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Home , North Asian tick typhus, Queensland tick typhus, Rickettsialpox, Rickettsia conorii, Rickettsia raoultii

6/19/2019

I have got 45 min……

First 15 min… •A travel medicine physician… •Evolution of epidemiology of rickettsial diseases in brief “Epidemiology of rickettsial •Expanded knowledge of rickettsioses vs travel medicine infections” •Determinants of Current epidemiology of Rickettsialinfections •Role of returning traveller in rickettsial diseaseepidemiology Ranjan Premaratna •Current epidemiology vs travel health physician Faculty of Medicine, University of Kelaniya Next 30 min… SRI LANKA •Clinical cases

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Human Travel & People travel… Human activity Regionally and internationally Increased risk of contact between Bugs travel humans and bugs Deforestation Regionally and internationally Habitat fragmentation Echo tourism

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This man.. a returning traveler.. down Change in global epidemiology with fever.. What can this be???

• This is the greatest challenge faced by an infectious disease / travel medicine physician

• compared to a physician attending to a well streamlined management plan of a non-communicable disease……...

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Rickettsial diseases

• A travel medicine physician… • Represent some of the oldest and most recently recognizedinfectious • Evolution of epidemiology of rickettsial diseases in brief diseases • Expanded knowledge of rickettsioses vs travel medicine • Determinants of Current epidemiology of Rickettsialinfections • Athens described during 5th century BC……? Epidemic • Role of returning traveller in rickettsial diseaseepidemiology • Current epidemiology vs travel health physician • Clinical cases

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In 1916...... By 1970s-1980s four endemic rickettsioses; a single agent unique to a given geography !!! • R. prowazekii was identified as the etiological agent of

• Rocky Mountain • Mediterranean spotted fever • North Asian typhus •

Walker DH, Fishbein DB. Epidemiology of rickettsial diseases. Eur J Epidemiol 1991

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Family Transitional group between SFG and TG Genera • R. australis • R. akari Spotted Fever Group (SFG) • R. felis Typhus Group (TG) • (evolutionary genetic relationships)

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Transmitted by….., , and lice..

Genera Orientia • SFG: mainly ticks, also fleas (R. felis), mites (R. akari)

[Separated from Genera Rickettsia in1995; antigenically diverse spp] • TG: R. prowazekii • Human body louse (Epidemic louse-borne typhus, recrudescent typhus) • flying squirrel ecto parasites (Flying squirrel associatedtyphus) (Amblyomma ticks)

R. typhi () –Fleas

• Orientia () • Larval (chigger) …??Leeches • (Thomas Weitzel)

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Eg: complex (2005)….. (based on epidemiological and clinical differences)

• R. conorii-conorii /Malish strain): Mediterranean spotted fever (MSF): Mediteranian and Africa • R. conorii-Astrakhan strain: Astrakhan fever, Southern Russia Identification of rickettsial spp from pathogenicto • R. conorii-Israeli: Israeli spotted fever non-pathogenic potential across the globe... • R. conorii-Indica: Indian tick typhus: India, Sri Lanka and Pakistan

• Rhipicephalus spp. ticks

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Rickettsia spp..

• 30 validated species, incl. 17 pathogens Effect of global warming? • > 100 unclassified rickettsial isolates • Major human pathogens

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Global warming linked to changing epidemiology of MSF 2003 heat wave

• Effect of on tick behavior •(↑ incidence of Rh. Sanguineus (Brown Dog Tick)-transmitted • Fatal MSF in France diseases) • one man; 22 attached ticks • Multiple eschars • ↑ period of activity • 2 – 6% fatality reaching 30% in hospitalized patients • ↑ aggressiveness • ↑ biting of unusual hosts (humans) (Socolovschi et al. 2009. Parola et al. 2008) • Multiple eschars, severe forms

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TBR: has become a worldwide disease (Parola et al. (Scrub typhus) 2014)

• More than 20 antigenically distinct strains

• Originally, 3 prototype strains; Gilliam, Karp and Kato

• Later, additional antigenic types: Kawasaki, Kuroki, Shimokoshi etc and other distinct serotypes in the tsutsugamushitriangle

• Novel orientia species being described outside the tsutsugamushi triangle; Dubai (O. chuto) and • in Chile (proved novel: “Named”, yet to be published (ThomasWeitzel)

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This Antigenic heterogeneity of Orientia tsutsugamushi

reason for

• frequent outbreaks and reinfection

• Differences in Virulence among the strains

• Variation in the general course of the disease and the prognosis dependingon the endemic strain

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Today......

