Mediterranean spotted fever (MSF) is a tick-borne disease caused by Rickettsia conorii. It was first described a century ago as a disease that caused high fever and spots ( 1 ). Our knowledge about MSF has evolved since its first description. First, we thought that MSF was only limited to some regions of the world, i.e., southern Europe, North Africa, and India. In fact, an increasing number of regions have been reporting MSF cases, such as central Europe and central and southern Africa. Serologic techniques cannot distinguish among different rickettsiae species of the spotted group. Consequently, all rickettsioses with spotted fever group (SFG) antibodies were considered to have MSF in countries where this disease was endemic. Early clinical descriptions that relied only on serologic test results were likely to include infections related to multiple rickettsial species and were probably not describing a unique entity. For example, in France, emerging rickettsioses caused by bacteria, including R. sibirica mongolitimonae, R. slovaca, R. felis, R. helvetica, and R. massiliae, have been recently described ( 1 ). The first description of patients with MSF in southern France may have included patients with these emerging rickettsioses. With new molecular tools such as PCR and sequencing, we can now identify much more precisely the rickettsial agent responsible for the disease. MSF is an emerging or a reemerging disease in some countries. For example, in Oran, Algeria, the first case of MSF was clinically diagnosed in 1993. Since that time, the number of cases has steadily increased ( 2 ). In some other countries of the Mediterranean basin, such as Italy and Portugal, incidence of MSF has substantially increased in the past 10 years. Another point is that MSF was considered for 70 years a benign disease when compared with Rocky Mountain spotted fever (RMSF). In fact, because of the lack of medical interest in MSF, its real severity was long ignored. Although the mortality rate was evaluated to be from 1% to 3% in the early reports in the literature, the first description of a highly severe form of MSF was published in the early 1980s ( 3 ). At present, we know that MSF is at least as severe as RMSF and has a mortality rate as high as 32.3%, which occurred in Portugal in 1997 ( 4 ). Although many hypotheses have been suggested, the nature and distribution of the reservoir of the rickettsiae in nature are still not answered. The aim of this review is to show the evolution in our knowledge of MSF in the past 10 years with an emphasis on epidemiology, clinical features, and severe forms. Historical Background The historical background of MSF is summarized in Table 1. MSF was described in Tunisia by Conor and Bruch ( 1 ) and was soon reported in other regions around the Mediterranean basin. The disease was thereafter also known as boutonneuse fever (spotted fever) because of the manifestation of a papular rather than a macular rash. The typical inoculation eschar, the tâche noire (black spot), was described in 1925 in Marseille by Boinet and Pieri ( 5 ). In the early 1930s, Durand and Conseil ( 6 ) proposed that the brown dog tick, Rhipicephalus sanguineus, was the vector in Europe after they inoculated humans with crushed ticks. Blanc and Caminopetros successfully repeated these experiments on humans and spermophiles ( 7 ). Brumpt showed that the SFG rickettsia was the causative agent, and in honor of Conor, this organism was named R. conorii. Blanc and Caminopetros showed that R. conorii could be transmitted through transovarial passage ( 7 ) in ticks and hypothesized that ticks could be the reservoir of R. conorii (Table 1). Table 1 Historical reports of MSF* Year Discovery Authors† 1910 Description of the “fièvre boutonneuse de Tunisie” (7 cases) Conor and Bruch 1925 Description of a cluster of MSF (8 cases) in Marseille, France, during the summer Olmer 1927 Description of the inoculation eschar, the tache noire (black spot). Description of the disease associating fever, spots, and eschar as “Marseille fever” Boinet and Pieri 1930 Experimental transmission of the disease by the brown dog tick Durand and Conseil 1932 Demonstration of the transstadial and transovarian transmission of the agent of MSF in ticks. Demonstration of Rickettsia in infected ticks Blanc and Caminopetros 1932 Isolation of the Rickettsia causing MSF in the vagina of infected guinea pigs and in infected ticks; named R. conorii Brumpt 1982 First description of cases of malignant MSF Raoult *MSF, Mediterranean spotted fever.
