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1 CHYPRE «Emerging Rickettsioses» Didier Raoult Marseille - France didier.raoult@gmail.com

2 Gram negative bacterium Strictly intracellular Transmitted by arthropods: ticks, fleas, lice, mites Mosquitoes? 2

3 Louse borne disease - typhus Tick borne : the big killer - RMSF Other: less severe Flea borne - Murine typhus (Maxcy 1925 and Mooser 1921 ) Mite borne diseases - Scrub typhus (tsutsugamushi disease) Rickettsial pox (Huebner 1946 ) Other rickettsia: non pathogenic Any Gram negative intracellular bacteria= Rickettsiales 3

4 New clinical features NEW RICKETTSIAL DISEASES Many new diseases comparable to Arboviruses no rash but adenopathy (R. slovaca, R. raoultii ) no rash, no inoculation eschar (R. helvetica ) others? Several species involved in a same area R. conorii and R. africae - Africa R. conorii, R. mongolotimonae - France R. conorii, R. aeschlimannii - Spain, North Africa R. typhi and R. felis - USA R. honei and R. australis - Australia R. rickettsii and R. parkeri - USA R. conorii and R. helvetica, R. slovaca - Switzerland 4

5 SITUATION DURING THE XX TH CENTURY One tick borne rickettsiosis per geographical area R. rickettsii agent of RMSF in the USA other found in ticks: non pathogenic rickettsia (such as Coxiella burnetii or Legionella pneumophila) R. conorii alone in Europe and Africa Diagnostic provided by unspecific tools never contradict this! 5

6 R. rickettsii TICK BORNE DISEASES IN THE 80 ties R. conorii R. sibirica R. australis Anything else : non pathogenic 6

7 END XXTH BEGINNING XXITH CENTURY Molecular Biology 16S rrna: first revolution Rickettsia specific genes: second revolution: Diagnostic PCR New Rickettsia and rickettsial disease Genotyping rickettsiae correlation: Genotype: epidemiology, pathotype? 7

8 Rickettsiales R. rickettsii R. prowazekii R. tsutsugamushi R. quintana C. burnetii E. canis E. phagocytophila E. sennetsu C. ruminantium N. helminthoeca W. pipientis W. persica R. grylli B. bacilliformis G. talpae A. marginale E. ovis H. felis a MOLECULAR BIOLOGY Rickettsia rickettsii R. prowazekii Orientia tsutsugamushi Ehrlichia chaffeensis E. ewingii E. canis E. ruminantium Anaplasma phagocytophilum A. Wolbachia marginale pipientis Neorickettsia sennetsu N.helminthoeca Bartonella quintana B. henselae B. talpae B. bacilliformis Brucella melitensis Coxiella burnetii Rickettsiella grylli Legionella pneumophila «Wolbachia persica» Francisella tularensis 8 Eperythrozoon ovis Hemobartonella felis Mycoplasma pneumoniae Ureaplasma urealyticum 1984 c b NOW a g Gram +

9 END XXTH BEGINNING XXITH CENTURY Molecular Biology 16S rrna: first revolution Rickettsia specific genes: second revolution: Diagnostic PCR New Rickettsia and rickettsial disease Genotyping rickettsiae correlation: Genotype: epidemiology, pathotype? 9

10 SKIN BIOPSY IS THE KEY OF DISCOVERY OF NEW RICKETTSIAL DISEASES 10

11 SWABING Bechah Y, Socolovschi C, Raoult D. Identification of rickettsial infections by using cutaneous swab specimens and PCR. Emerg Infect Dis Jan;17(1):83-6. Mouffok N, Parola P, Raoult D. Murine typhus, Algeria. Emerg Infect Dis Apr;14(4):

12 DIAGNOSTIC: PCR Tested R. prowazekii B. quintana B. recurrentis Ants Lice (36%) 5 (11%) 0 Tested gene Citrate synthase Citrate synthase ITS Negative controls are critical 16srRNA Two different genes for confirmation of atypical/unique case Avoid open nested PCR and positive controls 12