Many Organisms / Serotypes / Strains

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Historically • A travel medicine physician… • Evolution of epidemiology of rickettsial diseases in brief • Different species of prokaryotic pathogens were defined based • Expanded knowledge of rickettsioses vs travel medicine • Determinants of Current epidemiology of Rickettsialinfections • on the diseases they caused • regardless of other ecological or evolutionary considerations • Role of returning traveller in rickettsial diseaseepidemiology • Current epidemiology vs travel health physician • Clinical cases

Walker DH, Ismail N. Nature Reviews: 2008

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• Novel Rickettsia isolates •Clinical manifestations of most rickettsioses are neither specific to a •Vary much less from one another • Is an overenthusiastic designation of many new particular agent nor to a geographic species distribution

Walker DH, Ismail N. Nature Reviews: 2008 Walker DH, Ismail N. Nature Reviews: 2008

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• A travel medicine physician… • Evolution of epidemiology of rickettsial diseases in brief •R. africae and R. parkeri • Expanded knowledge of rickettsioses vs travel medicine •R. japonica and R. helongjiangiensis • Determinants of Current epidemiology of Rickettsialinfections • Role of returning traveller in rickettsial diseaseepidemiology • Current epidemiology vs travel health physician show minimal differences • Clinical cases

Walker DH, Ismail N. Nature Reviews: 2008

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Epidemiology of Tick borne Rickettsioses Most prevalent rickettsioses is

1. Is based mainly on Rickettsia isolated in Ticks • Based on • “Priority agents” for survaillance 2. Reporting error vs rickettsial epidemiology • Reportable rickettsial diseases

• Rickettsioses which require medical attention • Rickettsioses that standout for their morbidityand mortality

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“Reporting error”; RMSF in the Americas “cases”

• May reflect an unrelated exposure to a vector bearing a Rickettsial agent that caused an immune response rather than the occurrence of a true Most Rickettsial disease diagnosis is based on IFA

Is still the primary tool in thediagnosis

Has a marked cross-reactivity within the SFG

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IFA crossreactivity… • This fact led to the change in reporting of “RMSF” cases in the United States

• Low pathogenic agents may have contribute to the apparent • Now classified as “SPOTTED FEVER Gr oup” Rickettsioses overall increased incidence of RMSF in Americas?

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In most resource poor countries… Does this really mean… which are important for TravelMedicine…

• Rickettsial disease diagnosis is mainly on History and examination… • “In your clinical practice.. you do not want to know what the organism is..??” • Ix facilities are not widely available

• Evenif available, its mainly serology based; “will not identify” the causative organism.. Will end up with an umbrella term“SFG” • But simply know that the illness is one ofRickettsial ??

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Perspective of apragmatist

“The laboratory diagnosis of rickettsioses can appear an academic exercise: Is it really necessary to identify thecausative agent For each of > 25 ecologically, epidemiologically, and aetiologically distinct disease comprising ‘the rickettsioses’ responds to thesafe, in a returning traveler? inexpensive, widely distributed, and highly effective antibiotic ”

Paddock CD

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• ….newly described syndromes are a result of………… • A travel medicine physician… • Evolution of epidemiology of rickettsial diseases in brief • a single physician’s curiosity….. • Expanded knowledge of rickettsioses vs travel medicine • introduction of new diagnostictools • Determinants of Current epidemiology of Rickettsialinfections • improved knowledge of diseaseepidemiology • Role of returning traveller in rickettsial diseaseepidemiology • demonstration of pathogenic roles forhumans of • Current epidemiology vs travel health physician rickettsiae previously found only inarthropods • Clinical cases Raoult D, Roux V. Clinical Microbiology Reviews1997

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Newer Rickettsioses: are they really low in numbers?

Will their impact be alwayssmall? We have questions needing clarification.. • Low pathogenicity? • Low vector carriage? • Low transmission potential?

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• A travel medicine physician… • Evolution of epidemiology of rickettsial diseases in brief • Expanded knowledge of rickettsioses vs travel medicine Are we planning on preventive measures in travelers? • Determinants of Current epidemiology of Rickettsialinfections • Role of returning traveller in rickettsial diseaseepidemiology • Current epidemiology vs travel health physician • Clinical cases

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Clinical syndrome

Exposure risk

Fever in this returning traveler: Can this be rickettsial ??... Incubation period

Manageable DD • Epidemiology • Clinical judgement

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Expected clinical syndrome of rickettsioses… Important:.. !! Aneruptive fever

• Mostly a short incubation (6-7 days) • R. helvetica (although the pathogenic role isunclear) ( ticks) European and Asian countries Clinical triad: • Fever, Headache, Myalgia • Fever, • No inoculation eschar or cutaneous in the warm season

• Eschar, • More severe infections are reported as septicaemia and meningitis

• maculo-papular rash • Almost all Scrub typhus in Sri Lanka NO rash !! (40-60% eschar)

