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Home , Ehrlichia ewingii, Japanese spotted fever, Murine typhus, Queensland tick typhus, Rickettsialpox, Rickettsia africae

Disclosures Diagnosis and empirical treatment of suspected rickettsial Funding • National Institutes of Allergy and Infectious Diseases (R01AI044102) • PAT-74-3977 Uniformed Services University of the Health Sciences • CDMRP -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 Medical Center, and the Joint Pathology Center Services University of the Health Sciences (USUHS), the Department of Defense (DOD); or, the United States Army, Navy, or Air Force. Bethesda, MD

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Phylogeny of (rrs)

α‐ 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

Anaplasmataceae O tsutsugamushi

N sennetsu

B quintana

B henselae E coli B bacilliformis

0.1 γ‐proteobacteria

C burnetii 56 Rickettsial diseases: Pathogenesis of vasculotropic rickettsioses The genera , , and

• obligate intracellular endosome escape osmotic injury • Rickettsia and 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

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Rickettsia spp. with Standing in Nomenclature group vector human pathogenicity disease spotted tick yes tick yes Mediterranean spotted fever Spotted fever group rickettsioses Rickettsia heilongjiangensis spotted fever tick yes Far Eastern tick‐borne spotted fever tick yes Flinders Island spotted fever; Thai tick spotted fever tick yes spotted fever tick yes R. massiliae spotted fever spotted fever tick yes R. parkeri rickettsiosis; Maculatum disease spotted fever tick yes scalp and neck spotted fever tick yes Rocky Mountain spotted fever spotted fever tick yes Siberian tick typhus Rickettsia slovaca spotted fever tick yes scalp eschar and neck lymphadenopathy transitional tick yes Rickettsia aeschlimannii spotted fever tick potential Rickettsia helvetica spotted fever tick potential Rickettsia montanensis spotted fever tick potential 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 spotted fever tick unknown Rickettsia buchneri spotted fever tick unknown Rickettsia bellii ancestral tick unknown transitional yes typhus louse yes epidemic (louse‐borne) typhus Rickettsia asembonensis transitional unknown transitional flea yes flea‐borne spotted fever typhus flea yes murine (endemic or flea‐borne) typhus 910

Typhus fever group rickettsioses Orientia

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 / 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% 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% 92.7% scrub typhus 92.7% spotted fever group spotted fever group 86 9.7% 86 9.7% rickettsiosis 883 rickettsiosis 883 0% typhus group typhus group rickettsiosis 29 3.3% rickettsiosis 29 3.3%

indeterminate 32 3.6% indeterminate 32 3.6% 889 13 1.5% Q fever 889 13 1.5% 0% TOTAL 883‐1091 354 37.3% TOTAL 883‐1091 354 37.3% 37% 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.

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Etiology of Severe Febrile Illness in Low‐ and Middle‐Income Countries: A Systematic Review Case 1 - 8y boy from suburban Atlanta PLoS One. 2015; 10: e0127962. Percent of febrile patients as confirmed cases according to region and age in all eligible studies, 1980–2013 • 2 wk PTA - mild respiratory sx, low fever, vague rash - proventil, steroids, amoxicillin, quell East North West South South East West Pediatric All Regions Africa Africa* Africa Central Asia Asia Asia* All Regions • 2 d PTA - fever, rash - augmentin, deltasone, albuterol

Rickettsial infections 7.4 4.9 6.6 2.3 3.3 4.9 • unresponsive - plt 19K, Na 130, BUN 45, creat 1.2, AST 237, ALT 152 Spotted fever group 8 3.8 7.4 6.8 • diffuse cerebral edema - herniation, death • 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

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Clinical manifestations of spotted fever Case 1. 8y boy from rickettsioses: RMSF suburban Atlanta . fever, , , rash . rash - macular, maculopapular, skin lung R. rickettsii petechial <64 . gastrointestinal system lung . renal system . acute tubular necrosis 2 to hypotension Immunohistochemistry . shock and multi-organ failure For R. rickettsii + . cardiopulmonary system . non-cardiogenic pulmonary edema Final dx: RMSF . central nervous system – brain . cerebral edema, herniation

kidney

17 18 Frequent clinical features of rickettisoses Skin rash in RMSF (meta analysis median percentages of patients with clinical feature) R. rickettsii R. prowazekii R. typhi History, signs, or symptoms R. conorii MSF RMSF typhus macular maculopapular Fever 100 100 100 100

