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Home , African tick bite fever, Alphaproteobacteria, Anaplasma, Ehrlichia, Epidemic typhus, Eschar

Zoonoses: Emerging Rickettsial

Sharon Altmann, PhD, RBP (ABSA), CBSP (ABSA)

The science you expect. The people you know. Learning Objectives

Review the major groups of rickettsioses and their clinical manifestations

Identify risk factors for rickettsial

Understand the considerations for rickettsial diagnostics and treatments

2 Rickettsioses and Their Clinical Manifestations

3 What Are ?

• Members of the Spotted Group order •Rickettsia rickettsia (Rocky Mountain , RMSF) •R. parkeri (R. parkeri ) • Obligate of eukaryotic •R. conorii (Mediterranean spotted fever) cells •R. africae (African bite fever) Group • Gram negative bacilli •R. prowazekii ( typhus) • Primarily transmitted by •R. typhi () vectors Transitional Group •R. akari () • Laboratory acquired •R. felis (-borne spotted fever) associated with aerosols, accidental Group parenteral inoculation • tsutsugamushi • One report of nosocomial A. •Candidatus Orientia chuto phagocytophilum transmission from •Candidatus Orientia chiloensis China (Zhang et al. JAMA. Group •Anaplasma phagocytophilum (, formerly granulocytic 2008;300(19):2263-2270) (HGE)) • Anaplasmosis and ehrlichiosis have Group been contracted though contaminated • blood transfusion products or solid •E. ewingii organ transplant •E. muris eauclarensis

4 Transmission Vectors

Spotted Fever Group, Anaplasmas, Ehrlichias • Hard body (ixodid) tick bites

Typhus Group • R. prowazekii: bites from infected body lice (Pediculous humanus humanus) or ectoparasites from infected flying squirrels; inhalation or accidental mucosal or parenteral inoculation of body feces • R. typhi: accidental mucosal or parenteral inoculation of flea (Xenopsylla cheopsis)

Transitional Group • R. akari: accidental mucosal or parenteral inoculation of mouse (Liponyssoides sanguineus) feces • R. felis: bites from (Ctenocephalides felis)

Scrub Typhus Group • Trombiculid mite larvae (chigger) bites

5 U.S. Geographical Distribution Reported incidence rate per 1,000,000 persons per year, by county, 2000-2013

Spotted fever rickettsiosis, Ehrlichia chafeensis ehrlichiosis Anaplasmosis including Rocky Mountain Spotted Fever

Biggs HM et al. MMWR Recomm Rep. 2016;65(No. RR-2):1–44.

6 Vector (And ) Distribution Is Changing • Gulf Coast tick (Ambylomma maculatum) reported in Illinois for the first time during surveys in 2013 and 2019– 8 of 14 screened specimens were positive for R. parkeri (Phillips et al. J Parasitol. 2020;106(1):9-13) • Asian longhorned tick (Haemaphysalis longicornis) first confirmed in the U.S. in 2017, with archived samples suggesting introduction in 2010 or earlier; confirmed in 14 states as of August 2020. • Shown to carry at least 30 human naturally, including seven spotted fever group rickettsiae, three of Ehrlichia, and seven species of Anaplasma (Zhao et al. Lancet Planet Health. 2020;4(8):e320-e329) • Shown experimentally to support R. rickettsia infection (Stanley et al. J Med Entomol. 2020;57(5):1635-1639) • Murine typhus is re-emerging in areas of Texas where it was previously eradicated (Ruiz et al. Emerg Infect Dis.

2020;26(5):1044-1046) Historical and current expanded distribution of A. americanum. • Lone Start tick (A. americanum), a key vector for Ehrlichia From Monzón et al. Biol Evol. 2016:8(5):1351-1360 species, has markedly increased its range in the last 70 years (Monzón et al. Genome Biol Evol. 2016:8(5):1351-1360).

