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The increasing recognition of rickettsial pathogens in dogs and people
Review
Special Issue: Zoonoses of people and pets in the USA
The increasing recognition of rickettsial pathogens in dogs and people William L. Nicholson1, Kelly E. Allen2, Jennifer H. McQuiston1, Edward B. Breitschwerdt3 and Susan E. Little2 1
Division of Viral and Rickettsial Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, OK 74078, USA 3 College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27606, USA 2
Dogs and people are exposed to and susceptible to infection by many of the same tick-borne bacterial pathogens in the order Rickettsiales, including Anaplasma phagocytophilum, Ehrlichia canis, E. chaffeensis, E. ewingii, Rickettsia rickettsii, R. conorii, and other spotted fever group rickettsiae. Recent findings include descriptions of novel Ehrlichia and Rickettsia species, recognition of the occurrence and clinical significance of co-infection, and increasing awareness of Rhipicephalus sanguineus-associated diseases. Newer molecular assays are available, although renewed efforts to encourage their use are needed. This review highlights the ecology and epidemiology of these diseases, and proposes avenues for future investigation. Epidemiology of tick-borne rickettsial pathogens Humans are susceptible to many tick-borne rickettsial pathogens, including Anaplasma phagocytophilum, which causes human anaplasmosis; Ehrlichia canis, E. chaffeensis, and E. ewingii that induce different forms of ehrlichiosis; Rickettsia rickettsii, the agent of Rocky Mountain spotted fever (RMSF); R. conorii, the cause of Mediterranean spotted fever; and other recently recognized spotted fever group rickettsiae. With the exception of E. canis and perhaps E. ewingii, dogs are not considered a primary reservoir host for these pathogens. Rather, dogs, like people, are incidental hosts and can become infected through the bite of an ixodid tick (Acari: Ixodidae). Ehrlichia and Anaplasma species are transmitted through the bite of an infected nymphal or adult tick vector that had been previously infected in the larval or nymphal stage while feeding on a rickettsemic animal (usually wildlife) known as a reservoir host. In the case of R. rickettsii and other spotted fever group rickettsiae, transfer of the infection from adult female to her eggs (transovarial transmission) supports infection of larval ticks, which is maintained past molting in the subsequent stages. Dogs are frequently exposed to ticks, and evidence of current or past infection in dogs can be used to determine whether there is a risk of infection with rickettsial tick-borne disCorresponding author: Nicholson, W.L. ([email protected])
ease agents in a given geographic area [1–4]. All tick-borne pathogens are distributed focally within the ecologic landscape. Therefore documentation of infection in a dog, which presumably is more often in contact with ticks than humans, should prompt veterinary professionals to warn owners of an increased risk of tick-borne disease. The global distribution of tick-borne rickettsial pathogens varies according to the density and distribution of the predominant tick vectors and the population density of reservoir hosts [5–9]. For example, anaplasmosis is more common in the northeastern, upper midwestern, and western coastal states (Figure 1a) where dense populations of certain Ixodes spp. ticks maintain a reservoir of A. phagocytophilum in nature [4,8]. Ehrlichiosis due to E. chaffeensis and E. canis, which are transmitted primarily by Amblyomma americanum and R. sanguineus, respectively, are more common in the southern USA (Figure 1b) and disease distribution in humans and animals correlates with the distribution of those vector ticks [4,7,8]. RMSF, most often transmitted by Dermacentor ticks, is most commonly reported from southcentral and Mid-Atlantic states, although a recent focus of infection was identified in the southwestern USA [9,10,12], where a new vector was identified. Expansions in tick populations can introduce rickettsial agents to new geographic areas [4,10], and novel rickettsiae and vector–pathogen relationships continue to be described [14]. Because of the growing importance of these pathogens worldwide, a two-day summit among leading tick-borne disease researchers in veterinary medicine and public health was facilitated by the Companion Animal Parasite Council (CAPC) and the Centers for Disease Control and Prevention (CDC). This review focuses on the tick-borne rickettsial diseases most commonly recognized in people and dogs in the USA: anaplasmosis, ehrlichiosis and RMSF. Ecology of tick-borne pathogens affecting dogs and people Granulocytic anaplasmosis Anaplasma phagocytophilum is transmitted by Ixodes spp. ticks [15]. In North America, I. scapularis and I. pacificus
1471-4922/$ – see front matter . Published by Elsevier Ltd. doi:10.1016/j.pt.2010.01.007 Available online 6 March 2010
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Figure 1. One means of determining the distribution of rickettsial pathogens in a geographical area is to conduct serosurveys of domestic pets presenting to veterinarians. In these figures, we can begin to understand the distribution in dogs from throughout the USA of antibodies to Anaplasma species (a) and Ehrlichia species (b). It is important to note that this is representative of canine seroprevalence and that infections of tick, human, and wildlife species are not included. However, these are the largest serosurveys ever conducted for rickettsial agents. Reprinted, with permission, from Ref. [4].
are considered the most important vectors and sigmodontine rodents are considered the primary reservoir hosts, although a large variety of mammals are susceptible to infection and can play a supplementary role in maintaining a source of infected ticks (Figure 2a) [16]. Globally, a number of Ixodes spp. are the primary vectors and additional rodent and ruminant species serve as reservoirs. Several genetic variants of A. phagocytophilum have been described based on molecular subtyping, yet only one (Ap-ha) appears to be associated with disease in people and dogs in North America [16–18]. In dogs, disease caused by infection with A. phagocytophilum is typically characterized by acute onset of fever, depression, myalgia, anorexia, lameness and reduced platelets [8,19]. In people, A. phagocytophilum infection is characterized by fever, headache, lethargy, myalgia, elev206
ated liver function enzymes and reduced platelets. Human fatalities can occur, although reportedly in <1% of cases, and, usually in association with other opportunistic infections [15,16]. Because A. phagocytophilum is maintained largely in a vector–reservoir–host system similar to that of Borrelia burgdorferi, the geographic distribution of cases of granulocytic anaplasmosis in North America parallels that of Lyme borreliosis, with most confirmed cases reported from the Northeast, upper Midwest and along the West Coast [20,21]. In the largest serosurvey conducted to date, dogs with antibodies induced against Anaplasma species (either A. phagocytophilum or A. platys) were seen most commonly in the midwestern (6.7% of dogs tested were positive) and northeastern (5.5%) portions of the USA, as well as in California (4.8%) (Figure 1a). In some individual counties
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Figure 2. Transmission cycles responsible for maintaining rickettsial pathogens in tick populations and allowing infection of people and dogs. Transmission cycle for maintenance of Anaplasma phagocytophilum (a). The pathogen is acquired from sigmodontine rodents or other reservoir hosts during feeding by larval or nymphal Ixodes spp. ticks and then transmitted in subsequent feedings of nymphal or adult ticks. Transmission cycle for maintenance of Ehrlichia chaffeensis (b). By contrast to the Ixodes spp. vectors of A. phagocytophilum, in which only adults feed on deer, all three stages of Amblyomma americanum, the primary tick vector of E. chaffeensis, feed on deer as a preferred host. Infection with E. chaffeensis is acquired during feeding of larval or nymphal A. americanum on deer and then transmitted upon subsequent feeding of nymphs or adults. Transmission cycle for maintenance of Rickettsia rickettsii (c). Dermacentor spp. ticks acquire R. rickettsii upon feeding, as larvae or nymphs, on rodents; they then transmit during subsequent feeding as nymphs or adults. In addition, R. rickettsii infection can be maintained transovarially in Dermacentor ticks, resulting in some larvae hatching from the egg mass already harboring an infection.