13 RAPID ID OF A TICK FROM PATIENT BY MALDI-TOF Symtoms Date of symtoms : Fever Eschar only/ localisation : Eschar multiples / localisation : Adenopathy / localisation : Rash : Maculo-papulus Purpuric Vesiculus X Other manifestation: erythematous lesions EPIDEMIOLOGY Travel place / date : X Morphological identification: Ixodes ricinus X mass spectrometry: I.ricinus score 1,5 Single bite/ localisation : multiple bite / localisation : Animals contact: => Identify risk factor October Date smarlab Bartonella C. burnetii Rickettsies Coxiella-like Borrelia A. phagoc 08/10/ neg neg neg neg neg ec 13

14 R. parkerii R. amblyommii R. 364D R. rickettsii R. aeschlimannii TICK-BORNE RICKETTSIOSES R. massiliae R. helvetica R. mongolotimonae R. conorii conorii R. africae R. PA4 R. conorii caspia R.slovaca R. conorii israeli 14 R. sibirica sibirica R. conorii conorii R. australis R. honei R. monacensis R. sibirica mongolitimonae R. heilongjiangensis R. conorii indica R. japonica

15 HOW TO FIND NEW (RICKETTSIAL) DISEASE 1. Anything atypical is a candidate (seasonal variation, severity, atypical clinical symptoms, atypical host) Exemple in France - R.conorii summer, mild to severe, fever generalized rash, 1 inoculation escar on the body. - R.massiliae South est, adultes males no difference, co-infection with R.conorii - R.sibirica mongolitimonae Spring, mild, several inoculation escars, rope like lymphangitis, adenitis, generalized rash and fever - R.slovaca/R.raoultii Cold season, children and women, scalp inoculation, neck adenitis, post infection fatigue, no fever or rash - R.africae Traveler, very mild, no or low fever, several inoculation eschars, rash in 50 % (vesicular in half case) - R.helvetica fever, no rash, spring no escar 2. Swab escar or vesicule => PCR 15

16 What s new? In Europe P. Parola, C.D. Paddock, D. Raoult. Tick-Borne Rickettsioses around the World: Emerging diseases challenging old concepts. Clin Microbiol Rev. 2005; 18(4): From 1 to 9: Tick borne spotted fever since 1997.

17 More common Mediterranean Spotted Fever Rickettsia conorii More severe (2-10% mortality rate in Portugal) More multiple escars Known since 1909 Transmitted by Rhipicephalus sanguineus (world wide dog tick) Restricted to the old world: WHY!!!! 17

18 R.SANGUINEUS AGRESSIVITY INCREASE WITH TEMPERATURE R. sanguineus Warmer weather linked to tick attack and emergence of severe rickettsioses. Parola P, Socolovschi C, Jeanjean L, Bitam I, Fournier PE, Sotto A, Labauge P, Raoult D. PLoS Negl Trop Dis. 2008;2(11):e338. Epub 2008 Nov 18. May be true for RMSF 18

19 (Tibola-Debonel) Scalp Escar and Neck lymphadenopathy after tick bite - R. slovaca, R. raoultii Lymphangitis Associated Rickettsiosis - R. sibirica mongolitimonae Aneruptive rickettsiosis: R. helvetica 19

20 DERMACENTOR TICKS IN EUROPE Ambush strategy: waits, falls bites head children cold season R. SLOVACA 20

21 DERMACENTOR SEEKING HAIR 21

22 R. slovaca infection Based on 17 PCR confirmed cases More tick bite found Lesion in the hair Less fever More cervical lymph node Sequels : residual asthenia, localised alopecia Low death rate Young age Females > males Low serological titres (compared to MSF) (Raoult D, et al. Clin Infect Dis ;34: ) 22

23 Cases very closely related to TIBOLA Clinical cases identical to that caused by R. slovaca Present in Dermacentor, ¼ of that of R. slovaca Less pathogenic Present in all Eurasia 23

