Rickettsial Diseases or I ’ d rather die of one than learn them all

1. Rickettsial DiseasesorI’d rather die of one than learn them all Isaac I. Bogoch, MD, MS, FRCPC, DTM&H Divisions of Infectious Diseases and General Internal Medicine Toronto General Hospital ID/Med Micro Half Day November 9, 2016

2. What ID topics do ID docs know the least about? • Rickettsial diseases • Atypical mycobacterial infections • Some topics in Trop Med • What else?

3. “Doxycycline deficient state” “Never let a febrile patient die without a trial of doxycycline” Not entirely helpful, not really clinically useful, kind of clinically lazy, but you get the point

4. Roadmap • Microbiology and Pathogenesis • An approach to these Rickettsial infections • Clinical and epidemiology of select Rickettsial infections • Diagnosis • Treatment • Prevention

5. Microbiology and Pathogenesis • Historically defined by their phenotype • Very small • Obligate intracellular • Gram negative • Non-motile • Non-spore forming

6. Microbiology and Pathogenesis • Pleomorphic – can be many shapes • 0.1 – 10 microns long • Cocci • Bacilli • Threadlike

7. Microbiology and Pathogenesis • Tropism for vascular endothelial cells • Infection may increase vascular permeability • Responsible for the rash that is common in many infections • Can lead to DIC • Rare but occurs in severe Rickettsial infections

8. (Very) Brief History • Howard Taylor Ricketts • 1871 – 1910 • Discovered RMSF transmitted by ticks • Prone to self-experimentation • 1910 he isolated a strain of Murine typhus from an outbreak in Mexico – then died of the disease

9. Differential diagnosis • Fever, Rash, Headache, Myalgia • Bacterial meningitis • Or disseminated Neisseria • Leptospirosis • Measles • Dengue • West Nile Virus – encephalitis • Acute HIV • Acute mononucleosis-like syndrome • Occasionally influenza • Eschar • Bites – spider • Trauma • Cutaneous anthrax • Tularemia • Fungal – endemic mycosis • Non-infectious thoughts for systemic symptoms • TTP • Drug hypersensitivity – especially as rash is on day 3-5

10. An approach to Rickettsial infections

11. An Approach • Illnesses in the Rickettsial genus from 3 major “biogroups” • Remember that this is constantly growing and getting re-defined • There are additional “Rickettsial-like”infections that are phylogenically related and may have similar clinical presentations

12. Rickettsial illnesses Spotted Fever biogroup Typhus biogroup Scrub typhus biogroup Other related illnesses Many diseases Epidemic typhus R. prowazekii Bartonella spp. Orientia tsutsugamushi RMSF R. rickettsii Anaplasma Murine typhus R. typhi Ehrlichia Q fever

13. Terminology • Typhus • Greek for hazy or smoky • Describes mental status associated with infection • Typhoid • Greek for “typhus-like”

14. Rickettsial illnesses Spotted Fever biogroup Many diseases RMSF R. rickettsii Moraine Lake, Alberta

15. Spotted Fever Biogroup • Many pathogens • Exist worldwide except Antarctica • Each has a unique ecology • All are arthropod borne • Most are tick borne with only a couple of exceptions • Overlapping but not identical syndromes! • We will discuss the big ones

16. Spotted Fever Biogroup • Most will cause some combination of • Fever • Headache • Myalgia • Some will have one or more eschar • Many will have a rash • Illness may be mild to life-threatening

17. Rocky Mountain Spotted Fever • R. rickettsii • Found in: Canada, USA, Mexico, Central-South America • Other names • Brazilian spotted fever • Febre maculosa • São Paulo exanthematic typhus • Minas Gerais exanthematic typhus

18. Rocky Mountain Spotted Fever • Transmitted by multiple tick species • Dermacentor variabilis (American dog tick - USA) • Dermacentor andersoni (Rocky Mountain wood tick - USA) • Amblyomma cajennense (Central-South America) • Rhipicephalus sanguineus (Mexico)

19. Rocky Mountain Spotted Fever

20. Rocky Mountain Spotted Fever

21. Rocky Mountain Spotted Fever • Most do not recall tick bite • Tick needs to be attached for >6 hours for transmission • Symptoms occur after 2-14 day incubation period • Poor outcomes with antibiotic delay • “Failure to consider”diagnosisa problem

22. Rocky Mountain Spotted Fever • Fever, headache, myalgia – common • Rash in ~90% • Starts day 3-5, so may develop when already in medical care • Blanching erythematous rash • Macules turn to petichial, or may just start petichial • Begins at extremities and moves toward trunk • Commonly affects palms and soles in late disease

23. Rocky Mountain Spotted Fever CDC Redbook - American Academy of Pediatrics

24. Rocky Mountain Spotted Fever • Petichiae may be pruritic • Petichiae may form ecchymoses – bleeding into the skin • Eschars at the site of tick bite very rare • ~10% of cases do not have rash • Poor outcome as RMSF not considered

25. Rocky Mountain Spotted Fever • Complications • Encephalitis • Seizures • Multisystem organ failure • Arrhythmias • ARDS • DIC