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Rickettsialpox A case of in Northern Europe Tick-borne (TIBOLA) Scalp eschar and neck lymphadenopathy after tick bite (SENLAT) R. akari Renvoisé A et al; IJID 2012 (16) : e221-e222 Vesicular enanthema: Rickettsia slovaca, Palate , Tongue R candidatus and Mouth Rickettsia rioja Tonsils R genotype364D Pharynx (R. phillipii)

Europe and United States, Ukraine, Croatia, South Africa, Bosnia, France, Italy, Central Asia

Costa Rica and Turkey G. Földvári et al. / Diagnostic Microbiology Rieg S et al. BMC Infectious California and Infectious Disease 76 (2013) 387–389 Diseases 2011; 11:167 53 54

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Lymphangitis-associated rickettsiosis (LAR) Clinical features

Symptomatic Asymptomatic • mongolitimonae: Greece, Portugal, South Africa and Southern France. Less virulent Virulent

• Incidence is higher in spring or summer RMSF: (un Rx: 25% mortality) Med SF: (un Rx: 4% mortality) Af TBF: (un Rx: no mortality) ea ntediagnosis Delay in the • Fever, Headache, One or more frequently multiple eschars Non specific Resp Fever, Headache Ix Myalgia,Arthralgia • Maculopapular rash CNS, CVS Minimal Renal,Hepatic Nonspecific Rash derangements Multi-organ • Enlarged lymph nodes and Eschar

Severe complications Severe derangements • Case of retinal vasculitis reported

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The clinical outcome of Rickettsioses Severity of Rickettsioses: Is it solely the organism?

• Severity varies greatly from mild, self-limiting, to life-threatening diseases Spontaneous recovery severe illness/ death • Mortality • Likely to be multifactorial…. •0% (R. slovaca, R. africae, R. felis) • How the host responds to an infective aetiology… •1% (R. typhi) ( ) • Dengue •2 -5% R. conorii, R. rickettsii • • 30% (R. prowazekii) • Rickettsial Infections

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The most recent published paper on sever sepsis: Four types of sepsis JAMA, May 2019: Sepsis is NOT a Single Syndrome • α : commonest: (33%) Fewest abnormal laboratory, least organ dysfunction: • Comparison of parameters using artificial intelligence 2% death

• β : (27%) Older patients, most chronic illness and kidney dysfunction

• γ : (27%) elevated inflammatory measures, primary pulmonary dysfunction • δ : least common (13%) most deadly, often liver dysfunction and shock;

32% death

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Severity of rickettsial sepsissyndrome?

For Rickettsial illness: Early diagnosis is the Key to • What is the difference between a native (with prevent “severe sepsis syndrome” and subsequent background exposure) compared to apreviously multi-organ involvement and death… unexposed traveler?

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Case 1; Male patient- 26 Years • A travel medicine physician… • Evolution of epidemiology of rickettsial diseases in brief • Expanded knowledge of rickettsioses vs travel medicine • Determinants of Current epidemiology of Rickettsialinfections • A traveler from Zurich Switzerland • Current epidemiology vs travel health physician • Role of returning traveller in rickettsial diseaseepidemiology • Three months of holiday in South & Eastern Asia • Clinical cases

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In Pakistan one month: Flying to Thaiwan; January two weeks Early December’17 – Early January -18’ • Hiking • Camping • Living with a farmer family

• Looking after cattle • Farming in the paddy fields • Sleeping in the field tents

From Google images

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Flying to Thailand- Late January 7 days stay Last week in the city..

• First few days in Rural • Severe headache • body aches • fever

• on the day of departure

From Google images

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Arrives in Negombo Sri Lanka (major tourist destination) Negombo- April 21

• Stayed with a friend for 4days • Fever continues • Admits to Negombo hospital

• Ixs: Non conclusive • No response to treatment

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From Negombo to Ragama Teaching hospital : (40 min travel) Admission

What do you notice?

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Why was his illness missed?

• Did he evolve these signs over 40 min? How would you approach to this patient?

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Questions: Clinical syndrome • What is the most obvious clinical syndrome? Exposure risk • What is the most likely organism? (Where did he catch this illness?) Incubation period

• What more clues (History / Examination) are needed? Manageable DD • What are the confirmatory Ixs? • Epidemiology • Clinical judgement • What is the treatment?

