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Keywords:

  • Spotted fever group rickettsioses;
  • travel-associated rickettsioses;
  • emerging pathogens;
  • tick-borne diseases;
  • Canada

Summary

  1. Top of page
  2. Summary
  3. Impacts
  4. Introduction
  5. Spotted Fever Group Rickettsiae (SFGR) – Human Pathogens
  6. Spotted Fever Group Rickettsiae – Non-Pathogenic Species/Unknown Pathogens
  7. Rickettsia canadensis
  8. Recognition of Spotted Fever Group Rickettsial Infections
  9. Spotted Fever Group Rickettsiae in Canada
  10. Spotted Fever Group Rickettsiae as Emerging Pathogens
  11. Conflicts of interest
  12. References

Spotted fever group rickettsioses (SFGR) are infections caused by established and emerging human pathogens worldwide. These rickettsial agents are transmitted to humans via arthropods and may result in mild to severe and potentially fatal diseases. Spotted fever group rickettsioses are characterized by similar clinical features, including fever, rash, headache and myalgias, with the development of an inoculation eschar in many, but not all cases. Endemic rickettsial infections do occur but are infrequent in Canada, in contrast to the United States, where these infections are far more prevalent. Travel-associated rickettsioses, however, are being diagnosed with increasing frequency in Canadian travellers returning from international trips abroad, in particular in travellers returning from Africa. The diagnosis of rickettsial infections can be challenging owing to the non-specific nature of the clinical symptoms and the requirement for specialized testing. Serology cannot distinguish between the approximately 20 spotted fever group rickettsial species currently known or suspected to be capable of causing human infection. Molecular testing is required to determine the rickettsial species responsible for infection, but requires greater effort on the part of the clinician to collect appropriate samples, including cutaneous skin swabs from under the eschar or skin punch biopsies of the eschar or rash. Infections with spotted fever group rickettsiae likely occur more commonly than currently recognized and should be considered in patients with appropriate symptoms and exposure histories.


Impacts

  1. Top of page
  2. Summary
  3. Impacts
  4. Introduction
  5. Spotted Fever Group Rickettsiae (SFGR) – Human Pathogens
  6. Spotted Fever Group Rickettsiae – Non-Pathogenic Species/Unknown Pathogens
  7. Rickettsia canadensis
  8. Recognition of Spotted Fever Group Rickettsial Infections
  9. Spotted Fever Group Rickettsiae in Canada
  10. Spotted Fever Group Rickettsiae as Emerging Pathogens
  11. Conflicts of interest
  12. References
  •  Approximately 20 spotted fever group rickettsial species have been identified to date throughout the world, many of which are established or emerging human pathogens.
  •  Spotted fever group rickettsioses are transmitted to humans via arthropods, usually ticks, and can cause mild to serious and life-threatening infections, typically characterized by non-specific clinical symptoms, including fever, headache, myalgias and rash.
  •  Testing for possible infection with spotted fever group rickettsiae should be considered as part of the differential diagnosis for patients with histories of tick bite as well as individuals with appropriate symptoms following recent travel.

Introduction

  1. Top of page
  2. Summary
  3. Impacts
  4. Introduction
  5. Spotted Fever Group Rickettsiae (SFGR) – Human Pathogens
  6. Spotted Fever Group Rickettsiae – Non-Pathogenic Species/Unknown Pathogens
  7. Rickettsia canadensis
  8. Recognition of Spotted Fever Group Rickettsial Infections
  9. Spotted Fever Group Rickettsiae in Canada
  10. Spotted Fever Group Rickettsiae as Emerging Pathogens
  11. Conflicts of interest
  12. References

Rickettsioses are caused by established and emerging zoonotic pathogens distributed worldwide and are a significant cause of human illness. The Rickettsia genus is divided into 4 groups: the spotted fever group (SFG), consisting of approximately 20 species, including the best known species, Rickettsia rickettsii, the agent responsible for Rocky Mountain spotted fever; the typhus group, consisting of R. prowazekii and R. typhi, the agents responsible for epidemic and murine typhus, respectively; the ancestral group, consisting of R. canadensis and R. bellii; and the transitional group, consisting of R. akari, R. felis and R. australis. However, the species now included in the transitional group were historically considered members of the SFG, and continue to be viewed informally as SFG rickettsiae by many investigators. For this reason, these species will be discussed in this review. The classification of Rickettsia into separate groups was initially based on serology but these groupings have as been confirmed by molecular and phylogenetic analyses (Gillespie et al., 2007, 2008). All rickettsiae are Gram-negative, obligate intracellular bacteria which target the vascular endothelium for replication. Members of the spotted fever group of rickettsial (SFGR) species are transmitted to humans by arthropods, mainly ticks, and are notoriously difficult to diagnose, particularly with respect to the precise infecting species. These zoonoses are important emerging vector-borne infections of humans worldwide. Although there are exceptions to the rule, each SFGR species is associated with a defined geographic area, although more than one species may circulate in a particular region.

Infections by SFGR generally produce similar clinical features, including fever, headache, fatigue and myalgias. A maculopapular rash may be present and arouse suspicion of a SFGR infection, and in some cases, an eschar may develop at the site of inoculation. The presence or absence of an eschar is highly variable, but more significant eschars are associated with mildly pathogenic rickettsiae in humans compared with highly virulent rickettsiae, such as R. rickettsii and R. prowazekii, which are not associated with the presence of eschars. These observations in humans are consistent with recent work which established an animal model based on the intradermal injection of rickettsial species in guinea pigs. Using this model, the authors proposed that the presence of an eschar during infection reflects a strong localized control response associated with less virulent species (La Scola et al., 2009).