26. Rocky Mountain Spotted Fever • Thrombocytopenia • Hyponatremia • Elevated LFTs • CSF <100 wbc’s • Lymphocytic predominance • Confirmation • Serology - retrospective • Staining of skin biopsy via immunofluorescence • Cannot be cultured • Bacterial meningitis • Or disseminated Neisseria • Leptospirosis • Measles • Dengue • West Nile Virus – encephalitis • Acute HIV • Acute mononucleosis-like syndrome • Ehrlichiosis/Anaplasmosis • TTP • Drug hypersensitivity – especially as rash is on day 3-5

27. Rocky Mountain Spotted Fever • “Doxycycline is the first line treatment for adults and children of all ages and should be initiated immediately whenever RMSF is suspected” CDC, 2016

28. Rocky Mountain Spotted Fever “Use of antibiotics other than doxycycline is associated with a higher risk of fatal outcome. Treatment is most effective at preventing death if doxycycline is started in the first 5 days of symptoms. Therefore, treatment must be based on clinical suspicion alone and should always begin before laboratory results return or symptoms of severe disease, such as petechiae, develop” CDC, 2016

29. Rocky Mountain Spotted Fever • Chloramphenicol is the only alternative agent for RMSF • Very difficult to obtain in N. America on short notice • Severe allergy to doxycycline • May use in some pregnant women? • Associated with Gray Syndrome in fetus – accumulation of toxic metabolites: ashen colour, cardio-respiratory collapse • Fatal aplastic anemia in 1:25000 - 1:40000 • may occur days to months after use

30. Rickettsial illnesses Spotted Fever biogroup Other spotted fever biogroup illnesses beyond RMSF Many diseases RMSF R. rickettsii

31. African Tick Bite Fever • R. africae • Most common non-malarial fever in travelers from southern Africa • ~5 day incubation period • Fever, headache, myalgia • Eschar is pathognomonic with compatible epidemiology • “Tache noire”

32. Lancet ID, 2003

33. South Africa Malawi Mozambique “Tache noire”

34. Rickettsialpox • R. akari • From the bite of a mite (not tick!) • Russia, a few cases in NYC, Africa, South Europe • 7-10 day incubation • Fever, headache, myalgia • Eschar common • Maculapapular rash common • Some macules become vesicular - appears like varicella

35. Mediterranean Spotted Fever • “Boutonneuse fever” • R. conorii • Around Mediterranean, southern Europe, India, Africa • Fever, headache, myalgia • Eschar common • Typically less severe than RMSF

36. Rickettsia parkeri infection • R. parkeri • USA and all over Americas • Fever, headache, myalgia • One or more eschars • Typically more mild than RMSF • May have more GI symptoms than RMSF

37. Rickettsia parkeriinfection Green - Amblyomma americanum ticks distribution Red/Yellow - confirmed and suspected cases http://cdc.gov/eid/article/15/9/09-0330-f1

38. Queensland tick tyhphus • R. australis • East coast of Australia • Only 1 fatal case documented • Eschar in 50% • Maculopapular rash, in some cases vesicular and confused with varicella

39. Japanese Spotted Fever • R. japonica • Japan and Thailand • Eschar in >90% • All with fever, headache, myalgia and rash • Similar to RMSF

40. www.cdc.gov/otherspottedfever/

42. Rickettsial illnesses Typhus biogroup Epidemic typhus R. prowazekii Murine typhus R. typhi

43. Epidemic typhus • R. prowazekii • camp fever, jail fever, ship fever, famine fever, putrid fever • Historically deadly disease • Killed >10 million in past 20th Century • Outbreaks associated with war, famine, refugee camps, crowding and extreme poverty • Under diagnosed

44. Epidemic tyhphus - epidemiology • Transmitted by • Body louse - Pediculosis humanus*** • Head louse - P. humanus capitis • Found in flying squirrels in USA, and in squirrel fleas and lice • Body louse lives on clothes, eggs laid on clothes • Transmission from louse bite, or from louse feces on clothes rubbed into skin lesion

45. Epidemic typhus - epidemiology • Today, cases in • Africa – war torn regions • Mountainous regions of Algeria • Terminology • “Epidemic typhus”related to louse • “Sylvatic typhus”or “Sylvatic epidemic typhus” related to flying squirrels • All are R. prowazekii infections

46. Kingston, Ontario

47. Epidemic typhus - clinical • Acute syndrome • 7 - 14 days after exposure • 10 - 40% mortality without antibiotic use • Late syndrome • Brill-Zinsser disease • 1 - 5 decades after infection

48. Epidemic typhus - Acute • Fever, headache, myalgia – almost everyone • Rash starts within 3-5 days on trunk to limbs • Maculopapular • 15-50% will have petichial rash • Rash may be even less common in sylvatic typhus • CNS: confusion, obtundation common, seizures rare • Labs: thrombocytopenia, elevated LFTs

49. Epidemic typhus: Brill-Zinsser disease • Recrudescence of illness years-decades after infection • Can occur in the elderly • Symptoms are identical • Syndrome is typically more mild • Rash is typically more mild • Treatment: doxycycline

50. Epidemic typhus – Dx and Rx • Diagnosis • Serology – mainstay but impractical • Clinical suspicion • Treatment • Supportive care • Doxycycline – even single doses of 200 mg may be effective • Chloramphenicol