/ Scrub

Nick Day ESCMIDMahidol- Tropical eLibrary Medicine Research Unit © by author 23 year old Thai farmer presenting with 6 days of and acute bilateral hearing loss

Scrub typhus IgM rapid test +ve. ESCMIDSubsequently PCR +ve and OrientiaeLibrary tsutsugamushi cultured © by author Update on Rickettsial

• How common and where? • Under-diagnosis and under-recognition • CNS complications of rickettsial infections • Rickettisial infections in pregnancy • Treatment

ESCMID eLibrary © by author Rickettsioses • group – tsutsugamushi Scrub typhus – Orientia chuto

• Typhus group (TG) lesion after leech-bite, PCR / DNA seq. – Rickettsia prowazeckii typhusfelis – • group (SFG) – Many, many Spotted and unspotted except for R. akari and R. felis ESCMID eLibrary © by author -borne rickettsia in Asia Parola ESCMIDet al. Clin Microbiol Rev 2013 eLibrary © by author The importance of defining clinical epidemiology…

• To inform control programs • To inform empirical treatment guidelines • To inform on diagnostic and treatment algorithms • To inform which diagnostic tests are clinically useful • To help identify emerging infectious diseases • To define the disease ‘background’ • Diagnostic capacity in place ready to detect EIDs ESCMID“Knowing what’s eLibrary out there...” © by author Mahosot Hospital, Vientiane, Laos

Blood culture, smear negative fever in adults over 2 years (n = 427) -- 211/427 (49%) with a final diagnosis

Scrub typhus 63 (15%) 43 (10%) Dengu 43 (10%) Murine typhus 41 (10%) Spotted fever 11 (3%) JEV 10 (3%)

Typhus total 28 %

Doxycycline-responsive 38% Is this generalisable to the whole of Laos? Of SE Asia? Elsewhere? Phongmany et al. EID (2006) ESCMID eLibraryPhetsouvanh et al. Am J Trop Med Hyg (2006) © by author Causes of non-malaria fever in Laos 2008 - 2010 Rural Laos: n=1938 febrile patients admitted, 799 (41%) w/ diagnosis

Problem – , background titers (?) Only culture, , and nucleic acid detection assays (conservative)

Luang Namtha Province

Salavan Province ESCMID eLibrary © by author Mapping non-malarial fever in Most frequent reported diseases/pathogens:

• Dengue • Rickettsial infections 1986 – 2011 126 studies • Leptospirosis • Typhoid • • JEV Mapping the Aetiology of Non-Malarial Febrile Illness in Southeast Asia 2012 ESCMID eLibraryAcestor et al. PLoS One 2012 © by author Scrub typhus

• > One million cases per year • Mortality 2 to 8% • ~ Two billion exposed

“Scrub typhus is probably one of the most underdiagnosed and underreported febrile illnesses requiring hospitalization in the region” ESCMIDWorld Health eLibrary Organization, 1999 © by author Tsutsugamushi disease

• First described in in 1820 • Folklore for centuries before in China and Japan • Tsutsuga-mushi = “Harmful bug” • ‘Rickettsia orientalis’ isolated in 1930 (Nagayo et al)

ESCMID eLibrary © by author Scrub typhus distribution New…

Old…

ESCMID eLibrary © by author

• a- • Gram –ve coccobacillus • Obligate intracellular aerobe • Most repetitive bacterial sequenced to date • Highly recombinative

ESCMID eLibrary © by author ESCMID eLibrary © by author ESCMID eLibrarySalje. PLoS Pathogens 2017 © by author ESCMID eLibrary © by author Catching chigger

ESCMID eLibrary © by author Black plate (well used!) – can you spot the chigger mites?!

ESCMID eLibrary © by author Clinical features • 6-18 day • Eschar in ~ 50% • Regional • Fever, , • Hearing loss • Maculopapular rash • Conjunctival suffusion •

• Apathy, stupor, convulsions, coma • Interstitial • Acute renal failure • • • Coagulopathies ESCMID eLibrary © by author Rickettsial diagnostics • In vitro isolation • High specificity, Low sensitivity • Slow (weeks) • Requires lab • Serology • IFA the current ‘gold standard’ • Inaccurate with single acute phase sample • RDTs and now available • Molecular/genetic • Many PCRs / qPCRs now available • Blood, CSF, Eschar • Expensive • Antigen ESCMID• None available eLibrary © by author Clinical judgement studies Complete approach studies Over-reliance on eschar in the diagnosis of rickettsial infections

ESCMID eLibraryVan Eekeren et al. Travel Med Infect Dis 2018 © by author World II

ESCMID eLibrary © by author ESCMID eLibrary © by author • A total of 76 studies containing 89 patient series and 19,644 patients

• Median mortality of all patient series was 6.0% with a wide range of 0–70% • Most ESCMID recent ( era) case series eLibrary have a mortality of 2% - 8% © by author