Headache 91 100 75 70

Myalgia 72 70 50 58

Rash 90 32 45 98

Rash on palms and soles 82 na* 2 79 ecchymosis or 60 45 46 36

Abdominal pain 43 65 18 na

Conjunctivitis 30 34 33 36

Pneumonitis 15 8 7 10 Any severe neurologic complication 26 50 1 11

petechial na* data not available

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Laboratory abnormalities in (%) Laboratory finding RMSF HME HGA Rocky Mountain spotted fever White blood cell count diagnosis and risk > 10,000/L2811 < 5,000/L6649. risk of death 5 x in patients after day 5 of illness > 10% bands 69 76 . most patients are initially examined before day 5, but not Platelet count/L treated until after day 5 < 150,000 52 72 71 Serum sodium < 132 mEq/L 56 . major factors for ineffective diagnosis and delayed therapy: - absence of typical rash ALT or AST  2x normal value 62 76 71 - presentation during non-peak tick activity season Cerebrospinal fluid - presentation during first 3 days of illness Pleocytosis 48 60 rare mononuclear cell predominance 46 67 neutrophil predominance 50 33 Glucose  50 mg/dL 8 14 Protein  50 mg/dL 35 44

Opening pressure  250 mm H2O14

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Demographics of SFG rickettsiosis cases by hospitalization status and fatal Case 2 - 67 year old physician from Maryland outcome, 2008–2012 (CRFs) n (HR, %) RR n (CFR, %) RR • Traveled to Argentina and Brazil (6 weeks ago) Gender Male 1,474 (28) – 17 (0.3) – Female 711 (24) 1.2 19 (0.6) 2.0 • Traveled to Kenya and South Africa (returned 4d ago) Age group (years) • safari <10 131 (29) 1.0 8 (1.6) 7.7 10–19 140 (21) 0.8 2 (0.3) 1.4 • walked in/along ocean and brackish rivers 20–29 174 (23) 0.8 1 (0.1) 0.6 30–39 229 (23) 0.8 1 (0.1) 0.5 • drank local water 40–49 302 (22) 0.8 7 (0.5) 2.4 50–59 376 (24) 0.9 6 (0.4) 1.8 • exposed to feral dogs and cats 60–69 401 (28) – 3 (0.2) – 70+ 399 (40) 1.4 6 (0.6) 3.0 • ate partially cooked meats Race White 1,674 (27) – 23 (0.4) – Black 118 (44) 1.7 1 (0.4) 1.1 • Returned to US with fever (38.5C), headache, confusion for 24h, 20- American Indian/Alaska Native 67 (34) 1.3 7 (2.0) 5.4 Asian/Pacific Islander 19 (41) 1.5 1 (2.0) 5.7 30 petechiae on both calves; two on right thigh Ethnicity 9 9 Hispanic 104 (34) 1.4 4 (1.3) 3.2 • WBC 3.9 x 10 /L; platelets 210 x 10 /L Non‐Hispanic 1,570 (26) – 25 (0.4) – Immune status • Acute phase serology for viruses and rickettsiae negative; malaria Immunocompromised 205 (50) 2.0 7 (1.7) 4.4 Not immunocompromised 1,066 (25) – 17 (0.4) – smear neg. Life‐threatening complications One or more 241 (79) 11.7 17 (6.0) 27.9 • Skin biopsy performed None 1,949 (24) – 19 (0.2) –

23 24 Case 2 ‐ 67 year old physician from Maryland who traveled to Argentina, Brazil, Kenya, and South Africa Frequent clinical features of rickettisoses (meta analysis median percentages of patients with clinical feature) R. rickettsii R. typhi History, signs, or symptoms R. conorii MSF R. conorii MSF Convalescent spotted fever group RMSF murine typhus antibody titer ‐ 2560 Fever 100 100 100 100 Headache 91 70 75 70