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Approach to diagnosis Clinical syndrome

• Syndrome + Geography based approach •Fever • Erythematous maculo-popular rash • Syndrome + Geography + activity based approach • Lymphadenopathy

• Syndrome + Geography + activity + exposure based approach

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Can this syndrome…a result of… Most likely exposure Geography Yes Yes • Asia / EasternAsia No No • An European traveler Yes Yes No No

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2013: TBR: in Europe. 2013: TBR: in Asia. Pathogenic rickettsiae (Coloured) possible pathogenicity and unknown pathogenicity (White) Pathogenic rickettsiae (Coloured) possible pathogenicity and unknown pathogenicity (White)

Philippe Parola,,* Christopher D. Paddock, Didier Raoult et al Clin Microbiol Rev.2013 Philippe Parola,,* Christopher D. Paddock, Didier Raoult et al Clin Microbiol Rev.2013

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Ten human rickettsial pathogens circulate in ticks in different and often Major rickettsioses described by causative agent, clinical syndrome, and vector by region. overlapping parts of Eurasia

• R. conorii • R. massiliae • R. slovaca • R. raoultii • R. sibirica • R. mongolotimonae • Rickettsia heilongjiangensis • R. helvetica • R. rioja

• R. honei Mohammad Yazid Abdad et al. J. Clin. Microbiol.2018; doi:10.1128/JCM.01728-17

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Most likely TBR in this patient based on where he has travelled Borne: A traveler from Europe / to Asia…

• R. conorii • R. massiliae • R. slovaca • R. raoultii • R. sibirica • R. mongolotimonae • Rickettsia heilongjiangensis • R. helvetica • R. rioja • R. honei

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Typhus group: R. typhi (Flea borne) Transitional Group: (Flea borne)

Tropical Infectious Diseases: Guerrant, Walker & Weller 91 92

Orientia tsutsugamushi Mite Borne: A traveler from Europe / to Asia…

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Typhus group: R. prowazekii; Body louse / Amblyomma ticks This syndrome…a result of…

Yes Yes

Yes No Tropical Infectious Diseases: Guerrant, Walker & Weller

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Most likely etiology for the clinicalsyndrome Questions: (Fever/ Rash/Lymphadenopathy)

• Tick borne • What is the most likely illness? • R. conorii • Rickettsia heilongjiangensis • R. helvetica • What is the most likely organism? • R. honei • Flea borne • What more clues (History / Examination/ Ixs) are needed? • R. felis • R. typhi (Murine typhus) • Where did he catch this illness? • Mite borne • Orientia tsutsugamushi • What is the treatment?

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What further clues may help? While in Hospital

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What is the diagnosis?

In the field

From Google images

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Most likely etiology for the clinicalsyndrome (Fever /lymphadenopathy / Rash / eschar)

• Tick borne • R. conorii • Rickettsia heilongjiangensis • R. helvetica • R. honei • Flea borne • R. felis • R. typhi (Murine typhus) • Mite borne • Orientia tsutsugamushi

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Where did he acquire it? Where did he acquire it?

Switzerland Pakistan Taiwan Thailand Sri Lanka Switzerland Pakistan Taiwan Thailand Sri Lanka

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Case 2

• 39 years, housewife, two children

Rare clinical scenarios: Delay in the diagnosis • high intermittent fever (101-1030F), chills and rigors for 8days

• Noresponse to oral co-amoxyclav by GP

• Severe frontal headache, nausea and vomiting

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• Progressively severe pain in almost all large and small joints backache and neck pain limiting her movements; bedbound • Avictim of floods 2 weeks prior to the onset of illness • Yellowish discoloration of the sclerae and dark urine around the third day of • Not travels fever • Had two pet dogs at home • IUCD one year; Intermittent offensive vaginal discharge 2 months • No contact with animals • Denied recent pregnancy or gynecological interventions

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Examination Examination contd..

• Very ill, icteric, pale anddehydrated • HR 100 beats/min, blood pressure 110/60 mmHg • No skin rash, oral ulcers or lymphadenopathy • Severe neck stiffness and bilateral symmetrical large and small joint • No cardiac murmurs arthritis with distal interphalangeal joint sparing • Not tachypneic, lungs clear

• Abdominal examination non-tender enlarged liver 2 cm below the • Vaginal examination unremarkable right costal margin

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Investigations DD? • WBC 12.7x103/mL (N 80% L16%) • Blood picture showed toxic granules in polymorphonuclearleukocytes together with a left shift • Leptospirosis • Palindromic rheumatism with systemic involvement • C-reactive protein (CRP) 327 U/L (Normal<5U/L) • Severe bacterial sepsis with a meningitic process • ESR 7 2 m m / 1 sthr

• Urinalysis 2+ proteinuria with occasional leukocytes and red bloodcells

• Serum creatinine 229 µmol/L (normal 45-90)

