1. Armed Forces Research Institute of Medical Sciences EMERGING RICKETTSIAL DISEASES IN ALONG THAI-MYANMAR BORDER Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand Harvard School of Public Health, Boston, USA Unité des Rickettsies, Marseille, France Philippe Parola, M.D., Ph.D. R. Scott Miller, M.D.

2. Armed Forces Research Institute of Medical Sciences WHAT ARE RICKETTSIAL DISEASES ? Infectious diseases caused by bacteria of the order Rickettsiales Short, Gram-negative rods retaining basic fuchsin with Gimenez staining which live inside other cells Taxonomy: Rickettsia : Spotted Fever Group Typhus group Ehrlichia, Anaplasma, Neorickettsia and Wolbachia Excluded from Rickettsiales Orientia tsutsugamushi (scrub typhus) Coxiella burnetti (Q fever) Bartonella sp.

3. Armed Forces Research Institute of Medical Sciences WHAT ARE RICKETTSIAL DISEASES ? ARTHROPOD BORNE DISEASES TICKS: SFG rickettsioses, Ehrlichioses FLEAS: murine typhus (R. typhi), R. felis, Bartonella sp. LICE: epidemic typhus (R. prowazekii) TROMBICULIDS (chiggers): scrub typhus (O. tsutsugamushi) I. ricinus in Europe

4. Armed Forces Research Institute of Medical Sciences 12 tick-borne rickettsioses 7 since 1991 !! R. rickettsii R. africae R. conorii R. slovaca R. conorii Astrakhan R. conorii Israël R. australis R. honei Indian tick typhus Rickettsia R. japonica R. mongolotimonae R. helvetica R. mongolotimonae R. sibirica R. conorii R. conorii Israël « R. heilongjiangii » R. helvetica

5. Armed Forces Research Institute of Medical Sciences Tick collection: flagging Rubber plantation

6. Armed Forces Research Institute of Medical Sciences Tick collection on animals Dogs Dog kennels

7. Armed Forces Research Institute of Medical SciencesBACKGROUND Rickettsial Diseases in Thailand Murine Typhus due to R. typhi Rat fleas Know to occur in Thailand Poorly documented Scrub typhus due to Orientia tsutsugamushi Leptotrombidium sp. (Chiggers) Endemic in Thailand, especially northern region NONE WELL DOCUMENTED IN THE SANGKHLABURI DISTRICT

8. Armed Forces Research Institute of Medical SciencesBACKGROUND Rickettsial Diseases in Thailand Few Cases of SFG rickettsioses documented by serology in Thailand (Chiang Mai) Sirisanthana et.al., Am J Trop Med Hyg 1994; 50: 682-6 Human Ehrlichioses in Thailand ? Heppner et al. Lancet 1997; 350: 785-6 AFRIMS/ Kwai River Clinical Center Fever Project July 1999-February 2000 150 febrile volunteers enrolled 3%: acute Spotted Fever Group rickettsioses (IF R. rickettsii antigen) seroprevalence of SFG antibody in village surveys: 9% seroprevalence of Ehrlichia spp. : E. chaffeensis 2.8 %E. phagocytophila 5 %

9. Armed Forces Research Institute of Medical SciencesOBJECTIVES AFRIMS study of the etiology of undifferentiated fever syndromes Determine whether ehrlichiosis and / or SFG rickettsiosis may serve as etiologic agents for fevers of unknown origin there. Identify potential vectors Entomological risks

10. Armed Forces Research Institute of Medical Sciences 3 cases of scrub typhus (O. tsutsugamushi) Scrub typhus is quite rare 5% seroprevalance in 497 adults in Ban Viakadee and Ban Mong Satur 3 cases of murine typhus (R. typhi) 8 cases of SFG rickettioses (?) 14 CONFIRMED RICKETTSIOSES in 2002 No ehrlichiosis documented in humans