Myalgia 72 58 50 58

Rash 90 98 45 98

Rash on palms and soles 82 79 279

Nausea or vomiting 60 36 46 36

Abdominal pain 43 na 18 na

Eschar biopsy Conjunctivitis 30 36 33 36 15 10 710 Diagnosis: African tick bite fever Any severe neurologic complication 26 11 111 (R. africae or R. conorii) IHC for spotted fever group rickettsiae na* data not available

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Laboratory abnormalities in rickettsioses Comparison of clinical findings in various spotted fever rickettsioses (% of cases with finding) Laboratory finding Rocky Mountain Mediterranean Epidemic Mediterranean spotted fever spotted fever typhus spotted fever White blood cell count > 10,000/L28281428 100 <5,000/L20320 80 finding

> 10% bands 69 60

Platelet count/L with

< 150,000 52 35 43 35 40 patients Serum sodium < 132 mEq/L 56 25 25 20 of

Elevated ALT or AST 62 39 63 39 % 0 Cerebrospinal fluid Pleocytosis 48 mononuclear cell predominance 46 present 21 present neutrophil predominance 50 Glucose  50 mg/dL 8 Protein  50 mg/dL 35

Opening pressure  250 mm H2O14

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Eschars and skin lesions with SFGR Rickettsial infection in travelers to Sub-Saharan Africa

• GeoSentinel Surveillance Network 2007 2,451 travelers with fever • 21% malaria MSF – tache noire Japanese SF ‐ eschar R. parkeri ‐ eschar • 2% rickettsia • 22% undiagnosed • GeoSentinel Surveillance Network 2009 • 280 travelers with rickettsial infection • 231 (82.5%) had spotted fever (SFG) rickettsiosis African tick‐bite fever–multiple eschars African tick‐bite fever ‐ vesicles • 16 (5.7%) scrub typhus • 10 (3.6%) typhus group (TG) rickettsiosis • 4 (1.4%) indeterminable SFG/TG rickettsiosis • 1 (0.4%) human granulocytic • Swedish travelers 1997-2001 • 77 cases Rickettsialpox ‐ eschar Rickettsialpox ‐ vesicles • risk 4-5 x malaria risk in same region • 152 first time Norwegian travelers to Sub-Saharan Africa • 9% seropositive • 62% of seropositives symptomatic • 940 Norwegian travelers followed prospectively • 4 to 5% overall TIBOLA or DEBONEL TIBOLA or DEBONEL • 27% of those flu-like illnesses

29 30 Case 3 - 4 year old Hispanic boy with sudden onset fever Case 3 - 4 year old Hispanic boy with sudden onset fever • Lives in McAllen TX, but travels often to Mexico to visit family from South Texas who travels to Mexico • Physical exam • CXR Bilateral interstitial infiltrates • T 40.0C • generalized petechial rash (day 2) • Required PICU management: • Vomiting and diarrhea (day 6) • 13 units platelets • WBC 2.9 x 109/L (7% bands), platelets 51 x 109/L, Hct 30.1%, Na+ • 1 unit FFP over 3 days 132 meq/L, ALT 102 U/L • Acute phase serum • Started amoxicilin, then cefotaxime • Day 1: Weil-Felix OX19 160, OX2 160, OXK 40 • All blood, urine, stool cultures and O&P exams negative • Day 4: Weil-Felix OX19 320 • Treated with • Convalescent serum R. typhi titer 8192