24 Scalp eschar and neck lymphadenopathy caused by Bartonella henselae after Tick Bite. Angelakis E, Pulcini C, Waton J, Imbert P, Socolovschi C, Edouard S, Dellamonica P, Raoult D. Clin Infect Dis Feb 15;50(4): Abstract Rickettsia slovaca and Rickettsia raoultii have been associated with a syndrome characterized by scalp eschar and neck lymphadenopathy following tick bites. However, in many cases, the causative agent remains undetermined. We report 3 cases of this syndrome caused by Bartonella henselae, and we propose the term "SENLAT" to collectively describe this clinical entity. 24

25 OTHERS AGENTS MORE COMMON IN COLD MONTHS AND SCALP ESCAR Bartonella henselae Francisella tularensis Borrelia? 25

26 LYMPHANGITIS ASSOCIATED RICKETTSIOSIS (LAR) R.sibirica mongolitimonae Fever, rash in spring Lymphangitis (5/10 cases) 2 taches noires (3/10 cases) Lymphadenitis Clustered cases Lymphangitis-associated rickettsiosis, a new rickettsiosis caused by Rickettsia sibirica mongolotimonae: seven new cases and review of the literature. Fournier PE, Gouriet F, Brouqui P, Lucht F, Raoult D. Clin Infect Dis May 15;40(10): Lymphadenopathy Lymphangitis Eschar 26

27 RICKETTSIA SIBIRICA MONGOLITIMONAE 1993 : First isolation from Hyalomma asiaticum ticks from Inner Mongolia Yu X, et al. J Clin Microbiol. 1993;31: : 9 cases in Marseilles, from France and Algeria Raoult D, et al. Lancet ;348:412 Fournier PE, et al. Emerg Infect Dis. 2000;6: found in Hylomma sp. in Mali Parola P, et al.. Emerg Infect Dis ;7: In Greece in Hyalomma Psaroulaki A,et al. J Clin Microbiol Jul;43(7): : One case reported in South Africa Pretorius AM, Emerg Infect Dis. 2004;10: found in Rhipicephalus pusillus in Europe HISTORICAL ASPECTS 2006: in Portugal : in Greece

28 Unspotted fever R. helvetica Found in ticks from Europe to Japan - Cases in France, Switzerland, Thailand, Japan Fever, no rash, no tache noire Fournier PE., et al., J Clin Microbiol, 2002, 40:

29 A patient in Sicily in 1984 presented with fever, rash and tache noire A Rickettsia was isolated in the blood Identified in 2005: Vitale G, et al. Rickettsia massiliae human isolation. Emerg Infect Dis, 2006,12: Found in the USA : M. Eremeeva, 2006 (Appl Environ Microbiol, 72: ) Coinfection with R.conorii Warmer weather linked to tick attack and emergence of severe rickettsioses. Parola P, Socolovschi C, Jeanjean L, Bitam I, Fournier PE, Sotto A, Labauge P, Raoult D. PLoS Negl Trop Dis. 2008;2(11):e338. Epub 2008 Nov

30 R. monacensis Found in I. ricinus in Germany and Spain First case (typical MSF) found in la Rioja, Spain (Dr. Oteo) 30

31 What s new? In America P. Parola, C.D. Paddock, D. Raoult. Tick-Borne Rickettsioses around the World: Emerging diseases challenging old concepts. Clin Microbiol Rev. 2005; 18:

32 ROCKY MOUNTAIN SPOTTED FEVER Rickettsia rickettsii Transmitted by tick bites (Dermacentor andersoni and others) Summer disease USA : 500 cases/year (South-eastern states) Prevalent in Brazil and Central America Fever, eruption, 5-80 % mortality without treatment p p > 5 p U R 32

33 What is this? Raoult D, Parola P. Rocky Mountain spotted fever in the USA: a begnin disease or a common diagnostic error? Lancet Infect Dis, 2008: in press 33

34 A cluster of cases was recently found in Arizona R. sanguineus the dog tick (vector of R. conorii) was identified as the vector Demma LJ, et al. Rocky Mountain Spotted Fever from an Unexpected Tick Vector in Arizona. N Engl J Med,2005;353:

35 First isolation from Amblyoma maculatum in 1931 This tick is prevalent in South East USA and bite humans One isolate of a patient who died of RMSF in Ohio was similar to R. parkeri but considered R. rickettsii (Ralph et al. Ann N Y Acad Sci -1990) Found in A. maculatum, A. cajennense, A. triste 35