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Investigations Empiric treatment • AST 92 U/L (normal 0 – 35 U/L), • ALT 45 U/L (normal 0 – 35 U/L), • Treated as for leptospirosis or severe sepsis with intravenous ceftriaxone, • Bilirubin 95 µmol/L (normal 5.0–17.0 µmol/L) 1g twice daily together with intravenous hydration, antipyretics and analgesics • Direct 40 µmol/l • Serum alkaline phosphatase 255 U/L(normal 50-100 U/L) • Despite the above treatment, she continued to deterioraterapidly with • Anti-nuclear antibodies and rheumatoid factor were negative worsening of symptoms • Urine culture, blood culture were negative

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On the 2nd day of admission (10th day of illness) Further Ix • Blood picture showed fragmented red cells and thrombocytopenia suggesting early DIC

• Hemoglobin dropped to 8.6g/dL from 10g/dL and the plateletcount was 76x103/mL

• APTT 40 s with INR 1.3 and elevated D dimers of 1.2 ng/ml (normal<0.5ng/ml)

• No active bleeding

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DD? Further Ixs

• Infective endocarditis • Transesophageal and transthoracic echocardiograms normal • Meningococcal or gonococcal septicaemia • ASOT titre was < 200U • Severe staphylococcal or streptococcal sepsis • Chest radiograph normal • acute flare of connective tissue disease with vasculitis • Ultrasound scan of the abdomen; hepatomegaly • Cryoglobulinemia • Leptospira antibodies were negative • Hemorrhagic form of leptospirosis • Rickettsial infection • The IFA-IgG titre against Rickettsia conorii Ag titre of 1: 8192

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• Reduction in fever by the 2ndday of doxycycline (5th day of admission) • Oral doxycycline and azithromycin were added on the 3rd day of admission • Complete recovery from acute kidney and liver injury by the 4th treatment day

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Peeling off of the rash

• Skin rash and the joints became very painful over the 2nd-4th days of treatment

• All these resolved completely within 5 days of treatment (8th day of admission), and she was discharged on the 11thday of admission

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Katoch S, Kallappa R, Shamanur MB, Gandhi S. Purpura fulminans secondary to rickettsial infections: A case series. Indian Dermatol Online J Purpura fulminans Purpura fulminans 2016;7:24-8.

• Characterized by rapidly progressive purpuric lesions; develop into extensive areas of skin necrosis, and peripheral .

• Associated with consumptive coagulopathy and is often fatal

• PF is usually associated with many infections, meningococcal, staphylococcal, streptococcal infections

• SFG rickettsioses (R. conorii indica) • Queensland tick typhus (R. australis)

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Case 3

• 58yrs, School teacher

• Intermittent fever for 10 days - chills, rigors • Dry cough, SOB on exertion • Progressive confusion 1 day

•No visits • Previously healthy

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Examination Investigations

• Conscious • Mild neutrophil leucocytosis • Confused • No neck rigidity • Urine; Alb +, Red cells +, B. Urea normal • No kerning’s sign • Malaria film-ve • No focal neurological signs • ESR 6 0 m m 1 st Hr, • Fundi-normal • C-Reactive Protein 78 mg/dl • 2cm hepatomegaly • Slightly raised AST / ALT Normal bilirubin • Blood culture: negative • Electrolytes: normal • CT scan Brain: Normal

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Investigations Empiric treatment

• Lumbar Puncture: mild raised proteins • Iv ceftriaxone (High dose) • Lymphocytes (30-40) • Iv acyclovir • Neutrophils (5-8) • Iv Quinine • Sugar: 2/3 of blood levels

• DD: Bacterial? Viral? Partially treated bacterial? TB?

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Rapid clinical deterioration DD? Third day of admission (13th day of illness)

• clinical evidence of pneumonitis and myocarditis (confirmed by chest X ray/ ECHO)

• Patient developed progressive hearing loss, coarse tremors on extremities, oscillating eye movements in alldirections

• In matter of few hours .. was stoneDeaf…!!

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• Careful Re-examination of the patient Tr eat m e n t

• Doxycycline 100mg b.i.d • iv

Left axilla • Afebrile within 48hours • Rapid improvement in her clinicalcondition • 50% hearing improvement in 2weeks

• IFA- IgG against OT (Carp) > 1: 8192

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Clinical Infectious Diseases 2006 Case 4

• 62-years, healthy male

• High fever associated with chills and rigors for 17days

• Complained of malaise, myalgia and arthralgia

• Treatment from a local hospital; no clinical improvement

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• 5th day of the clinical illness; intermittent resting tremor in his right arm and leg

• Generalized stiffness

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Acknowledgements • Difficulty to carryout normal work with the right hand

• Difficult to walk due to unusual stiffness and heaviness of the right leg • For all authors of google images included in this presentation

• Difficulty to smile with others and felt very distressed

• Denied similar previous episodes

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• No associated psychiatric illness, seizures, or altered level of consciousness

• Had been working in his garden 7 days prior to the onset

• No previous medication

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Ix DD?