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Frequent clinical features of rickettisoses (meta analysis median percentages of patients with clinical feature) Laboratory abnormalities in rickettsioses R. typhi R. prowazekii History, signs, or symptoms R. rickettsii RMSF R. conorii MSF (% of cases with finding) murine typhus typhus Laboratory finding Rocky Mountain Mediterranean Murine Epidemic Fever 100 100 100 100 spotted fever spotted fever typhus typhus White blood cell count Headache 91 70 75 100 > 10,000/L282830 14 Myalgia 72 58 50 70 <5,000/L2028 3 > 10% bands 69 Rash 90 98 45 32 Platelet count/L Rash on palms and soles 82 79 2na* < 150,000 52 35 48 43 Serum sodium < 132 mEq/L 56 25 50 Nausea or vomiting 60 36 46 45 Elevated ALT or AST 62 39 50 63 Abdominal pain 43 na 18 65 Cerebrospinal fluid Pleocytosis 48 21 Conjunctivitis 30 36 33 34 mononuclear cell predominance 46 present 100 21 neutrophil predominance 50 0 Pneumonitis 15 10 78 Glucose  50 mg/dL 8 0 Any severe neurologic Protein  50 mg/dL 35 (sl ) complication 26 11 150

Opening pressure  250 mm H2O14 na* data not available

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Murine typhus ecology

urban Sylvatic/suburban

Rat flea (Xenopsylla cheopis) (Ctenocephalides felis)

Rattus spp. Didelphus virginianus

35 36 Case 4 - 51 year old business executive from Minnesota • Recreational travel to Thailand near Burmese border • walked through rugged, hilly country • Returned to St. Paul, MN 8-12 days later • Within 1 week • fever (40.6C), headache, confusion, eschar on left scapula • bilateral CN IV palsy, facial diplegia, bilateral evoked nystagmus; motor 0/5 lower extremeties; DTR 3+ symmetrical • WBC 14 x 109/L; platelets 115 x 109/L; ALT 462 U/L; CSF – 25 WBC/μL, protein 49 mg/dL, glucose 57 mg/dL • Illness progressed rapidly • ARDS requiring prolonged ventilation and tracheostomy • Renal failure requiring hemodialysis • Coma • Blood cultures negative • JE and dengue antibodies negative • malaria smear neg.

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Case 4- 51 year old business executive from Scrub typhus Minnesota with recreational travel to Thailand near Burmese border •

• Convalescent serum rickettsia serologic results • transmitted by larval • Spotted fever group rickettsiae (R. rickettsii) <64 trombiculid mites • Typhus group rickettsiae (R. typhi) <64 (chiggers) http://www.mikebaker.com/animals/chiggers.html • Scrub typhus (Orientia tsutsugamushi) 10,240 • 6 month follow-up • febrile illness • Stable, partially blind, nerve deafness, significant cognitive deficits, gait ataxia • 50% with eschar • Diagnosis: Scrub typhus • > 1 billion at risk • 1 million infections/year

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Frequent clinical features of undifferentiated febrile illnesses (meta analysis median percentages of patients with clinical feature) Laboratory abnormalities in acute undifferentiated History, signs, or febrile diseases spotted fever typhus scrub typhus dengue leptospirosis symptoms (% of cases with finding) Fever 100 100 100 100 100 Laboratory finding spotted scrub Headache 82 77 100 78 85 typhus dengue leptospirosis fever typhus Myalgia 70 45 32 77 77 White blood cell Rash 94 55 49* 11-53 5 count Rash on palms and soles 79 1 na** na na > 10,000/L 28 22 34 639 Nausea or vomiting 54 31 28 53 45 <5,000/L 24 13 3 25 8 Abdominal pain 33 18 na na 33 Platelet count/L Conjunctivitis 21 35 29 na 61

Pneumonitis/ 11 31 28 35 37 < 150,000/μL 44 46 25 59 26

Any severe Elevated ALT or neurologic 17 10 10 1-6 <25 50 57 70 64 78 complication AST * includes eschars; **na data not available 41 42 Differential diagnosis of rickettsial diseases • Viral syndromes and • Rheumatic fever • Human Herpes virus 6 infection • Hemolytic uremic syndrome • Human parvovirus B19 • Acute gastrointestinal illness • Enteroviral infection • Acute abdomen • Epstein-Barr virus infection • Hepatitis • Dengue fever • Hemophagocytic and macrophage activation syndromes • • Kawasaki disease • Disseminated gonococcal infection • TTP • pneumoniae infection •ITP • Leptospirosis • Drug reactions • Secondary • Immune complex-mediated illness • Meningococcemia • Post-group A Streptococcal infections • • Secondary syphilis The global expansion of • scrub typhus • -bite fever •

