Rickettsia felis Infection

Rickettsiae are strict intracellular bacteria requiring a host cell to replicate. Within the genus Rickettsia three groups are differentiated, one of which is the spotted fever group (SFG), whose members are associated mainly with ticks, but also with fleas and mites (Raoult and Roux, 1997). Within the SFG Rickettsia felis is an emerging insect-borne rickettsial human pathogen and the causative agent of flea-borne spotted fever, also named cat flea typhus. The primary vector and reservoir of R. felis is suggested to be the cat flea Ctenocephalides felis. Dogs and cats have been screened for their prevalence of R. felis and may act as an important reservoir host for R. felis and thus as a potential source of human rickettsial infection (Ahmed et al., 2016; Hii et al., 2011; Ng-Nguyen et al., 2020).

Pathogens

Rickettsia felis is an obligate intracellular bacterium in the order Rickettsiales (Merhej et al., 2014). It is classified in the spotted fever group (SFG) of Rickettsia and according to Angelakis et al. (2016) was probably first detected in European cat fleas (Ctenocephalides felis felis) in 1918 and tentatively named ‘Rickettsia ctenocephali’ (Adams et al., 1990; Parola, 2011). In 1990, a Rickettsia-like organism originally named ELB agent that resembled Rickettsia typhi was observed by electron microscopy in the cytoplasm of midgut cells of a colony of cat fleas (Adams et al., 1990; Parola, 2011). The first isolation of R. felis was achieved in 2001 (Raoult et al., 2001).

Epidemiology

Rickettsia felis was first described as a human pathogen from the USA in 1991 and is now identified throughout the world and considered a common cause of fever in Africa (Brown and Macaluso, 2016). The cosmopolitan distribution of this pathogen may be due to the wide-spread occurrence of cat fleas (Ctenocephalides felis), which have been suggested as vectors and reservoirs of R. felis. Nevertheless, a direct transmission of the human R. felis infection through the bite of an infected flea has never been documented according to Angelakis et al. (2016). Skin contamination of human patients, contaminated dust samples and other non-haematophageous arthropods may play further roles in the epidemiology of R. felis transmission (Angelakis et al., 2016).

R. felis may not be described by a classical ‘reservoir–vector’ epidemiology where the reservoir host is an organism that harbours and multiplies the pathogen and the vector is any agent (often an arthropod) that carries and transmits an infectious pathogen into another living organism (Angelakis et al., 2016).

Since the first clinical descriptions of R. felis associated fever, cat and dog fleas (C. felis, Ctenocephalides canis) have been implicated as the most probable vectors (Parola, 2011; Reif and Macaluso, 2009). Cats and dogs are reported to carry rickettsial DNA in their blood, but it is still unclear whether the infection is long and stable enough to justify the host competence (Angelakis et al., 2016). However, they play an important role as the main hosts for fleas and, probably, amplifying hosts for R. felis, facilitating horizontal transmission among fleas. R. felis has been shown to be maintained by transstadial and transovarial transmission in C. felis (Hirunkanokpun et al., 2011), so cat fleas may potentially be a vector and reservoir of R. felis.

Additionally, R. felis has been detected molecularly in cat fleas in more than 40 countries spanning five continents (Reif and Macaluso, 2009; Abdad et al., 2011). It has also been identified in more than 20 different haematophagous species of fleas, mosquitoes, soft and hard ticks, and mites all over the world (Abdad et al., 2011; Socolovschi et al., 2012). R. felis was also shown to successfully infect Anopheles gambiae mosquitoes, the primary malarial vector in sub-Saharan Africa. More recently, it was shown in an experimental model that An. gambiae has the potential to be a vector of R. felis infection (Dieme et al., 2015).

Transmission

Cat and dog fleas (Ctenocephalides felis, Ctenocephalides canis) have been implicated as the most probable vectors for Rickettsia felis (Parola, 2011; Reif and Macaluso, 2009), but the pathogen has also been identified in other arthropods such as mosquitoes, soft and hard ticks, and mites all over the world (Abdad et al., 2011; Socolovschi et al., 2012). R. felis has been shown to be maintained by transstadial and transovarial transmission in C. felis (Hirunkanokpun et al., 2011), so cat fleas may potentially be a vector and a reservoir of R. felis. Nevertheless, a direct transmission of the human R. felis infection through the bite of an infected flea has never been documented according to Angelakis et al. (2016).

