Disclosures Diagnosis and empirical treatment of suspected rickettsial infections Funding • National Institutes of Allergy and Infectious Diseases (R01AI044102) • PAT-74-3977 Uniformed Services University of the Health Sciences • CDMRP Tick-borne Disease Research Program (W81XWH-17-1-0668) J. Stephen Dumler, M.D. • CDMRP Tick-borne Disease Research Program (TB180110) • Global Emerging Infections Surveillance / Armed Forces Health Surveillance Branch (P0019_17_HS) Professor and Chairperson Integrated Departments of Pathology Uniformed Services University, Walter Reed National Military The opinions expressed herein are those of the author(s) and are not necessarily representative of those of the Uniformed Services University of the Health Sciences (USUHS), the Department of Defense (DOD); or, the United States Army, Navy, or Medical Center, and the Joint Pathology Center Air Force. Bethesda, MD 1 2 3 4 Phylogeny of Rickettsiales ( rrs ) α‐ proteobacteria E chaffeensis E ewingii A phagocytophilum E muris R prowazekii R australis R typhi R akari R felis R honei R rickettsii Neoehrlichia mikurensis R conorii R parkeri W pipientis R africae R sibirica O tsutsugamushi Anaplasmataceae Rickettsiaceae N sennetsu B quintana E coli B henselae B bacilliformis 0.1 γ‐ proteobacteria C burnetii 5 6
Rickettsial diseases: Pathogenesis of vasculotropic rickettsioses The genera Rickettsia, Ehrlichia, and Anaplasma • obligate intracellular bacteria endosome escape osmotic injury • Rickettsia and Orientia Rickettsia • cytoplasmic endothelial cells • Ehrlichia and Anaplasma • vacuolar spread • contain DNA, RNA, ribosomes • divide by binary fission • Gram-negative cell wall • genomes with typical bacterial genes • lack genes for glycolysis • genes for transmembrane transport e.g. ATP, amino acids 7 8 Rickettsia spp. with Standing in Nomenclature species group vector human pathogenicity disease Rickettsia africae spotted fever tick yes African tick bite fever Spotted fever group rickettsioses Rickettsia conorii spotted fever tick yes Mediterranean spotted fever Rickettsia heilongjiangensis spotted fever tick yes Far Eastern tick ‐ borne rickettsiosis Rickettsia honei spotted fever tick yes Flinders Island spotted fever; Thai tick typhus Rickettsia japonica spotted fever tick yes Japanese spotted fever Rickettsia massiliae spotted fever tick yes R. massiliae spotted fever Rickettsia parkeri spotted fever tick yes R. parkeri rickettsiosis; Maculatum disease Rickettsia raoultii spotted fever tick yes scalp eschar and neck lymphadenopathy Rickettsia rickettsii spotted fever tick yes Rocky Mountain spotted fever Rickettsia sibirica spotted fever tick yes Siberian tick typhus Rickettsia slovaca spotted fever tick yes scalp eschar and neck lymphadenopathy Rickettsia australis transitional tick yes Queensland tick typhus Rickettsia aeschlimannii spotted fever tick potential Rickettsia helvetica spotted fever tick potential Rickettsia montanensis spotted fever tick potential Rickettsia peacockii spotted fever tick potential Rickettsia rhipicephali spotted fever tick potential Rickettsia tamurae spotted fever tick potential Rickettsia hoogstraalii transitional tick potential Rickettsia canadensis ancestral tick potential Rickettsia amblyommatis spotted fever tick unknown Rickettsia asiatica spotted fever tick unknown Rickettsia buchneri spotted fever tick unknown Rickettsia bellii ancestral tick unknown Rickettsia akari transitional mite yes rickettsialpox Rickettsia prowazekii typhus louse yes epidemic (louse ‐ borne) typhus Rickettsia asembonensis transitional flea unknown Rickettsia felis transitional flea yes flea ‐ borne spotted fever Rickettsia typhi typhus flea yes murine (endemic or flea ‐ borne) typhus 9 10 Orientia Typhus fever group rickettsioses 11 12
Febrile illness in Southern Sri Lanka, March ‐ October, 2007 Febrile illness in Southern Sri Lanka; March ‐ October, 2007 no. with serologic % with acute no. with serologic % with acute % initial dx Infection / Disease no. tested Infection / Disease no. tested evidence infection evidence infection correct bacteremia/sepsis 1091 11 1.0% bacteremia/sepsis 1091 11 1.0% HIV 1079 0 0% HIV 1079 0 0% leptospirosis 889 120 13.5% leptospirosis 889 120 13.5% 23% dengue (serotypes 2,3,4) 859 54 6.3% dengue (serotypes 2,3,4) 859 54 6.3% 14% any rickettsial infection 156 17.7% any rickettsial infection 156 17.7% scrub typhus scrub typhus 9 2.7% 9 2.7% spotted fever group spotted fever group 86 9.7% 86 9.7% rickettsiosis rickettsiosis 883 883 0% typhus group typhus group 29 3.3% 29 3.3% rickettsiosis rickettsiosis indeterminate 32 3.6% indeterminate 32 3.6% Q fever 889 13 1.5% Q fever 889 13 1.5% 0% TOTAL TOTAL 37% 883 ‐ 1091 354 37.3% 883 ‐ 1091 354 37.3% Reller ME, et al . Emerg Infect Dis. 2011; 17:1678-84; Reller ME, et al. Emerg Infect Dis. 2012; 18:256-63; Reller ME, et al. Emerg Infect Dis. 2012; 18:825-9. Reller ME, et al . Emerg Infect Dis. 2011; 17:1678-84; Reller ME, et al. Emerg Infect Dis. 2012; 18:256-63; Reller ME, et al. Emerg Infect Dis. 2012; 18:825-9. 13 14 Case 1 - 8y boy from suburban Atlanta Etiology of Severe Febrile Illness in Low ‐ and Middle ‐ Income Countries: A Systematic Review PLoS One. 2015; 10: e0127962. • 2 wk PTA - mild respiratory sx, low fever, vague rash - proventil, Percent of febrile patients as confirmed cases according to region and age in all eligible studies, 1980–2013 steroids, amoxicillin, quell East North West South South East West Pediatric All Regions • 2 d PTA - fever, rash - augmentin, deltasone, albuterol Africa Africa* Africa Central Asia Asia Asia* All Regions • unresponsive - plt 19K, Na 130, BUN 45, creat 1.2, AST 237, ALT Rickettsial infections 7.4 4.9 6.6 2.3 3.3 4.9 152 • diffuse cerebral edema - herniation, death Spotted fever group 8 3.8 7.4 6.8 • Post-mortem examination performed Typhus group 0.4 1.1 6.6 2.3 1.9 3.3 Scrub typhus 4.9 8 8 7.8 * None tested 15 16 Clinical manifestations of spotted fever Case 1. 8y boy from rickettsioses: RMSF suburban Atlanta fever, headache, myalgias, rash skin lung rash - macular, maculopapular, petechial R. rickettsii serology gastrointestinal system < 64 renal system lung acute tubular necrosis 2 to hypotension I mmunohistochemistry shock and multi-organ failure For R. rickettsii + cardiopulmonary system non-cardiogenic pulmonary edema Final dx: RMSF central nervous system – meningoencephalitis brain cerebral edema, herniation kidney 17 18
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