Over the last few decades, the development of molecular diagnostic assays has enhanced the detection of new rickettsial species, of varying degrees of virulence or unknown pathogenicity, from various arthropod vectors. Many newly identified rickettsial species have been detected in ticks but have yet to be definitively demonstrated to cause disease in humans. At the same time, the number of human cases of SFGR infection has increased in the United States, with a corresponding decrease in the mortality rate associated with these infections (Openshaw et al., 2010). This has led to speculation that many cases of Rocky Mountain spotted fever previously attributed to R. rickettsii are actually caused by less virulent SFGR species (Openshaw et al., 2010). Owing to cross-reactivity, routine serological assays will detect all members of the SFG when R. rickettsii is used as the antigen. Thus, it is problematic to differentiate between infections with these species in humans in the absence of molecular diagnostic testing. Unfortunately, routine submission of samples suitable for molecular testing from patients with suspected rickettsial infections is infrequent.

Spotted Fever Group Rickettsiae (SFGR) – Human Pathogens

  1. Top of page
  2. Summary
  3. Impacts
  4. Introduction
  5. Spotted Fever Group Rickettsiae (SFGR) – Human Pathogens
  6. Spotted Fever Group Rickettsiae – Non-Pathogenic Species/Unknown Pathogens
  7. Rickettsia canadensis
  8. Recognition of Spotted Fever Group Rickettsial Infections
  9. Spotted Fever Group Rickettsiae in Canada
  10. Spotted Fever Group Rickettsiae as Emerging Pathogens
  11. Conflicts of interest
  12. References

A total of 19 species of SFGR have been shown to be associated with human disease to varying degrees. The specific species identified to date as well as their geographic distribution and known/potential arthropod vectors is summarized in Table 1 and Fig. 1. Overall, SFGR display a widespread distribution including the Americas, Europe, Africa, Asia and Australia. Migratory birds have been implicated in the spread of SFGR-infected ticks and may help to account for this widespread distribution (Elfving et al., 2010).

Table 1.   Known human spotted fever group rickettsial pathogens
Rickettsia speciesDiseaseKnown DistributionKnown or potential vector(s)
R. rickettsii Rocky Mountain spotted fever (RMSF), Brazilian spotted feverNorth America, Central America, South America Dermacentor andersoni Dermacentor variabilis Rhipicephalus sanguineus Amblyomma americanum Amblyomma cajennense
R. conorii conorii Mediterranean spotted fever (MSF), Boutonneuse spotted feverSouthern Europe, Africa R. sanguineus
R. conorii indica Indian tick typhusSouth Asia R. sanguineus
R. conorii israelensis Israeli spotted feverSouthern Europe, Middle East R. sanguineus
R. conorii caspiae Astrakhan spotted feverRussia R. sanguineus
R. parkeri R. parkeri rickettsiosisUnited States, Argentina A. maculatum A. triste
R. africae African tick bite fever (ATBF)Africa, Caribbean A. variegatum Amblyomma hebraeum
R. akari RickettsialpoxUnited States, Russia, Korea, South Africa Lyponyssoides sanguineus
Rickettsia species 364DUnnamedUnited States D. occidentalis
R. heilongjiangensis Far Eastern spotted feverNorthern China, Eastern Asia D. silvarum H. concinna
R. australis Queensland tick typhusAustralia Ixodes holocyclus I. tasmani
R. honei Flinders Island spotted feverAustralia Aponomma hydrosauri A. cajennense I. granulatus
R. massiliae UnnamedUnited States, Europe Rhipicephalus sp.
R. sibirica North Asian tick typhus, Siberian tick typhus, Lymphangitis-associated rickettsiosisEurope, Africa, North Asia Hyalomma asiaticum H. truncatum D. marginatus D. nuttalli
R. slovaca Tick-borne lymphadenopathy (TIBOLA), Dermacentor-borne necrosis and lymphadenopathy (DEBONEL)Europe, central Asia D. marginatus D. reticulatus
R. japonica Japanese spotted feverJapan Ixodes ovatus D. taiwanensis Haemaphysalis flava H. formosensis H. longicornis
R. aeschlimannii UnnamedEurope, South Africa Hyalomma marginatum
R. helvetica UnnamedEurope, Asia Ixodes ricinus Dermacentor reticulatus
R. felis Flea-borne spotted feverWorldwide Ctenocephalides felis
image

Figure 1.  Geographical distribution of known human spotted fever group of rickettsial pathogens.

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Rocky Mountain spotted fever (RMSF), caused by R. rickettsii, is the best known SFGR infection in North America. RMSF is the most severe of the SFG rickettsioses and is the most frequently reported fatal tick-borne infection in the United States. This rickettsial species is transmitted by several tick species, including Dermacentor andersoni, D. variabilis, Rhipicephalus sanguineus and Amblyomma americanum in North America (Breitschwerdt et al., 2011). RMSF has also been identified in several countries in Central and South America, including Brazil where this infection is known as Brazilian spotted fever. The primary vector of R. rickettsii in Brazil is Amblyomma cajennense, the Cayenne tick. Ticks serve as a natural reservoir for R. rickettsii, with both transovarial and transstadial transmission of the agent. Small rodents, including squirrels, voles and chipmunks, also serve as reservoirs and amplifying hosts (Parola et al., 2005).

RMSF is not associated with the development of an eschar at the inoculation site, in contrast to many other SFGR infections. The incubation period ranges from approximately 2–14 days, followed by non-specific symptoms, including fever, headache, malaise, myalgias, nausea, vomiting and abdominal pain. A maculopapular to petechial rash typically appears 2–5 days after the onset of fever, but may not be apparent in up to 20% of all patients (Table 2) (Minniear and Buckingham, 2009). Severe complications of RMSF include skin necrosis and gangrene, acute renal failure, pneumonia and neurological manifestations, including confusion and hearing loss (Dantas-Torres, 2007; Minniear and Buckingham, 2009).

