Research and Reports in Tropical Medicine Dovepress open access to scientific and medical research Open Access Full Text Article R E V I E w An update on the detection and treatment of Rickettsia felis Laya Hun Abstract: Rickettsia felis was described as a human pathogen almost two decades ago, and Adriana Troyo human infection is currently reported in 18 countries in all continents. The distribution of this Centro de Investigación en species is worldwide, determined by the presence of the main arthropod vector, Ctenocephalides Enfermedades Tropicales, Facultad de felis (Bouché). The list of symptoms, which includes fever, headache, myalgia, and rash, keeps Microbiología, Universidad de Costa increasing as new cases with unexpected symptoms are described. Moreover, the clinical presen- Rica, San José, Costa Rica tation of R. felis infection can be easily confused with many tropical and nontropical diseases, as well as other rickettsial infections. Although specific laboratory diagnosis and treatment for this flea-borne rickettsiosis are detailed in the scientific literature, it is possible that most human cases are not being diagnosed properly. Furthermore, since the cat flea infests different common domestic animals, contact with humans may be more frequent than reported. In this review, we provide an update on methods for specific detection of human infection by R. felis described in the literature, as well as the treatment prescribed to the patients. Considering advances in molecular detection tools, as well as options for as-yet-unreported isolation of R. felis from patients in cell culture, increased diagnosis and characterization of this emerging pathogen is warranted. Keywords: Rickettsia felis, human cases, laboratory diagnosis, treatment Introduction Rickettsia felis is considered an emerging human pathogen and the etiologic agent of flea-borne rickettsiosis, also known as flea-borne spotted fever and cat flea typhus. Rickettsioses are arthropod-borne diseases caused by obligate rod-shaped, intracellular Gram-negative α-proteobacteria of the genus Rickettsia, which can infect humans and different animals.1 The genus Rickettsia has been divided into three major groups based on their antigenic and genetic characteristics: (1) the spotted fever group (SFG), which includes several nonpathogenic as well as pathogenic species such as the etiological agents of Rocky Mountain spotted fever/Brazilian spotted fever (Rickettsia rickettsii), Mediterranean spotted fever (R. conorii), flea-borne spotted fever (R. felis), rickettsial pox (R. akari), R. massiliae, and R. slovaca; (2) the typhus group (TG), which includes the etiological agents of epidemic and endemic typhus (R. prowazekii and R. typhi); Correspondence: Laya Hun Sección de Virología, Centro de and (3) the ancestral group, containing R. belli and R. canadensis. 2–4 Although a Investigación en Enfermedades Tropicales, fourth group has been proposed more recently, which separates R. akari, R. australis, Facultad de Microbiología, Universidad de Costa Rica, Sede Rodrigo Facio Brenes, and R. felis from the SFG and places them in a separate group called the transitional Montes de Oca, San José 2060, Costa Rica group,5,6 the validity of a separate group for these species has been debated.7,8 Tel +506 2511 4363 Fax +506 2225 4384 R. felis was first observed by electron microscopy from midgut epithelial cells and Email ruchlia.hun@ucr.ac.cr other tissues of adult cat fleas (Ctenocephalides felis felis), and it was named “ELB” submit your manuscript | www.dovepress.com Research and Reports in Tropical Medicine 2012:3 47–55 47 Dovepress © 2012 Hun and Troyo, publisher and licensee Dove Medical Press Ltd. This is an Open Access http://dx.doi.org/10.2147/RRTM.S24753 article which permits unrestricted noncommercial use, provided the original work is properly cited. Hun and Troyo Dovepress after El-Labs (Soquel, CA).9 A close affinity of ELB to Given that the cat flea is cosmopolitan in distribution, the R. typhi was demonstrated initially by immunofluorescence presence of R. felis follows this same pattern, and has been assays.9,10 Additional characterization of the ELB agent fol- already reported in every continent except Antarctica.10,17,35–41 lowed, and evidence from polymerase chain reaction (PCR) However, R. felis is not restricted to C. felis, and molecular amplification, restriction fragment length polymorphism evidence of infection, although less frequent, has been (RFLP) analyses, and sequencing of the 17 kDa protein and reported in other species of arthropods, such as fleas, ticks, and citrate synthase gene (gltA) fragments indicated that ELB was mites, including the familiar species Ctenocephalides canis, distinct from R. typhi.10–12 Other studies confirmed this same Xenopsylla cheopis, Pulex irritans, Tunga penetrans, fact, and description of the organism as R. felis was performed Echidnophaga gallinacea, Rhipicephalus sanguineus, by Higgins et al in 1996.13 Initial isolation and cultivation Amblyomma cajennense, chiggers (Trombiculidae), and even had been reported by Radulovic et al,11 but maintenance in in nonbiting insects.19,20,22–28,34,35 culture was not possible at the time, and contamination with In most of these cases, the presence of R. felis in arthro- R. typhi was suspected.14 In 2001, Bouyer et al amplified the pods has been confirmed by detection and sequencing or recombinant outer membrane protein A gene (ompA) by PCR, RFLP analyses of rickettsia-specific gene fragments, the a gene present only in SFG rickettsiae.14 Although previous most common being gltA, htrA (17 kDa protein), ompA, and evidence from analysis of other gene sequences suggested ompB.22 Quantitative real-time PCR (qPCR) assays to detect placement of R. felis in the SFG,2,10 this