• Full blood count was 13.4x109/L (N-43%, L-56%) • Acute febrile illness with a Parkinson syndrome

• ESR was 80mm/1st hour •??

• Urine analysis, liver and renal function tests normal

• The CT scan of the brain and the EEGnormal

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• Careful examination …< 2mm !!

• IFA-IgG titre against Orientia carp antigen was 1:1024 which rose up to 1:16384 after two weeks

• Rx oral doxycycline: within 48 hours and demonstrated some improvement in his Parkinsonism features, discharged from hospital in 4 days

• Reviewed after two weeks of discharge: showedcomplete improvement

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Case 5 Nervous system presentations

• Late onset meningitis / meningo encephalitis syndrome • 54 years, male (Medical student’s father) • High intermittent fever for 6days • Acute Parkinson syndrome in a febrile patient • Loss of appetite • Transverse myelitis in late febrile phase (Case presented in November 2011: • Frontal headache with fever and vomited twice Manchester, UK, a doctor returning from an endemic country) • Mild joint pains

• Vasculitis related focal neurological syndromes • Obtained treatment from GP • Watery diarrhea on the 10th day of illness

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DD: Fever with late onset diarrhoea

• Typhoid

• Paratyphoid Can this be considered a “travelers diarrhea”??

• Viral: Dengue

• Antibiotic induced?

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Ixs • Hb- 12.4g/dL Clinical examination • WBC-3500, N-35%, L52% • Not pale, not icteric, NoLN • Blood picture: Leucopenia with relative lymphocytosis • Mild dehydrated • CRP-24mg/dL • CVS, RS, CNS- normal • UFR- Al b u m i n +, RBC – few/HPF • Abdomen- soft spleen 2cm below LCM • LFTs-mild deranged • S. creatinine-1.8mg/dL

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Likely diagnosis?

• Typhoid / Paratyphoid • Examination revealed an eschar hidden (Not noticed) IFA: 1: 1024 for O.tsutsugamushi

Rx: Oral Doxycycline

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Scrub typhus mimicking enteric fever

Case 6: A group of soldiers

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Examination

• Very ill; some were dyspnoic at rest • An acute outbreak of fever andcough

(severe ) among a group of • Chest examination: scattered coarse crepitations military serving in the Forward Defense line • Reduction in capillary oxygen saturation in seriously ill patients in Palali Jaffna during late 2008; Some were air lifted to National Hospital, Colombo, Sri Lanka on a Sunday

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Investigations

• Chest X ray • FBC: WBC 5600; N 58%, L38% • UFR: Alb ++, RBC4-8, • Blood culture: A/W • CRP-94 mg/dL • BU/ SE/ S. creatinine (Mild elevations) •LFTs Mild derangements: AST 210iu/L, ALT: 156 iu/L

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DD? • What do you notice?

• Atypical pneumonia

• Bacterial pneumonia

• ?Bio-terrorism (ANTHRAX)

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Why many affected?

•Mite Eschar islands……………

• Detected on the face…. • Final diagnosis of Scrub typhus resulting in severepneumonia

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Case 7

• A 24-yr-old bus driver who used to sleep in the bus over night

• Admitted during CHKGoutbreak

• Intermittent high Fever 14 days (101-102F)

• Progressive severe multiple joint pains:Ankles, knees, Shoulders; Difficult to walk

• Stooped posture

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Investigations Examination • Hb: 11.7g/dL • Not pale, not icteric, mild conjuctival injection, No LN • WBC: 7600; N-56%, L-38% • Platelets: 110,000 • Blood picture: Non reactive, few toxic granules in neutrophils, nopus • Erythema nodosum over both shins, obviousarthritis cells

• ESR-108 1st Hr • Hepato-splenomegaly • CRP-64 mg/dL (Normal <6) • Urine- Red cells 5-10/HPF,Alb-+, • AST-98 iu/L, ALT – 65 iu/L Alk Po4- 114iu/L • S. Creatinine –1.2mg/dL • ANA - ve, Rheumatoid Fact - ve, S. Ferritin - Normal

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DD?

