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
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
Epidemiology
Angelakis E, Mediannikov O, Parola P, et al.: Rickettsia felis: The complex journey of an emergent human pathogen. Trends Parasitol. 2016, 32, 554‐64
Reif KE, Macaluso KR: Ecology of Rickettsia felis: A review. J Med Entomol. 2009, 46, 723‐36
Transmission
Angelakis E, Mediannikov O, Parola P, et al.: Rickettsia felis: The complex journey of an emergent human pathogen. Trends Parasitol. 2016, 32, 554‐64
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
Diagnosis
Angelakis E, Mediannikov O, Parola P, et al.: Rickettsia felis: The complex journey of an emergent human pathogen. Trends Parasitol. 2016, 32, 554‐64
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
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
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
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
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
Reif KE, Macaluso KR: Ecology of Rickettsia felis: A review. J Med Entomol. 2009, 46, 723‐36
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
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