evidence of ompA R. felis DNA in fleas have also been developed and are useful finally confirmed that the new Rickettsia was in fact a member in determining infection load and kinetics.42,43 Conversely, of the SFG. Rickettsia felis was further characterized and successful isolation and culture of R. felis directly from cat redescribed, and descriptions were emended in 2002.14,15 fleas has been reported only from laboratories in France, A study by Merhej et al showed that most genes of R. felis the US, Brazil, and Costa Rica using cell lines of verte- genome place it in the SFG clade.8 However, phylogenetic brate (XTC-2 and Vero) and arthropod (ISE6 and C6/36) analyses of R. felis genes revealed that some of them come origin.36,44–46 No isolation of R. felis from vertebrates has been from a variety of origins, as has been shown for other bac- reported. The conditions of cultivation and growth of R. felis teria like Escherichia coli, which demonstrates that not all in different cell lines are described later in this review. genes show vertical inheritance during evolutionary history Rickettsia felis is maintained in flea populations mainly and that horizontal gene transfer probably occurs. Rickettsia by transovarial transmission.10,47 Evidence also suggests felis can acquire new genes horizontally, since it has been horizontal transmission from other infected fleas or infection shown that this species is present in many different hosts,16–28 through a rickettsemic blood meal is likely.48,49 Although and concomitant infections by more than one intracellular there is no evidence of fitness loss or increased mortality in bacterium may lead to recombination events.8 It has also been infected C. felis, results of some studies suggest that R. felis demonstrated that R. felis can have one, two, or no plasmids, may actually increase fitness to facilitate transmission to the which were probably acquired through horizontal exchange next generation of fleas or a vertebrate host.43 by conjugation.5,29–31 Although studies have recognized all Infection of vertebrates probably occurs during blood genes in the different R. felis studied, their function is not all feeding of infected fleas, although transmission through clear. It would be important in future to determine if those infective flea feces is possible.47,50 Various domestic and newly acquired genes could change characteristics like tro- peridomestic animals may exhibit evidence of R. felis natu- pism or antigenicity. ral infection. Antibodies against R. felis can be present in animals, including dogs, cats, and opossums, and the pres- R. felis infection in invertebrate ence of specific DNA fragments has also been detected in and vertebrate animals animals.51–62 Since acquisition of R. felis from blood meal and The ecology of R. felis has been reviewed previously,22,32–34 transmission from fleas to animals has been demonstrated in and although it is not the focus of this review, some general laboratory experiments,47,49 cats, dogs, and opossums have considerations are presented concerning infection and detec- been considered possible reservoirs.13,53,57,62 tion in vertebrate and invertebrate hosts. Symptomatic disease caused by R. felis infection in The cat flea, C. felis felis, is considered the primary vector domestic or wild animals may vary, but a direct causal asso- and reservoir of R. felis. Detection of R. felis DNA in these ciation has not been proven. One study showed no statisti- fleas has been successful everywhere it has been investigated. cal association between presence of R. felis antibodies and 48 submit your manuscript | www.dovepress.com Research and Reports in Tropical Medicine 2012:3 Dovepress Dovepress Detection and treatment of Rickettsia felis illness in cats,56 and another report mentions a PCR-positive aminotransferase (85–108 U/L) and alanine aminotransferase dog with fatigue and digestive symptoms.54 In addition, an (135–160 U/L).69,70,81 experimental infection of opossums with R. felis resulted in Knowledge of epidemiological context, clinical history, antibody response, although bacteremia was undetectable.61 signs, symptoms, and general laboratory tests are important Given that isolation of R. felis directly from sick animals for diagnosis of rickettsial diseases. Since infection with has not been performed so far and that prevalence of infec- R. felis can cause illness anywhere from mild to moderate to tion and/or rickettsemia may not be high,56,63–65 there is no severe, it may be confused with signs and symptoms of other conclusive evidence at this time to confirm the role of these infectious and noninfectious diseases. Therefore, diagnosis animals as reservoirs or victims of disease. of flea-borne spotted fever requires specific laboratory tests to detect R. felis infection. Human cases of flea-borne spotted fever Laboratory detection Human infection with R. felis has already been reported in the of R. felis infection in humans US,66 Mexico,67–69 Brazil,36 France,36,70 Germany,52 Spain,54,71 Methods for detection of R. felis infection in humans are Sweden,72 Israel,73 South Korea,74 Taiwan,75 Thailand,76 derived from the general methods used in diagnosis for rick- Laos,77 Tunisia,78,79 Egypt,80 Australia,81 Senegal,82 Kenya,83,84 ettsial diseases. Although the general principles and applica- and New Zealand.85 tions of these methods have been reviewed previously,3,87,88 Clinical findings for R. felis infection may be confused the following section describes their applications in detection with infection due to other rickettsial agents like R. typhi of specific R. felis infection. and some members of the SFG, as well as other infectious diseases like dengue, malaria, brucellosis, leptospirosis, or Detection of antibodies even other clinical