• Chikungunya

• Sero negative arthritis

Careful clinical examination

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Clinical Rheumatology 2009

• Resolved completely with oral doxycycline over 7 days (afebrile within 48 hours)

• Diagnosis: scrub typhus

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Case 8

• 58 yrs, female with low grade intermittent fever for 16 days • Intermittent cough • Mild joint pains • Mild loss of appetite

• Worked abroad: (Returned from Middle East 5 years back)

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Examination Ixs • Hb: 9.8g/dl • WBC: 5600, N 45%, L 52%, Platelets 154,000/ • Average built (Says has lost weight) • Blood picture: No abnormal cells, no toxic granules, no viral • Few cervical nodes 0.5cm lymphocytes • 2 finger splenomegaly • ESR: 78 1 st hr, CRP96iu/l • CVS: nomurmurs • Normal Chest Xray • Resp: normal • UFR: albumin +, RBC 2-4/HPF, Pus cells: negative, B. urea: 45mg/dl • CNS/ Optic fundi: normal • AST: 125 iu/L, ALT: 256 iu/L • Mantoux test -ve • ANA, RF –ve, S. ferritin –ve

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Rxs

• USS abdomen L & Sp enlarged, ? Pelvic mass • Antibiotics: (short courses: penicillins / 3rd gencephalosphorins) • Anti malarials: CHQ • CT abdomen and pelvis normal

• ECHO cardiography Normal (Trans thoracic + Trans oesophageal)

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Treatment trials Viral screen

• No response to Co-amoxyclav + clarythromicin over 5 days • CMV- negative • No response to ceftrioxone for 4days • EBV-negative • Toxoplasma- negative • No response to meropenum for 4days • HIV - negative

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Repeat blood counts- illness > 3 weeks DD

•Hb: 8.2g/dl • WBC: 3200, N 34%, L62% • Infiltrative illness / BM / Liver involvement • Platelets: 96,000 •TB • Blood picture: No abnormal cells. Few large lymphocytes with normal morphology • Malaria (Previous experience of a child with falciparum malaria)

• LDH-760 •

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• Being planned for anti-TB treatment trial • BM Bx: Reactive with haemo-phagocytosis • BM Biopsy carried out: + sent for TB cultures / PCR • Cells are being engulfed by macrophages

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•Re examined the patient: Transactions of Royal Society of Tropical Medicine and Hygiene 2009

Patient was strongly positive for Orientia tsutsugamushi and had a dramatic recovery with oraldoxycycline.

189 190

Conclusion … Be the next clinician to describe a…. Consider rickettsial illness following a travel to an “endemicregion”

• Fever and a rash • New endemic region • Fever and lymphadenopathy • Fever and any systemic manifestation especially when not respondingto “appropriate non-rickettsial antibiotics” • Or a novel rickettsial agent.. !! • Fever alone…!! • Do not delay the diagnosis • Try to identify the offendingorganism…

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We are trying hard to figure out what is unseen…

• We have utterly failed to prevent what was obviously seen…

More important!!!

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April 21’ 2019

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This lecture is dedicated to all those who died ofthis brutal attack..

Ensure safe travel

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I wouldn’t have been here today…. notfortheirgeneroussharingwith me….

Greg David Stephen Lord Buddha… Thank you… Mareena Yupin Amanda Blanton 201 202

How do I suspect rickettsioses? What are the problems in the diagnosis? •Fever

• Associated with chills, severe headache, and • Lack of awareness body aches • Poor attempt at historytaking • Poor examination • Not feeling very illin between fever spikes

• Acute phase: more frequent, high grade

203 204

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Feve r Common clinical syndromes

• Untreated chronic phase: Low grade intermittent • Early signs and symptoms usually are nonspecific or mimic benign viral illnesses

• Chills, and headache (possibly severe). • Associated with malaise and myalgia. Nausea, vomiting, and anorexia are common in early illness

205 206

Exposure Risk??? Signs: Conjunctival injection and sub conjunctival haemorrhages

• Outdoor recreational or occupationalactivities • A patch of redness in the lateral limbus of eacheye, • If the activity takes place near high vegetation/scrub land (e.g.,camping, more prominent when febrile hiking, gardening) • Sever conjunctival injection • Frequent contact with animals and those who havepets • A history of tick bites (most do not realize they have beenbitten) • Rarely associated with sub-conjunctival hemorrhages • Mite bites are never noticed..

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Lymphadenopathy Eschar: Presumptive diagnosis

• Regional

• Generalized

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Eschar Eschar

211 212

Eschar

• Chang-Seop Lee, & Jeong-Hwan Hwang; N Engl J Med 373;25 nejm.org December 17, 2015

213 214

Eschar: Commoner in Scrub typhus ( 20-87%) Eschar: DD In Some SFG;

R conorii (Except in Israel / Indian) – 80% in MSF R australis • Cutaneous anthrax • Tularaemia Rjaponica • Necrotic arachnidism (brown recluse spider bite) • Rat bite fever (Spirillum minus) R africae (Usually multiple) • Staphylococcal or streptococcal Rparkeri • henselae

Rslovaca

R honei Didier Raoult et al; N Engl J Med 2001; 344:1504-1510 215 216

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Eschar What are the other sites you will seethem? • Vector climbs until finds a Basically any where.. resistance

