The circulation of Rickettsia spp. causing TBR in Europe has been well described, including reports of R. conorii transmitted by ticks belonging to R. sanguineus complex; R. helvetica and R. monacensis by Ixodes ricinus; R. slovaca, R. raoultii and Candidatus Rickettsia rioja by Dermacentor marginatus; R. aeschlimannii by Hyalomma spp. and Rhipicephalus spp. and R. sibirica mongolotimonae, whose involved vectors are no less than Hyalomma spp. and Rhipicephalus pusillus ^[1][2][6,35] and in the case of R. massiliae, apart from its allochthonous case, ticks infected with this SFG Rickettsia were: R. pusillus ^[3][36], R. sanguineus s.l. ^{[4][5][6][7][8][9]}[37,38,39,40,41,42] and R. turanicus ^[10][11][12][43,44,45].

According to the European Centre for Disease Prevention and Control (ECDC)CDC, most cases of rickettsioses are reported from Italy, Portugal, and Spain ^[2][35].

Mediterranean Spotted-Fever (MSF) was first described in 1910 by Conor and Brunch, in Tunisia and later, in 1923, described by Delfim Pinheiro in Portugal ^[13][46]. The causative agent of MSF is R. conorii, which encompasses a complex of four subspecies, R. conorii conorii, R. conorii caspia, R. conorii israelensis and R. conorii indica ^[14][47]. To date, R. conorii conorii and R. conorii israelensis are the subspecies reported in the Iberian Peninsula, with human cases associated to R. conorii conorii in Spain and human cases associated to R. conorii israelensis in Portugal ^[1][6].

The tick R. sanguineus s.l. is recognized as the main vector of the MSF. The subspecies R. conorii israelensis have been successfully isolated from a R. sanguineus collected in Portugal ^[15][48]. This tick species can also be considered a reservoir of R. connorii in the Mediterranean region due to transstadial and transovarian transmission that maintain the infection in the tick population ^[16][49]. There is still some debate regarding this subject since early studies have demonstrated the persistence of R. conorii along tick generations but in nature low infection prevalence in ticks are reported, suggesting that ticks pay a fitness “toll” when infected by this rickettsiae species ^[17][11]. Such observations have made researchers speculate about the role of vertebrate hosts as potential reservoirs. In nature, levels of infection of vertebrates are low and are often transient, which does not support maintenance of infection in these hosts. However, there is experimental evidence that dogs can act as reservoirs of R. conorii, as dogs became infected by inoculation or after feeding of infected ticks, naïve ticks feeding in infected dogs acquire the bacteria (one-month post-infection and even when infection was not detectable by PCR) and are able to transmit Rickettsia to their progeny ^[18][19][20][12,50,51]. Seroprevalence of Rickettsia species in dogs from endemic regions (such as the Iberian Peninsula) also sustains this hypothesis ^[21][22][52,53] and the fact that R. sanguineus is the “dog tick” should also be considered ^[23][21]. Therefore, and even though the role of vertebrates in the perpetuation of TBR remains unclear, it has been accepted that dogs contribute for the persistence of MSF in nature and can act as sentinels of infection in endemic areas ^[24][54]. It is important to point out that while other mammals such as lagomorphs or hedgehogs can be affected by MSF, there are no studies focusing on their potential role as reservoirs ^[1][25][6,55].

The dependency of MSF transmission on its vector tightly associates the appearance of human cases with the activity of R. sanguineus ticks. Consequently, MSF can be considered a summer illness, since most of the cases occur between July and September, overlapping with the peak of questing activity of immature stages of R. sanguineus s.l, although there are records of cases diagnosed in February, November, and December ^[13][26][27][7,46,56]. It has been demonstrated that climate influences host-seeking behavior of ticks, including of R. sanguineus ^[28][29][30][57,58,59]. Noteworthy, a study conducted in 2007 experimentally showed that R. sanguineus is more likely to bite humans after exposition to warmer temperatures, as a consequence of an increased aggressivity on host seeking, and thus, resulting in more cases of human rickettsiosis ^[30][59]. Adding to the patterns of tick´s activity, summer season also corresponds to holidays, thus to an increase of outdoor activities and consequently a greater chance of encountering questing ticks.

As referred previously, after a tick biting, the bacteria take from 3 to 24 h to be efficiently transmitted and in average, MSF latent period takes about 6 days with an abrupt onset. Clinical conditions are characterized by fever, flu-like symptoms, prostration, maculopapular or petechial rash and eschar at the tick bite site ^{[1][15][25][26][27][31][32]}[6,7,48,55,56,60,61]. In addition, severe manifestations such as encephalitis ^[33][62] may occur in patients with advanced age, immunocompromised, chronic alcoholism, glucose 6-phosphate dehydrogenase (G6PD) deficiency, inappropriate use of antibiotics, and delayed of diagnostic and treatment ^[1][15][34][6,48,63].