Table 2.   Description of rashes observed in patients with rickettsial infections
Type of rashDescription
MaculopapularFlat, confluent, red spots (macules) covered with small, raised bumps (papules)
PetechialSmall, flat, red or purple spots of <3 mm diameter which do not blanche upon the application of pressure
VesicularRaised blisters or vesicles filled with clear, serous fluid
PustularRaised blisters or vesicles filled with purulent fluid (pus)

Rickettsia parkeri is a pathogenic SFGR transmitted primarily by the Gulf Coast tick, Amblyomma maculatum, an aggressive human-biting tick (Paddock et al., 2004, 2010; Paddock, 2005). Infections with this species have been detected in the United States and recently Argentina, where the vector responsible for transmission is Amblyomma triste, a tick species prevalent in South America (Romer et al., 2011). Rickettsia parkeri causes a disease milder than RMSF, and may explain, in part, why the case-fatality rate for RMSF has decreased from 2.2% in 2000 to 0.3% in 2007 (Openshaw et al., 2010). The use of serological assays for the diagnosis of SFG rickettsioses does not permit the identification of the infecting species, and as such, infection due to R. parkeri may be attributed instead to R. rickettsii, the antigen used in most commercial assays. Infection with R. parkeri is associated with the development of an eschar, which is characteristically absent in RMSF. Clinically, R. parkeri rickettsiosis can also be distinguished from classic RMSF by the relative absence of nausea, vomiting and diarrhoea, and the presence of a vesicular or pustular rash (Table 2), similar to the rash observed in patients with rickettsialpox (Paddock et al., 2008).

Rickettsialpox is a self-limited febrile illness characterized by vesicular skin lesions resembling chickenpox. This infection is caused by Rickettsia akari and is transmitted to humans via Lyponyssoides sanguineus, a haematophagous mite that infests the common house mouse, Mus musculus. Infection begins with an eschar at the site of inoculation, followed by fever, headache and a papulovesicular rash (Table 2). This infection has been detected in patients in large cities in the United States, most notably New York City, but has also been reported in Ukraine, Croatia, France, Italy, Russia, Korea and South Africa, Costa Rica and Mexico (Koss et al., 2003).

Rickettsia species 364D has been detected in Dermacentor occidentalis, the Pacific Coast tick, in California, and has been confirmed as the cause of mild SFGR disease in this region associated with a single cutaneous eschar as the principal manifestation, with headache and fever reported in some patients (Philip et al., 1981; Wikswo et al., 2008; Shapiro et al., 2010).

Rickettsia conorii is divided into four subspecies: R. conorii subsp. conorii is the aetiologic agent of Mediterranean spotted fever or Boutonnneuse fever in Southern Europe and Africa; R. conorii subsp. indica is the agent responsible for Indian tick typhus in South Asia; R. conorii subsp. israelensis is the agent responsible for Israeli spotted fever in Southern Europe and the Middle East; and R. conorii subsp. caspiae is the aetiologic agent of Astrakhan spotted fever in Russia. The different R. conorii strains vary in clinical presentation and severity, with complications and case-fatality rates similar to RMSF (De Sousa et al., 2008; Rovery and Raoult, 2008; Fournier and Raoult, 2009). The primary vector responsible for R. conorii infection is Rhipicephalus sanguineus, the Brown dog tick (Fournier and Raoult, 2009). Dogs are only transient reservoirs of R. conorii but are responsible for bringing infected R. sanguineus ticks in proximity to humans. Wild rabbits, hedgehogs and other small rodents may serve as reservoirs of R. conorii conorii (Rovery and Raoult, 2008).

Unlike most spotted fever rickettsial species, R. felis is transmitted by the cat flea, Ctenocephalides felis, and not ticks. Rickettsia felis has been detected in cat fleas worldwide (Kamrani et al., 2008; Perez-Osorio et al., 2008). Consistent with the widespread nature of the cat flea, human cases of this emerging rickettsial infection have also been reported worldwide (Perez-Osorio et al., 2008; Reif and Macaluso, 2009; Richards et al., 2010). The cat flea is currently the only defined biological vector and reservoir of R. felis with both transovarial and transstadial transmission of the agent in fleas (Reif and Macaluso, 2009). The cat flea is commonly found on cats and dogs, but can also infest opossums, raccoon and rats (Bitam et al., 2010; Parola, 2011). Human infection is consistent clinically with other SFGR infections, with symptoms including fever, headache, myalgia and eschar at the inoculation site, and is often referred to as flea-borne spotted fever.

Rickettsia australis causes a disease called Queensland tick typhus which is endemic to Queensland and New South Wales, Australia (Campbell et al., 1979; Hudson et al., 1993). Patients with Queensland tick typhus experience malaise, headache and myalgia with a maculopapular rash appearing in most patients (Sexton et al., 1991; Pinn and Sowden, 1998; McBride et al., 2007). An eschar may be evident in approximately half of the cases and lymphadenopathy in at least 70% of cases. Additional clinical manifestations may include sore throat, nausea, cough, joint and/or abdominal pain, splenomegaly, conjunctivitis and photophobia. Although generally a mild disease, a fatal case has been described that exhibited progressive renal failure, bilateral pulmonary infiltrates, acidosis, abnormal liver function indices, thrombocytopenia and hypoprothrombinemia (Sexton et al., 1990). Rickettsia australis is transmitted to humans through the bite of Ixodes holocyclus and I. tasmani ticks with reservoir hosts that include the red rat, opossum and kangaroo (Sexton et al., 1991).