•Skinfold • Strap of agarment

• Usually one bite by one vector

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Rash • Wide variability in the evolution, distribution, and Rash appearance

• Appears 3-5 days after fever but may occur early or late • Most central distribution (May spareface)

• “RMSP- Peripheral eruptions: start in wrists andankles and spread centripetally” : rarely observed

• Sometimes confined to one body area

• Erythematous maculopapular, vesicular etc

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Rash

Discrete, erythematous, maculopapular

Prominent with fever

Mostly trunk arms palms soles • Commoner in SFG than ST

221 222

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Malignant Mediterranean spotted fever in the setting ofdiabetes mellitus: Mediterranean spotted fever An uncommon cutaneous entity

Rossio R et al; IJID 2015; 35: 34-36 Goyal T, et al. Community Acquir Infect 2014;1:29-31 223 224

Rocky mountain spotted fever Rickettsialpox A case of rickettsialpox in Northern Europe Renvoisé A et al; IJID 2012 (16) : e221-e222

Anna R. Thorner, David H. Walker, William A. Petri, Jr; CID 1998

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Tick-borne lymphadenopathy (TIBOLA) Rash: Chikungunya

G. Földvári et al. / Diagnostic Microbiology and Infectious Rieg S et al. BMC Infectious Diseases 2011; 11:167 Disease 76 (2013) 387–389 227 228

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Approach based on the regional epidemiology

229 230

Tick borne rickettsiosis: A returning traveler from Reported incidence rate of spotted fever rickettsiosis, by county — Americas… United States, 2000–2013

231 232

2013: Tick-borne rickettsiae (TBR): 2013: TBR: in Mexico and Central America in North America (except Mexico) Pathogenic rickettsiae (Coloured) possible pathogenicity and unknown pathogenicity (White) Pathogenic rickettsiae (Coloured) possible pathogenicity and unknown pathogenicity (White)

Philippe Parola,,* Christopher D. Paddock, Didier Raoult et al Clin Microbiol Rev.2013 Philippe Parola,,* Christopher D. Paddock, Didier Raoult et al Clin Microbiol Rev.2013

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2013: TBR: in SouthAmerica Pathogenic rickettsiae (Coloured) possible pathogenicity and unknown pathogenicity (White) Main rickettsial pathogens circulate in the Americas

• R. rickettsii • R. parkeri • R. massiliae

Philippe Parola,,* Christopher D. Paddock, Didier Raoult et al Clin Microbiol Rev.2013

235 236

2013: TBR: in NorthAfrica. TBR: A returning traveler fromAfrica… Pathogenic rickettsiae (Coloured) possible pathogenicity and unknown pathogenicity (White)

Philippe Parola,,* Christopher D. Paddock, Didier Raoult et al Clin Microbiol Rev.2013

237 238

2013: TBR: in Sub SaharanAfrica. Pathogenic rickettsiae (Coloured) possible pathogenicity and unknown pathogenicity (White) At least four in Africa

• R. africae • R. conorii • R. massiliae • R. aeschlimanni

Philippe Parola,,* Christopher D. Paddock, Didier Raoult et al Clin Microbiol Rev.2013

239 240

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2013: TBR: in Australia. TBR: A returning traveler fromAustralia Pathogenic rickettsiae (Coloured) possible pathogenicity and unknown pathogenicity (White)

Philippe Parola,,* Christopher D. Paddock, Didier Raoult et al Clin Microbiol Rev.2013

241 242

Typhus group: R. prowazekii; Body louse / Amblyomma ticks Four in Australia

• R. australis • R. honei • R. honei subsp. marmionii • R. gravesii

Tropical Infectious Diseases: Guerrant, Walker & Weller 243 244

Typhus group: R. typhi (Flea borne) Transitional Group: Rickettsia felis (Flea borne)

Tropical Infectious Diseases: Guerrant, Walker & Weller 245 246

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Tr eat m e n t

• In vitro susceptibility: • R. massiliae, R. aeschlimanii and R. raoultii are resistant to rifampicin • doxycycline, thiamphenicol and fluoroquinolone. • All SFG Rickettsiae are resistant to erythromycin • Not susceptible to • Beta-lactams, aminoglycosides and cotrimoxazole • Susceptibility in vitro of Rickettsiae to other macrolides is variable

• Josamycin seems to be the most active compared to clarithromycin and pristinamycin

247 248

• Fluoroquinolone are also used for treatment of spotted fevergroup Rickettsiosis:

• Fluoroquinolone are significantly associated with more severespotted fever infection, particularly for patients presentingMSF.

• Using fluoroquinolone for Rickettsioses treatment is not recommended.

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