in these regions, over 60% of all dogs tested had antibodies to Anaplasma species [4]. Anaplasma platys has long been known to infect dogs, and to cause febrile illness and canine cyclic thrombocytopenia. The ability of A. platys to infect humans has been questioned, although morphologically-compatible organisms have been identified in platelets from humans with apparent anaplasmosis [22]. Ehrlichiosis Several species in the genus Ehrlichia infect and cause disease in both dogs and people [15,21]. Infection by E. canis causes the most severe disease in dogs and can result in fever, myalgia, depression, reduced white cells and reduced platelets. which may lead to bleeding disorders, particularly nosebleeds. Although apparently rare, ehrlichiosis in humans due to E. canis infection has been reported from Venezuela [23]. Dogs and wild canids are
the natural hosts of both E. canis and its primary vector tick, R. sanguineus. Interestingly, E. canis can sometimes be transmitted by Dermacentor variabilis [24]. Human infection by E. chaffeensis causes a potentially severe ehrlichial disease; acute infections result in a moderate to severe illness characterized by fever, headache, lethargy, myalgia, reduced sodium levels, reduced platelets and elevated liver enzymes. Patients are often hospitalized and infections can be fatal in up to 3% of cases [15]. White-tailed deer (Odocoileus virginianus) are considered the primary reservoir hosts for E. chaffeensis, and A. americanum ticks are the predominant vectors to both humans and animals (Figure 2b) [25]. Natural infection of coyotes is common in Oklahoma [26]. Canine infections are subclinical or mild [7,27]. Although both E. canis in dogs and E. chaffeensis in people occur predominately in the southern USA, infections have been reported throughout the country and on five continents [7,28,29]. 207
Review In a large serosurvey conducted in the USA, antibodies to Ehrlichia species, which may have been induced by exposure to either E. canis or E. chaffeensis, were more common in the southern states than in the rest of the country (1.3% versus 0.6%, respectively) (Figure 1b). Indeed, individual counties were identified where 15% of dogs tested positive, a prevalence that is 25-fold greater than the national (USA) prevalence of 0.6% [4]. Molecular surveys of dogs suggest that E. ewingii infection can be more prevalent than E. canis in certain endemic areas [30]. Ehrlichia canis was first isolated and molecularly characterized from asymptomatic humans in Venezuela in 1996, but its role as a pathogen was not immediately recognized. In 2006, further efforts resulted in isolation of E. canis from human patients with clinical findings compatible with ehrlichiosis [23]. This pathogen must now be considered in compatible human illness in endemic areas, especially when high PCR prevalence has been found in dogs from those areas [31]. Infection with E. ewingii generally results in mild to moderate febrile disease in dogs and in people [32], although many dogs may harbor subclinical infections. While generally considered to induce a milder form of disease than E. canis or E. chaffeensis in dogs or people, respectively, anemia, thrombocytopenia, polyarthritis and neurological sequelae have been reported. The most important reservoir host of E. ewingii has not been conclusively determined, but both dogs and deer are considered prime candidates [30,33]. In the USA, A. americanum is considered the most important vector of E. ewingii, although this organism has also been detected in D. variabilis and R. sanguineus [7,34,35]. Accordingly, granulocytic ehrlichiosis caused by E. ewingii is more common in both dogs and people in the southern USA, where lone star tick populations are high and feed readily on both hosts [7]. Deer and dogs are also susceptible to both natural and experimental infection with E. ewingii. In more recent years, E. ewingii has been found in additional countries of the world [36,37]. Spotted fever group rickettsiae Infection with R. rickettsii, the causative agent of RMSF, induces an extremely severe, potentially fatal disease in people and in dogs. Indeed, among the tick-borne diseases in the Americas, RMSF is the most severe, and can result in an acute-onset illness accompanied by a rapid course of disease and a high fatality rate. Mortality rates have been estimated at 20% in people in the absence of appropriate antibiotic treatment and 5% in patients who receive antibiotics [38]. Disease in people initially presents as sudden onset of fever, severe headache and generalized malaise, although patients often also develop myalgia, nausea, vomiting and photophobia. Within two weeks of infection the classic triad of fever, headache and generalized maculopapular rash is present in the majority of patients. The appearance of skin rash is more prevalent as the disease progresses, although some individuals never develop the typical rash [38,39]. Canine patients present with fever, lethargy, vomiting and anorexia. As infection progresses, additional signs can develop in dogs, including ocular lesions, bleeding disorders, joint pain and neurologic 208
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abnormalities [9]. Fatalities can occur in both people and dogs, particularly if appropriate anti-rickettsial treatment is delayed or never instituted [39]. In the USA, infection with R. rickettsii is acquired through the bite of infected D. variabilis or D. andersoni ticks. In Central and South America, A. cajennense has been implicated as the vector to humans and dogs. Recently, R. sanguineus was shown to transmit the pathogen to dogs and to people in Arizona, and there was a recent outbreak in northern Mexico [13,40]. Infected R. sanguineus have been identified in the states of California and Texas, Mexico, and recently in Brazil [41]. Because R. rickettsii is focally distributed in tick populations, dogs can serve as immediate proximal sentinels of infection and disease [42,43]. Several case reports in the literature describe diagnosis of RMSF in dogs associated with and, in some cases, leading to identification of the infection in people in the same household or vicinity [2,42,44]. Infection is transmitted by ticks, rather than directly from infected dogs; however, manual removal of engorged ticks from dogs has been identified as a potential risk factor for human infection [45], and can occur by inoculation of the pathogen onto mucus membranes by contaminated fingers as has been shown with R. conorii. In its natural cycle, R. rickettsii is maintained in persistently infected tick populations and small rodent reservoir hosts (Figure 2c). Transovarial transmission from infected females to eggs and transmission between adults during mating can maintain the infection within the population without additional infectious feedings. The disease is reported throughout the continental USA, Central America and South America. The infection is most commonly identified in males, those from rural areas, and children (5–9 years of age) and older adults (40–64 years of age). Mediterranean spotted fever in humans results from R. conorii infection [46]. The pathogen is transmitted through bites of R. sanguineus or by accidental mucus membrane inoculation of the rickettsiae from crushed ticks. The disease is widely distributed across southern Europe, northern Africa, the Middle East, the Indian subcontinent and Asia. Clinical disease in humans is similar to other spotted fever group rickettsial infections, and is characterized by the development of a lesion with a necrotic center, known as an eschar. Dogs play an important role as biological hosts of the ticks, and serve to increase the infected tick population in close association with human habitation. Seroprevalence of dogs in endemic areas is quite high (26–60%). Dogs are usually subclinically infected, although more overt disease has recently been reported [47]. There are a number of other spotted fever group rickettsial species that have been identified for which dogs may play some role in their ecology. Many of these were identified from ticks that can bite dogs and humans. In some cases, laboratory evidence for canine exposure or infection has been presented. Rickettsia parkeri has only recently been recognized as a pathogen of humans in the USA and possibly Uruguay [48]. The pathogen has been identified in ticks from USA, Uruguay and Brazil [49,50]. Serologic
