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

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

“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

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

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

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

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

(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

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

An approach to Rickettsial infections

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

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

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

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

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

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

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

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)

Rocky Mountain Spotted Fever

Rocky Mountain Spotted Fever

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” diagnosis a problem

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

Rocky Mountain Spotted Fever CDC Redbook - American Academy of Pediatrics

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

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

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

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

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

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

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

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”

Lancet ID, 2003

South Africa Malawi Mozambique “Tache noire”

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

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

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

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

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

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

www.cdc.gov/otherspottedfever/ Disease Species Geographic Distribution Clinical Symptoms Rickettsiosis Rickettsia aeschlimannii Africa, Mediterranean region Fever, eschar, maculopapular rash African tick- bite fever Rickettsia africae Sub-Saharan Africa, West Indies Queensland tick typhus Rickettsia australis Australia, Tasmania Fever, eschar, regional adenopathy, rash on extremities Mediterranean spotted fever or Boutonneuse fever Rickettsia conorii‡ Mediterranean region and Africa to  Indian subcontinent Fever, eschar (usually single), regional adenopathy, maculopapular rash on extremities Far eastern spotted fever Rickettsia heilongjiangensis Northern China, Eastern Asia Fever, eschar,  maculopapular rash, regional adenopathy Aneruptive fever Rickettsia helvetica Central and northern Europe Fever, headache, myalgia www.cdc.gov/otherspottedfever/

Disease Species Geographic Distribution Clinical Symptoms Flinders Island spotted fever, Thai tick typhus Rickettsia honei Australia, Thailand Mild spotted fever, eschar and adenopathy are rare Japanese spotted fever Rickettsia japonica Japan Fever, eschar(s), regional adenopathy, rash on extremities Australian spotted fever Rickettsia marmionii subspecies Australia Fever, eschar, maculopapular or vesicular rash, adenopathy Rickettsia massiliae rickettsioses Rickettsia massiliae France, Greece, Spain, Portugal, Switzerland, Sicily, Central Africa and Mali Fever, maculopapular rash, necrotic eschar Rocky Mountain spotted fever, febre maculosa, Sao Paulo exanthematic typhus, Minas Gerais exanthematic typhus, Brazillian spotted fever Rickettsia rickettsii North, Central and South America Fever, headache, abdominal pain, maculopapular rash progressing into papular or petechial rash (generally originating on extremities) North Asian tick typhus, Siberian tick typhus Rickettisa sibirica Broadly distributed through north Asia Fever, eschar(s), regional adenopathy, maculopapular rash Lymphangitis associated rickettsiosis Rickettsia sibirica mongolotimonae Southern France, Portugal, China, Sub-saharan Africa Fever, multiple eschars, regional adenopathy and lymphangitis, maculopapular rash Tick-borne lymphadenopathy (TIBOLA), Dermacentor-borne necrosis and lymphadenopathy (DEBONEL) Rickettsia slovaca Southern and eastern Europe, Asia Necrosis erythema, cervical lymphadenopathy and enlarged lymph nodes, rare maculopapular rash

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

Epidemic typhus R. prowazekii Historically deadly disease 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

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

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

Kingston, Ontario

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

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

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

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

Murine typhus Rickettsia typhi Other names: Endemic typhus, Flea borne typhus Transmitted by fleas Urban areas commonly in tropical and subtropical seaboard centers USA: suburban cases found Much more mild illness than Epidemic typhus

Murine typhus - epidemiology Transmitted by fleas worldwide Typically fleas that feed on rats In USA, fleas that feed on cats and opossums implicated Texas and California Reservoir: Rats, cats, opossums Fleas preferentially feed on host, humans are accidental hosts if preferred host not around

Murine typhus - clinical 8-14 day incubation period Abrupt onset fever, headache, myalgia Children commonly have GI symptoms Maculopapular rash in most (>80%) but may be hard to see in those with darker skin Rare complications Confusion, pulmonary edema, meningitis

Civen, Clin Infect Dis, 2008

Murine typhus – Dx and Rx Diagnosis Serology – mainstay but impractical PCR if available Clinical suspicion Treatment Doxycycline – even single doses of 200 mg may be effective Chloramphenicol – treatment failures reported

Rickettsial illnesses Scrub typhus biogroup Orientia tsutsugamushi

Scrub typhus Previously Rickettsia tsutsugamushi Now Orientia tsutsugamushi Common febrile illness in Asia/Pacific Mild-severe illness Known for centuries, but most data comes from WWII as it was common in soldiers

Scrub typhus - epidemiology Vast majority of cases in Asia/Pacific Korea, China, Japan, Pakistan, India, Thailand, Malaysia, and northern Australia 3 cases found on an island of the coast of Chile! Mostly a rural infection Increasingly in suburban areas

Scrub typhus - epidemiology From the bite of larval mites (aka “chiggers”) Leptotrombidium genus Can transmit infection tranovarially – so can pass infection on to successive generations Very focal disease where vector lives “Mite islands” as small as a few square feet of vegetation

Scrub typhus - clinical Incubation period 6-16 days Acute febrile illness Fever, myalgia, headache Eschar in >50% Rash: maculopapular in 50%, rarely pruritic, chest limbs Mild illness to MSOF Complications: delirium, myocarditis, pneumonitis

Scrub typhus - clinical Other findings: Cough is common – may have pneumonitis in 45% Relative bradycardia GI symptoms: nausea and vomiting +/- diarrhea in >50% Labs: thrombocytopenia and elevated LFTs common Diagnosis: Serology, biopsy of an eschar with EIA

Scrub typhus - treatment Doxycycline 100 mg po BID x 3-7 days Mostly susceptible, but some reports of resistance Azithromycin 500 mg po x 1 successful in mild illness Pregnancy with mild illness? Azithro

NEJM, 2016

Rickettsial illnesses Other related illnesses Bartonella spp. Anaplasma Ehrlichia Q fever

Human ehrlichiosis and anaplasmosis Many species worldwide The two most important (to date): Ehrlichia chaffeensis human monocytic ehrlichiosis, or “HME” Anaplasma phagocytophilum human granulocytic anaplasmosis, or “HGA”

Human ehrlichiosis and anaplasmosis E. chaffeensis Lone start tick (Amblyomma americanum) main vector, but there are others A. phagocytophilum Ixodes scapularis is common vector Also transmits Lyme and Babesia 5-20% of ticks are co-infected

Human ehrlichiosis and anaplasmosis E. chaffeensis reservoir: White tailed deer A. phagocytophilum reservoir: Other deer, white footed mouse

CDC, 2016

Human ehrlichiosis and anaplasmosis Wide spectrum of disease Asymptomatic to severely ill 5-18 day incubation period Most with fever, myalgia, headache Rash is rare Leukopenia and thrombocytopenia is common

Human ehrlichiosis and anaplasmosis Diagnosis is with serology and PCR PCR not standardized, but common and validated in many high-burden areas Serology may not distinguish between E. chaffeensis and A. phagocytophilum Remember to screen for Lyme and Babesia co-infection Blood film or PCR for Babesia, serology for Lyme

Human ehrlichiosis and anaplasmosis Treatment is: Doxycycline Chloramphenicol Rifampin alone has been used successfully May be used in less severe cases – pregnancy, children <45kg 2-10% mortality if untreated Likely no lifelong immunity

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