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rickettsiosis diagnosis Median clinical sensitivity of PCR methods for detection of spotted fever group and typhus group rickettsia in blood and skin/eschar biopsy samples. • Clinical suspicion most important % clinical sensitivity Sample rickettsia method no. assays • Exposure to or known vector bites median (IQR) • Appropriate clinical manifestations all PanRick all 145 23 (15‐34) SFGR 331 48 (34‐65) • diagnosis of active infection TGR 257 5 (3‐7) • skin biopsy with rickettsial antigen demonstration skin all all 233 43 (7‐55) • PCR (blood, buffy coat, eschar swab/biopsy) SFGR 101 67 (55‐79) •culture TGR 88 6 (5‐6) blood all all 331 18 (4‐30) • serologic confirmation PanRick 101 18 (12‐23) - not useful during the first 7 to 14 days – need paired sera SFGR 230 42 (24‐56) - IgG vs. IgM TGR 169 3 (2‐10) all PanRick real‐time PCR 525 7 (4‐23) - IFA, ELISA, RDT SFGR real‐time PCR 123 23 (14‐33) - routinely unable to distinguish TG from SFG TGR real‐time PCR 257 5 (3‐7) - routinely unable to distinguish among species SFGR nested PCR 29 31 (31‐31) - Weil-Felix febrile agglutinins insensitive and nonspecific SFGR conventional PCR 179 69 (61‐80)

Curr Opin Infect Dis. 2016; 29:433-439

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Kinetics of serological response in RMSF Sensitivity and specificity of serological tests for confirmation of scrub typhus, spotted fever rickettsiosis, and murine typhus Disease* Serological assay Sensitivity Specificity Scrub typhus IFA IgG 91% 96% IFA IgM 70‐87% 84‐100% ELISA IgG 80‐97% 89‐98% ELISA IgM 84‐100% 73‐99% ImmChrom IgG RDT 86‐95% 96‐100% ImmChrom IgM RDT 82 ‐ 94% 86‐100% Dot EIA 60‐100% 94‐99% Spotted fever rickettsiosis IFA IgG 85‐100% 99‐100% IFA IgM 83‐85% 100% ELISA IgG 83% 87% ELISA IgM 98% 94% Murine typhus IFA IgG 83% 93% IFA IgM 53 ‐ 85% 99%

47 48 Predictive value of R. rickettsii serology Rickettsiosis treatment 1 Arkansas – fever, headache, 0.9 rash 0.8 • adults: doxycycline, 0.7 • children: doxycycline, tetracycline, , rifampin? 0.6 IgG PPV • chloramphenicol associated with excess mortality as compared with 0.5 IgG PPV doxycycline or tetracycline when controlled for all other factors 0.4 IgG NPV • Possibly useful for MSF, other SFG rickettsioses, scrub typhus Post-test probability Post-test Post-test probability Post-test 0.3 Arkansas • Fluoroquinolones (, pefloxacin, ofloxacin) 0.2 • Macrolides (, clarithromycin) 0.1

0 0.8000 0.5000 0.2000 0.1000 0.0100 0.0010 0.0001 800,000 500,000 200,000 100,000 10,000 1000 100 pretest probability (prevalence) pretest probability (cases/million population/year)

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Case 5 – 70 year old woman with MCTD syndrome in Wisconsin Case 5 – 70 year old woman with MCTD syndrome in Wisconsin • 70y female from Shell Lake, Wisconsin • History of MCTD syndrome with ANA+; no current medications • Peripheral blood smear: inclusions in ~1% • 24h sudden onset fever, rigors, headache, N&V, myalgias neutrophils and bands • Peripheral blood PCR + for A. phagocytophilum • ED: ill-appearing, T 38.3ºC, no focal physical findings, WBC DNA 10,400, platelets 244,000 • Convalescent serum rickettsia serologic results • Admitted with increasing fever (T40.0ºC) and transient right- • E. chaffeensis IgG titer <80 sided seizure; Rx: ceftriaxone without response; blood culture • A. phagocytophilum IgG titer 1280 x3 negative • Diagnosis: human granulocytic anaplasmosis (HGA) • WBC 6,400, platelets 53,000, peripheral blood smear shown