Despite the fact that transmission of R. felis is not completely clarified, especially dogs are suspected as potential reservoir for the pathogen and one of its presumable vectors. Non-domestic or wild animals including opossums and feral raccoons have also been shown to harbour R. felis (Schriefer et al., 1994; Sashika et al., 2010). Although they have been implicated as potential mammal hosts, their roles as reservoir hosts for human infection requires further elucidation.

Additionally, successful transmission of pathogens between actively blood-feeding arthropods in the absence of a disseminated vertebrate infection is possible (reviewed in Randolph, 2011). This so-called co-feeding is reliant on the temporal and spatial dynamics of infected and uninfected arthropods as they blood feed. The infected arthropod is then both, the vector and the reservoir for the pathogen, while the vertebrate acts as a conduit for infection of naïve arthropods. The potential for co-feeding transmission of R. felis between cat fleas has been demonstrated (Hirunkanokpun et al., 2011). Both, intra- and interspecific transmission of R. felis between co-feeding arthropods on a vertebrate host was demonstrated (Brown et al., 2015).

 

Pathogenesis

Rickettsia felis is an obligate intracellular bacterium in the order Rickettsiales, belonging to the spotted fever group (SFG) of Rickettsia. Generally, SFG rickettsiae can grow in the nucleus or in the cytoplasm of the host cell. Once inside the host, the rickettsiae multiply, resulting in damage and death of these cells. Information on the pathogenesis regarding R. felis is scarce.

Diagnosis

The diagnosis of Rickettsia felis in humans is challenging among others as human symptoms are nonspecific (Angelakis et al., 2016). Like in other rickettsioses, R. felis infections can be diagnosed by serological testing. The most important limitation of serologic tests is the cross-reaction that occurs between species of rickettsiae within the same group and sometimes even between groups. Although this cross-reaction is common between species (Anacker et al., 1987; Ormsbee et al., 1978; Bernabeu-Wittel et al., 2006), immunofluorescence is considered the reference method for diagnosis of rickettsial infection (Fenollar et al., 2007; La Scola and Raoult, 1997; Parola et al., 2005). R. felis infection also has been frequently diagnosed by PCR amplification of targeted genes. Several of the published molecular reports indicate that R. felis was detected by amplifying more than two genes, and amplicons were confirmed as R. felis by sequencing in most cases (summarized in Hun and Troyo, 2012). Sequencing of PCR products is usually necessary in order to get a definitive identification, considering that these genes are present in all spotted fever group (SFG) rickettsiae and only specific variations in each sequence allow differentiation (Hun and Troyo, 2012). Generally, molecular tools reduce the delay in diagnosis and allow convenient, rapid detection and identification of rickettsiae (Angelakis et al., 2016). Finally, culture is less sensitive than serology and molecular tools but can give a positive result even when molecular tests are negative (Angelakis et al., 2012).

In dogs, serological testing using microimmunofluorescence for the detection of R. felis antibodies (Hii et al., 2013) as well as molecular testing using a SFG-specific PCR targeting the ompB gene followed by a R. felis-specific PCR targeting the gltA gene of R. felis followed by sequencing, has been performed (Hii et al., 2011) to diagnose seropositivity respectively infection with R. felis.

In cats, serological and molecular testing has also been conducted to clarify potential infection and seropositivity of cats (Bayliss et al., 2009).

Besides direct testing of dogs and cats, fleas collected from dogs and cats have also been examined by PCR to clarify their potential reservoir status (e.g., Capelli et al., 2009; Troyo et al., 2012).