Review evidence of canine exposure has also been demonstrated in Brazil [49]. Whether dogs become rickettsemic is not known, but they certainly could facilitate transport of infected ticks into the peridomestic environment. Another organism found in R. sanguineus is R. massiliae [14]. It was originally described from France, but has since been identified in several other countries. One genotype of R. massiliae, known as Bar29, has been shown to infect humans [14,51,59]. Additional work is needed to define the importance of these rickettsial organisms in human and animal health. Insights into changing ecology and epidemiology Co-infection Recently, there has been an increased emphasis on the possibility of co-infection by multiple tick-borne pathogens and its effect on transmission, expression of disease, and our ability to treat patients effectively. A recent analysis found that co-infections with A. phagocytophilum and B. burgdorferi occur in ticks at prevalences of 0.1% to 28.1%, and that occurrence was somewhat unpredictable [52]. Evidence of co-infections with these, or other agents, in dogs and in humans has usually been noted in endemic areas where the prevalence of both organisms is high [4,53,54,55]. In a recent, nationwide, serologic survey, 40.8% of dogs tested from one county in Minnesota had antibodies to both A. phagocytophilum and B. burgdorferi [4]. Additional experimental and epidemiological studies are needed to explore further the effects of co-infection on surveillance of rickettsial diseases. New pathogens There has been an increasing number of novel rickettsial organisms described since the advent of molecular detection and characterization [14]. These organisms are often described from amplicons and without cultivation of isolates, so their validity can be questioned. These organisms are often detected in arthropod populations and might not subsequently be transmitted to vertebrate hosts or cause disease in these hosts. Studies are needed to better understand the potential role of dogs in the ecology of these pathogens and to determine the pathogenicity of these microorganisms to pets and their owners. One example is the Panola Mountain Ehrlichia, a genotype genetically grouped with Ehrlichia ruminantium [56]. Both of these organisms have recently been shown to infect humans, albeit infrequently [57,58]. Many other related organisms have been identified globally through molecular assays of ticks that bite humans and their pets; it is anticipated that some of these will be identified as pathogens of people and of dogs. Our changing environment Our concepts of distribution and intensity of tick-borne pathogens are strongly influenced by many factors, including environmental parameters, changing land use, changing human and animal activities, surveillance efforts and diagnostic practices. Changing landscape ecology may result in expansion of numbers of ticks or of their biological hosts, and the consequent expansion of areas of risk to human or animal health. In recent years, much attention
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to the effects of climate change has shown that many tickborne diseases are experiencing a global increase. Several R. sanguineus–associated diseases are being increasingly reported in many parts of the world [59]. As a veterinary parasite, R. sanguineus has long been recognized as a vector for Rickettsia and Ehrlichia species [60]. Over the years, much information has been gained on the intimate role that this tick plays in the epidemiology of Mediterranean spotted fever in humans. Indeed, there is a strong association with dog contact, proximity, tick loads and tick densities in the environment and the subsequent human risk for infection [46]. In all life stages, R. sanguineus prefers to feed on dogs, and reports of human biting are uncommon, although all stages of this tick have been reported from humans [60]. Because of limited human biting, the species has long been discounted as a vector of human rickettsial pathogens in the USA, whereas the species is still recognized elsewhere in the world as a primary vector of rickettsiae to humans. Recently, preliminary studies were reported to indicate that R. sanguineus biting of humans is more frequent as temperature increases [59]. It has also been shown that these ticks can move from one host to another during active feeding [61], which may enhance contact among pathogens, humans and dogs. During investigations of RMSF in the southwestern USA, R. sanguineus was shown to be the only vector to humans [13,40]. High tick numbers in the peridomestic environment and close contact with dogs or tick-infested homesites were associated with human cases. Interestingly, the prevalence of infection in ticks from the peridomestic environment was much greater than the <1% seen in the two Dermacentor species associated with RMSF in other parts of the USA [13]. Thus, although R. sanguineus biting of humans is infrequent, the risk for rickettsial transmission to humans is likely higher than that of a Dermacentor bite. Need for improved diagnostic strategies Diseases caused by tick-borne rickettsial agents can be diagnosed in a number of different ways; each approach has its advantages and its limitations, and the best option(s) will be dictated by both the infection characteristics of the organism(s) suspected to be causing disease and the suspected persistence of infection (for general guidance, see Refs. [38,62–64]). Effective methods include: direct visualization of organisms in stained blood smears, impression smears, or tissue sections; cell culture isolation; PCR assays; and serology [Figure 3]. Direct visualization of morulae within circulating leukocytes of Wright-Giemsa stained blood smears, which can be achieved more often during the initial stages of infection, can allow rapid diagnosis of Ehrlichia spp. and Anaplasma spp., but the low level and short duration of rickettsemia limits the utility of this approach in many infected individuals [38]. Cell culture isolation is not routinely performed as a diagnostic approach, but can be achieved for most of the organisms in a research laboratory setting, but enhanced biocontainment facilities and select agent registration are needed for R. rickettsii isolation. Successful culture of E. ewingii has not yet been reported. Owing to the difficulties involved with both direct visualization and cell culture 209
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Figure 3. Generalized timing of events and optimal specimen collection periods in tick-borne rickettsial infections of humans and of animals. Upon initiation of tick feeding, there is a ‘grace period’ before which the pathogen is transferred to the mammalian host. After infection, there is a varying period of time before clinical symptoms or signs appear. Detection of the pathogen by direct visualization, molecular analysis, or cultivation is possible in the earlier phase of illness; culture might be more sensitive than PCR assays due to the amplification of pathogen numbers upon cultivation. Later, serology is most useful, and can be used for both clinical and seroepidemiological purposes. Collection of specimens should be targeted to the appropriate phase of the disease development to ensure optimal results.