conditions like Kawasaki disease.69,77,81,83 Specific methods for the diagnosis of rickettsial diseases of One example of misdiagnosis is a case reported as murine the SFG in humans started in the late 1960s utilizing sero- typhus diagnosed by serology in 2008, which in 2010 was logic tests, the immunofluorescent antibody assay being the confirmed by PCR as an infection by R. felis and not R. typhi, reference method for detection of specific antibodies to SFG using the patient’s same frozen serum.73 rickettsiae.89,90 The most important limitation of serologic Fever (greater than 38°C), headache, myalgia, and tests is the cross-reaction that occurs between species of rick- maculopapular rash are the most common symptoms.66 The ettsiae within the same group and sometimes even between presence of a cutaneous eschar at the bite site is possible, groups. Although this cross-reaction is common between although it may be infrequent.52,70 Respiratory and digestive species,91–93 immunofluorescence is considered the reference symptoms, including cough, pulmonary edema, pneumonia, method for diagnosis of rickettsial infection.3,87,88 It is also nausea, vomiting, and diarrhea, have been reported.35,67,70,86 the first step towards the diagnosis and screening of rick- Neurological signs have also been documented, such as the ettsial diseases for mainly nonendemic geographic areas.94 reports of infection in patients presenting subacute meningitis Twofold serial dilutions of the sera should be performed to and acute polyneuropathy-like symptoms from Sweden and determine an end titer using antigens from one or more spe- Taiwan, respectively.72,75 Although R. felis infection in most cies of rickettsiae. Absorption of sera with complementary cases has been observed as a mild to moderate illness, respi- rickettsiae can be useful when cross-reactivity occurs, and ratory, neurologic, and visceral affections can occur, leading Western blot may also aid in species identification.3,95 to complications such as those reported in severe cases from Detection of antibodies to SFG or TG rickettsiae in human Mexico.69 Although no deaths attributed to R. felis infection infections with R. felis has been performed by immunofluo- are reported in the literature, the first two cases reported from rescence methods in some of the cases reported, although Brazil presented stupor, and one of them coma.36 species confirmation has been determined by other means During R. felis infection, laboratory results for tests (Table 1). A general guideline used for identification of the like hematocrit and hemoglobin are usually in the normal rickettsial agent responsible is mentioned in several of the range, but some patients have severe thrombocytopenia reports.3 According to this, if cross-reactivity occurs, a higher and elevated bilirubin (2.7–3.1 mg/dL), which presents as titer of antibodies to R. felis in comparison to other species jaundice.69 The most common abnormalities are associ- (usually by two or more serial dilutions) would suggest ated with increased aminotransferase levels: aspartate specific infection by R. felis or a very similar species.36,76 Research and Reports in Tropical Medicine 2012:3 submit your manuscript | www.dovepress.com 49 Dovepress Hun and Troyo Dovepress Table 1 Summary of Rickettsia felis–specific diagnostic/confirmatory methods and treatment reported in human infection Country Year of N cases R. felis-specific detection Specific R. felis treatment Reference publication confirmed and identification methods* and outcome USA 1994 1 PCR 17-kDa protein gene fragment Doxycycline 66 RFLP Southern hybridization Brazil 2001 2 MIF antibody titers to R. felis higher NI 36 by two or more dilutions Nested PCR gltA gene fragment, sequencing (1 patient) Mexico 2000 3 PCR 17-kDa protein gene Doxycycline 2 weeks (one patient), 67 fragment; sequencing recovered 2006 1 PCR 17-kDa protein gene Doxycycline, discharged after 1 week 68 fragment, sequencing Chloramphenicol 2009 2 PCR gltA, ompA, ompB, gene (IV 75 mg/kg per day for 10 days), 69 fragments, sequencing and RFLP both recovered within 5 days France 2001 2 MIF antibody titers to R. felis NI 36 higher by two or more dilutions 2009 1 MIF, R. felis confirmed by Western Doxycycline, rapid improvement 70 blot with cross-adsorption Germany 2002 1 Seroconversion, MIF antibody titers to Doxycycline (200 mg/day for 7 days), 52 R. felis higher by two or more dilutions, recovered within 3 days species confirmed by Western blot Nested PCR for PS120 protein gene fragment Thailand 2003 1 MIF antibody titers to R. felis higher by Doxycycline (200 mg/day for 7 days) 76 two or more dilutions, species confirmed by Western blot South 2005 3 Nested PCRs ompB and gltA gene NI 74 Korea fragments, RFLP and sequencing Spain 2005 5 MIF antibody titers to R. felis higher by NI 54 two or more dilutions, species confirmed by western blot with cross-adsorption 2006 2 Nested PCRs gltA and ompB gene fragment, Doxycycline (200 mg/day for 10 days), 71 seminested PCR ompA, sequencing recovered within 2 days Tunisia 2006 8 MIF, western blot with cross-adsorption NI 78 2009 1 MIF, western blot with cross-adsorption Tetracycline and doxycycline 79 Laos 2006 1 MIF, western blot with cross-adsorption NI 77 Egypt 2007 1 Quantitative real-time PCR specific NI 80 for R. felis ompB gene fragment Israel 2010 1 Quantitative real-time PCR specific Doxycycline 73 for R. felis ompB gene fragment Kenya 2010 6 Quantitative real-time and nested PCR NI 83 17 kDa protein gene fragments, sequencing Quantitative real-time PCR specific for R. felis ompB gene fragment Nested PCR ompB gene fragment, sequencing 2012 21 PCR R. felis plasmid NI 84 PCR 17-kDa protein gene, ompB, R. felis plasmid gene fragments, sequencing Quantitative real-time PCR specific