Clinical Signs

The clinical findings in humans for Rickettsia felis infection are often unclear and are thought to be similar to those of flea-borne murine typhus and other rickettsioses. They can range in severity (summarized in Reif and Macaluso, 2009). Typical symptoms can include fever, rash, headache, myalgia, and eschar at the bite site (Brouqui et al., 2007). More severe symptoms can result from visceral (abdominal pain, nausea, vomiting, and diarrhoea) and neurologic (photophobia and hearing loss) involvement (Galvão et al., 2006; Zavala-Velázquez et al., 2000), while recent evidence also shows R. felis to be present in samples from healthy people from Africa (Mediannikov et al., 2013), respectively afebrile people from Africa and Asia (Mourembou et al., 2015). It seems that the clinical findings in humans are dependent on the region of infection and mostly manifest as fever in patients from the tropics or fever associated with cutaneous manifestations in patients from Europe or the Americas. Fever is the only consistent manifestation of R. felis infection in patients from tropical areas. In patients from Europe and the Americas R. felis infection often manifests as febrile rash similar to murine typhus (Galvão et al., 2006; Raoult et al., 2001). This variable presentation of clinical disease can make diagnosis difficult (Azad and Radulovic, 2003), and refinement of the full spectrum of clinical disease associated with R. felis infection will expedite accurate diagnoses.

The pathogenicity of R. felis infection in dogs is unclear at this time. To date, association of clinical disease and R. felis infection in animals has not been reported according to Hii et al. (2011). In Spain, R. felis has been detected by PCR in two patients and their dog, which showed signs of fatigue, vomiting, and diarrhoea (Oteo et al., 2006), but elaboration on the clinical signs in the positive dog as well as a further work-up was not performed. In a study by Hii et al. (2011) even PCR-positive pound dogs appeared healthy. Based on the high prevalence of R. felis in the pound dogs in this Australian study the authors suggest that dogs may have the potential to act as an important reservoir and sentinel host for human infection (Oteo et al., 2006; Richter et al., 2002).

Although the domestic cat has been implicated as a potential primary reservoir for R. felis (Case et al. 2006; Higgins et al., 1996), recent evidence from a number of studies does not support this hypothesis. A prevalence study using molecular techniques reported 19.8% of flea sets collected from cats in eastern Australia harboured R. felis DNA (Barrs et al., 2010). However, the pathogen was not detected in the blood of these cats, and thus, it was speculated that domestic cats are unlikely to act as the primary vertebrate reservoir (Barrs et al., 2010). Studies conducted in the United States (Bayliss et al., 2009) and Canada (Kamrani et al., 2008) on high-risk groups of cats did not result in the detection of R. felis DNA, but only detected antibodies against R. felis (Bayliss et al., 2009). R. felis DNA has been detected using PCR assays in cats’ blood in an experimental infection study (Wedincamp and Foil, 2000) and in skin biopsy and gingival swabs of cats (Lappin and Hawley, 2009) in the United States. However, natural infection in cats with active rickettsaemia has not been verified by PCR assays.

Treatment & Prevention

Whenever signs and symptoms suggest rickettsial disease in humans, treatment should be started immediately, even before laboratory diagnosis is complete (Hun and Troyo, 2012). Generally for spotted fever rickettsioses doxycycline is the antibiotic of choice (Holman et al., 2001; Masters et al., 2003; Purvis and Edwards, 2000; Raoult and Maurin, 2002). These general treatment guidelines are also applied in flea-borne rickettsiosis (Hun and Troyo, 2012), although chloramphenicol has been used successfully to treat severe cases (Zavala-Castro et al., 2009).

Regarding dogs and cats, as there is no conclusive evidence at this time to confirm their role as reservoirs or victims of disease, general treatment is not recommended right now.

As with other vector-transmitted infections, ectoparasite control is the basis of prevention and might also enable a potential influence on human exposure.

References

Introduction

Ahmed R, Paul SK, Hossain MA, et al.: Molecular detection of Rickettsia felis in humans, cats, and cat fleas in Bangladesh, 2013-2014. Vector Borne Zoonotic Dis. 2016, 16, 356‐8 

Hii SF, Kopp SR, Abdad MY, et al.: Molecular evidence supports the role of dogs as potential reservoirs for Rickettsia felis. Vector Borne Zoonotic Dis. 2011, 11, 1007‐12 

Ng-Nguyen D, Hii SF, Hoang MT, et al.: Domestic dogs are mammalian reservoirs for the emerging zoonosis flea-borne spotted fever, caused by Rickettsia felis. Sci Rep. 2020, 10, 4151 