Rickettsia honei has been detected in Flinders Island and South Australia near Adelaide and is closely related to another strain of R. honei demonstrated to occur in Thailand (Stenos et al., 1998; Kollars et al., 2001; Dyer et al., 2005). This agent appears to be present on three continents as it is also closely related to a SFGR in the United States (Billings et al., 1998). It has been speculated that migratory birds may have played a role in transporting R. honei to geographically disparate areas (Stenos et al., 1998). In Thailand, R. honei was initially isolated from a pool of larval Ixodes and Rhipicephalus ticks and subsequently demonstrated in Ixodes granulatus ticks removed from Rattus rattus (Graves and Stenos, 2003). The United States strain was isolated from Amblyomma cajennense taken from cattle and the Australian strain of R. honei has been associated with Aponomma hydrosauri ticks taken from blue-tongue lizards as well as tiger and copperhead snakes. General symptoms owing to infection with R. honei (Flinders Island spotted fever) in Australian patients include fever, myalgia, arthralgia, headache, maculopapular rash and coughing may also occur (Graves et al., 1991; Stewart, 1991). The findings from seven cases in eastern Australia included: acute onset with fever (100%), headache (71%), myalgia (43%), arthralgia (43%), cough (43%), maculopapular rash (43%), pharyngitis (29%), lymphadenopathy (29%), eschar (29%) and cough (29%) (Unsworth et al., 2007). Human disease owing to R. honei has also been confirmed in Thailand by molecular-based detection of the agent in a patient with a febrile illness (Jiang et al., 2005).

Rickettsia japonica has been detected in several Asian countries including Japan, Korea and Thailand (Lee et al., 2003; Mahara, 2006). Tick species reported positive for R. japonica in Japan include Ixodes ovatus, Dermacentor taiwanensis, Haemaphysalis flava, H. formosensis and H. longicornis (Fournier et al., 2002). Isolation of this agent from wild mice, Apodemus speciosus, suggests that mice may be a mammalian reservoir for R. japonica (Yamamoto et al., 1992). The disease caused by R. japonica has been called Japanese or Oriental spotted fever. A total of 144 cases of Japanese spotted fever were reported by the National Institutes of Health in Japan between 1984 and 1995 (Jang et al., 2004). Mahara described 31 cases diagnosed in the Tokushima Prefecture of Japan which typically had the following composite clinical picture: acute high fever in all patients often accompanied by shaking chills, malaise, headache in 80% of patients, and a characteristic exanthema with eschar observed in 90% of cases (Mahara, 1997). The characteristic erythemas developed on all extremities and spread rapidly to all parts of the body including palms and soles. The erythemas became petechial after 3–4 days and disappeared within 2 weeks; although in severe petechial cases, the brown pigmentation remained for 2 months or more. Rare manifestation included swelling of the liver and spleen in a few cases as well as one patient each with cardiomegaly and central nervous system involvement.

Rickettsia sibirica has been detected in China, France, Portugal, Israel and sub-Saharan Africa including Algeria, Niger and south Africa (Parola et al., 2001; Pretorius and Birtles, 2004; Fournier et al., 2005; de Sousa et al., 2006; Zhang et al., 2006; Harrus et al., 2011). Ticks associated with R. sibirica include Hyalomma asiaticum and H. truncatum (Parola et al., 2001). The disease caused by R. sibirica has been called lymphangitis-associated rickettsiosis. Clinical manifestations commonly seen included fever (all patients), myalgias, headaches, maculopapular rash and one or more eschars. Enlarged regional lymph nodes and lymphangitis were documented in some but not all patients (Fournier et al., 2005). Retinal vasculitis has been reported in one case (Caron et al., 2008).

Rickettsia heilongjiangensis has been demonstrated in Northern China and eastern Asia (Mediannikov et al., 2004). This agent has been detected in Dermacentor sylvarum and Hyalomma concinna ticks (Fan et al., 1999; Mediannikov et al., 2004). The disease caused by infection with R. heilongjiangensis is known as Far eastern spotted fever. Clinical findings from 13 patients included: malaise, chills, headache, anorexia, myalgias and arthralgias in all 13, dizziness (11/13), maculopapular rash (12/13) and nausea (2/13) (Mediannikov et al., 2004). The disease reported has generally been mild with no serious complications or deaths reported.

Rickettsia helvetica has been demonstrated in ticks throughout Europe including France, Switzerland, Croatia, Italy, Germany, Netherlands, Portugal, Poland, Hungary, Denmark and Sweden (Burgdorfer et al., 1979; Parola et al., 1998; Nilsson et al., 1999a,b; Beninati et al., 2002; Hartelt et al., 2004; Nielsen et al., 2004; Sreter et al., 2005; Santos-Silva et al., 2006; Stanczak, 2006; Wolfel et al., 2006; Nijhof et al., 2007; Boretti et al., 2009; Dobec et al., 2009). This species has also been demonstrated by molecular procedures in sika deer blood and ticks in Japan (Fournier et al., 2002; Inokuma et al., 2008). Rickettsia helvetica is transmitted primarily by Ixodes ricinus, a tick species in which it is maintained both transstadially and transovarially (Sprong et al., 2009) but has also been demonstrated in Dermacentor reticulatus ticks (Dobec et al., 2009). It is possible that large mammals such as deer may act as reservoir hosts for this agent although DNA from this agent has also been found in mice and wild boar (Nielsen et al., 2004; Inokuma et al., 2008; Sprong et al., 2009). Rickettsia helvetica is a pathogen of humans with symptoms including fever, headache, arthralgia and myalgia (Baumann et al., 2003; Fournier et al., 2004; Sreter et al., 2005; Blanco and Oteo, 2006). This agent has also been implicated in two fatal cases of perimyocarditis (Nilsson et al., 1999a,b; Nilsson et al., 2005).

Rickettsia slovaca has been demonstrated in southern and eastern Europe including France, Hungary, Slovakia, Armenia, Ukraine, Switzerland, Yugoslavia and Portugal (Raoult et al., 2002b; Parola et al., 2009). It is also found in Central Asia as far as to the western border of China (Sekeyova et al., 1998). This agent has been detected in Dermacentor marginatus and D. reticulatus ticks throughout Europe (Parola et al., 2005). The disease caused by R. slovaca is commonly called tick-borne lymphadenopathy (TIBOLA) or Dermacentor-borne necrosis erythema and lymphadenopathy (DEBONEL). Cervical lymph node enlargement is common (Gouriet et al., 2006). Clinical manifestations may include fever, painful eschar, adenopathies, face oedema, rash, headache, alopecia (may be chronic) and asthenia which may be prolonged (Parola et al., 2009).