7 Clinical Manifestations- Tick-borne Rickettsioses Estimated Incubation Common initial signs and Cutaneous signs Common laboratory findings Severe disease case-fatality period symptoms rate Rocky Mountain spotted 3–12 days Fever, , chills, Maculopapular rash , slightly , acute 5%–10% fever malaise, , , approximately 2–4 days increased hepatic renal failure, ARDS, cutaneous (treated), , abdominal pain, after fever onset in most, transaminase levels, normal or , , arrhythmia, 25% , anorexia might become petechial slightly increased white blood seizure, focal neurologic (untreated) and involve palms and cell count with increased deficits, fulminant , soles immature neutrophils, sudden transient hearing loss hyponatremia Rickettsia 2–10 days Fever, myalgia, headache , sparse Mild thrombocytopenia, mild Vasculitis —* parkeri rickettsiosis maculopapular or , increased hepatic vesiculopapular rash that transaminase levels might involve palms and soles RMSF maculopapular rash, late-stage petechial Ehrlichia 5–14 days Fever, headache, malaise, Rash in approximately Leukopenia, thrombocytopenia, Anemia, ARDS, DIC-like 1% (treated), purpuric rash, and late-stage of the digits. chaffeensis ehrlichiosis myalgia, nausea, diarrhea, 30% of adults and 60% of increased hepatic coagulopathies, central 3% Photos/CDC (human monocytic vomiting children, variable rash transaminase levels, nervous system involvement, (untreated) ehrlichiosis) pattern that might involve hyponatremia, anemia renal failure palms and soles, appears a median of 5 days after illness onset Ehrlichia —† Fever, headache, malaise, Rash rare Leukopenia, thrombocytopenia, —* ewingii ehrlichiosis myalgia increased hepatic transaminase levels -like agent —† Fever, headache, malaise, Rash in approximately Thrombocytopenia, —* ehrlichiosis myalgia 12% lymphopenia, leukopenia, increased hepatic transaminase levels, anemia Human anaplasmosis 5–14 days Fever, headache, malaise, Rash rare, in <10% Thrombocytopenia, leukopenia, ARDS, peripheral <%1 (human granulocytic myalgia, chills mild anemia, increased hepatic neuropathies, DIC-like (treated), 1% anaplasmosis) transaminase levels, increased coagulopathies, hemorrhagic (untreated) numbers of immature manifestations, neutrophils rhabdomyolysis, , R. parkeri rickettsiosis and acute renal failure, secondary vesiculopapular rash. Photos/CDC opportunistic infections

*No known . †Not documented. Adapted from Biggs et al. MMWR Recomm Rep. 2016;65(No. RR-2):1-44.

8 Clinical Manifestations- Other Rickettsioses

Estimated Incubation Common initial signs Disease Cutaneous signs Common laboratory findings Severe disease case-fatality period and symptoms rate Murine typhus 7-14 days Fever, headache, Rash in 20-80% Thrombocytopenia, , anorexia, nausea, 1-4% hyponatremia, increased vomiting, myalgia, encephalitic hepatic transaminase levels, signs, acute kidney injury dissociated cholestasis, haematuria

Epidemic typhus 10-14 days Fever, headache, Erythematous rash Thrombocytopenia, increased ARDS, , <5% tachypnoea, chills, myalgia progressing to petechial hepatic transaminase levels, hypotension, vascular (treated), and purpuric lesions increased blood urea collapse, renal insufficiency, 60% encephalitic signs, ecchymosis (untreated) with gangrene, , multiple organ failure Diffuse rash in murine typhus patient. Gorchynski et al. West J Emerg Med. 2009;10(3);207 Rickettsialpox 7-10 days Fever, chills, sore throat, Eschar, papulovesicluar Leukopenia with relative —† __* rigor and profuse sweating, rash developing 2-3 days lyphocytosis and mild myalgia, anorexia after symptom onset that proteinuria, thrombocytopenia might involve palms and soles, occasional oropharyngeal enanthem

Flea-borne spotted fever —† Fever, fatigue, headache, Eschar in 13%, Increased aspartate and Acute meningoencephalitis __* myalgia maculopapular rash in alanine aminotransferase 75% levels

*No known deaths. †Not documented. Blanton et al. Am J Trop Med. 2017;96(1):53-56. Rickettsialpox eschar and papulovesicles. Hun et al. Res Rep Trop Med. 2012;3:47-55. Photos/CDC https://www.ecdc.europa.eu/en/epidemic-louse-borne-typhus/facts https://emedicine.medscape.com/article/227956-overview#a5

9 Risk Factors for Rickettsial Infection

10 Risk Factors for Severe Rickettsiosis

Epidemic Risk Factor RMSF Murine typhus Anaplasmosis Ehrlichiosis typhus

Age (< 10) XX Age (≥ 40) X Age (≥ 60) XX X X Race (Black) XX X Glucose 6-phosphate dehydrogenase XX deficiency Immunosuppression XX XX Hepatic and/or renal dysfunction X Lung infiltrates on admission XX on admission XX Treatment with sulfa XX Delayed treatment XX X X X (onset-to-treatment ≥ 5 days) Blood product transfusion XXX Solid XXX XX

11 Environmental And Behavioral Risk Factors For Exposure • Occupational or recreational exposure to brushy or wooded areas with tall Examples of at-risk populations: grasses or shrubs •Hunters •Surveyors