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Pathogens

Adams JR, Schmidtmann ET, Azad AF: Infection of colonized cat fleas, Ctenocephalides felis (Bouché), with a rickettsia-like microorganism. Am J Trop Med Hyg. 1990, 43, 400‐9 

Angelakis E, Mediannikov O, Parola P, et al.: Rickettsia felis: The complex journey of an emergent human pathogen. Trends Parasitol. 2016, 32, 554‐64 

Merhej V, Angelakis E, Socolovschi C, et al.: Genotyping, evolution and epidemiological findings of Rickettsia species. Infect Genet Evol. 2014, 25, 122‐37 

Parola P: Rickettsia felis: from a rare disease in the USA to a common cause of fever in sub-Saharan Africa. Clin Microbiol Infect. 2011, 17, 996-1000 

Raoult D, La Scola B, Enea M, et al.: A flea-associated Rickettsia pathogenic for humans. Emerg Infect Dis. 2001, 7, 73‐81

Epidemiology

Abdad MY, Stenos J, Graves S: Rickettsia felis, an emerging flea-transmitted human pathogen. Emerg Health Threats J. 2011, 4, 7168

Angelakis E, Mediannikov O, Parola P, et al.: Rickettsia felis: The complex journey of an emergent human pathogen. Trends Parasitol. 2016, 32, 554‐64 

Brown LD, Macaluso KR: Rickettsia felis, an emerging flea-borne rickettsiosis. Curr Trop Med Rep. 2016, 3, 27‐39 

Dieme C, Bechah Y, Socolovschi C, et al.: Transmission potential of Rickettsia felis infection by Anopheles gambiae mosquitoes. Proc Natl Acad Sci USA. 2015, 112, 8088‐93 

Hirunkanokpun S, Thepparit C, Foil LD, et al.: Horizontal transmission of Rickettsia felis between cat fleas, Ctenocephalides felis. Mol Ecol. 2011, 20, 4577‐86 

Parola P: Rickettsia felis: from a rare disease in the USA to a common cause of fever in sub-Saharan Africa. Clin Microbiol Infect. 2011, 17, 996-1000 

Reif KE, Macaluso KR: Ecology of Rickettsia felis: A review. J Med Entomol. 2009, 46, 723‐36

Socolovschi C, Pages F, Ndiath MO, et al.: Rickettsia species in African Anopheles mosquitoes. PLoS One. 2012, 7, e48254 

Transmission

Abdad MY, Stenos J, Graves S: Rickettsia felis, an emerging flea-transmitted human pathogen. Emerg Health Threats J. 2011, 4, 7168  

Angelakis E, Mediannikov O, Parola P, et al.: Rickettsia felis: The complex journey of an emergent human pathogen. Trends Parasitol. 2016, 32, 554‐64 

Brown LD, Christofferson RC, Banajee KH, et al.: Cofeeding intra- and interspecific transmission of an emerging insect-borne rickettsial pathogen. Mol Ecol. 2015, 24, 5475‐89 

Hirunkanokpun S, Thepparit C, Foil LD, et al.: Horizontal transmission of Rickettsia felis between cat fleas, Ctenocephalides felis. Mol Ecol. 2011, 20, 4577‐86 

Parola P: Rickettsia felis: from a rare disease in the USA to a common cause of fever in sub-Saharan Africa. Clin Microbiol Infect. 2011, 17, 996-1000

Randolph SE: Transmission of tick-borne pathogens between co-feeding ticks: Milan Labuda's enduring paradigm. Ticks Tick Borne Dis. 2011, 2, 179‐82 

Reif KE, Macaluso KR: Ecology of Rickettsia felis: A review. J Med Entomol. 2009, 46, 723‐36

Sashika M, Abe G, Matsumoto K, et al.: Molecular survey of rickettsial agents in feral raccoons (Procyon lotor) in Hokkaido, Japan. Jpn J Infect Dis. 2010, 63, 353-4 

Schriefer ME, Sacci JB, Taylor JP, et al.: Murine typhus – updated roles of multiple urban components and a second typhuslike Rickettsia. J Med Entomol. 1994, 31, 681-5 