for R. felis ompB gene fragment Australia 2011 5 (probable) MIF, high titers or seroconversion Doxycycline (one patient), 81 to TG rickettsiae improved PCR gltA gene fragment from cat fleas, sequencing Senegal 2010 8 Quantitative real-time and nested NI 82 PCR gltA gene fragments, sequencing Quantitative real-time PCR biotin synthase R. felis-specific gene fragment (Continued) 50 submit your manuscript | www.dovepress.com Research and Reports in Tropical Medicine 2012:3 Dovepress Dovepress Detection and treatment of Rickettsia felis Table 1 (Continued) Country Year of N cases R. felis-specific detection Specific R. felis treatment Reference publication confirmed and identification methods* and outcome Taiwan 2008 1 Quantitative real-time PCR 17-kDa protein, Doxycycline (oral 100 mg 75 groEL, ompB gene fragments, sequencing every 12 hours for 5 days) Sweden 2010 2 Quantitative real-time PCR gltA; nested Nonspecific antibiotics 72 PCR 17-kDa protein and ompB gene fragments, sequencing New 2012 2 MIF, R. felis confirmed by Western NI 85 Zealand blot with cross-adsorption Note: *PCRs not specific for R. felis unless otherwise stated. Abbreviations: PCR, polymerase chain reaction; RFLP, restriction fragment length polymorphism; MIF, microimmunofluorescence; NI, not indicated or not applicable. In addition, confirmation of R. felis antibodies has been synthase gene.42,82,97 This approach has been used to detect performed by Western blot and/or cross-adsorption R. felis-specific infection in humans, which eliminates the analyses.70,71,76–78 However, these methods may not determine need for sequencing (Table 1).73,80,82,83 the species of Rickettsia responsible in every case.52,71,78,85 The presence of immunoglobulin G (IgG) antibodies in Isolation in cell culture humans, which probably represent past infection with R. felis, Isolation of R. felis from human cases in cell culture has has been demonstrated and may be relatively frequent.85,93,96 not been reported; it has only been documented from Considering that the presence of IgG antibodies to R. felis invertebrates. The best samples for isolation attempts, as is does not necessarily mean current infection, demonstration true for other SFG rickettsiae, would be blood and skin biop- 3,87 of specific seroconversion to R. felis is required and has been sies, mainly from the eschar zone if present. Although used to confirm the presence of R. felis using immunological different cells like Vero (primate), XTC-2 (amphibian), methods.52 However, this is not without limitations, since C6/36 (Aedes albopictus), ISE6 (tick), Aa23 (A. albopic- seroconversion for IgG may appear a month or more after tus), Sua5B (Anopheles gambiae), L929 (mouse), and rickettsial infection. HUVEC (human) have been shown to support R. felis growth,11,36,44–46,98–101 the cell lines have either not been suc- Molecular methods cessful for isolation of R. felis from human samples, or this Rickettsia felis infection has been frequently diagnosed by has not been attempted. PCR amplification of targeted genes. Samples are usually Successful isolates from fleas reported, for instance, that whole blood or serum, although highly sensitive nested R. felis was detected in XTC-2 cells after 14 days in initial and/or real-time PCR assays may be required to detect very isolation and after 6 days in subsequent passages, while low concentrations of rickettsial DNA present in serum. In growth was half the rate in Vero cells.36 Initial detection a recent report from Sweden, R. felis DNA was detected of R. felis growth in cell culture is usually determined by in cerebrospinal fluid from two patients.72 The genes Giménez stain. Growth is optimal at 28°C in XTC-2 cells, most commonly amplified are gltA, ompB, and htrA. The and growth has been demonstrated at 28°C and 32°C in ompA gene has also been used, although detection can be Vero, room temperature in Aa23 and Sua5B, 25°C and variable.54,69 Several of the published reports indicate that 28°C in C6/36, and 32°C in ISE6 cell lines.36,44–46,98 Plaque R. felis was detected by amplifying more than two genes, production is reported at 9 and 18 days in XTC-2 and Vero and amplicons were confirmed as R. felis by sequencing in cells, respectively,15 while almost 100% infection is reported most cases (Table 1). in Aa23 and Sua5B cells within 7 days of passaging.98 Sequencing of PCR products is usually necessary in Isolation and propagation reports show that R. felis grows order to get a definitive identification, considering that better at lower temperatures, in agreement with the usual con- these genes are present in all SFG rickettsiae and only ditions of their invertebrate host. Since optimal temperature specific variations in each sequence allow differentia- for growth of mammalian cells is usually higher, replication tion. It has been difficult to properly standardize qPCR to of R. felis may be reduced or does not occur. Nevertheless, separate between different SFG rickettsiae; nevertheless, Saisongkorh et al report the establishment of R. felis for up real-time PCR methods have been developed specifically to ten passages in mammalian cells (Vero and L 929) at for R. felis gene fragments, including ompB and the biotin 28°C, enhanced by using 4% of tryptose phosphate broth Research and Reports in Tropical Medicine 2012:3 submit your manuscript | www.dovepress.com 51 Dovepress Hun and Troyo Dovepress as a supplement in minimum essential medium (MEM) cell is a common ectoparasite of dogs and cats globally, infection culture medium with 2% fetal bovine serum.101 by R. felis is probably more common than reported. Misdi- Growth of R. felis in these various vertebrate and inver- agnosis may be frequent in many cases due to poor aware- tebrate cell lines is possible, although isolation