•

• 19 untreated • mean FCT 17 days 69 treated mean FCT 30 hrs ESCMID eLibrary © by author ESCMID eLibrary © by author ESCMID eLibrary © by author Treatment • Eleven trials for scrub typhus • Chloramphenicol, and azithromycin (limited evidence for , telithromycin, levofloxacin and ) had equal efficacy to doxycycline in achieving clinical cure • Limited clinical evidence for murine typhus and SFG rickettsial infections • Oral doxycycline preferred agent for uncomplicated disease – but for 1 or 7 days? 2mg/kg twice a day after a loading dose of 4mg/kg? • Scrub typhus intrinsically resistant to fluoroquinolones ESCMID• Severe disease – no clinical eLibrary trial data © by author 30 year old Vietnamese building worker admitted with 4 days fever, headache, neck pain, myalgia. Deteriorating conscious level. Not improving on ICU on ceftriaxone. Lymphocytes and neutrophils in CSF. Normal glucose, raised protein

Rickettsia typhi rapid diagnostic test positive

Therefore, Rx doxycycline

Took the bus back to Hanoi 2 days ESCMID eLibrarylater © by author Murine or Endemic Typhus • -borne rickettsiosis caused by R. typhi • Oriental flea Xenopsylla cheopis is the principal and , mainly norvegicus and R. rattus, act as reservoirs • via flea faeces self-inoculation of skin • Recent evidence for involvement of dog sanguineus • Can cause severe disease, CNS, interstitial , cholecystitis…. • Little awareness • Diagnostics rarely available ESCMID eLibrary © by author CNS infections in Laos

N = 1,112 consecutive patients 271 (33%) children ≤ 15 yrs

(‘Conventional ’ = S. pneumoniae, N. meningitidis, H. influenzae, S. suis)

Mortality Overall 27% Conventional bacteria 33% R. typhi / Rickettsia spp 27% O. tsutsugamushi 14% Leptospira spp. 14%

Only 48% of patients with rickettsial diagnosis received appropriate antibiotics ESCMID eLibraryDittrich et al. Lancet Glob Health 2015; 3(2): 104 –112. © by author Kaplan-Meier plot of fever clearance for patients with PCR confirmed murine typhus only (N=49, Log-rank test P=0.007)

ESCMID eLibrary © by author Under-studied and under appreciated… • Reported cases: 97 over 18 years Typhus and pregnancy • Literature review • Patients from India, Thailand- border, Korea & Taiwan • Median gestation 25 weeks (range 6 to 39) • Scrub typhus 82, murine typhus 14, both ST and MT 1

• 17% before 28 weeks • Of women with deliveries: • 15% • 33% preterm births • 33% low birth weight • 43% poor neonatal outcomes or miscarriage

Prospective comparison to malaria: same study site / period (SMRU) • Typhus: Preterm 14% LBW (10) 22% • Malaria: ESCMID Preterm 7% LBW (10) 17% eLibraryMcGready et al. PLoS Negl Trop Dis. 2014 © by author Scrub typhus in Thai children • 73 children (median age 9, range 3-14) in Hat Yai Hospital • Clinical features • 59% Hepatomegaly • 22% Pneumonia • 8% Neurological involvement • 7% Eschar • 7% Skin rash

• Treatment Drug Doxycycline Chloramphenicol n=15 Other or none n=17 n=41 Median fever 1 day 3 days 5 days clearance

• One death p=0.006 p<0.001 ESCMIDSilpapojakul eLibraryet al. Trans R Soc Trop Med Hyg . 2004 © by author Currently a class D drug, contraindicated in pregnancy and in children under 8 yrs

So… Systematic review of literature and databases

• Safety profile of doxycycline that differs significantly from that of tetracycline • No correlation between the use of doxycycline and teratogenic effects during pregnancy or dental staining in children was found

“Doxycycline is safe in early pregnancy, possibly throughout pregnancy and for children at the current dosage regimes; the restraints on doxycycline could be lifted for targeted or empiric treatment during the first half of pregnancy and for children under 8 years of age, if the ESCMIDdaily dosage does not exceed 200mg/day eLibrary for a maximum duration of 14 days.” © by author Conclusions

• Rickettsial infections, especially scrub and murine typhus, are common diseases • They are often serious, life-threatening illnesses • Scrub typhus and murine typhus are common causes of CNS infection • In pregnancy they are a threat to both and child • Diagnosis is difficult and often unavailable • Treatment with doxycycline is safe and effective, and the ESCMIDtreatment of choice eLibrary © by author ESCMID eLibrary © by author ESCMID eLibrary © by author Acknowledgements • Paul Newton • Daniel Paris • Stuart Blacksell • Tri Wangrangsimakul • Jeanne Salje • Liz Batty • Ivo Elliott • Staff of MORU, SMRU and LOMWRU ESCMID• Wellcome Trust & DTRA eLibrary © by author