Socolovschi C, Pages F, Ndiath MO, et al.: Rickettsia species in African Anopheles mosquitoes. PLoS One. 2012, 7, e48254 

Diagnosis

Anacker RL, Mann RE, Gonzales C: Reactivity of monoclonal antibodies to Rickettsia rickettsii with spotted fever and typhus group rickettsiae. J Clin Microbiol. 1987, 25, 167-71 

Angelakis E, Mediannikov O, Parola P, et al.: Rickettsia felis: The complex journey of an emergent human pathogen. Trends Parasitol. 2016, 32, 554‐64 

Angelakis E, Richet H, Rolain JM, et al.: Comparison of real-time quantitative PCR and culture for the diagnosis of emerging Rickettsioses. PLoS Negl Trop Dis. 2012, 6, e1540 

Bayliss DB, Morris AK, Horta MC, et al.: Prevalence of Rickettsia species antibodies and Rickettsia species DNA in the blood of cats with and without fever. J Feline Med Surg. 2009, 11, 266-70 

Bernabeu-Wittel M, del Toro MD, Nogueras MM, et al.: Seroepidemiological study of Rickettsia felis, Rickettsia typhi, and Rickettsia conorii infection among the population of southern Spain. Eur J Clin Microbiol Infect Dis. 2006, 25, 375-81 

Capelli G, Montarsi F, Porcellato E, et al.: Occurrence of Rickettsia felis in dog and cat fleas (Ctenocephalides felis) from Italy. Parasit Vectors. 2009, 2 (Suppl 1), S8 

Fenollar F, Fournier PE, Raoult D: Flea-borne spotted fever. In: Raoult D, Parola P (eds.): Rickettsial Diseases. 2007, pp. 315-30, Informa Healthcare, New York 

Hii SF, Abdad MY, Kopp SR, et al.: Seroprevalence and risk factors for Rickettsia felis exposure in dogs from Southeast Queensland and the Northern Territory, Australia. Parasite Vectors. 2013, 6, 159 

Hii SF, Kopp SR, Thompson MF, et al.: Molecular evidence of Rickettsia felis infection in dogs from Northern Territory, Australia. Parasit Vectors. 2011, 4, 198 

Hun L, Troyo A: An update on the detection and treatment of Rickettsia felis. Res Rep Trop Med. 2012, 3, 47‐55 

La Scola B, Raoult D: Laboratory diagnosis of rickettsioses: current approaches to diagnosis of old and new rickettsial diseases. J Clin Microbiol. 1997, 35, 2715-27 

Ormsbee R, Peacock M, Philip R, et al.: Antigenic relationships between the typhus and spotted fever groups of rickettsiae. Am J Epidemiol. 1978, 108, 53-9 

Parola P, Paddock CD, Raoult D: Tick-borne rickettsioses around the world: emerging diseases challenging old concepts. Clin Microbiol Rev. 2005, 18, 719-56 

Troyo A, Álvarez D, Taylor L, et al.: Rickettsia felis in Ctenocephalides felis from Guatemala and Costa Rica. Am J Trop Med Hyg. 2012, 86, 1054-6 

Clinical Signs

Azad AF, Radulovic S: Pathogenic rickettsiae as bioterrorism agents. Ann NY Acad Sci. 2003, 990, 734-8 

Barrs VR, Beatty JA, Wilson BJ, et al.: Prevalence of Bartonella species, Rickettsia felis, haemoplasmas and the Ehrlichia group in the blood of cats and fleas in eastern Australia. Aust Vet J. 2010, 88, 160-5 

Bayliss DB, Morris AK, Horta MC, et al.: Prevalence of Rickettsia species antibodies and Rickettsia species DNA in the blood of cats with and without fever. J Feline Med Surg. 2009, 11, 266-70 

Brouqui P, Parola P, Fournier PE, et al.: Spotted fever rickettsioses in southern and eastern Europe. FEMS Immunol Med Microbiol. 2007, 49, 2-12 