• Lack of use of appropriate tick • Outdoor enthusiasts • Pet / livestock owners repellents • Utility workers • Agricultural workers • Lack of appropriate clothing worn in high-risk areas • Veterinarians / animal • Scientists / students control involved in fieldwork • Exposure to animals and birds (wild, livestock, and/or peridomestic) • International travelers • Unhomed individuals • Those working or living in • Those working with or near • International travel / detention camps unhomed populations • Exposure to individuals living with • Forestry / park workers • Military personnel poor sanitation and hygiene availability

12 Considerations for Diagnostics and Treatment

13 Diagnostic Challenges

• Poor awareness of vector exposure • Poor public awareness of their risks of vector-transmitted diseases • Review of responses to the 2009, 2011, and 2012 HealthStyles surveys found 13.9% of respondents from New England and 20.8% from the Mid-Atlantic reported that no tickborne diseases were present in their area (Hook et al.2015. Tick Borne Dis;6(4)- 483-488).

• Initial symptoms nonspecific Select differential diagnoses for tickborne rickettsioses. From Biggs HM et al. MMWR Recomm Rep. 2016;65(No. RR-2):1–44. • Characteristic rashes often develop after initial clinical visit • Characteristic rashes under-identified in patients with darker skin • For , late relapse can occur months or years after the initial infection, with a similar but milder clinical presentation (Brill-Zinsser disease)

Select differential diagnoses for typhus group rickettsioses. From https://emedicine.medscape.com/article/231374-differential

14 Diagnostic Recommendations Assay Pathogen Specimen Pros Cons Spotted fever group, Requires 3 facility; may Whole blood; punch biopsy Typhus group, Microbiological reference require ≥ 10 days; effectiveness Culture of eschar or rash; Anaplasmas, standard decreases after first week of illness, specimens Ehrlichias commencement of therapy Increasingly common; Nucleic acid easier differentiation Most sensitive when performed on Spotted fever group, Whole blood; serum; eschar detection between pathogens; short eschar biopsy; most sensitive within Anaplasmas, swab; punch biopsy; turnaround time; no first week of illness and before/within (polymerase chain Ehrlichias autopsy specimens reaction (PCR)) specialized facilities 48 hours of commencing therapy required Low sensitivity; requires specialized Anaplasmas, Blood smear Whole blood Rapid stains; requires experienced Ehrlichias microscopist to read Antibodies generally absent during Current reference Spotted fever group, first week of illness; confirmation Indirect standard; short turnaround Typhus group, requires fourfold or greater increase in immunofluorescent Serum time; effective independent Anaplasmas, titer between acute and convalescent of commencement of assay (IFA) Ehrlichias serum specimens; antibodies usually therapy specific to rather than species Spotted fever group, Effective with spotted Punch biopsy (spotted fever Typhus group, fever eschars and rash Availability restricted to reference group); autopsy specimens; Anaplasmas, lesions; effective post- centers or research laboratories formalin-fixed Ehrlichias mortem

15 Treatment Challenges • Treatment is less effective at preventing severe complications and when started ≥ 5 days after the onset of symptoms • for untreated RMSF is 20-25%, with most deaths within 7-9 days of symptom onset • Case fatality rate for untreated epidemic typhus can be up to 60% • Diagnostic tests are not typically helpful for making a timely diagnosis of rickettsial disease • Laboratory findings often remain within normal ranges until disease is severe • Microbiological reference standard test ( culture) can take 10 or more days to complete • IFA requires at least 2 weeks (need paired acute and convalescent sera, 2-4 weeks apart) • Sensitivity of PCR assays vary by species, specimen type, time since onset of symptoms, and whether treatment has been started

16 Current Treatment Recommendations TREATMENT SHOULD BE INITIATED IMMEDIATELY IN PERSONS WITH OF RICKETTIAL DISEASE!

† Treatment for patients with anaplasmosis should be extended to 10 days if concurrent is suspected, or alternatively, another antimicrobial with efficacy against should be included. From CDC. Tickborne diseases of the : A reference manual for healthcare providers, 5th ed. Fort Collins, CO: US Department of Health and Human Services, CDC; 2018.

• Rifampin has been reported to be effective in a small number of pregnant women and young children treated for anaplasmosis, but no clinical trials have been performed. Rifampin is not recommended for treatment of RMSF.