from human ness and information, as well as minimum or no availability or other vertebrates has not been reported in the literature. of specific laboratory testing required to implicate R. felis In other species such as R. rickettsii, different strains have directly. Although symptomatic cases are usually mild, there shown varying virulence depending on the vector or host are reports of severe disease where treatment is essential. species of isolation.102,103 Therefore it is of utmost importance Considering that R. felis infections can be treated in the to attempt isolation of the bacterium, especially from human same manner as other rickettsiae (doxycycline is the drug cases with apparent disease. If culture is successful, isolates of choice), timely diagnosis and treatment is important to of R. felis from symptomatic patients would allow further prevent complications and severe outcomes. Therefore, public characterization of virulence factors, pathogenic potential, health authorities should increase awareness and diagnosis and course of infection of these pathogenic strains. of R. felis, especially in developing countries, in order to recognize the presence of this global emerging disease. Clinical treatment Whenever signs and symptoms suggest rickettsial disease, Disclosure treatment should be started immediately, even before laboratory The authors report no conflicts of interest in this work. diagnosis is complete. Doxycycline (200 mg per day) is the antibiotic of choice for spotted fever rickettsioses.104–106 References 1. Raoult D, Roux V. Rickettsioses as paradigms of the new or emerging These general guidelines have also been applied in flea-borne infectious diseases. Clin Microbiol Rev. 1997;10(4):694–719. rickettsiosis (Table 1). For pregnant patients or patients 2. Stothard D, Fuerst P. Evolutionary analysis of the spotted fever and thyphus groups of rickettsia using 16S rRNA gene sequences. Syst Appl who are allergic to this drug, disease may be treated with Microbiol. 1995;18(1):52–61. chloramphenicol. In severe cases, intravenous antibiotic is 3. Parola P, Paddock CD, Raoult D. Tick-borne rickettsioses around the recommended for at least 24–48 hours after defervescence world: emerging diseases challenging old concepts. Clin Microbiol Rev. 2005;18(4):719–756. of fever. As with other rickettsioses, doxycycline is the anti- 4. Vitale G, Mansuelo S, Rolain JM, Raoult D. Rickettsia massiliae human biotic of choice for complicated cases of flea-borne typhus, isolation. Emerg Infect Dis. 2006;12(1):174–175. 5. Gillespie JJ, Beier MS, Rahman MS, et al. Plasmids and rickettsial although chloramphenicol has been used successfully to treat evolution: insight from Rickettsia felis. PloS One. 2007;2(3):e266. severe cases.69 Recently, josamycin, a macrolide antibiotic, 6. Weinert LA, Werren JH, Aebi A, Stone GN, Jiggins FM. Evolution and fluoroquinolones have been used in other rickettsioses,3,107 and diversity of Rickettsia bacteria. BMC Biology. 2009;7(6):1–15. 7. Fournier PE, Raoult D. Current knowledge on phylogeny and taxonomy and they could also be effective against R. felis. of Rickettsia spp. Ann N Y Acad Sci. 2009;1166:1–11. Although infection with R. felis may be self-limiting, 8. Merhej V, Notredame C, Royer-Carenzi M, Pontarotti P, Raoult D. The rhizome of life: the sympatric Rickettsia felis paradigm dem- disease should be treated due to the possibility of severe ill- onstrates the random transfer of DNA sequences. Mol Biol Evol. ness and complications.62,72,75 The prompt and specific labo- 2011;28(11):3213–3223. ratory diagnosis of the diseases is very important, not only 9. Adams JR, Schmidtmann ET, Azad AF. Infection of colonized cat fleas, Ctenocephalides felis (Bouché), with a Rickettsia-like microorganism. because it will help the patient’s condition, but also in order Am J Trop Med Hyg. 1990;43(4):400–409. to avoid using other antibiotics that may lead to selection of 1 0. Azad AF, Sacci JBJ, Nelson WM, et al. Genetic characterization and transovarial transmission of a typhus-like rickettsia found in cat fleas. resistant bacteria, or other useless therapies like intravenous Proc Natl Acad Sci U S A. 1992;89:43–46. immunoglobulin in cases where Kawasaki disease has been 11. Radulovic S, Higgins J, Jaworski D, Dasch G, Azad A. Isolation, suspected.81 cultivation, and partial characterization of the ELB agent associated with cat fleas. Infect Immun. 1995;63(12):4826–4829. 1 2. Williams SG, Sacci JB, Schriefer ME, et al. Typhus and typhuslike Conclusion rickettsiae associated with opossums and their fleas in Los Angeles County, California. J Clin Microbiol. 1992;30(7):1758–1762. The present review endorses the importance of R. felis as 13. Higgins J, Radulovic S, Schriefer ME, Azad AF. Rickettsia felis: a new a pathogen to be considered in human cases presenting species of pathogenic rickettsia isolated from cat fleas. J Clin Microbiol. clinical symptoms that are common to many infectious 1996;34(3):671–674. 14. Bouyer DH, Stenos J, Crocquet-Valdes P, et al. Rickettsia felis: molecular diseases caused by different rickettsial species and other characterization of a new member of the spotted fever group. Int J Syst microorganisms. Human cases of flea-borne spotted fever Evol Microbiol. 2001;51:339–347. 15. Scola B La, Meconi S, Fenollar F, Rolain JM. Emended description of have been described to date in almost 20 countries around Rickettsia felis (Bouyer et al, 2001), a temperature-dependent cultured the world. Since the main vector and reservoir, C. felis felis, bacterium. Int J Syst Evol Microbiol. 2002;52:2035–2041. 