isolation, diagnosis of rickettsial pathogens is usually achieved by PCR assays, serologic assays or response to treatment in most clinical cases [7–9,38,65–67]. Ehrlichia spp. and Anaplasma spp. are present in circulating leukocytes during acute infection and PCR assay of whole blood for these organisms early in the course of disease is often rewarding [67]. Presumably because organisms are often present in sloughed endothelial cells in circulation, R. rickettsii can also be detected by PCR of whole blood [65], but sensitivity is low. DNA detectability increases as the disease progresses to more severe or terminal stages. Detection of R. rickettsii by PCR or immunohistochemistry in skin biopsy specimens of rash sites seems to have a higher degree of sensitivity in detecting infection than use of whole blood specimens [38]. The detection of pathogens after initiation of effective antimicrobial therapy is reduced each day that it continues, so specimens should be collected early in the illness, and ideally prior to antibiotic administration. When PCR is not practical or available, serology, particularly documentation of seroconversion in an acutely ill individual, should be used to confirm the etiological agent as the cause of the infection. This is often the only diagnostic option in many cases, although the limitations of serology must be kept in mind. Because of the severity of these infections, obtaining an acute-phase sample as early as possible during the course of illness, and a convalescent sample 2–4 weeks later, should allow for documentation of seroconversion, even in patients who are treated with an appropriate anti-rickettsial antibiotic. Patients with acute ehrlichiosis and anaplasmosis might present with clinical disease before they seroconvert [67,68], and patients with RMSF are usually seronegative at the time of clinical presentation [9,69]. To complicate matters further, a high percentage of dogs (up to 60% to A. phagocytophilum; 15% to E. canis) might be serologically positive in areas where 210
these infections are endemic [4], and interpretation of serologic results alone will be difficult to assess in sick dogs. In both veterinary and human patients with these diseases, fever, thrombocytopenia and elevated liver enzymes are often present, alerting both veterinarians and physicians that a rickettsial infection is a likely etiology. Challenges in treatment, prevention and control Doxycycline is considered the treatment of choice for ehrlichiosis, anaplasmosis and RMSF in both dogs and people [39,62,66]. However, delay in treatment can have severe consequences, so a negative acute serology, or a negative PCR result on whole blood, should not be used to guide treatment decisions. Clinical disease can develop prior to an antibody response, so patients presenting with clinical evidence of disease due to rickettsial infections, particularly those with a history of exposure to ticks, should be treated with appropriate antibiotics regardless of the outcome of initial laboratory testing. Concerns regarding tooth discoloration are not substantiated by current literature, and should not preclude the use of doxycycline in children or young dogs suspected to have a severe, potentially fatal tick-borne disease [38]. Antibiotic treatment of all of these agents is most effective when instituted early in the course of disease, and a single course of antibiotics is considered adequate to clear the infection in most human and animal cases [38,62,66]. However, dogs infected with E. canis have been shown capable of infecting ticks after antibiotic treatment [70]. Dogs appear to develop protective immunity to R. rickettsii with exposure, but re-infection with Ehrlichia species and perhaps Anaplasma species can occur [7–9]. Prevention of infection by these pathogens relies upon public education of people about ticks, tick-bite prevention, and tick control. However, these messages are ineffective if these efforts are not inclusive of the pets and environment.
Review Prevention of rickettsial infection by chemical treatment of animals for ticks has been shown [71–73]. Reduction in seroconversion and disease due to E. canis and A. phagocytophilum through the use of topical acaricides has been achieved, but the routine use of such products by the public varies. New methods for community-based prevention efforts must be developed for specific situations. In the ongoing RMSF outbreak in the southwestern USA, tick control has been difficult; this is due, in part, to the nature of the human–animal relationship in the area. Dogs are treated more often as community property and not as individually owned pets. They are allowed to roam freely throughout the community, making application of products difficult or impossible while the dogs continue to disseminate ticks into new areas or areas where ticks have previously been eliminated. Regular veterinary care is not given, so standard veterinary small-animal approaches are not possible [13]. Because tick populations remain high and RMSF continues to cause high morbidity and mortality in this region, novel tick-control methods must be developed. Tick-borne rickettsial pathogens of humans and dogs in the future The impact of tick-borne rickettsial pathogens on both human and canine health will continue to grow. We anticipate that even more novel tick-borne rickettsial pathogens will be described from ticks. There is a need for renewed vigilance in monitoring human and canine populations to obtain viable cultures and identify whether these newly described organisms are pathogenic to either species. A better understanding of the ecology of these new species is needed to improve prevention and control efforts. There has been increasing appreciation of the clinical significance of co-infection with multiple pathogens in both tick populations and individual patients. Widespread biogeographical changes, largely induced by changes in agricultural practices and exurban development trends, as well as climate changes, have led to increased geographical distribution of both tick vectors and wildlife reservoirs. This change has resulted in the subsequent spread of tick-borne pathogens into new areas [10,11,74], a trend that is likely to continue. Enhanced surveillance efforts by serosurveys and molecular surveys will better define the geographic ranges of these agents, which might increase as global mobility of people and their pets expands. A multidisciplinary approach, involving physicians, veterinarians, entomologists and other tickborne disease specialists, will provide greater understanding of rickettsial infections of both dogs and people that will be critical to mitigating the negative impact of these pathogens in both public health and veterinary medicine. Acknowledgements This summary resulted from the Centers for Disease Control-Companion Animal Parasite Council Round-table on Selected Zoonoses of Companion Animals (Dogs & Cats) held in Atlanta, Georgia (USA), 14–15 August, 2009. More information on the mission and resources of CAPC are available at the website www.capcvet.org. The findings and conclusions in this review are those of the author(s), and do not necessarily represent the official position of the CDC. The authors express their thanks to Blaine Mathison for preparing the life cycle diagrams and to multiple reviewers who helped improve the manuscript.