36 Emerging Infectious Diseases, 2007;13:

37 Now in Argentina and Brazil Rickettsia parkeri rickettsiosis and its clinical distinction from Rocky Mountain spotted fever. Paddock CD, Finley RW, Wright CS, Robinson HN, Schrodt BJ, Lane CC, Ekenna O, Blass MA, Tamminga CL, Ohl CA, McLellan SL, Goddard J, Holman RC, Openshaw JJ, Sumner JW, Zaki SR, Eremeeva ME. Clin Infect Dis Nov 1;47(9): BACKGROUND: Rickettsia parkeri rickettsiosis, a recently identified spotted fever transmitted by the Gulf Coast tick (Amblyomma maculatum), was first described in We summarize the clinical and epidemiological features of 12 patients in the United States with confirmed or probable disease attributable to R. parkeri and comment on distinctions between R. parkeri rickettsiosis and other United States rickettsioses. METHODS: Clinical specimens from patients in the United States who reside within the range of A. maculatum for whom an veschar or esicular rash was described were evaluated by > or =1 laboratory assays at the Centers for Disease Control and Prevention (Atlanta, GA) to identify probable or confirmed infection with R. parkeri. RESULTS: During , clinical samples from 12 patients with illnesses epidemiologically and clinically compatible with R. parkeri rickettsiosis were submitted for diagnostic evaluation. Using indirect immunofluorescence antibody assays, immunohistochemistry, polymerase chain reaction assays, and cell culture isolation, we identified 6 confirmed and 6 probable cases of infection with R. parkeri. The aggregate clinical characteristics of these patients revealed a disease similar to but less severe than classically described Rocky Mountain spotted fever. CONCLUSIONS: Closer attention to the distinct clinical features of the various spotted fever syndromes that exist in the United States and other countries of the Western hemisphere, coupled with more frequent use of specific confirmatory assays, may unveil several unique diseases that have been identified collectively as Rocky Mountain spotted fever during the past century. Accurate assessments of these distinct infections will ultimately provide a more valid description of the currently recognized distribution, incidence, and case-fatality rate of Rocky Mountain spotted fever. 37

38 Detection of Rickettsia amblyommii in association with a tick bite rash. Billeter SA, Blanton HL, Little SE, Levy MG, Breitschwerdt EB. Vector Borne Zoonotic Dis Winter;7(4): In the summer of 2006, an Amblyomma americanum tick was removed from a woman in central North Carolina, who subsequently developed a rash at the site of tick attachment. When examined by polymerase chain reaction (PCR) for Borrelia, Anaplasma, Ehrlichia, Babesia, Rickettsia, and Bartonella DNA, only the Rickettsia primers generated an amplicon, which was identified as "R. amblyommii" by sequencing. To our knowledge, this is the first case in which R. amblyommii was temporally associated with a rash. Tick-borne diseases in North Carolina: is "Rickettsia amblyommii" a possible cause of rickettsiosis reported as Rocky Mountain spotted fever? Apperson CS, Engber B, Nicholson WL, Mead DG, Engel J, Yabsley MJ, Dail K, Johnson J, Watson DW. Vector Borne Zoonotic Dis Oct;8(5): Given the low relative abundance of American dog ticks, the high relative abundance of lone star ticks around residences and, the prevalence of R. amblyommii in lone star tick pools, we reasoned that the probable RMSF case patients were being exposed to and possibly infected with another SFGR, most likely R.amblyommii. 38

39 Rickettsia 364D: a newly recognized cause of escharassociated illness in California. Shapiro MR, Fritz CL, Tait K, Paddock CD, Nicholson WL, Abramowicz KF, Karpathy SE, Dasch GA, Sumner JW, Adem PV, Scott JJ, Padgett KA, Zaki SR, Eremeeva ME. Clin Infect Dis Feb 15;50(4): Conclusions. This is the first confirmation of human disease associated with the SFGR 364D, which was likely transmitted by D. occidentalis. Although the patients described here presented with a single cutaneous eschar as the principal manifestation, the full spectrum of illness associated with 364D has yet to be determined. Possible infection with 364D or other SFGR should be confirmed through molecular techniques in patients who present with spotless Rocky Mountain spotted fever or have serum antibodies to R. rickettsii with group-specific assays. 39