52 submit your manuscript | www.dovepress.com Research and Reports in Tropical Medicine 2012:3 Dovepress Dovepress Detection and treatment of Rickettsia felis 1 6. Stevenson HL, Labruna MB, Montenieri JA, et al. Detection of Rickettsia 3 9. Rolain JM, Franc M, Davoust B, Raoult D. Molecular detection of felis in a New World flea species, Anomiopsyllus nudata (Siphonaptera: Bartonella quintana, B. koehlerae, B. henselae, B. clarridgeiae, Ctenophthalmidae). J Med Entomol. 2005;42(2):163–167. Rickettsia felis, and Wolbachia pipientis in cat fleas, France. Emerg 1 7. Bitam I, Parola P, De La Cruz KD, et al. First molecular detection of Infect Dis. 2003;9(3):338–342. Rickettsia felis in fleas from Algeria. Am J Trop Med Hyg. 2006;74(4): 40. Parola P, Sanogo OY, Lerdthusnee K, et al. Identification of Rickettsia 532–535. spp. and Bartonella spp. in from the Thai-Myanmar border. Ann N Y 18. Venzal JM, Martinez-Perez L, Felix ML, et al. Prevalence of Rickettsia Acad Sci. 2003;990:173–181. felis in Ctenocephalides felis and Ctenocephalides canis from Uruguay. 4 1. Kelly PJ, Meads N, Theobald A, Fournier PE, Raoult D. Rickettsia felis, Ann N Y Acad Sci. 2006;1078:305–308. Bartonella henselae, and B. clarridgeiae, New Zealand. Emerg Infect 19. Horta MC, Chiebao DP, de Souza DB, et al. Prevalence of Rickettsia Dis. 2004;10(5):967–968. felis in the fleas Ctenocephalides felis felis and Ctenocephalides canis 4 2. Henry KM, Jiang J, Rozmajzl PJ, et al. Development of quantitative from two Indian villages in Sao Paulo Municipality, Brazil. Ann N Y real-time PCR assays to detect Rickettsia typhi and Rickettsia felis, the Acad Sci. 2006;1078:361–363. causative agents of murine typhus and flea-borne spotted fever. Mol 20. Oliveira K, Oliveira L, Dias C, et al. Molecular identification of Rick- Cell Probes. 2007;21(1):17–23. ettsia felis in ticks and fleas from an endemic area for Brazilian Spotted 43. Reif KE, Stout RW, Henry GC, Foil LD, Macaluso KR. Prevalence Fever. Mem Inst Oswaldo Cruz. 2008;103(2):191–194. and infection load dynamics of Rickettsia felis in actively feeding cat 2 1. Eremeeva ME, Warashina W, Sturgeon M, et al. Rickettsia typhi and fleas. PloS One. 2008;3(7):e2805. R. felis in rat fleas (Xenopsylla cheopis), Oahu, Hawaii. Emerg Infect 44. Pornwiroon W, Pourciau SS, Foil LD, Macaluso KR. Rickettsia felis Dis. 2008;14(10):1613–1615. from cat fleas: isolation and culture in a tick-derived cell line. Appl 22. Reif KE, Macaluso KR. Ecology of Rickettsia felis: a review. J Med Environ Microbiol. 2006;72(8):5589–5595. Entomol. 2009;46(4):723–736. 4 5. Horta MC, Labruna MB, Durigon EL, Schumaker TTS. Isolation of 2 3. Behar A, McCormick LJ, Perlman SJ. Rickettsia felis infection in a Rickettsia felis in the mosquito cell line C6/36. Appl Environ Microbiol. common household insect pest, Liposcelis bostrychophila (Psocoptera: 2006;72(2):1705–1707. Liposcelidae). Appl Environ Microbiol. 2010;76(7):2280–2285. 4 6. Hun L, Troyo A, Taylor L, Barbieri AM, Labruna MB. First report of 24. Nogueras MM, Pons I, Ortuño A, Lario S, Segura F. Rickettsia felis the isolation and molecular characterization of Rickettsia amblyommii in fleas from Catalonia (Northeast Spain). Vector Borne Zoonotic Dis. and Rickettsia felis in Central America. Vector Borne Zoonotic Dis. 2011;11(5):479–483. 2011;11(10):1395–1397. 25. Reeves WK, Loftis AD, Sanders F, et al. Borrelia, Coxiella, and 47. Wedincamp J, Foil LD. Vertical transmission of Rickettsia felis in the Rickettsia in Carios capensis (Acari: Argasidae) from a brown pelican cat flea (Ctenocephalides felis Bouché). J Vector Ecol. 2002;27(1): (Pelecanus occidentalis) rookery in South Carolina, USA. Exp Appl 96–101. Acarol. 2006;39(3–4):321–329. 48. Hirunkanokpun S, Thepparit C, Foil LD, Macaluso KR. Horizontal 2 6. Gilles J, Just FT, Silaghi C, et al. Rickettsia felis in fleas, Germany. transmission of Rickettsia felis between cat fleas, Ctenocephalides felis. Emerg Infect Dis. 2008;14(8):1294–1296. Mol Ecol. 2011;20(21):4577–4586. 2 7. Boudebouch N, Sarih M, Beaucournu J, et al. Bartonella clarridgeiae, 49. Reif KE, Kearney MT, Foil LD, Macaluso KR. Acquisition of B. henselae and Rickettsia felis in fleas from Morocco. Ann Trop Med Rickettsia felis by cat fleas during feeding. Vector Borne Zoonotic Dis. Parasitol. 2011;105(7):493–498. 2011;11(7):963–968. 2 8. Loftis AD, Reeves WK, Szumlas DE, et al. Rickettsial agents in 50. Macaluso KR, Pornwiroon W, Popov VL, Foil LD. Identification of Egyptian ticks collected from domestic animals. Exp Appl Acarol. Rickettsia felis in the salivary glands of cat fleas. Vector Borne Zoonotic 2006;40:67–81. Dis. 2008;8(3):391–396. 29. Rolain JM, Bitam I, Buffet S, et al. Presence or absence of plasmid in 5 1. Boostrom A, Beier MS, Macaluso JA, et al. Geographic association of Rickettsia felis depending on the source of fleas. Clin Microbiol Infect. Rickettsia felis-infected opossums with human murine typhus, Texas. 2009;15 Suppl 2:S296–S297. Emerg Infect Dis. 2002;8(6):549–554. 30. Baldridge GD, Burkhardt NY, Labruna MB, et al. Wide dispersal and 5 2. Richter J, Fournier PE, Petridou J, Häussinger D, Raoult D. Infection possible multiple origins of low-copy-number plasmids in Rickettsia acquired in Europe and documented by polymerase chain reaction. species associated with blood-feeding arthropods. Appl Environ Emerg Infect Dis. 2002;8(2):207–208. Microbiol. 2010;76(6):1718–1731. 53. Case JB, Chomel B, Nicholson W, Foley JE. Serological survey of 31. Fournier PE, Belghazi L, Robert C, et al. Variations of plasmid content vector-borne zoonotic pathogens in pet cats and cats from animal in Rickettsia felis. PloS One. 2008;3(5):1–6. shelters and feral colonies. J Feline Med Surg. 2006;8(2):111–117. 3 2. Pérez–Osorio CE, Zavala-Velázquez JE, Arias León JJ, Zavala-Castro JE. 54. Oteo JA, Portillo A, Santibañez S, et al. Cluster of cases of human Rickettsia felis as emergent global threat for humans. Emerg Infect Dis. Rickettsia felis infection from Southern Europe (Spain) diagnosed by 2008;14(7):1019–1023. PCR. J Clin Microbiol. 