MSF diagnosis based on clinical, epidemiological, and laboratorial findings in Portugal between 1989 and 2012, has shown 250 positive cases, in which, mortality rate reached 3.6% ^[13][46]. In Spain, from 2005 to 2015, there were 1603 notified MSF cases, and 49.5% were confirmed, with no fatal cases occurring during this period ^[25][55]. However, regarding death, it is important to denote such indicator is not well documented in many of the reports. According to RENAVE, in 2016, from the 115 notified cases of MSF, 91 were confirmed ^[35][64], and in 2017–2018, from the 557 notifications, 473 cases were confirmed, including 18 imported ^[36][30]. It is important to refer that in Spain, until 2015, MSF was considered endemic to certain regions and not all cases were reported to RENAVE which may have led to a under recording of MSF cases in the country ^[35][64]. In the particular case of patients diagnosed with MSF caused by R. conorii israelensis, nausea and vomiting apart from common clinical manifestations already pointed out, were observed ^[1][6]. In addition, reports of eschar inoculation were rarely observed. In Portugal, mortality rate of this subspecies reaches 29% when compared to other MSF (3%), from 1994 to 2006 ^[15][27][32][48,56,61]. Until the present date, there is no report of human infection caused by R. conorii israelensis in Spain. Regarding to the enzootic cycle of R. conorii israelensis, in southern Portugal, Maia et al, ^[27][56] found dogs and cats infected with this SFG rickettsiae, in medical centers, animal shelters, supporting that these pets may act as reservoirs and/or sentinels of this bacteria, as they were asymptomatic during rickettsial infections.

To date, MSF is the most prevalent zoonosis, and it appears to be endemic throughout the Iberian Peninsula. Moreover, positive cases are not only registered in endemic regions, but also in non-endemic areas ^[13][25][46,55].

The known causative agents of DEBONEL / TIBOLA or SENLAT rickettsioses are R. slovaca, R. raoultii and Ca.R. rioja. It is the most prevalent tick-borne rickettsioses in Europe, after MSF ^[26][37][7,65]. The main vector of these SFG-rickettsial agents is D. marginatus but at least for R. raoultii, there’s evidence that D. reticulatus can also transmit this bacterium ^[38][66] while for the others, it remains a potential vector ^[34][37][63,65]. Clinical manifestations include fever, headache, rash, myalgia, vertigo and persistent asthenia, neck lymphadenopathy, and a necrotic eschar surrounded by a perilesional erythematous halo at the site of the tick attachment ^[39][40][67,68]. As Dermacentor spp. usually bite animals with high fur density, these ticks are frequently found on the scalp of humans, thus the most common symptoms observed in patients are alopecia around the tick-bite site, and facial edema ^[39][41][67,69]. When ticks are not located on the scalp, other hairy zones like thorax, arms and even axillae might be spots for tick-bites, and an erythema, similar to the erythema migrans from Lyme borreliosis, typically appears ^[26][7].

DEBONEL’s cases are frequently diagnosed during the late fall and winter to mid spring, which is compatible with higher activity period of its vector ^[37][41][65,69]. D. marginatus adult ticks are active from late August/September through April/May (extreme cold and snow interrupt activity). July and August are the months where larvae and nymphs have their activity peak, respectively ^[37][42][65,70].

There are more than 200 reported human cases from Spain since 2000 ^[37][41][65,69] and, at least three from Portugal, since 2010 ^[40][68]. Furthermore, most recently in Spain, there was an unprecedent report of I. ricinus ticks infected with R. slovaca, R. raoultii and Ca. R. rioja ^[34][63]. Although this is the first report of I. ricinus infected with Rickettsia that cause DEBONEL, further studies should be carried out to understand which possible roles this tick species may play either in the maintenance and/or the transmission of these bacteria, and thus, possibly influencing or interfering directly or indirectly, in the epidemic and enzootic cycles ^[30][59].