40 R. AFRICAE INVASION OF THE NEW WORLD Parola P, et al. N Engl J Med ;338:

41 THEN NOW IN THE US NAME WHERE RMSF - R.rickettsii severe/rare rash no eschar SE,W? - R.parkeri mild vesicular rash inoculation eschar SE? - R.amblyommii, mild, rarely rash, no fever SE - R.massiliae mild rash eschar (dog tickles)? - Rickettsia 364D mild no rash inoculation eschar California ATBF - R.africae Travellers 41

42 WHAT S NEW? In Asia R.sibirica sibirica (Russia, Mongolia, China) R.sibirica mongolitimonae R.heilongjiangensis R.japonica R.helvetica R.kellyi 42

43 LYMPHANGITIS ASSOCIATED RICKETTSIOSIS (LAR) R.sibirica mongolitimonae Fever, rash in spring Lymphangitis (5/10 cases) 2 taches noires (3/10 cases) Lymphadenitis Clustered cases Lymphangitis-associated rickettsiosis, a new rickettsiosis caused by Rickettsia sibirica mongolotimonae: seven new cases and review of the literature. Fournier PE, Gouriet F, Brouqui P, Lucht F, Raoult D. 43 Clin Infect Dis May 15;40(10): Lymphadenopathy Lymphangitis Eschar

44 Rickettsia japonica Courtesy of Dr. Mahara 44

45 JAPANESE OR ORIENTAL SPOTTED FEVER Emerging infectious disease (1984) Rickettsia japonica Transmitted by tick bite (Dermacentor taïwanensis, Haemaphysalis flava) Described by Dr. Mahara, associated with a positive Weil Felix Test Prevalent in Japan Fever, eruption, eschar Mild 45

46 R. heilongjangensis Described in 2004 by O. Mediannikov Close to R. japonica 13 cases for Russian Far East diagnosed by PCR and serology Tick bite: 6 Fever (13), rash (12), eschar (12), local adenopathy (10), lymphangitis (2) Mediannikov OY, Sidelnikov Y, Ivanov L, Mokretsova E, Fournier PE, Tarasevich I, Raoult D. Acute tick-borne rickettsiosis caused by Rickettsia heilongjiangensis in Russian Far East. Emerg Infect Dis. 2004;10:

47 R. sibirica (cluster) R. Japonica (cluster) CHINEESE SF RICKETTSIA - R. sibirica - HA-90 R. sibirica mongolitimonae R. sibirica - R. mongolotimonae (Hyalomma asiaticum) (HA-91) - «R. heilongjiangii» (D. silvaticus) 054 (a case with fever rash, «tache noire» and regional lymphadenopathy) - «R. hulinii» (Haemaphysalis concinna) (HL-93) R. heilongjiangensis 47

48 "Candidatus Rickettsia kellyi," India. Rolain JM, Mathai E, Lepidi H, Somashekar HR, Mathew LG, Prakash JA, Raoult D. Emerg Infect Dis Mar;12(3): Abstract We report the first laboratory-confirmed human infection due to a new rickettsial genotype in India, "Candidatus Rickettsia kellyi," in a 1-year-old boy with fever and maculopapular rash. The diagnosis was made by serologic testing, polymerase chain reaction detection, and immunohistochemical testing of the organism from a skin biopsy specimen. 48

49 - R.australis - R.honei - R.gravesi IN AUSTRALIA 49

50 Rickettsia australis QUEENSLAND TICK TYPHUS Transmitted by tick bite (Ixodes holocyclus) Fever, eruption (vesicular), eschar, enlarged lymph nodes Mild to severe 50

51 FLINDER'S ISLANDS SPOTTED FEVER Emerging infectious disease (1991) Rickettsia honei Identical to Tick Thai Typhus Rickettsia? Transmitted by? Located to the Flinder's Islands Fever, eruption, eschar, enlarged lymph nodes Described by Dr. Stewart 51