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Review 26 Kocan, A. et al. (2000) Naturally occurring Ehrlichia chaffeensis infection in coyotes from Oklahoma. Emerg. Infect. Dis. 6, 477–480 27 Zhang, X-F. et al. (2003) Experimental Ehrlichia chaffeensis infection in beagles. J. Med. Microbiol. 52, 1021–1026 28 Wimberly, M.C. et al. (2008) Enhanced spatial models for predicting the geographic distributions of tick-borne pathogens. Int. J. Health Geogr. 7, 15 29 Yabsley, M.J. (2010) Natural history of Ehrlichia chaffeensis: vertebrate hosts and tick vectors from the United States and evidence for endemic transmission in other countries. Vet. Parasitol. 167, 136–148 30 Liddell, A.M. et al. (2003) Predominance of Ehrlichia ewingii in Missouri dogs. J. Clin. Microbiol. 41, 4617–4622 31 Diniz, P.P.V.P. et al. (2007) Surveillance for zoonotic vector-borne infections using sick dogs from southeastern Brazil. Vector-Borne Zoonotic Dis. 7, 689–697 32 Buller, R.S. et al. (1999) Ehrlichia ewingii, a newly recognized agent of human ehrlichiosis. N. Engl. J. Med. 341, 148–155 33 Yabsley, M.J. et al. (2002) Ehrlichia ewingii infection in white-tailed deer (Odocoileus virginianus). Emerg. Infect. Dis 8, 668–671 34 Murphy, G.L. et al. (1998) A molecular and serologic survey of Ehrlichia canis, E. chaffeensis, and E. ewingii in dogs and ticks from Oklahoma. Vet. Parasitol. 79, 325–339 35 Anziani, O.S. et al. (1990) Experimental transmission of a granulocytic form of the tribe Ehrlichieae by Dermacentor variabilis and Amblyomma americanum to dogs. Am. J. Vet. Res. 51, 929–931 36 Ndip, L.M. et al. (2007) Ehrlichia species in Rhipicephalus sanguineus ticks in Cameroon. Vector Borne Zoonotic Dis. 7, 221–227 37 Ndip, L.M. et al. (2005) Ehrlichial infection in Cameroonian canines by Ehrlichia canis and Ehrlichia ewingii. Vet. Microbiol. 111, 59–66 38 Chapman, A.S. et al. (2006) Diagnosis and management of tickborne rickettsial diseases: Rocky Mountain spotted fever, ehrlichioses, and anaplasmosis–United States: a practical guide for physicians and other health-care and public health professionals. MMWR Recomm. Rep. 55 (RR-4), 1–27 39 Dantas-Torres, F. (2007) Rocky Mountain spotted fever. Lancet Infect. Dis. 7, 724–732 40 McQuiston, J.H. et al. Evidence of exposure to spotted fever group rickettsiae among Arizona dogs outside a previously documented outbreak area. Zoonoses Publ. Hlth. (in press) DOI:10.111/j.18632378.2009.01300.x 41 Moraes-Filho, J. et al. (2009) New epidemiological data on Brazilian spotted fever in an endemic area of the state of Sao Paulo, Brazil. Vector-Borne Zoonotic Dis. 9, 73–78 42 Levy, C. et al. (2004) Fatal cases of Rocky Mountain spotted fever in family clusters – three states, 2003. MMWR Morb. Mortal. Wkly Rep 53, 407–410 43 Demma, L.J. et al. (2006) Serologic evidence for exposure to Rickettsia rickettsii in eastern Arizona and recent emergence of Rocky Mountain spotted fever in this region. Vector-Borne Zoonotic Dis. 6, 423–429 44 Elchos, B.N. and Goddard, J. (2003) Implications of presumptive fatal Rocky Mountain spotted fever in two dogs and their owner. J. Am. Vet. Med. Assoc. 223, 1450–1452 45 Goddard, J. (1997) Rickettsial organisms in ticks: Rocky Mountain spotted fever. Infect. Med. 14, 18–20 46 Rovery, C. et al. (2008) Questions on Mediterranean spotted fever a century after its discovery. Emerg. Infect. Dis. 14, 1360–1367 47 Solano-Gallego, L. et al. (2006) Febrile illness associated with Rickettsia conorii infection in dogs from Sicily. Emerg. Infect. Dis. 12, 1985–2188 48 Paddock, C.D. et al. (2008) Rickettsia parkeri rickettsiosis and its clinical distinction from Rocky Mountain spotted fever. Clin. Infect. Dis. 47, 1188–1196 49 Labruna, M.B. et al. (2007) Prevalence of Rickettsia infection in dogs from the urban and rural areas of Monte Negro Municipality, Western Amazon, Brazil. Vector-Borne Zoonotic Dis. 7, 249–255 50 Venzal, J.M. et al. (2008) Amblyomma triste Koch, 1844 (Acari: Ixodidae): Hosts and seasonality of the vector of Rickettsia parkeri in Uruguay. Vet. Parasitol. 155, 104–109 51 Cardenosa, N. et al. (2003) Serosurvey among Mediterranean spotted fever patients of a new spotted fever group rickettsial strain (Bar29). Eur. J. Epidemiol. 18, 351–356
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Special Issue: Zoonoses of people and pets in the USA
The increasing recognition of rickettsial pathogens in dogs and people William L. Nicholson1, Kelly E. Allen2, Jennifer H. McQuiston1, Edward B. Breitschwerdt3 and Susan E. Little2 1
Division of Viral and Rickettsial Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, OK 74078, USA 3 College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27606, USA 2
Dogs and people are exposed to and susceptible to infection by many of the same tick-borne bacterial pathogens in the order Rickettsiales, including Anaplasma phagocytophilum, Ehrlichia canis, E. chaffeensis, E. ewingii, Rickettsia rickettsii, R. conorii, and other spotted fever group rickettsiae. Recent findings include descriptions of novel Ehrlichia and Rickettsia species, recognition of the occurrence and clinical significance of co-infection, and increasing awareness of Rhipicephalus sanguineus-associated diseases. Newer molecular assays are available, although renewed efforts to encourage their use are needed. This review highlights the ecology and epidemiology of these diseases, and proposes avenues for future investigation. Epidemiology of tick-borne rickettsial pathogens Humans are susceptible to many tick-borne rickettsial pathogens, including Anaplasma phagocytophilum, which causes human anaplasmosis; Ehrlichia canis, E. chaffeensis, and E. ewingii that induce different forms of ehrlichiosis; Rickettsia rickettsii, the agent of Rocky Mountain spotted fever (RMSF); R. conorii, the cause of Mediterranean spotted fever; and other recently recognized spotted fever group rickettsiae. With the exception of E. canis and perhaps E. ewingii, dogs are not considered a primary reservoir host for these pathogens. Rather, dogs, like people, are incidental hosts and can become infected through the bite of an ixodid tick (Acari: Ixodidae). Ehrlichia and Anaplasma species are transmitted through the bite of an infected nymphal or adult tick vector that had been previously infected in the larval or nymphal stage while feeding on a rickettsemic animal (usually wildlife) known as a reservoir host. In the case of R. rickettsii and other spotted fever group rickettsiae, transfer of the infection from adult female to her eggs (transovarial transmission) supports infection of larval ticks, which is maintained past molting in the subsequent stages. Dogs are frequently exposed to ticks, and evidence of current or past infection in dogs can be used to determine whether there is a risk of infection with rickettsial tick-borne disCorresponding author: Nicholson, W.L. ([email protected])
ease agents in a given geographic area [1–4]. All tick-borne pathogens are distributed focally within the ecologic landscape. Therefore documentation of infection in a dog, which presumably is more often in contact with ticks than humans, should prompt veterinary professionals to warn owners of an increased risk of tick-borne disease. The global distribution of tick-borne rickettsial pathogens varies according to the density and distribution of the predominant tick vectors and the population density of reservoir hosts [5–9]. For example, anaplasmosis is more common in the northeastern, upper midwestern, and western coastal states (Figure 1a) where dense populations of certain Ixodes spp. ticks maintain a reservoir of A. phagocytophilum in nature [4,8]. Ehrlichiosis due to E. chaffeensis and E. canis, which are transmitted primarily by Amblyomma americanum and R. sanguineus, respectively, are more common in the southern USA (Figure 1b) and disease distribution in humans and animals correlates with the distribution of those vector ticks [4,7,8]. RMSF, most often transmitted by Dermacentor ticks, is most commonly reported from southcentral and Mid-Atlantic states, although a recent focus of infection was identified in the southwestern USA [9,10,12], where a new vector was identified. Expansions in tick populations can introduce rickettsial agents to new geographic areas [4,10], and novel rickettsiae and vector–pathogen relationships continue to be described [14]. Because of the growing importance of these pathogens worldwide, a two-day summit among leading tick-borne disease researchers in veterinary medicine and public health was facilitated by the Companion Animal Parasite Council (CAPC) and the Centers for Disease Control and Prevention (CDC). This review focuses on the tick-borne rickettsial diseases most commonly recognized in people and dogs in the USA: anaplasmosis, ehrlichiosis and RMSF. Ecology of tick-borne pathogens affecting dogs and people Granulocytic anaplasmosis Anaplasma phagocytophilum is transmitted by Ixodes spp. ticks [15]. In North America, I. scapularis and I. pacificus
1471-4922/$ – see front matter . Published by Elsevier Ltd. doi:10.1016/j.pt.2010.01.007 Available online 6 March 2010
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Figure 1. One means of determining the distribution of rickettsial pathogens in a geographical area is to conduct serosurveys of domestic pets presenting to veterinarians. In these figures, we can begin to understand the distribution in dogs from throughout the USA of antibodies to Anaplasma species (a) and Ehrlichia species (b). It is important to note that this is representative of canine seroprevalence and that infections of tick, human, and wildlife species are not included. However, these are the largest serosurveys ever conducted for rickettsial agents. Reprinted, with permission, from Ref. [4].