2006;44(7):2669–2671. 3 3. Znazen A, Raoult D. Flea-borne spotted fever. In: Raoult D, Parola P, 55. Labruna MB, Horta MC, Aguiar DM, et al. Prevalence of Rickettsia editors. Rickettsial Diseases. New York, NY: Informa Heathcare; infection in dogs from the urban and rural areas of Monte Negro 2007:87–96. Municipality, Western Amazon, Brazil. Vector Borne Zoonotic Dis. 3 4. Abdad MY, Stenos J, Graves S. Rickettsia felis, an emerging flea- 2007;7(2):249–255. transmitted human pathogen. Emerg Health Threats J. 2011;4:7168. 56. Bayliss DB, Morris AK, Horta MC, et al. Prevalence of Rickettsia spe- 35. Parola P. Rickettsia felis: from a rare disease in the USA to a common cause cies antibodies and Rickettsia species DNA in the blood of cats with of fever in sub-Saharan Africa. Clin Microbiol Infect. 2011;17: and without fever. J Feline Med Surg. 2009;11(4):266–270. 996–1000. 57. Nogueras M, Pons I, Ortuño A, Segura F. Seroprevalence of Rickettsia 36. Raoult D, Scola B La, Enea M, et al. A flea-associated Rickettsia typhi and Rickettsia felis in dogs from north-eastern Spain. Clin pathogenic for humans. Emerg Infect Dis. 2001;7(1):73–81. Microbiol Infect. 2009;15 Suppl 2:S237–S238. 3 7. Márquez FJ, Muniain MA, Pérez JM, Pachón J. Presence of Rickettsia 58. Lappin MR, Hawley J. Presence of Bartonella species and Rickettsia felis in the cat flea from Southwestern Europe. Emerg Infect Dis. species DNA in the blood, oral cavity, skin and claw beds of cats in 2002;8(1):89–91. the United States. Vet Dermatol. 2009;20(5–6):509–514. 3 8. Oliveira RP, Galvao MA, Mafra CL, et al. Rickettsia felis in 59. Silva Fortes F, Silveira I, Moraes-Filho J, et al. Seroprevalence of Rick- Ctenocephalides spp. fleas, Brazil. Emerg Infect Dis. 2002;8(3): ettsia bellii and Rickettsia felis in dogs, São José dos Pinhais, State of 317–319. Paraná, Brazil. Rev Bras Parasitol Vet. 2010;19(4):222–227. Research and Reports in Tropical Medicine 2012:3 submit your manuscript | www.dovepress.com 53 Dovepress Hun and Troyo Dovepress 6 0. Horta MC, Scott FB, Correia TR, et al. Rickettsia felis infection 83. Richards AL, Jiang J, Omulo S, et al. Human infection with Rickettsia in cat fleas Ctenocephalides felis. Braz J Microbiol. 2010;41: felis, Kenya. Emerg Infect Dis. 2010;16(7):1081–1086. 813–818. 84. Maina A, Knobel D, Jiang J, et al. Rickettsia felis infection on 6 1. Horta MC, Sabatini GS, Moraes-Filho J, et al. Experimental infection of febrile patients, Western Kenya, 2007–2010. Emerg Infect Dis. the opossum Didelphis aurita by Rickettsia felis, Rickettsia bellii, and 2012;18(2):328–331. Rickettsia parkeri and evaluation of the transmission of the infection 85. Lim M, Brady H, Hambling T, et al. Rickettsia felis infections, to ticks Amblyomma cajennense and Amblyomma dubitatum. Vector New Zealand. Emerg Infect Dis. 2012;18(1):167–169. Borne Zoonotic Dis. 2010;10(10):959–967. 86. Galvão MAM, Mafra C, Chamone CB, et al. Clinical and laboratorial 62. Hii SF, Kopp SR, Abdad MY, et al. Molecular evidence supports the evidence of Rickettsia felis infections in Latin America. Rev Soc Bras role of dogs as potential reservoirs for Rickettsia felis. Vector Borne Med Trop. 2004;37(3):238–240. Zoonotic Dis. 2011;11(8):1007–1012. 87. Scola B La, Raoult D. Laboratory diagnosis of rickettsioses: current 6 3. Hawley JR, Shaw SE, Lappin MR. Prevalence of Rickettsia felis DNA approaches to diagnosis of old and new rickettsial diseases. J Clin in the blood of cats and their fleas in the United States. J Feline Med Microbiol. 1997;35(11):2715–2727. Surg. 2007;9:258–262. 88. Fenollar F, Fournier PE, Raoult D. Flea-borne spotted fever. In: 64. Kamrani A, Parreira VR, Greenwood J, Prescott JF. The prevalence Raoult D, Parola P, editors. Rickettsial Diseases. New York: Informa of Bartonella, hemoplasma, and Rickettsia felis infections in domestic Heathcare; 2007:315–330. cats and in cat fleas in Ontario. Can J Vet Res. 2008;72:411–419. 89. Philip RN, Casper EA, Ormsbee RA, Peacock MG, Burgdorfer W. 6 5. Barrs VR, Beatty JA, Wilson BJ, et al. Prevalence of Bartonella species, Microimmunofluorescence test for the serological study of Rocky Rickettsia felis, haemoplasmas and the Ehrlichia group in the blood of Mountain spotted fever and typhus. J Clin Microbiol. 1976;3(1):51–61. cats and fleas in eastern Australia. Aust Vet J. 2010;88(5):160–165. 90. Newhouse VF, Shepard CC, Redus MD, Tzianabos T, McDade JE. 6 6. Schriefer ME, Sacci JB, Dumler JS, Bullen MG, Azad AF. Identification A comparison of the complement fixation, indirect fluorescent anti- of a novel rickettsial infection in a patient diagnosed with murine typhus. body, and microagglutination tests for the serological diagnosis of J Clin Microbiol. 1994;32(4):949–954. rickettsial diseases. Am J Trop Med Hyg. 1979;28(2):387–395. 6 7. Zavala-Velázquez JE, Ruiz-Sosa JA, Sánchez-Elias RA, 91. Anacker RL, Mann RE, Gonzales C. Reactivity of monoclonal anti- Becerra-Carmona G, Walker DH. Rickettsia felis rickettsiosis in bodies to Rickettsia rickettsii with spotted fever and typhus group Yucatán. Lancet. 2000;356(9235):1079–1080. rickettsiae. J Clin Microbiol. 1987;25(1):167–171. 6 8. Zavala-Velazquez J, Laviada-Molina H, Zavala-Castro J, et al. Rickettsia 92. Ormsbee R, Peacock M, Philip R, et al. Antigenic relationships felis, the agent of an emerging infectious disease: report of a new case between the typhus and spotted fever groups of rickettsiae. Am J in Mexico. Arch Med Res. 2006;37(3):419–422. Epidemiol. 1978;108(1):53–59. 6 9. Zavala-Castro J, Zavala-Velazquez J, Walker D, Perez-Osorio J, 93. Bernabeu-Wittel M, del Toro MD, Nogueras MM, et al. Peniche-Lara G. Severe human infection with Rickettsia felis Seroepidemiological study of Rickettsia felis, Rickettsia typhi, and associated with hepatitis in Yucatan, Mexico. Int J Med Microbiol. Rickettsia conorii infection among the population of southern Spain. 