52 What s new? In Africa P. Parola, C.D. Paddock, D. Raoult. Tick-Borne Rickettsioses around the World: Emerging diseases challenging old concepts. Clin Microbiol Rev. 2005; 18:

53 Rickettsia africae AFRICAN TICK BITE FEVER Emerging infectious disease (1992) Transmitted by tick bite (Amblyomma haebraeum) High incidence in Southern Africa Fever, "tache noire" (multiple) rare eruption (vesicular) Mild Discovered twice Considered identical to MSF until 1992 Extremely common in travellers (second only to Malaria) 53

54 Attack strategy: bites legs several ticks attacks AMBLYOMMA TICKS R. AFRICAE 54

55 Clinical specificity : Less febrile Local lesion * more inoculation eschars * multiple inoculation eschars * more locations on legs of eschars * more regional lymphadenopathies Rash * less rash * no purpuric rash * vesicular rash Clustered cases Low death rate Late seroconversion Raoult D,et al.n Engl J Med. 2001;344: U 55 R

56 LYMPHANGITIS ASSOCIATED RICKETTSIOSIS Fever, rash in spring Lymphangitis (5/10 cases) 2 taches noires (3/10 cases) Lymphadenitis Clustered cases (LAR) Lymphangitis-associated rickettsiosis, a new rickettsiosis caused by Rickettsia sibirica mongolotimonae: seven new cases and review of the literature. Fournier PE, Gouriet F, Brouqui P, Lucht F, Raoult D. Lymphadenopathy Lymphangitis Eschar Clin Infect Dis May 15;40(10):

57 R. aeschlimanii Found in Hyalomma sp. Camel tick in Northern Africa and other species in Southern Europe 2 cases described: one in France from Morocco, one in South Africa Case in Algeria In tick: R.sibirica mongolotimonae R.massiliae 57

58 IN TICKS IN AFRICA Tick-borne rickettsioses, neglected emerging diseases in rural Senegal Mediannikov O, Diatta G, Fenollar F, Sokhna C, Trape JF, Raoult D. PLoS Negl Trop Dis Sep 14;4(9). BACKGROUND: Rickettsioses are one of the most important causes of systemic febrile illness among travelers from developed countries, but little is known about their incidence in indigenous populations, especially in West Africa. METHODOLOGY/PRINCIPAL FINDINGS: Overall seroprevalence evaluated by immunofluorescence using six rickettsial antigens (spotted fever and typhus group) in rural populations of two villages of the Sine-Saloum region of Senegal was found to be 21.4% and 51% for spotted fever group rickettsiae for Dielmo and Ndiop villages, respectively. We investigated the role of tick-borne rickettsiae as the cause of acute non-malarial febrile diseases in the same villages. The incidence of rickettsial DNA in 204 blood samples from 134 (62M and 72F) febrile patients negative for malaria was studied. DNA extracted from whole blood was tested by two qpcr systems. Rickettsial DNA was found in nine patients, eight with Rickettsia felis (separately reported). For the first time in West Africa, Rickettsia conorii was diagnosed in one patient. We also tested 2,767 Ixodid ticks collected in two regions of Senegal (Niakhar and Sine-Saloum) from domestic animals (cows, sheep, goats, donkeys and horses) by qpcr and identified five different pathogenic rickettsiae. We found the following: Rickettsia aeschlimannii in Hyalomma marginatum rufipes (51.3% and 44.8% in Niakhar and Sine-Saloum region, respectively), in Hyalomma truncatum (6% and 6.8%) and in Rhipicephalus evertsi evertsi (0.5%, only in Niakhar); R. c. conorii in Rh. e. evertsi (0.4%, only in Sine-Saloum); Rickettsia massiliae in Rhipicephalus guilhoni (22.4%, only in Niakhar); Rickettsia sibirica mongolitimonae in Hyalomma truncatum (13.5%, only in Sine-Saloum); and Rickettsia africae in Rhipicephalus evertsi evertsi (0.7% and 0.4% in Niakhar and Sine-Saloum region, respectively) as well as in Rhipicephalus annulatus (20%, only in Sine-Saloum). We isolated two rickettsial strains from H. truncatum: R. s. mongolitimonae and R. aeschlimannii. CONCLUSIONS/SIGNIFICANCE: We believe that together with our previous data on the high prevalence of R. africae in Amblyomma ticks and R. felis infection in patients, the presented results on the distribution of pathogenic rickettsiae in ticks and the first R. conorii case in West Africa show that the rural population of Senegal is at risk for other tick-borne rickettsioses, which are significant causes of febrile disease in this area. 58

