Rickettsia felis as Emergent Global Threat for Humans

The reported incidences of human cases and infected vectors have increased during the past 5 years.

, and Xenopsylla cheopis (18); ticks, Haemaphysalis fl ava (19), Rhipicephalus sanguineus (20), and Ixodes ovatus (19); and mites from South Korea (21) (Table 1). Despite the large number of potential vectors reported, the only vector currently recognized is C. felis because it has been demonstrated that this fl ea is able to maintain a stable infected progeny through transovarial transmission (4). In addition, production of antibody to R. felis has been noted in animals after they have been exposed to infected cat fl eas (9). Other evidence to be considered is the fact that 68.8% of the reports state that the cat fl ea is the most recurrent vector in which R. felis has been detected. These data further support the wide distribution of rickettsiae because they correlate with the worldwide distribution of C. felis; this distribution represents a threat to the human population because of lack of host specifi city of the cat fl ea.
R. felis infection is diagnosed by PCR amplifi cation of targeted genes. The genes most commonly amplifi ed by researchers are gltA and ompB; followed by the 17-kDa gene. Also, 25% of published articles report that R. felis was detected by amplifying >2 genes, and all report that amplicons were confi rmed as R. felis by sequencing. The animal hosts from which the infected ectoparasites were recovered represent a diversity of mammals (Table  1), which included 9 different naturally infested animal species. However, in 16 of 33 articles, ectoparasites were recovered from dogs. Other hosts for ectoparasites were cats (in 13 of 33 reports); rodents (5 of 33 reports); opossums and hedgehogs (2 reports each); and horses, sheep, goats, gerbils, and monkeys (1 report for each animal species).
In summary, the presence of R. felis in a diverse range of invertebrate and mammalian hosts represents a high potential risk for public health and the need for further studies to establish the role of ectoparasites other than C. felis as potential vectors. To date, whether any vertebrate may serve as the reservoir of this emergent pathogen has not been determined. However, preliminary data from our laboratory suggest that opossums are the most likely candidates.

World Distribution of Human Cases
In 1994, the fi rst human case of infection with the new cat fl ea rickettsia was reported in the United States (2). This became the fi rst evidence of R. felis' potential as a human pathogen. R. felis infection had a similar clinical manifestation as murine typhus (including high fever [39°-40°C], myalgia, and rash). Although the initial idea was that the murine typhus-like rickettsia had a transmission cycle involving cat fl eas and opossums (2,5,9), no viable R. felis has yet been isolated from a vertebrate host. Three more cases of R. felis infection were reported from southeastern Mexico in 2000. The patients had had contact with fl eas or animals known to carry fl eas. The clinical manifestations were those of a typical rickettsiosis: all patients had fever and myalgia; but the skin lesions, instead of a rash, were similar to those described for rickettsialpox. In addition, for 3 patients, central nervous system involvement developed, manifested as photophobia, hearing loss, and signs of meningitis (33).
As occurred with the fast-growing reports of the worldwide detection of R. felis in arthropod hosts, the reports of human cases of R. felis infection increased rapidly in the following years (Table 2). But, in contrast, only 11 articles reported human infection by R. felis compared with 32 that reported ectoparasite infection with the new rickettsia. Nevertheless, these fi ndings indicate that an effective surveillance system is urgently needed to distinguish R. felis rickettsiosis from other rickettsial infections such as murine typhus and Rocky Mountain spotted fever, and from other febrile illnesses such as dengue. Although PCR is still a method of choice for many laboratories, its high cost prevents many from using the technique, particularly in developing countries. Important advances have been achieved in diagnostics, such as the recent establishment of a stable culture of R. felis in cell lines that allows its use as antigen in serologic assays differentiating the cat fl ea rickettsia from others. Use of this culture in the immunofl uorecent assay has enabled detection of additional human cases (38).
The fi rst autochthonous human case in Europe was reported in 2002, which demonstrated that R. felis has a potential widespread distribution and is not confi ned to the Americas. It also confi rmed the risk for human disease anywhere in the world. After the fi rst report in Europe of a human infection of R. felis, other human cases have appeared in other countries around the world, including Thailand (36), Tunisia (38), Laos (39), and Spain (40); additional cases have been reported in Mexico and Brazil (34). All the data support the conclusion that the incidence of R. felis rickettsiosis and the simultaneous worldwide distribution of the fl ea vector plausibly explain its endemicity.
At present, the involvement of domestic animals (e.g., dogs and cats) or wild animals coexisting in urban areas (e.g., opossums) maintains R. felis infection in nature. C. felis fl eas serve as the main reservoir and likely have a central role in transmission of human illness.

Conclusions
R. felis is an emergent rickettsial pathogen with a worldwide distribution in mammals, humans, and ectoparasites. The clinical manifestations of R. felis infections resemble those of murine typhus and dengue, which makes them diffi cult to diagnose without an appropriate laboratory test. For this reason, infections due to this emergent pathogen are likely underestimated and misdiagnosed. Although R. felis may require only fl eas for its maintenance in nature, we still do not know the role of animals in the life cycle of fl ea-borne spotted fever rickettsia. In addition, fl ea-borne spotted fever should be considered in the differential diagnosis of infectious diseases. Further research should be conducted to determine the actual incidence of R. felis infection in humans, the spectrum of clinical signs and symptoms, and the severity of this infection and also to assess the impact on public health.