17 National Reporting Requirements

• Spotted fever group rickettsioses (including RMSF), ehrlichioses, and anaplasmosis are nationally notifiable in the U.S. • State or local health departments should be notified of potential cases of tickborne disease • Health department should be able to help obtain confirmatory laboratory testing • Health department staff may contact the healthcare provider and patient for information to determine the surveillance case definition. • Typhus group rickettsioses are no longer nationally notifiable, although murine typhus is reportable in at least 14 states, including DE, MA, NH, OH, and PA. However… • R. prowazekii is listed as a Health and Human Services under 42 CFR Part 73. Clinical or diagnostic specimens used for diagnosis are considered exempt from the requirements within the regulation provided: • The specimens are secured against theft, loss, or release during the period of time between the identification of R. prowazekii and the transfer or destruction of the specimens; and • Any theft, loss, or release of the specimens is reported; and • Unless otherwise directed by the HHS Secretary, the specimens collected from the positive patient are transferred to a registered entity or destroyed on-site by a recognized sterilization or inactivation process within 7 calendar days of the conclusion of patient care; and • The laboratory notifies the specimen provider, CDC, and other appropriate authorities of the identification of R. prowazekii by telephone, fax, or email, and must submit an APHIS/CDC Form 4 to CDC within 7 calendar days of identification.

18 Select References

1. Zhang L, Liu Y, Ni D, et al. Nosocomial Transmission of Human Granulocytic Anaplasmosis in China. JAMA. 2008;300(19):2263-2270. https://jamanetwork.com/journals/jama/fullarticle/182918. Accessed September 10, 2020.

2. Biggs HM, Behravesh CB, Bradley KK, et al. Diagnosis and management of tickborne rickettsial diseases: Rocky mountain spotted fever and other spotted fever group rickettsioses, ehrlichioses, and anaplasmosis - United States a practical guide for health care and public health professionals. MMWR Recomm Rep. 2016;65(No. RR-2):1-44. doi:10.15585/mmwr.rr6502a1

3. Phillips VC, Zieman EA, Kim C-H, Stone CM, Tuten HC, Jiménez FA. Documentation of the Expansion of the Gulf Coast Tick ( ) and : First Report in Illinois. J Parasitol. 2020;106(1):13. doi:10.1645/19-118

4. Zhao L, Li J, Cui X, et al. Distribution of Haemaphysalis longicornis and associated pathogens: analysis of pooled data from a China field survey and global published data. Lancet Planet Heal. 2020;4(8):e320-e329. doi:10.1016/S2542-5196(20)30145-5

5. Stanley HM, Ford SL, Snellgrove AN, et al. The Ability of the Invasive Asian Longhorned Tick Haemaphysalis longicornis (: ) to Acquire and Transmit (Rickettsiales: ), the Agent of Rocky Mountain Spotted Fever, Under Laboratory Conditions. J Med Entomol. 2020;57(5):1635-1639. doi:10.1093/jme/tjaa076

6. Ruiz K, Valcin R, Keiser P, Blanton LS. Rise in murine typhus in Galveston County, Texas, USA, 2018. Emerg Infect Dis. 2020;26(5):1044-1046. doi:10.3201/eid2605.191505

7. Monzón JD, Atkinson EG, Henn BM, Benach JL. Population and evolutionary genomics of , an expanding arthropod disease vector. Genome Biol Evol. 2016;8(5):1351-1360. doi:10.1093/gbe/evw080

8. Blanton LS. The Rickettsioses: A Practical Update. Infect Dis Clin North Am. 2019;33(1):213-229. doi:10.1016/j.idc.2018.10.010

9. Hun L, Troyo A. An update on the detection and treatment of . Res Rep Trop Med. 2012;3:47-55. doi:10.2147/RRTM.S24753

10. Facts about epidemic louse-borne typhus. https://www.ecdc.europa.eu/en/epidemic-louse-borne-typhus/facts. Accessed September 11, 2020.

11. Typhus: Background, Pathophysiology, Epidemiology. https://emedicine.medscape.com/article/231374-overview. Accessed September 11, 2020.

12. Rickettsialpox: Background, Pathophysiology, Epidemiology. https://emedicine.medscape.com/article/227956-overview#a5. Accessed September 11, 2020.

13. Hook SA, Nelson CA, Mead PS. U.S. public’s experience with ticks and tick-borne diseases: Results from national HealthStylessurveys. Ticks Tick Borne Dis. 2015;6(4):483-488. doi:10.1016/j.ttbdis.2015.03.017

14. CDC. Tickborne Diseases of the United States: A Reference Manual for Healthcare Providers. 5th ed. Fort Collins, CO: US Department of Health and Human Services, CDC; 2018. https://www.cdc.gov/ticks/tickbornediseases/TickborneDiseases-P.pdf. Accessed September 8, 2020.

19 THANK YOU

Contact information: www.mriglobal.org [email protected]

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