in horses, and plasma from immunized horses dramatically lessens the severity of disease in foals [44].
Cell-mediated immunity — Because of its intracellular location and the propensity for infection to occur in HIV-infected individuals, CMI mechanisms are thought to be a major means of defense against R. equi. Delayed-type hypersensitivity reactions are widespread in horses demonstrating ubiquitous exposure to R. equi. Experimental equine infections can induce such immune responses as well [45].
Euthymic mice treated with antibodies to either interferon gamma or tumor necrosis factor-(TNF) alpha had higher colony counts of R. equi in tissues compared to untreated animals in a model where the organism was injected intravenously [46]. This experiment suggests that both T cell- and macrophage-secreted cytokines play a role in a CMI response.
In humans, most R. equi infections have been associated with profound impairment of CMI, predominantly AIDS with CD4 lymphocyte counts below 200/microL [14].
Highly active antiretroviral therapy (HAART) may improve prognosis; one study showed that mortality in R. equi-infected HIV patients was reduced in the HAART era (8 percent) compared with the pre-HAART era (56 percent; p<0.0001) [47]. Other immunocompromised hosts at risk include those with lymphoproliferative malignancies and solid organ transplants, primarily reported in kidney transplant recipients [48-51]. Most immunocompromised hosts without HIV infection who develop R. equi infections also have been taking immunosuppressive therapy, either steroids and/or cytotoxic agents.
Interactions between cell-mediated and humoral immune responses — Interactions between cell-mediated and humoral immunity have been revealed by in vitro studies of macrophage killing of R. equi. In athymic mice, transfer of spleen cells from mice previously immunized with live bacteria protected against R. equi infection, while passive transfer of immune serum from such mice [52]. However, in vitro killing by macrophages was enhanced by exposure to supernatants from lymphocyte cultures stimulated with R. equi antigens. Phagosome-lysosome fusion within macrophages was markedly increased with opsonized compared to non-opsonized bacteria. The combination of specific antibody and activated macrophages resulted in complete killing by incubated macrophages in vitro [53].
A possible expression of this dual role of cell-mediated and humoral immune function may be found in AIDS patients. Despite cellular immunosuppression, some AIDS patients with R. equi pneumonia can develop antibodies to the organism; the magnitude of this antibody response may correlate with a potential for recovery [54].
SUMMARY AND RECOMMENDATIONS
●Rhodococcus equi has been recognized as an animal pathogen since its original isolation in 1923 from foals with pneumonia. R. equi only rarely causes human infections. (See 'Introduction' above.)
●R. equi is easily cultivated on ordinary nonselective media when incubated aerobically at 37ºC. Large, smooth, highly mucoid colonies develop by 48 hours. After four to seven days of incubation, colonies usually develop a salmon pink color. (See 'Microbiology' above.)
●R. equi is widespread in the environment, including soil and the gut of many herbivores. It is likely that humans and animals acquire infection by either inhalation or ingestion of contaminated liquids or solids. Human and animal infection can also be acquired by traumatic inoculation or superinfection of wounds. (See 'Animal/Environmental Reservoirs' above and 'Transmission' above.)
●The pathogenic potential of R. equi results from its ability to persist within and destroy macrophages. The organism evades killing by interfering with phagosome-lysosome fusion. Nonspecific lysosome degranulation leads to destruction of infected macrophages and the surrounding tissues. (See 'Virulence' above.)
●The typical histologic appearance of R. equi infection includes a necrotizing granulomatous reaction dominated by macrophages filled with granular cytoplasm. Periodic acid Schiff (PAS) staining may demonstrate large numbers of gram-positive coccobacillary forms, representative of the organism. (See 'Histopathology' above.)
●Histologically, R. equi pulmonary and extrapulmonary infections have been associated with an unusual chronic granulomatous inflammation called "malacoplakia," characterized by aggregates of PAS-positive histiocytes containing lamellated iron and calcium inclusions. These structures may result from incomplete intracellular digestion of engulfed bacteria by macrophages. (See 'Malacoplakia' above.)
●In humans, most R. equi infections have been associated with profound impairment of cell-mediated immunity, as seen in patients with AIDS, lymphoproliferative malignancies, and solid organ transplant recipients taking immunosuppressive therapy. (See 'Cell-mediated immunity' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Leonard Slater, MD, who contributed to an earlier version of this topic review.
آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟