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Human infections (human ehrlichiosis) Pathogenesis of leukocytotropic rickettsioses • Human monocytic ehrlichiosis (HME) - E. chaffeensis phagolysosome fusion • Human granulocytic anaplasmosis (HGA) - Anaplasma inhibition phagocytophilum • Other human ehrlichioses – ehrlichiosis “Ewingii” - caused by E. ewingii, genetically like E. chaffeensis, phenotypically like HGA – Ehrlichia muris-like agent ehrlichiosis (Upper Midwest USA) – Panola Mountain Ehrlichia - genetically similar to Ehrlichia ruminantium A. phagocytophilum (Southeast USA) – (Venezuela) – Neoehrlichia mikurensis (Europe and Asia) – Anaplasma capra (China) • Ehrlichioses are undifferentiated febrile illnesses with typical laboratory findings. E. ewingii

53 54 The “new” human ehrlichioses…. Geographic distribution of proven and serologically suspected ehrlichiosis and anaplasmosis in humans infection of humans • 82% of patients are immune compromised • No fatalities have been identified Ehrlichia muris eauclairensis ehrlichiosis (Upper Midwest USA only) • 27% of patients are immune compromised • 23% of patients are hospitalized; no fatalities Neoehrlichia mikurensis ehrlichiosis (Europe and Asia) • 15/16 European patients with immune compromise and persistent fever • > 50% with vascular or thromboembolic events • 0/7 Chinese patients had immunocompromising conditions • ≥ 7 subjects (in tick-bite studies) had asymptomatic or very mild infection Anaplasma capra infection (Asia only) • 14% with underlying disorders • 18% of patients are hospitalized, but no fatalities have been identified

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Frequent clinical features of ehrlichiosis (meta analysis median % with clinical feature) Table 2. Antibiotic Recommendations

E. muris Candidatus Drug Category Dosage, administration and comments E. E. ewingii Anaplasma capra History, signs, or A. phagocytophilum eauclairensis N. mikurensis chaffeensis ehrlichiosis infection symptoms infection infection HGA n=797 n=8 n=28 HME n=464 n=48 n=23 Doxycycline hyclate effective Fever 100 97 100 87 78 82 Adults 100 mg orally or intravenously at 12 hour intervals Children (<100 lbs.) 4.4 mg/kg/day orally or intravenously in two divided doses Rash 529003525 Duration of therapy HME 7-10 days, or at least 3 days after fever has abated Headache 82 70 63 66 35 50 Duration of therapy HGE 10 days

Myalgia/ 73 68 38 69 35/17 14 Tetracycline hydrochloride effective Nausea 40 57 25 - 22 21 Adults 500 mg orally in four divided doses Children (<100 lbs.) i) 25-50 mg/kg/day orally in two to four divided doses or 2 Vomiting 22 43 25 - 22 4 ii) 0.6-1.2 g/m /day in two to four divided doses. Pneumonitis or Duration of therapy As for doxycycline hyclate cough 24 30 0 - 17 4 Confusion/ altered MS 17 20 0 - 4 4 Rifampin probably effective

Case fatality rate 0.3 1.0 0 deaths 0 deaths 1 death 0 deaths Adults 300 mg orally twice daily. Children (<100 lbs.) 10 mg/kg/day orally twice daily, maximum dose 300 mg each Duration of therapy Unknown (7-10 days?) 57 58

Prevention of RMSF, HME, and HGA in humans prompt tick removal transmission of A. phagocytophilum may require as little as 4h

Thanks for listening. Questions?

No currently available for humans Prophylaxis for RMSF contraindicated Prophylaxis for HME and HGA after tick bite not investigated

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