2009;299:529–533. Eur J Clin Microbiol Infect Dis. 2006;25(6):375–381. 7 0. Renvoise A, Joliot AY, Raoult D. Rickettsia felis infection in man, 94. Parola P, Raoult D. Ticks and tickborne bacterial diseases in France. Emerg Infect Dis. 2009;15(7):1126–1127. humans: an emerging infectious threat. Clin Infect Dis. 2001;32(6): 7 1. Pérez-Arellano J, Fenollar F, Angel-Moreno A, et al. Human 897–928. Rickettsia felis infection, Canary Islands, Spain. Emerg Infect Dis. 95. Jensenius M, Fournier PE, Vene S, et al. Comparison of immu- 2005;11(12):1961–1964. nofluorescence, Western blotting, and cross–adsorption assays 7 2. Lindblom A, Severinson K, Nilsson K. Rickettsia felis infection in for diagnosis of African tick bite fever. Clin Diagn Lab Immunol. Sweden: report of two cases with subacute meningitis and review of 2004;11(4):786–788. the literature. Scand J Infect Dis. 2010;42(11–12):906–909. 96. Nogueras MM, Cardeñosa N, Sanfeliu I, et al. Serological evidence of 73. Ben-Zvi I, Meltzer E, Nogueras M, Segura F, Bank I. First detection infection with Rickettsia typhi and Rickettsia felis among the human of human infection with Rickettsia felis in Israel. Am J Med Sci. population of Catalonia, in the Northeast of Spain. Am J Trop Med 2010;340(4):343. Hyg. 2006;74(1):123–126. 74. Choi YJ, Kim JH, Jang WJ, et al. Spotted fever group and typhus 97. Blair PJ, Jiang J, Schoeler GB, et al. Characterization of spotted fever group rickettsioses in humans, South Korea. Emerg Infect Dis. group rickettsiae in flea and tick specimens from Northern Peru. J Clin 2005;11(2):237–244. Microbiol. 2004;42(11):4961–4967. 7 5. Tsai KH, Lu HY, Tsai JJ, et al. Human case of Rickettsia felis infection, 98. Sakamoto JM, Azad AF. Propagation of arthropod-borne Taiwan. Emerg Infect Dis. 2008;14(12):1970–1972. Rickettsia spp. in two mosquito cell lines. Appl Environ Microbiol. 76. Parola P, Miller R, McDaniel P, et al. Emerging rickettsioses of the 2007;73(20):6637–6643. Thai-Myanmar border. Emerg Infect Dis. 2003;9(5):592–595. 99. Sunyakumthorn P, Bourchookarn A, Pornwiroon W, et al. 7 7. Phongmany S, Rolain J, Phetsouvanh R, et al. Rickettsial infections Characterization and growth of polymorphic Rickettsia felis in a tick and fever, Vientiane, Laos. Emerg Infect Dis. 2006;12(2):256–262. cell line. Appl Environ Microbiol. 2008;74(10):3151–3158. 78. Znazen A, Rolain J, Hammami N, et al. Rickettsia felis infection, 100. Thepparit C, Sunyakumthorn P, Guillotte ML, et al. Isolation of a Tunisia. Emerg Infect Dis. 2006;12(1):138–140. rickettsial pathogen from a non-hematophagous arthropod. PLoS One. 79. Kaabia N, Letaief A. Characterization of rickettsial diseases in a 2011;6(1):1–11. hospital-based population in central Tunisia. Ann N Y Acad Sci. 1 01. Saisongkorh W, El Karkouri K, Patrice JY, et al. Tryptose phosphate 2009;1166:167–171. broth improves Rickettsia felis replication in mammalian cells. FEMS 80. Parker TM, Murray CK, Richards AL, et al. Concurrent infections in Immunol Med Microbiol. 2012;64(1):111–114. acute febrile illness patients in Egypt. Am J Trop Med Hyg. 2007;77(2): 102. Parker R, Pickens E, Lackman D, Bell E, Thraikill F. Isolation and 390–392. characterization of Rocky Mountain spotted fever rickettsiae from the 81. Williams M, Izzard L, Graves SR, Stenos J, Kelly JJ. First probable rabbit tick Haemaphysalis leporis-palustris Packard. Public Health Australian cases of human infection with Rickettsia felis (cat-flea Rep. 1951;66(15):455–463. typhus). Med J Aust. 2011;194(1):41–43. 103. Fuentes L, Calderon A, Hun L. Isolation and identification of Rickettsia 82. Socolovschi C, Mediannikov O, Sokhna C, et al. Rickettsia felis- rickettsii from the rabbit tick (Haemaphysalis leporispalustris) in associated uneruptive fever, Senegal. Emerg Infect Dis. 2010;16(7): the Atlantic zone of Costa Rica. Am J Trop Med Hyg. 1985;34(3): 1140–1142. 564–567. 54 submit your manuscript | www.dovepress.com Research and Reports in Tropical Medicine 2012:3 Dovepress Dovepress Detection and treatment of Rickettsia felis 1 04. Holman RC, Paddock CD, Curns AT, et al. Analysis of risk factors 1 06. Masters EJ, Olson GS, Scott JW, Paddock CD. Rocky Mountain for fatal Rocky Mountain spotted fever: evidence for superiority of spotted fever: a clinician’s dilemma. Arch Intern Med. 2003;16: tetracyclines for therapy. Infect Dis. 2001;184:1437–1444. 3769–3774. 105. Purvis JJ, Edwards MS. Doxycycline use for rickettsial disease in 1 07. Segura F, Antón E. Clarithromycin for the treatment of Mediterranean pediatric patients. Pediatr Infec Dis J. 2000;19(9):871–874. spotted fever. Clin Infect Dis. 2002;15;34(4):560. Research and Reports in Tropical Medicine Dovepress Publish your work in this journal Research and Reports in Tropical Medicine is an international, peer- science and new technology in tropical medicine; Parasitology; Public reviewed, open access journal publishing original research, case reports, health medicine/health care policy in tropical regions; and Microbiology. editorials, reviews and commentaries on all areas of tropical medicine, The manuscript management system is completely online and includes including: Diseases and medicine in tropical regions; Entomology; a very quick and fair peer-review system. Visit http://www.dovepress. Epidemiology; Health economics issues; Infectious disease; Laboratory com/testimonials.php to read real quotes from published authors. Submit your manuscript here: http://www.dovepress.com/research-and-reports-in-tropical-medicine-journal Research and Reports in Tropical Medicine 2012:3 submit your manuscript | www.dovepress.com 55 Dovepress