R. massiliae appears to have a wide geographic distribution that includes Europe (France, Greece, Spain, Portugal, Switzerland, Sicily), Middle East (Israel), Canary Islands, Africa (Central Africa, Mali, Ivory Coast) and the United States (Arizona, California) (Beati and Raoult, 1993; Dupont et al., 1994; Eremeeva et al., 2006; Berrelha et al., 2009; Fernández De Mera et al., 2009; Beeler et al., 2011; Harrus et al., 2011). This agent has been detected in Rhipicephalus genera ticks including R. turanicus, R. bursa, R. sanguineus, R. mushamae, R. sulcatus, R. lunulatus and R. pusillus, and R. senegalis, (Beati and Raoult, 1993; Dupont et al., 1994; Fernández De Mera et al., 2009; Harrus et al., 2011). Wild rabbits, Oryctolagus cuniculus, appear to play a role in the natural cycle (Fernández De Mera et al., 2009). Rickettsia massiliae has not commonly been associated with human disease. However, this species was confirmed as a human pathogen by isolation of the agent from a 45-year-old male with symptoms that included fever, maculopapular rash, a necrotic eschar on his right ankle and with slight hepatomegaly (Vitale et al., 2006).

Rickettsia aeschlimannii has been detected in Africa (Egypt, Morocco, Zimbabwe) and the Mediterranean region (Portugal) (Beati et al., 1997; Loftis et al., 2006). The agent has been isolated from Hyalomma marginatum ticks in Africa (Beati et al., 1997). The first documented human infection with R. aeschlimannii occurred in a 36-year-old Moroccan man in August 2000. Shortly after returning from France, he observed a vesicular lesion on his ankle which became necrotic (Raoult et al., 2002a). The patient had fever of 39.5°C and a generalized maculopapular rash. An early serum sample was seropositive to selected rickettsial antigens and R. aeschlimannii DNA was amplified by PCR.

Spotted Fever Group Rickettsiae – Non-Pathogenic Species/Unknown Pathogens

  1. Top of page
  2. Summary
  3. Impacts
  4. Introduction
  5. Spotted Fever Group Rickettsiae (SFGR) – Human Pathogens
  6. Spotted Fever Group Rickettsiae – Non-Pathogenic Species/Unknown Pathogens
  7. Rickettsia canadensis
  8. Recognition of Spotted Fever Group Rickettsial Infections
  9. Spotted Fever Group Rickettsiae in Canada
  10. Spotted Fever Group Rickettsiae as Emerging Pathogens
  11. Conflicts of interest
  12. References

Rickettsia peacockii is a non-pathogenic SFGR species found as an endosymbiont of D. andersoni and is maintained in these ticks by transovarial and transstadial transmission. Its presence in ticks is correlated with the reduced prevalence of R. rickettsii in tick populations. Historically, R. peacockii was known as the East side agent, owing to its presence in ticks on the eastern side of the Bitterroot valley in Montana (Burgdorfer et al., 1981). Notably, R. peacockii was detected in a very high frequency in D. andersoni from the eastern side of the Bitterroot valley, whereas virulent R. rickettsii was essentially absent. In contrast, R. rickettsii-infected ticks were detected at a much higher rate on the western side of the Bitterroot valley, consistent with the fact that most human cases of RMSF were associated with exposure to ticks on the western side of the valley. This led to the interference hypothesis, which proposed that the presence of R. peacockii in D. andersoni ticks may prevent the transovarial transmission of R. rickettsii and reduce its spread in the tick population (Niebylski et al., 1997). Ticks carrying R. peacockii also have a reproductive advantage because they do not suffer from reduced fecundity associated with R. rickettsii infection of ticks (Felsheim et al., 2009).

Rickettsia montanensis has been detected in D. variabilis ticks throughout the United States and Canada, although at a much lower frequency than R. peacockii in D. andersoni (Ammerman et al., 2004; Dergousoff et al., 2009; Dergousoff et al., 2009; Moncayo et al., 2010). Rickettsia montanensis is a non-pathogenic species that may also affect the epidemiology of RMSF by interfering with transovarial transmission of R. rickettsii in ticks or by conferring protective immunity to infected mammalian hosts subsequently exposed to R. rickettsii, thereby preventing these mammals from becoming amplifying hosts for virulent rickettsial species (Baldridge et al., 2010; Ceraul et al., 2011).

Rickettsia rhipicephali has been detected in R. sanguineus, D. occidentalis, D. variabilis and D. andersoni from the United States and Canada. (Burgdorfer et al., 1975; Wikswo et al., 2008; Shapiro et al., 2010). This SFGR has also been detected in Rhipicephalus lunulatus from Central African Republic (Cazorla et al., 2008). The role of R. rhipicephali as a human pathogen is currently unknown.

Rickettsia amblyommii has been detected in a high proportion of A. americanum ticks in the United States, although there is currently no evidence to support the role of this rickettsial species as a human pathogen. This SFGR has also been detected in Amblyomma species in Mexico, Brazil, Argentina, Costa Rica, Panama and French Guyana (Labruna et al., 2004; Parola et al., 2007; Labruna, 2009; Jiang et al., 2010; Bermudez et al., 2011).