Rickettsia sibirica mongolitimonae, the causative agent of LAR, is a subspecies of R. sibirica and was originally isolated from Hyalomma asiaticum tick species collected in the Mongolia in 1991 ^[43][71], and recognized as responsible for a human infection in France in 1996 ^[44][72]. Even though experimental proven vectors are not recognized, in the Iberian Peninsula, this SFG-rickettsia was found in Rhipicephalus bursa, R. pusillus and in Hyalomma marginatum from birds in Spain ^[45][46][73,74] while in Portugal it was detected in a R. pusillus tick ^[47][48][75,76]. R. pusillus is known to infest wild rabbits but it also can be found on wild carnivorous animals, dogs, and domestic cats, and occasionally humans ^[49][77]. R. bursa ticks are widely distributed throughout the Mediterranean region, it is very possible an underestimation of the pathogen in this tick species. This tick species can parasitize many different mammals such as, cattle, sheep and goats ^[49][50][51][77,78,79] emphasizing the need to better understand the role of this vector in the transmission and maintenance of LAR. Even being considered a rare infection, the particular and main clinical manifestation, lymphangitis, makes ground for separating LAR from the remaining TBR ^[52][80]. Other signs and symptoms include fever, headache, myalgia, rash, and inoculation eschar ^{[53][54][55][56][57][58]}[81,82,83,84,85,86]. In Spain, until 2011, there were a total of 24 human cases of LAR ^[57][85]. In addition, at least, seven more human cases were reported, including two children ^{[55][56][57][58][59][60][61]}[83,84,85,86,87,88,89]. Thus far, in Portugal, two confirmed cases of LAR confirm the importance of this disease in the Iberian Peninsula region ^[47][53][75,81].

Rickettsia monacensis also belongs to the SFG, and it was first isolated and identified in Germany, infecting I. ricinus ticks ^[62][90]. In Portugal and Spain, R. monacensis was detected in I. ricinus ticks ^{[34][48][63][64]}[63,76,91,92], the suspected natural vector. Also, in Portugal there is a report of infected lizard tissues (Teira dugesii), suggesting a possible involvement of the reptile in the maintenance of the enzootic cycle and as well as its potential as a reservoir for this rickettsial agent ^[65][93]. So far there are no studies confirming the competency of the later tick species to vector R. monacensis. However, the frequency of natural infection in I. ricinus suggests a role on the maintenance and transmission of the bacteria at least in Europe ^[66][67][94,95]. There are reports of two cases in Spain, whose patients showed general symptoms such as fever, headache and rash of their trunk and extremities. There was no eschar-inoculation at the tick bite sites. Both patients have recovered without sequelae ^[68][96]. In Portugal, one recent case has been reported in an elder patient with a background of cardiomyopathy, diabetes mellitus type 2 and alcohol abuse ^[4][37]. All affected patients by R. monacensis infection were over 59 years old, raising the suspicion that older people may be susceptible to infection by this Rickettsia SFG ^[48][63][65][76,91,93].

Rickettsia massiliae, is another human pathogenic SFG-Rickettsia, which was first isolated from R. turanicus and R. sanguineus s.l. ticks in 1990 and 1993, respectively, in France ^[5][38]. To date, there has been only four reported human cases in Europe, only one from Spain. However, this case was imported from South America. Patient showed MSF-like symptoms, such as fever, purpuric rash on the upper and lower extremities, and eschar ^[6][39]. In Portugal, R. massiliae was first detected in 1995 from R. turanicus ^[12][45]. Most recently, surveillance studies from Portugal, have reported R. sanguineus s.l. collected from dogs and from hedgehogs (Erinaceus europaeus) infected with this SFG-rickettsiae ^[69][70][97,98]. In addition, dogs and R. pusillus were also infected with R. massiliae ^[48][70][76,98]. In Spain, R. sanguineus s.l. ^{[7][9][64][71][72][73]}[40,42,92,99,100,101], R. turanicus and R. pusillus ^[3][36] were all found infected with this Rickettsia species.

To date, there are no human cases reported in both Iberian countries caused by Rickettsia helvetica. However, this SFG Rickettsia has been reported infecting lizard tissues (T. dugesii) in Portugal ^[65][93] as well as its main vector, I. ricinus, in both Portugal and Spain ^[3][64][65][36,92,93]. In addition, this bacterium, was also found in Ixodes ventalloi in Portugal ^[10][43], a poorly studied and permissive tick species known to parasitize mainly Oryctolagus cuniculus but also birds ^[74][102]. Patients around Europe have generally shown mild fever, headache, myalgia, and occasionally rash. Isolated case from Sweden, whom patient was immunocompetent, evolved to septicemic fever, myalgias, arthralgias, severe headache and photophobia ^[75][103].

Another MSF-like infection is caused by R. aeschlimannii, however the first documented human case caused by this SFG Rickettsia in Europe was an allochthonous one, as the patient was returning from Africa to his home country, France ^[75][103]. No records of autochthonous cases have been reported in the Iberian Peninsula. However, there have been reports of this bacterium in six anthropophilic tick species in Spain (H. marginatum, H. punctata, I. ricinus, R. bursa, R. sanguineus s.l., and R. turanicus) ^{[3][8][46][76][77][78]}[36,41,74,104,105,106], and infecting H. marginatum in Portugal ^[10][43].