†First or senior authors. Knowledge Gained about MSF in the Past 10 Years New Information about the Agent R. conorii is an obligate, intracellular, gram-negative bacterium (Figures 1, 2). In recent years, the rickettsial field has undergone a substantial evolution, particularly because of the technologic advances in molecular genetics. In the past decade, several rickettsial genomes, including that of R. conorii ( 8 ), have been sequenced. Availability of these genomic data have allowed, in turn, the development of global approaches, including proteomics and transcriptomics, powerful tools to gain a better knowledge of cell biology and interaction of rickettsiae with their host cells. Due to genome sequencing, the taxonomy of rickettsiae has undergone extensive reorganization. Until 2005, opinions were divided as to whether rickettsial strains related to R. conorii belonged to the same species or were distinct species. This included Israeli spotted fever rickettsia, Indian R. conorii strain (Indian tick typhus rickettsia [ITTR]), and Astrakhan spotted fever rickettsia (AFR) (Table 2). In fact, phylogenetically, these rickettsiae and R. conorii strain Malish (the agent of MSF) constitute a homogeneous cluster supported by significant bootstrap values and distinct from other Rickettsia spp. By estimating the degrees of genotypic variation among isolates of the R. conorii strains Malish, ISFR, ITTR, and AFR, Zhu et al. proposed that R. conorii species nomenclature should be modified through the creation of the following subspecies: R. conorii conorii, R. conorii caspia, R. conorii israelensis, and R. conorii indica ( 9 ). These rickettsiae have discernable serotypes and cause diseases with distinct clinical features in defined geographic locations, but they are not genetically different enough to be considered as new species. Figure 1 Rickettsia conorii conorii observed in Vero cells (red rods; magnification ×1,000). Figure 2 Rickettsia conorii conorii localized in cytoplasm of host cells as seen by electron microscopy (magnification ×100,000). Table 2 Distribution, vector, and main clinical features of the different subspecies of Rickettsia conorii complex Rickettsia Vector tick Geographic repartition Human disease name Symptoms present, % patients Fatal forms? (% patients) Fever Inoculation eschar Rash R. conorii conorii, isolates Malish, Moroccan Kenyan Rhipicephalus sp., Haemaphysalis leachii Mediterranean area (southern Europe, northern Africa), Croatia, Slovenia, Kenya, Somalia, South Africa, and surrounding the Black Sea (Turkey, Bulgaria, Ukraine, Romania) Mediterranean spotted fever 91–100 20–87 93–100 Yes
(0–18.1) R. conorii israelensis Rh. sanguineus Israel, Portugal, Sicily Israeli spotted fever 100 0–46 98–100 Yes
(0–3.5) R. conorii caspia Rh. sanguineus, R. pumilio Astrakhan region, Chad, Kosovo Astrakhan spotted fever 100 23 94 No R. conorii indica Rh. sanguineus, Boophilus microplus, H. leachii India, Pakistan Indian tick typhus 100 Rare 100 (frequently purpuric) No New Information about Epidemiologic Features MSF is endemic to the Mediterranean area, including northern Africa and southern Europe. Cases are still identified in new locations within this region. Thus, some cases were recently described in Algeria, Malta, Cyprus, Slovenia, Croatia, Kenya, Somalia, South Africa, and in areas surrounding the Black Sea (Turkey, Bulgaria, and Ukraine). Spotted fever cases have been confirmed as MSF by the use of molecular tools in Portugal, Italy, Malta, Greece, Croatia, Spain, France, Turkey, Algeria, Tunisia, Morocco, Zimbabwe, Kenya, and South Africa. MSF is suspected to be endemic in Slovenia, Albania, Ukraine, Georgia, and Zimbabwe, but R. conorii conorii has not been isolated in human clinical samples in these countries. MSF appears to be waxing and waning, as indicated by peaks in the number of MSF cases (Figure 3). Incidence of the disease sharply increased in the 1980s in Italy ( 10 ), Spain, and southern France ( 11 ). In some countries, MSF is reemerging. During the past decade in Portugal, the number of hospitalizations has increased from 400 cases per year ( 4 ). In Italy, a notable increase in case numbers was reported during the 1990s; cases peaked in 1999 at 699. In Bulgaria, MSF cases started to sharply decrease at the beginning of the 1960s and completely disappeared in the 1970s. However, in 1995, a peak of MSF disease with 236 cases was noticed in this country and reached 716 cases in 1997 ( 12 ). In Oran, Algeria, the first case of MSF was diagnosed in 1993; since that time, the number of cases has steadily increased to reach 134 in 2004 ( 2 ). Figure 4 illustrates the distribution and incidence of R. conorii conorii infection in countries where MSF is endemic. Figure 3 Fluctuation of incidence of Mediterranean spotted fever (MSF) in Italy and Portugal and of Rocky Mounted spotted fever (RMSF) in the United States, by year. Figure 4 Distribution of the cases of Mediterranean spotted fever (MSF) in the world