are considered the most important vectors and sigmodontine rodents are considered the primary reservoir hosts, although a large variety of mammals are susceptible to infection and can play a supplementary role in maintaining a source of infected ticks (Figure 2a) [16]. Globally, a number of Ixodes spp. are the primary vectors and additional rodent and ruminant species serve as reservoirs. Several genetic variants of A. phagocytophilum have been described based on molecular subtyping, yet only one (Ap-ha) appears to be associated with disease in people and dogs in North America [16–18]. In dogs, disease caused by infection with A. phagocytophilum is typically characterized by acute onset of fever, depression, myalgia, anorexia, lameness and reduced platelets [8,19]. In people, A. phagocytophilum infection is characterized by fever, headache, lethargy, myalgia, elev206
ated liver function enzymes and reduced platelets. Human fatalities can occur, although reportedly in <1% of cases, and, usually in association with other opportunistic infections [15,16]. Because A. phagocytophilum is maintained largely in a vector–reservoir–host system similar to that of Borrelia burgdorferi, the geographic distribution of cases of granulocytic anaplasmosis in North America parallels that of Lyme borreliosis, with most confirmed cases reported from the Northeast, upper Midwest and along the West Coast [20,21]. In the largest serosurvey conducted to date, dogs with antibodies induced against Anaplasma species (either A. phagocytophilum or A. platys) were seen most commonly in the midwestern (6.7% of dogs tested were positive) and northeastern (5.5%) portions of the USA, as well as in California (4.8%) (Figure 1a). In some individual counties
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Figure 2. Transmission cycles responsible for maintaining rickettsial pathogens in tick populations and allowing infection of people and dogs. Transmission cycle for maintenance of Anaplasma phagocytophilum (a). The pathogen is acquired from sigmodontine rodents or other reservoir hosts during feeding by larval or nymphal Ixodes spp. ticks and then transmitted in subsequent feedings of nymphal or adult ticks. Transmission cycle for maintenance of Ehrlichia chaffeensis (b). By contrast to the Ixodes spp. vectors of A. phagocytophilum, in which only adults feed on deer, all three stages of Amblyomma americanum, the primary tick vector of E. chaffeensis, feed on deer as a preferred host. Infection with E. chaffeensis is acquired during feeding of larval or nymphal A. americanum on deer and then transmitted upon subsequent feeding of nymphs or adults. Transmission cycle for maintenance of Rickettsia rickettsii (c). Dermacentor spp. ticks acquire R. rickettsii upon feeding, as larvae or nymphs, on rodents; they then transmit during subsequent feeding as nymphs or adults. In addition, R. rickettsii infection can be maintained transovarially in Dermacentor ticks, resulting in some larvae hatching from the egg mass already harboring an infection.
in these regions, over 60% of all dogs tested had antibodies to Anaplasma species [4]. Anaplasma platys has long been known to infect dogs, and to cause febrile illness and canine cyclic thrombocytopenia. The ability of A. platys to infect humans has been questioned, although morphologically-compatible organisms have been identified in platelets from humans with apparent anaplasmosis [22]. Ehrlichiosis Several species in the genus Ehrlichia infect and cause disease in both dogs and people [15,21]. Infection by E. canis causes the most severe disease in dogs and can result in fever, myalgia, depression, reduced white cells and reduced platelets. which may lead to bleeding disorders, particularly nosebleeds. Although apparently rare, ehrlichiosis in humans due to E. canis infection has been reported from Venezuela [23]. Dogs and wild canids are
the natural hosts of both E. canis and its primary vector tick, R. sanguineus. Interestingly, E. canis can sometimes be transmitted by Dermacentor variabilis [24]. Human infection by E. chaffeensis causes a potentially severe ehrlichial disease; acute infections result in a moderate to severe illness characterized by fever, headache, lethargy, myalgia, reduced sodium levels, reduced platelets and elevated liver enzymes. Patients are often hospitalized and infections can be fatal in up to 3% of cases [15]. White-tailed deer (Odocoileus virginianus) are considered the primary reservoir hosts for E. chaffeensis, and A. americanum ticks are the predominant vectors to both humans and animals (Figure 2b) [25]. Natural infection of coyotes is common in Oklahoma [26]. Canine infections are subclinical or mild [7,27]. Although both E. canis in dogs and E. chaffeensis in people occur predominately in the southern USA, infections have been reported throughout the country and on five continents [7,28,29]. 207
Review In a large serosurvey conducted in the USA, antibodies to Ehrlichia species, which may have been induced by exposure to either E. canis or E. chaffeensis, were more common in the southern states than in the rest of the country (1.3% versus 0.6%, respectively) (Figure 1b). Indeed, individual counties were identified where 15% of dogs tested positive, a prevalence that is 25-fold greater than the national (USA) prevalence of 0.6% [4]. Molecular surveys of dogs suggest that E. ewingii infection can be more prevalent than E. canis in certain endemic areas [30]. Ehrlichia canis was first isolated and molecularly characterized from asymptomatic humans in Venezuela in 1996, but its role as a pathogen was not immediately recognized. In 2006, further efforts resulted in isolation of E. canis from human patients with clinical findings compatible with ehrlichiosis [23]. This pathogen must now be considered in compatible human illness in endemic areas, especially when high PCR prevalence has been found in dogs from those areas [31]. Infection with E. ewingii generally results in mild to moderate febrile disease in dogs and in people [32], although many dogs may harbor subclinical infections. While generally considered to induce a milder form of disease than E. canis or E. chaffeensis in dogs or people, respectively, anemia, thrombocytopenia, polyarthritis and neurological sequelae have been reported. The most important reservoir host of E. ewingii has not been conclusively determined, but both dogs and deer are considered prime candidates [30,33]. In the USA, A. americanum is considered the most important vector of E. ewingii, although this organism has also been detected in D. variabilis and R. sanguineus [7,34,35]. Accordingly, granulocytic ehrlichiosis caused by E. ewingii is more common in both dogs and people in the southern USA, where lone star tick populations are high and feed readily on both hosts [7]. Deer and dogs are also susceptible to both natural and experimental infection with E. ewingii. In more recent years, E. ewingii has been found in additional countries of the world [36,37]. Spotted fever group rickettsiae Infection with R. rickettsii, the causative agent of RMSF, induces an extremely severe, potentially fatal disease in people and in dogs. Indeed, among the tick-borne diseases in the Americas, RMSF is the most severe, and can result in an acute-onset illness accompanied by a rapid course of disease and a high fatality rate. Mortality rates have been estimated at 20% in people in the absence of appropriate antibiotic treatment and 5% in patients who receive antibiotics [38]. Disease in people initially presents as sudden onset of fever, severe headache and generalized malaise, although patients often also develop myalgia, nausea, vomiting and photophobia. Within two weeks of infection the classic triad of fever, headache and generalized maculopapular rash is present in the majority of patients. The appearance of skin rash is more prevalent as the disease progresses, although some individuals never develop the typical rash [38,39]. Canine patients present with fever, lethargy, vomiting and anorexia. As infection progresses, additional signs can develop in dogs, including ocular lesions, bleeding disorders, joint pain and neurologic 208