Rickettsia canadensis

  1. Top of page
  2. Summary
  3. Impacts
  4. Introduction
  5. Spotted Fever Group Rickettsiae (SFGR) – Human Pathogens
  6. Spotted Fever Group Rickettsiae – Non-Pathogenic Species/Unknown Pathogens
  7. Rickettsia canadensis
  8. Recognition of Spotted Fever Group Rickettsial Infections
  9. Spotted Fever Group Rickettsiae in Canada
  10. Spotted Fever Group Rickettsiae as Emerging Pathogens
  11. Conflicts of interest
  12. References

Although R. canadensis, along with R. bellii, is now classified as a member of the ancestral group, this agent was historically considered a SFGR species. Detailed phylogenetic analyses have indicated that R. canadensis and R. bellii were the first to diverge from the common ancestor of rickettsiae, accounting for their placement into a separate clade (Roux and Raoult, 2000; Gillespie et al., 2007, 2008). Rickettsia canadensis was first isolated from Haemaphysalis leporispalustris ticks removed from rabbits in Ontario, Canada, in 1963 (McKiel et al., 1967). Rickettsia canadensis was isolated from a H. leporispalustris tick removed from a black-tailed jack rabbit in California in 1980 (Philip et al., 1982). However, R. canadensis has not been associated with human infection, and has not been detected in ticks in North America during recent surveillance studies, although these studies have not involved the collection of H. leporispalustris ticks, likely accounting for the lack of detection of this agent in recent years.

Recognition of Spotted Fever Group Rickettsial Infections

  1. Top of page
  2. Summary
  3. Impacts
  4. Introduction
  5. Spotted Fever Group Rickettsiae (SFGR) – Human Pathogens
  6. Spotted Fever Group Rickettsiae – Non-Pathogenic Species/Unknown Pathogens
  7. Rickettsia canadensis
  8. Recognition of Spotted Fever Group Rickettsial Infections
  9. Spotted Fever Group Rickettsiae in Canada
  10. Spotted Fever Group Rickettsiae as Emerging Pathogens
  11. Conflicts of interest
  12. References

As with all infectious diseases, proper recognition of SFGR infections starts with clinical diagnosis or suspicion that prompts laboratory testing for confirmation. Clinical symptoms may range from fevers with possible rashes to rare instances of fatal cases simulating viral haemorrhagic fever (de Almeida et al., 2010). Clinicians must consider clinical symptoms as well as travel/exposure histories when requesting diagnostic tests in order for proper laboratory tests to be undertaken. These tests may include serology, molecular detection, immunohistochemistry and culture (Table 3).

Table 3.   Summary of key laboratory diagnostic tests for SFGR
Diagnostic testSamples for collectionPoints to rememberTesting available in Canada
  1. IFA, immunofluorescence assay; ELISA, enzyme-linked immunosorbent assay; ATBF, African tick bite fever; NML, National Microbiology Laboratory; OPHL, Ontario Public Health Laboratory; SFGR, spotted fever group of rickettsial.

Serology (IFA, ELISA)Acute and convalescent serum samples collected 2–3 weeks apartAntibodies to R. africae develop more slowly than antibodies to other SFGR – the convalescent sample should be drawn a minimum of 4 weeks after the acute sample if ATBF is suspected Serology cannot distinguish between SFGR speciesYes: IFA testing performed by the NML (all provinces/territories except for Ontario) and the OPHL (Ontario only)
Molecular detection (real-time PCR, conventional PCR with sequencing)Skin punch biopsy of eschar Cutaneous skin swab under eschar Skin biopsy of rash Eschar Whole bloodCutaneous skin swabs are a reliable alternative to skin punch biopsies but have the advantage of being painless The sensitivity of PCR testing on whole blood is low Samples should be collected prior to the initiation of antibiotic therapy Can distinguish between SFGR speciesYes: testing performed by the NML for all provinces/territories
ImmunohistochemistrySkin punch biopsy of eschar Skin biopsy of rashCannot distinguish between SFGR speciesNot available
CultureSkin punch biopsy of eschar Skin biopsy of rash Cutaneous skin swab under eschar EscharNot used for routine confirmatory testingNot routinely available; consult NML for specific cases

Whereas serology may be performed by a number of laboratories, referral of appropriate diagnostic specimens to a specialized reference laboratory will allow a more precise identification of the infecting species, as well as potentially more conclusive diagnostics as paired sera may simply display static titres if precise timing of specimen collection is not achieved to demonstrate a diagnostic change in titres. Antibodies may not be present early in infection, and are known to be delayed in African tick bite fever patients, making the collection of both acute and convalescent samples critical. Hence complementing serology with other test procedures such as PCR is desirable. Molecular and culture-based detection methods are limited to reference laboratories and are not readily available in many countries. Even when this testing is available, patients are often unwilling to agree to the collection of invasive samples, such as skin punch biopsies, required for determination of the SFGR species responsible for infection. However, a cutaneous swab under the eschar or skin lesion can be collected when biopsies are not possible and are useful for the molecular detection of SFGR (Bechah et al., 2011). Whole blood specimens are limited in their usefulness for detection by PCR as rickettsiae do not circulate in the blood in large numbers unless the patient has progressed to very severe infection. Samples for molecular detection should be collected ideally prior to the administration of antibiotics, although treatment should never be withheld to collect these samples.

Physicians should be aware that travel-associated rickettsioses are not rare infections. In fact, Rickettsia africae, the agent of African tick bite fever, is one of the most common causes of systemic febrile illness in travellers returning from Africa, in particular, sub-Saharan Africa (Wilson et al. 2007; Jensenius et al. 2009; Mendelson et al. 2010). Most infections appear to be relatively mild although complications have been reported (Jensenius et al., 2006). Rickettsia africae is transmitted by Amblyomma hebraeum and A. variegatum which are common throughout west, central and southern Africa. A. variegatum is also widespread in the Caribbean and R. africae-infected ticks have been detected in the West Indies (Kelly et al., 2010). Amblyomma hebraeum and A. variegatum are aggressive, host-seeking ticks that readily bite humans. This factor, combined with the high frequency of infected ticks, likely accounts for the high prevalence of antibodies detected in humans from Africa and the West Indies, and the increasing reports of travel-associated infections in tourists returning from these areas (Parola et al., 1999). ATBF should be included in the differential diagnosis of travellers returning from endemic regions presenting with fever particularly if a skin lesion is present. ATBF is also frequently associated with multiple eschars, again owing to the aggressive biting habits of Amblyomma ticks, and this clinical feature is highly suggestive of infection with R. africae.