and incidence of the disease in countries where MSF is endemic. Such variations have also been noted for RMSF ( 13 ). In the United States, the disease is in the midst of its third emergence since 1920, after peaking from 1939 to 1949, and again from 1974 to 1984 ( 13 , 14 ) (Figure 3). The causes of these variations in the incidence of MSF and other SFG rickettsioses are unknown. In most countries, no national epidemiologic surveillance of MSF cases is conducted. Only Italy and Portugal have a formal surveillance program. However, in these countries, surveillance is passive and not mandatory. Thus, in many countries, reported cases depend on the observers and can be affected by such variables as the need for international publications by physicians. For example, the dramatic increase in MSF cases in Oran, Algeria, is mainly due to the renewed interest in the disease by 1 physician ( 2 ). However, in countries that have a surveillance program, incidence of MSF cases actually varies in time. Another factor that limits the study of incidence of MSF in European countries is that nonspecific serologic tests are used for the diagnosis of MSF and could include other SFG rickettsioses. However, in Orán, when specific tests are used such as Western blot and molecular tools, R. conorii conorii appears to be the main etiologic agent of SFG rickettsioses in this area (D. Raoult, unpub. data). An increased number of ticks and increased human contact with the habitat of infected ticks are possible factors that would explain variations of incidence. In addition, the ecologic changes in the outskirts of large cities during the 1980s may have played an important role by moving rural sources to suburban zones. Climatic factors could also intervene, such as the increase of temperature, the lack of rainfall (for example, in Spain [ 15 ]), or the reduced number of days of frost during the past year in France ( 16 ). Climatic variations are suspected to play an important role in tick activity and, consequently, on rickettsial prevalence ( 15 ). It is also conceivable that undetected reservoir–vector systems have emerged or that the size of the reservoir has increased. This increase in MSF cases in the 1970s could also have been caused by a shift in effectiveness of prescribed antimicrobial drugs. In fact, before the 1970s, doxycline was used as an empiric therapy for patients with a fever of unknown origin. Finally, dramatic increases in MSF cases during the 1970s may be related to the advent of new diagnostic methods, such as microimmunofluorescence and the increased interest in traveling to several countries such as France, Italy, and Spain. Sporadic cases in non–disease-endemic countries are also observed as a consequence of tourism ( 17 ). New Information about Clinical Features The clinical description of MSF has not really changed since its it was first described. MSF is characterized, just as the other rickettsioses, by fever, headaches, and maculopapular rash. Most of the studies reporting series of patients with MSF could have been affected by many factors. Descriptions of the first clinical cases, which were diagnosed on the basis of serologic test results alone, surely included infections related to other species of rickettsiae. Clinical descriptions with a series of patients are also subject to biased observations. For example, the eschar (Figure 5) can be difficult to retrieve and can sometimes be atypical, for example, having the aspect of a furuncle, which is difficult to recognize. This could explain wide variations in the reported presence of an eschar (20%–86%) ( 4 , 11 ). Figure 5 Typical eschar and spots on the leg of a patient with Mediterranean spotted fever. Eschars are rarely multiple. This observation was, however, reported in the early description of the disease by Olmer ( 5 ). More recently, 2 studies in Sicily found multiple eschars in 7 (1.08%) of 645 children ( 18 ) and in 6 (1.4%) of 415 children ( 19 ), respectively. In studies in Spain ( 20 , 21 ), multiple eschars were found in 3%–11.5% of patients and involved more children. These findings should, however, be interpreted with care. The role of R. aeschlimannii circulating in Hyalomma spp. in Spain has to be considered in the cases of multiple eschars. Indeed, Rh. sanguineus has a low probability of biting humans, and the infection rate by rickettsiae is low ( 1 rickettsiosis can be present in the same country. Patients who have been included in series of MSF cases may have had other rickettsioses. Moreover, MSF has a wider distribution than previously described. The disease has emerged and reemerged in several countries in the Mediterranean basin. New clinical features, such as multiple eschars, previously suggested in the early description, have now been confirmed in MSF. MSF is becoming an increasingly severe disease with death rates ranging from 3.2% to 32%. However, questions persist regarding the vector and reservoir for this disease, which need to be addressed.