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abnormalities [9]. Fatalities can occur in both people and dogs, particularly if appropriate anti-rickettsial treatment is delayed or never instituted [39]. In the USA, infection with R. rickettsii is acquired through the bite of infected D. variabilis or D. andersoni ticks. In Central and South America, A. cajennense has been implicated as the vector to humans and dogs. Recently, R. sanguineus was shown to transmit the pathogen to dogs and to people in Arizona, and there was a recent outbreak in northern Mexico [13,40]. Infected R. sanguineus have been identified in the states of California and Texas, Mexico, and recently in Brazil [41]. Because R. rickettsii is focally distributed in tick populations, dogs can serve as immediate proximal sentinels of infection and disease [42,43]. Several case reports in the literature describe diagnosis of RMSF in dogs associated with and, in some cases, leading to identification of the infection in people in the same household or vicinity [2,42,44]. Infection is transmitted by ticks, rather than directly from infected dogs; however, manual removal of engorged ticks from dogs has been identified as a potential risk factor for human infection [45], and can occur by inoculation of the pathogen onto mucus membranes by contaminated fingers as has been shown with R. conorii. In its natural cycle, R. rickettsii is maintained in persistently infected tick populations and small rodent reservoir hosts (Figure 2c). Transovarial transmission from infected females to eggs and transmission between adults during mating can maintain the infection within the population without additional infectious feedings. The disease is reported throughout the continental USA, Central America and South America. The infection is most commonly identified in males, those from rural areas, and children (5–9 years of age) and older adults (40–64 years of age). Mediterranean spotted fever in humans results from R. conorii infection [46]. The pathogen is transmitted through bites of R. sanguineus or by accidental mucus membrane inoculation of the rickettsiae from crushed ticks. The disease is widely distributed across southern Europe, northern Africa, the Middle East, the Indian subcontinent and Asia. Clinical disease in humans is similar to other spotted fever group rickettsial infections, and is characterized by the development of a lesion with a necrotic center, known as an eschar. Dogs play an important role as biological hosts of the ticks, and serve to increase the infected tick population in close association with human habitation. Seroprevalence of dogs in endemic areas is quite high (26–60%). Dogs are usually subclinically infected, although more overt disease has recently been reported [47]. There are a number of other spotted fever group rickettsial species that have been identified for which dogs may play some role in their ecology. Many of these were identified from ticks that can bite dogs and humans. In some cases, laboratory evidence for canine exposure or infection has been presented. Rickettsia parkeri has only recently been recognized as a pathogen of humans in the USA and possibly Uruguay [48]. The pathogen has been identified in ticks from USA, Uruguay and Brazil [49,50]. Serologic
Review evidence of canine exposure has also been demonstrated in Brazil [49]. Whether dogs become rickettsemic is not known, but they certainly could facilitate transport of infected ticks into the peridomestic environment. Another organism found in R. sanguineus is R. massiliae [14]. It was originally described from France, but has since been identified in several other countries. One genotype of R. massiliae, known as Bar29, has been shown to infect humans [14,51,59]. Additional work is needed to define the importance of these rickettsial organisms in human and animal health. Insights into changing ecology and epidemiology Co-infection Recently, there has been an increased emphasis on the possibility of co-infection by multiple tick-borne pathogens and its effect on transmission, expression of disease, and our ability to treat patients effectively. A recent analysis found that co-infections with A. phagocytophilum and B. burgdorferi occur in ticks at prevalences of 0.1% to 28.1%, and that occurrence was somewhat unpredictable [52]. Evidence of co-infections with these, or other agents, in dogs and in humans has usually been noted in endemic areas where the prevalence of both organisms is high [4,53,54,55]. In a recent, nationwide, serologic survey, 40.8% of dogs tested from one county in Minnesota had antibodies to both A. phagocytophilum and B. burgdorferi [4]. Additional experimental and epidemiological studies are needed to explore further the effects of co-infection on surveillance of rickettsial diseases. New pathogens There has been an increasing number of novel rickettsial organisms described since the advent of molecular detection and characterization [14]. These organisms are often described from amplicons and without cultivation of isolates, so their validity can be questioned. These organisms are often detected in arthropod populations and might not subsequently be transmitted to vertebrate hosts or cause disease in these hosts. Studies are needed to better understand the potential role of dogs in the ecology of these pathogens and to determine the pathogenicity of these microorganisms to pets and their owners. One example is the Panola Mountain Ehrlichia, a genotype genetically grouped with Ehrlichia ruminantium [56]. Both of these organisms have recently been shown to infect humans, albeit infrequently [57,58]. Many other related organisms have been identified globally through molecular assays of ticks that bite humans and their pets; it is anticipated that some of these will be identified as pathogens of people and of dogs. Our changing environment Our concepts of distribution and intensity of tick-borne pathogens are strongly influenced by many factors, including environmental parameters, changing land use, changing human and animal activities, surveillance efforts and diagnostic practices. Changing landscape ecology may result in expansion of numbers of ticks or of their biological hosts, and the consequent expansion of areas of risk to human or animal health. In recent years, much attention
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to the effects of climate change has shown that many tickborne diseases are experiencing a global increase. Several R. sanguineus–associated diseases are being increasingly reported in many parts of the world [59]. As a veterinary parasite, R. sanguineus has long been recognized as a vector for Rickettsia and Ehrlichia species [60]. Over the years, much information has been gained on the intimate role that this tick plays in the epidemiology of Mediterranean spotted fever in humans. Indeed, there is a strong association with dog contact, proximity, tick loads and tick densities in the environment and the subsequent human risk for infection [46]. In all life stages, R. sanguineus prefers to feed on dogs, and reports of human biting are uncommon, although all stages of this tick have been reported from humans [60]. Because of limited human biting, the species has long been discounted as a vector of human rickettsial pathogens in the USA, whereas the species is still recognized elsewhere in the world as a primary vector of rickettsiae to humans. Recently, preliminary studies were reported to indicate that R. sanguineus biting of humans is more frequent as temperature increases [59]. It has also been shown that these ticks can move from one host to another during active feeding [61], which may enhance contact among pathogens, humans and dogs. During investigations of RMSF in the southwestern USA, R. sanguineus was shown to be the only vector to humans [13,40]. High tick numbers in the peridomestic environment and close contact with dogs or tick-infested homesites were associated with human cases. Interestingly, the prevalence of infection in ticks from the peridomestic environment was much greater than the <1% seen in the two Dermacentor species associated with RMSF in other parts of the USA [13]. Thus, although R. sanguineus biting of humans is infrequent, the risk for rickettsial transmission to humans is likely higher than that of a Dermacentor bite. Need for improved diagnostic strategies Diseases caused by tick-borne rickettsial agents can be diagnosed in a number of different ways; each approach has its advantages and its limitations, and the best option(s) will be dictated by both the infection characteristics of the organism(s) suspected to be causing disease and the suspected persistence of infection (for general guidance, see Refs. [38,62–64]). Effective methods include: direct visualization of organisms in stained blood smears, impression smears, or tissue sections; cell culture isolation; PCR assays; and serology [Figure 3]. Direct visualization of morulae within circulating leukocytes of Wright-Giemsa stained blood smears, which can be achieved more often during the initial stages of infection, can allow rapid diagnosis of Ehrlichia spp. and Anaplasma spp., but the low level and short duration of rickettsemia limits the utility of this approach in many infected individuals [38]. Cell culture isolation is not routinely performed as a diagnostic approach, but can be achieved for most of the organisms in a research laboratory setting, but enhanced biocontainment facilities and select agent registration are needed for R. rickettsii isolation. Successful culture of E. ewingii has not yet been reported. Owing to the difficulties involved with both direct visualization and cell culture 209
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Figure 3. Generalized timing of events and optimal specimen collection periods in tick-borne rickettsial infections of humans and of animals. Upon initiation of tick feeding, there is a ‘grace period’ before which the pathogen is transferred to the mammalian host. After infection, there is a varying period of time before clinical symptoms or signs appear. Detection of the pathogen by direct visualization, molecular analysis, or cultivation is possible in the earlier phase of illness; culture might be more sensitive than PCR assays due to the amplification of pathogen numbers upon cultivation. Later, serology is most useful, and can be used for both clinical and seroepidemiological purposes. Collection of specimens should be targeted to the appropriate phase of the disease development to ensure optimal results.