59 Geographic repartition of scrub typhus Among the 3 first causes of infection in rural areas in far east (with murine typhus and Leptospirosis) Currently re-emerging in India very common in South Asia : Thailand, Vietnam 1 Billion people exposed 1 Million cases per year (?) 59

60 Fever Headaches (95%) SCRUB TYPHUS Generalized lymphadenopathies (50%) Eschar (50%) Rash (25%) Severe form (27%) Abortion (Lao Study by P. Newton et al.) 60

61 Rickettsia prowazekii Borrelia recurrentis Bartonella quintana TRANSMITTED DISEASES BY BODY LICE Acinetobacter baumanii? 61

62 Infection Typhus TYPHUS EPIDEMIOLOGY Apparent cure (Years) Stress Relapse Brill Zinsser Disease WAR Cold weather Bad hygiene Body lice outbreak Infected lice 62 TYPHUS OUTBREAK

63 New disease : "SUTAMA" (Crouching) Typhus Outbreak Burundi GIANT OUTBREAK Fever, severe myalgias of the legs, headache, resistance to antimalarial drugs, presence of body lice 103 patients were sampled (serum and body louse) 70 % of them had biological confirmation of epidemic typhus Estimated cases: 100,000 in 1997 (D. Raoult, et al. Lancet, 1998, 352: ) 63

64 TYPHUS SPORADIC CASES Russia: 1997: 23 cases in a psychiatric institution (Tarasevich I, et al. 1998, Lancet, 352: 1151) Peru: outbreak near Cusco (Raoult D., et al. 1999, Clin Infect Dis, 29: ) Algeria: cases near Batna ( ) (Niang M, et al. 1999, Emerg Infect Dis. 5: Mokrani K, et al. 2004, J Clin Microbiol, 42: ) France: a case in a homeless (Brouqui P, et al. Medicine (Baltimore). 2005; 84:61-8) 64

65 Back in the XIX th century Napoleon retreat of Russia 65

66 VILNIUS-CEMETERY

67 We identified 5 lice, confirmed their identification by PCR and sequencing. We identified B. quintana by PCR in 3 lice. Raoult D, et al. Evidence for louse transmitted diseases in soldiers of Napoleon s Grand Army in Vilnius. JID, Jan

68 We extracted DNA from dental pulp of 35 soldiers and found B. quintana in 7 and R. prowazekii in 3. 68

69 In conclusion 30% of Napoleon s soldiers suffered louse borne disease. 69

70 FLEA TRANSMITTED DISEASES R. felis R. typhi B. henselae B. quintana? Y. pestis 70

71 Rickettsia typhi (R. mooseri) Vector: Rat flea Widespread in the South of the USA, Central America and South, Africa, Asia (Indonesia, Thailand) and Mediterranean (Greece, Cyprus, Spain, North Africa) Fever, rash(40 50%) Discret rash First or second cause of fever of rural origin in Southeast Asia Typhus murin 71

72 In 1970, changes in the distribution of murine typhus a disease caused by R.typhi transmitted by the rat fleas (Xenopsylla cheopis) Cases are more prevalent in a wealthy county Orange (CA) than in poor counties Opossums are identified as major actors They are infested by cat fleas (Cenocephalides felis) 72

73 Rickettsia felis-associated uneruptive fever, Senegal Socolovschi C, Mediannikov O, Sokhna C, Tall A, Diatta G, Bassene H, Trape JF, Raoult D. Emerg Infect Dis Jul;16(7): Abstract During November 2008-July 2009, we investigated the origin of unknown fever in Senegalese patients with a negative malaria test result, focusing on potential rickettsial infection. Using molecular tools, we found evidence for Rickettsia felisassociated illness in the initial days of infection in febrile Senegalese patients without malaria. 73