11. Armed Forces Research Institute of Medical Sciences H 535 Cases of scrub typhus : H 535 35-year-old Thai Man Severe: 3-day fever + chills + headache + vomiting Failure of a 5-day ceftriaxone Recovered with Doxycycline Removed multiple arthropods after jungle trips

12. Armed Forces Research Institute of Medical Sciences H 535: multiple bites

13. Armed Forces Research Institute of Medical Sciences H 541: 3 eschars Shoulder: 4 cmLeft calf: 3 cmRight calf: 4 cm

14. Armed Forces Research Institute of Medical Sciences H 541: Macular rash

15. Armed Forces Research Institute of Medical Sciences Serology IF (IgG/IgM)AcuteLate O. tsutsugamushiGilliam128/64128/16 Karp0/00/0 Kato0/00/0 Kawazaki0/00/0 R. japonica0/320/32 R. helvetica0/320/32 R. honei0/160/16 PCR biopsy: negative Biopsy/Blood culture: negative H 541: diagnosis

16. Armed Forces Research Institute of Medical Sciences Cases of murine typhus: R. typhi Age (y) FeverDiffuse Rash Eschars Local Nodes Other IF R. typhi TITERS IgG/IgM 35YesNo Femoral left Chilliness Chills Headach e N°1: 16/256 N°2: 512/256 37YesNo Chilliness Chills Headach e Nausea vomiting N°1: 64/8 N°2: 512/256 20YesNo Headache N°1: 0/64 N°2: 128/256

17. Armed Forces Research Institute of Medical Sciences Cases of SFG rickettsioses 49-year-old Karen Woman 3-day Fever + Chills Empiric TRT: cotrimoxazole Recovered Retrospective questionning: Removed a tick from her body 10 days prior fever

18. Armed Forces Research Institute of Medical Sciences H 492: tick-bite eschar 3 weeks after removing the tick

19. Armed Forces Research Institute of Medical Sciences Cases of SFG rickettsioses R. conorii - like AgeFeverRashEschar NodesOtherIF SFG IgG/IgM 50Yes Severe Illness Yes Left Knee No Chills Abdom. Pain Rales Confusion Low PLTs Anemia R. conorii Indian N°1: 128/16 N°2: 128/16 45 Jungle trips Yes Severe illness No Nausea Vomiting Diarrhea HMG SPM R. conorii Indian N°1: 64/32 N°2: 64/32

20. Armed Forces Research Institute of Medical Sciences Cases of SFG rickettsioses R. helvetica - like AgeFeverRashEschar NodesOtherIF SFG IgG/IgM 35 Jungle trips Tick bite one week before Yes Severe illness NoYes heaped edge 0.8 cm No Chilliness Headache Nausea vomiting Coughing Myalgia HMG WBC 14 R. helvetica N°1: 64/256 N°2: 16/128 37 Tick bite not noted YesYes ?No Headache Chilliness Nausea vomiting Coughing Myalgia WBC 19.8 LFTs R. helvetica N°1: 0/16 N°2: 128/32

21. Armed Forces Research Institute of Medical SciencesCONCLUSIONS Rickettsial disease as a cause of fever in the Thai- Burma Border, Sangkhlaburi district, Thailand include: Scrub typhus Murine typhus SFG rickettsioses SFG Rickettsioses – not previously described in Thailand R. conorii India ? R. helvetica ? Other cross reacting rickettsia or new species ? \ Clinically all respond well to doxycycline for 7 days

22. Armed Forces Research Institute of Medical Sciences Fever Study Conclusions Most fevers are difficult to classify by organ involvement –Rapid diagnostic tests are needed Leptospirosis is common and underrecognized –~7% of fevers in adults coming to hospital –Major cause of morbidity and febrile jaundice –Further epidemiology studies are needed There are 3 other rickettsial illnesses in addition to scrub typhus. Not all have rash or eschar. All respond well to doxycycline or tetracycline