isolation, diagnosis of rickettsial pathogens is usually achieved by PCR assays, serologic assays or response to treatment in most clinical cases [7–9,38,65–67]. Ehrlichia spp. and Anaplasma spp. are present in circulating leukocytes during acute infection and PCR assay of whole blood for these organisms early in the course of disease is often rewarding [67]. Presumably because organisms are often present in sloughed endothelial cells in circulation, R. rickettsii can also be detected by PCR of whole blood [65], but sensitivity is low. DNA detectability increases as the disease progresses to more severe or terminal stages. Detection of R. rickettsii by PCR or immunohistochemistry in skin biopsy specimens of rash sites seems to have a higher degree of sensitivity in detecting infection than use of whole blood specimens [38]. The detection of pathogens after initiation of effective antimicrobial therapy is reduced each day that it continues, so specimens should be collected early in the illness, and ideally prior to antibiotic administration. When PCR is not practical or available, serology, particularly documentation of seroconversion in an acutely ill individual, should be used to confirm the etiological agent as the cause of the infection. This is often the only diagnostic option in many cases, although the limitations of serology must be kept in mind. Because of the severity of these infections, obtaining an acute-phase sample as early as possible during the course of illness, and a convalescent sample 2–4 weeks later, should allow for documentation of seroconversion, even in patients who are treated with an appropriate anti-rickettsial antibiotic. Patients with acute ehrlichiosis and anaplasmosis might present with clinical disease before they seroconvert [67,68], and patients with RMSF are usually seronegative at the time of clinical presentation [9,69]. To complicate matters further, a high percentage of dogs (up to 60% to A. phagocytophilum; 15% to E. canis) might be serologically positive in areas where 210
these infections are endemic [4], and interpretation of serologic results alone will be difficult to assess in sick dogs. In both veterinary and human patients with these diseases, fever, thrombocytopenia and elevated liver enzymes are often present, alerting both veterinarians and physicians that a rickettsial infection is a likely etiology. Challenges in treatment, prevention and control Doxycycline is considered the treatment of choice for ehrlichiosis, anaplasmosis and RMSF in both dogs and people [39,62,66]. However, delay in treatment can have severe consequences, so a negative acute serology, or a negative PCR result on whole blood, should not be used to guide treatment decisions. Clinical disease can develop prior to an antibody response, so patients presenting with clinical evidence of disease due to rickettsial infections, particularly those with a history of exposure to ticks, should be treated with appropriate antibiotics regardless of the outcome of initial laboratory testing. Concerns regarding tooth discoloration are not substantiated by current literature, and should not preclude the use of doxycycline in children or young dogs suspected to have a severe, potentially fatal tick-borne disease [38]. Antibiotic treatment of all of these agents is most effective when instituted early in the course of disease, and a single course of antibiotics is considered adequate to clear the infection in most human and animal cases [38,62,66]. However, dogs infected with E. canis have been shown capable of infecting ticks after antibiotic treatment [70]. Dogs appear to develop protective immunity to R. rickettsii with exposure, but re-infection with Ehrlichia species and perhaps Anaplasma species can occur [7–9]. Prevention of infection by these pathogens relies upon public education of people about ticks, tick-bite prevention, and tick control. However, these messages are ineffective if these efforts are not inclusive of the pets and environment.
Review Prevention of rickettsial infection by chemical treatment of animals for ticks has been shown [71–73]. Reduction in seroconversion and disease due to E. canis and A. phagocytophilum through the use of topical acaricides has been achieved, but the routine use of such products by the public varies. New methods for community-based prevention efforts must be developed for specific situations. In the ongoing RMSF outbreak in the southwestern USA, tick control has been difficult; this is due, in part, to the nature of the human–animal relationship in the area. Dogs are treated more often as community property and not as individually owned pets. They are allowed to roam freely throughout the community, making application of products difficult or impossible while the dogs continue to disseminate ticks into new areas or areas where ticks have previously been eliminated. Regular veterinary care is not given, so standard veterinary small-animal approaches are not possible [13]. Because tick populations remain high and RMSF continues to cause high morbidity and mortality in this region, novel tick-control methods must be developed. Tick-borne rickettsial pathogens of humans and dogs in the future The impact of tick-borne rickettsial pathogens on both human and canine health will continue to grow. We anticipate that even more novel tick-borne rickettsial pathogens will be described from ticks. There is a need for renewed vigilance in monitoring human and canine populations to obtain viable cultures and identify whether these newly described organisms are pathogenic to either species. A better understanding of the ecology of these new species is needed to improve prevention and control efforts. There has been increasing appreciation of the clinical significance of co-infection with multiple pathogens in both tick populations and individual patients. Widespread biogeographical changes, largely induced by changes in agricultural practices and exurban development trends, as well as climate changes, have led to increased geographical distribution of both tick vectors and wildlife reservoirs. This change has resulted in the subsequent spread of tick-borne pathogens into new areas [10,11,74], a trend that is likely to continue. Enhanced surveillance efforts by serosurveys and molecular surveys will better define the geographic ranges of these agents, which might increase as global mobility of people and their pets expands. A multidisciplinary approach, involving physicians, veterinarians, entomologists and other tickborne disease specialists, will provide greater understanding of rickettsial infections of both dogs and people that will be critical to mitigating the negative impact of these pathogens in both public health and veterinary medicine. Acknowledgements This summary resulted from the Centers for Disease Control-Companion Animal Parasite Council Round-table on Selected Zoonoses of Companion Animals (Dogs & Cats) held in Atlanta, Georgia (USA), 14–15 August, 2009. More information on the mission and resources of CAPC are available at the website www.capcvet.org. The findings and conclusions in this review are those of the author(s), and do not necessarily represent the official position of the CDC. The authors express their thanks to Blaine Mathison for preparing the life cycle diagrams and to multiple reviewers who helped improve the manuscript.
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