Almost all spotted fever rickettsioses detected in Canadian travellers have been associated with travel to Africa. Between 2006 and 2011, 24 probable or confirmed cases of spotted fever rickettsioses have been detected at our National Microbiology Laboratory in Winnipeg based on molecular and/or serological testing and history of travel to Africa. A confirmed case is defined as illness in a patient with at least a 4-fold change in SFGR antibody titre between paired serum specimens or a PCR-positive eschar biopsy (confirmed by sequencing of the PCR product to determine the species responsible for infection). A probable case is defined as illness in a patient with a single SFGR antibody titre ≥256. Although most cases were detected by serology, preventing the assignment of a specific SFGR species responsible for infection, the most likely species responsible for these infections is R. africae, the most common SFGR associated with infection in travellers returning from Africa (McQuiston et al., 2004). Unfortunately, very limited epidemiological and clinical data are available for the SFGR cases in Canada, prohibiting a detailed analysis of these infections.

Travel-associated cases of SFGR have also been detected at the National Microbiology Laboratory in Canadian travellers with a history of travel to the United States preceding the onset of illness, specifically to the states of Missouri, Arizona and Montana, although these cases are infrequent compared to spotted fever rickettsioses in Canadians returning from Africa. Probable cases of SFGR have also been detected in travellers returning from India and Australia, consistent with the worldwide distribution of these pathogens.

Spotted Fever Group Rickettsiae in Canada

  1. Top of page
  2. Summary
  3. Impacts
  4. Introduction
  5. Spotted Fever Group Rickettsiae (SFGR) – Human Pathogens
  6. Spotted Fever Group Rickettsiae – Non-Pathogenic Species/Unknown Pathogens
  7. Rickettsia canadensis
  8. Recognition of Spotted Fever Group Rickettsial Infections
  9. Spotted Fever Group Rickettsiae in Canada
  10. Spotted Fever Group Rickettsiae as Emerging Pathogens
  11. Conflicts of interest
  12. References

Established and emerging rickettsial species are significant causes of endemic and potentially severe tick-transmitted human illness in the United States, but are infrequently associated with illness in Canada. The annual reported incidence of RMSF in the United States rose from 1.7 to 7 cases per million persons from 2000 to 2007, the highest rate ever recorded (Openshaw et al., 2010). Interestingly, an increase in SFGR cases was not detected in Canada during this same period of time, based on passive surveillance of cases detected at the National Microbiology Laboratory. Spotted fever rickettsioses, including RMSF, are not reportable infections in Canada, unlike in the United States, making it difficult to determine the true frequency of these infections. However, D. variabilis and D. andersoni are common throughout Canada, with D. andersoni found in western Canada and D. variabilis found in central and eastern Canada, with an overlapping population of these species in Saskatchewan.

Rickettsia rickettsii has been isolated from D. andersoni collected in Alberta and British Columbia (Humphreys and Campbell, 1947). In central and eastern Canada, R. rickettsii has been isolated from Dvariabilis collected in southwestern Ontario (Six Nations reserve, Cardoc, Walpole Island) during 1965–1971, from H. leporispalustris collected from the Ottawa region during 1965–1972 and from D. variabilis and H. leporispalustris collected on the south shore of Nova Scotia during 1976–1980 (M. Garvie, personal communication).

However, more recent but limited studies of the prevalence of rickettsiae in ticks from across Canada have failed to detect R. rickettsii in Dermacentor andersoni and D. variabilis ticks. With the exception of five ticks from British Columbia, which were positive by PCR for R. rhipicephali and three ticks which were positive for an unidentified rickettsial agent, only R. peacockii has been detected in D. andersoni and only R. montanensis has been detected in D. variabilis ticks from across Canada, suggesting that the risk of acquiring tick-transmitted spotted fever rickettsial infections in Canada is low (Dergousoff et al., 2009; Teng et al., 2011). More work is needed to determine if R. rickettsii or less virulent SFGR are circulating among ticks and small mammal reservoirs in Canada.

The extremely low frequency of detection of R. rickettsii in D. variabilis is well documented and may be the result of the lethal effects of this virulent SFGR on tick hosts (Stromdahl et al., 2010). However, SFGR cases continue to be reported in the United States from areas with D. variabilis populations, and yet the lack of detection of R. rickettsii-infected D. variabilis ticks suggests that this species is not responsible for most SFGR cases detected within these geographical regions. It has been proposed that other ticks species known to transmit SFGR, such as R. sanguineus, A. maculatum and A. americanum, may actually be responsible for SFGR cases in geographical regions where these species exist in sympatry with D. variabilis (Stromdahl et al., 2010). This is consistent with the spatial clustering of SFGR cases in the United States in regions where the range of Dermacentor, Amblyomma and Rhipicephalus ticks overlap, but the extremely low number of reports of SFGR cases in from areas with D. variabilis alone (Adjemian et al., 2009; Stromdahl et al., 2010).

Amblyomma americanum is introduced into Canada each year and can be found over a wide geographic range, although these are adventitious ticks carried from the United States – there are no established populations of this species in the country. Rhipicephalus sanguineus is established in focal populations throughout Canada, mostly associated with dog kennels (L. R. Lindsay, personal communication). In contrast, the geographical range of A. maculatum does not extend into Canada. As a result, fewer potential tick vectors of SFGR may be present in Canada compared to the United States. Environmental factors are also critical in influencing the distribution and abundance of tick species in a geographical region (Ogden et al., 2008). In this regard, there is a distinct difference in the climate of even the southern-most regions of Canada compared to many areas of the United States, where some tick vectors may be active throughout the year. As a result, the potential for exposure to tick species known to transmit SFGR is likely much lower in Canada compared to the United States, perhaps accounting in part for the differences in reported rates of infection between these two countries.