Case JB, Chomel B, Nicholson W, et al.: Serological survey of vector-borne zoonotic pathogens in pet cats and cats from animal shelters and feral colonies. J Feline Med Surg. 2006, 8, 111-7 

Galvão MA, Zavala-Velazquez JE, Zavala-Castro JE, et al.: Rickettsia felis in the Americas. Ann NY Acad Sci. 2006, 1078, 156‐8 

Higgins JA, Radulovic S, Schriefer ME, et al.: Rickettsia felis: a new species of pathogenic Rickettsia isolated from cat fleas. J Clin Microbiol. 1996, 34, 671-4 

Hii SF, Kopp SR, Abdad MY, et al.: Molecular evidence supports the role of dogs as potential reservoirs for Rickettsia felis. Vector Borne Zoonotic Dis. 2011, 11, 1007‐12 

Kamrani A, Parreira VR, Greenwood J, et al.: The prevalence of Bartonella, hemoplasma, and Rickettsia felis infections in domestic cats and in cat fleas in Ontario. Can J Vet Res. 2008, 72, 411-9 

Lappin MR, Hawley J: Presence of Bartonella species and Rickettsia species DNA in the blood, oral cavity, skin and claw beds of cats in the United States. Vet Dermatol. 2009, 20, 509-14 

Mediannikov O, Socolovschi C, Edouard S, et al.: Common epidemiology of Rickettsia felis infection and malaria, Africa. Emerg Infect Dis. 2013, 19, 1775‐83 

Mourembou G, Lekana-Douki JB, Mediannikov O, et al.: Possible role of Rickettsia felis in acute febrile illness among children in Gabon. Emerg Infect Dis. 2015, 21, 1808‐15 

Oteo JA, Portillo A, Santibanez S, et al.: Cluster of cases of human Rickettsia felis infection from Southern Europe (Spain) diagnosed by PCR. J Clin Microbiol. 2006, 44, 2669-71 

Raoult D, La Scola B, Enea M, et al.: A flea-associated Rickettsia pathogenic for humans. Emerg Infect Dis. 2001, 7, 73‐81

Reif KE, Macaluso KR: Ecology of Rickettsia felis: A review. J Med Entomol. 2009, 46, 723‐36

Richter J, Fournier PE, Petridou J, et al.: Rickettsia felis infection acquired in Europe and documented by polymerase chain reaction. Emerg Infect Dis. 2002, 8, 207-8 

Wedincamp J, Foil LD: Infection and seroconversion of cats exposed to cat fleas (Ctenocephalides felis Bouché) infected with Rickettsia felis. J Vector Ecol. 2000, 25, 123-6 

Zavala-Velázquez JE, Ruiz-Sosa JA, Sánchez-Elias RA, et al.: Rickettsia felis rickettsiosis in Yucatán. Lancet. 2000, 356, 1079‐80 

Treatment & Prevention

Holman RC, Paddock CD, Curns AT, et al.: Analysis of risk factors for fatal Rocky Mountain spotted fever: evidence for superiority of tetracyclines for therapy. Infect Dis. 2001, 184, 1437-44 

Hun L, Troyo A: An update on the detection and treatment of Rickettsia felis. Res Rep Trop Med. 2012, 3, 47‐55 

Masters EJ, Olson GS, Scott JW, et al.: Rocky Mountain spotted fever: a clinician’s dilemma. Arch Intern Med. 2003, 16, 3769-74 

Purvis JJ, Edwards MS: Doxycycline use for rickettsial disease in pediatric patients. Pediatr Infec Dis J. 2000, 19, 871-4 

Raoult D, Maurin M: Rickettsia species: (R. africae, R. australis, R. conorii, R. felis, R. helvetica, R. honei, R. japonica, R. mongolotimonae, R. slovaca, R. sibirica). In: Yu VL, Weber R, Raoult D (eds.): Antimicrobial Therapy and Vaccines Volume 1: Microbes. 2002, pp. 913–921, Apple Trees Production, LLC, New York 

Zavala-Castro J, Zavala-Velazquez J, Walker D, et al.: Severe human infection with Rickettsia felis associated with hepatitis in Yucatan, Mexico. Int J Med Microbiol. 2009, 299, 529-33 

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