74 Human Infection with Rickettsia felis, Kenya. Richards AL, Jiang J, Omulo S, Dare R, Abdirahman K, Ali A, Sharif SK, Feikin DR, Breiman RF, Njenga MK. Emerg Infect Dis Jul;16(7): Abstract To determine the cause of acute febrile illnesses other than malaria in the North Eastern Province, Kenya, we investigated rickettsial infection among patients from Garissa Provincial Hospital for 23 months during Nucleic acid preparations of serum from 6 (3.7%) of 163 patients were positive for rickettsial DNA as determined by a genusspecific quantitative real-time PCR and were subsequently confirmed by molecular sequencing to be positive for Rickettsia felis. The 6 febrile patients' symptoms included headache; nausea; and muscle, back, and joint pain. None of the patients had a skin rash. 74

75 November- June: 205 E/134 P Dielmo: 8 R. felis/172 E/103 P Ndiop: 1 R. Felis/33 E/ 31 P Total: 9 samples Sampling: 87 pos R. felis 2010 June-December: 384 E/323 P Site Sine Saloum Dielmo: 18 R. felis/210 E/144 P Ndiop: 8 R. felis/104 E/78 P Site Niakhar : 13 R. felis/ 70 E/P Total: 39 samples January-March: 409E Site Sine Saloum Dielmo: 2 R. felis /86E Ndiop: 3 R. felis/ 31E Site Niakhar : 2 R. felis/ 9E Site Casamance: 12 R. felis/ 122E Site Kedougou: 17 R. felis/ 80E Site Keur Momar Sarr: 3 R. felis/ 81E Total: 39 samples en

76 Description of "yaaf", the vesicular fever caused by acute Rickettsia felis infection in Senegal. Mediannikov O, Fenollar F, Bassene H, Tall A, Sokhna C, Trape JF, Raoult D. J Infect Oct 13. Rickettsiosis caused by Rickettsia felis is an emerging infection in Africa and may account for 3-4% of ambulatory febrile fevers. We report herein a case of R. felis infection, for which we propose the name "yaaf", meaning vesicle, in an 8-month-old girl who was diagnosed in the field by real-time PCR analysis of a skin lesion; these PCR analysis was performed at a local experimental point-of-care laboratory. The clinical presentation was polymorphous skin lesions, including papules, vesicles, erosions and ulcers. The patient did not produce antibodies against Rickettsia. We suggest that this disease may be a primary infection caused by R. felis. 76 Skin lesions of the patient with a primary infection with R. felis. a general appearance; b ulcerative lesions; c vesicles.

77 Now look for Rickettsia felis in mosquitos Rickettsia felis in Aedes albopictus Mosquitoes, Libreville, Gabon. Socolovschi C, Pagés F, Raoult D. Emerg Infect Dis Oct;18(10): Rickettsia species in African Anopheles mosquitoes Cristina Socolovschi,Frederic Pages,Mamadou Ousmane Ndiath, Pavel Ratmanov, Didier Raoult PLOS ONE. In press 77

78 Molecular evidence for the presence of Rickettsia felis in the feces of wild-living African apes. AK.Keita,C.Ahuka-Mundeke,P.Ratmanov,C.Butel,A.Ayouba,B-I Inogwabini,JJ.MuyembeTamfum,E.MpoudiNgole,E.Delaporte,M.Peeters,F.Fenollar,D.Raoult. Submitted PlosOne. 78 Figure 4. A map of the prevalence of Plasmodium falciparum [17] and R. felis in gorillas and chimpanzees found in our study at different collection sites in Cameroon (Table 4). The map shown is from Google 2012.

79 CONCLUSION Fastidious organisms such as Rickettsia need specific molecular tools That cause many of unexplained fevers (leptospiroses, Murine typhus, scrub typhus in S.E Asia, Borrelioses and Rickettsioses in Africa) Are easy to teat with Doxycycline 79