Spotted Fever Group Rickettsiae as Emerging Pathogens

  1. Top of page
  2. Summary
  3. Impacts
  4. Introduction
  5. Spotted Fever Group Rickettsiae (SFGR) – Human Pathogens
  6. Spotted Fever Group Rickettsiae – Non-Pathogenic Species/Unknown Pathogens
  7. Rickettsia canadensis
  8. Recognition of Spotted Fever Group Rickettsial Infections
  9. Spotted Fever Group Rickettsiae in Canada
  10. Spotted Fever Group Rickettsiae as Emerging Pathogens
  11. Conflicts of interest
  12. References

Spotted fever group rickettsiae are excellent examples of newly recognized or emerging infectious diseases. Tick-borne rickettsiae have been identified as emerging pathogens including R. honei in Australia, R. japonica in Japan, R. heilongjiangensis in China and the Russian Far East, R. sibirica in China, Europe and Africa, R. aeschlimannii and R. massiliae in Africa and Europe, R. conorii in Astrakhan, Africa and Kosovo, and R. africae in sub-Saharan Africa and the West Indies (Parola and Raoult, 2006).

Rickettsiae have long been overlooked as aetiological agents of disease due mainly to specialized reagents and tests required for their diagnosis not available to most laboratories. However, the use of cell culture and molecular biology in recent years has deepened our knowledge on rickettsiae including members of the SFG. Prior to 1990, only 7 pathogenic species of rickettsial species were identified including R. prowazekii, R. typhi, R. conorii, R. rickettsii, R. sibirica, R. australis and R. akari (Raoult, 2009). At least nine additional tick-transmitted pathogens have been identified since 1991 including R. japonica, R. honei, R. africae, R. slovaca, R. parkeri, R. helvetica, R. aeschlimannii and R. heilongjiangensis. That trend is expected to continue particularly in view of the fact that there are many rickettsial agents that have been identified in ticks to which no role in human disease is currently ascribed.

Raoult (2009) has identified three scenarios under which new rickettsial diseases have been found. They include (i) places where no disease has been identified previously; (ii) places where Rickettsial disease is already recognized but where additional related species are causing disease but have been misdiagnosed by confusion with the established-related species; and (iii) cases where atypical clinical findings for rickettsial disease (no fever, no rash) have been observed.

Rickettsial infections are anticipated to be on the increase and have been reported to represent the third most common vector-borne disease that is acquired during international travel (Parola et al., 2005). They appear to be important causes of fever of unknown origin encountered in travellers returning to their country (O’Brien et al., 2001). Most are likely owing to SFG rickettsiae for which diagnostics are not readily available to many laboratories. Similarly, it is anticipated that rickettsial infections in companion animals such as dogs are not readily detected and likely to be on the increase (Boretti et al., 2009). Rickettsioses are considered important companion animal vector-borne diseases (Day, 2011). Domestic dogs can serve as sentinels for rickettsial infections, as the early diagnosis of canine rickettsiosis may precede the onset and/or recognition of infection in the owner. Dogs are also responsible for transporting ticks into close contact with their owners, and owners may be exposed to infected ticks when removing the ticks from their pets (Day, 2011). For some tick species, such as R. sanguineus, dogs serve as the primary blood source for all stages of the tick. In 2003, an outbreak of RMSF was reported in eastern Arizona, and R. sanguineus ticks were identified as the vectors responsible for infection. Subsequent studies demonstrated that 77% of dogs in the outbreak communities had serological evidence of exposure to SFGR (Demma et al., 2005, 2006a,b; Demma et al., 2007; McQuiston et al., 2011). A large outbreak of RMSF with multiple fatalities associated with R. sanguineus-infested stray dogs was also reported in Mexicali, Baja California, Mexico, in 2009 (Eremeeva et al., 2011). Rural dogs in the southwestern Canadian prairies have also been demonstrated to be seropositive to RMSF antigen by the immunofluorescent antibody test (Leighton et al., 2001).

It has been suggested that the interaction between humans and R. sanguineus ticks, which thrive in peridomestic environments, may be more common than currently realized and that these interactions may increase in the future owing to increases in warmer temperatures globally which have been shown to increase the aggressiveness of R. sanguineus ticks and thus human attacks (Dantas-Torres, 2008; Parola et al., 2008). Domestic pets, namely cats and dogs, may also introduce fleas into the home of their owners, which could serve as a source of infection for R. felis. The presence of vectors known to transmit SFGR in the home environment should also be considered in patients with suspected SFGR infection.

Improved diagnosis of rickettsial diseases starts with an alert clinician making the appropriate initial diagnosis and/or having the insight to order a wide range of diagnostics in suspect cases. Patients with histories of tick bites should be tested for SFG rickettsiae as well as other potential agents such as Borrelia burgdorferi or Colorado tick fever virus. Travellers returning home from tropical countries with symptoms such as fever, rash and myalgias should be tested for SFG rickettsial infection in addition to the more commonly ordered tests for malaria, dengue and leptospirosis. In particular, patients with atypical rash or fever after arthropod bite should be targeted. Apart from routine tests available in regional or provincial/state laboratories, specimens should be referred to appropriate reference laboratories for additional testing where deemed appropriate. Improved diagnostics and better diagnostic surveillance will undoubtedly uncover many additional rickettsial infections particularly of the SFG.

References

  1. Top of page
  2. Summary
  3. Impacts
  4. Introduction
  5. Spotted Fever Group Rickettsiae (SFGR) – Human Pathogens
  6. Spotted Fever Group Rickettsiae – Non-Pathogenic Species/Unknown Pathogens
  7. Rickettsia canadensis
  8. Recognition of Spotted Fever Group Rickettsial Infections
  9. Spotted Fever Group Rickettsiae in Canada
  10. Spotted Fever Group Rickettsiae as Emerging Pathogens
  11. Conflicts of interest
  12. References
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