Rickettsial infections in children

3rd Annual Healthcare Conference of Angkor Hospital for Children

Paediatric Tropical Diseases
Dr Tri Wangrangsimakul BSc (Hons) MBChB MRCP FRCPath DTM&H
Chiangrai Clinical Research Unit, Chiangrai, Thailand
18th October 2019
Contents
• Defining “rickettsial infections”

• Epidemiology of rickettsial infections in SE Asia

• Scrub typhus in children

• Murine typhus in children

• Other important rickettsial diseases

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Rickettsial infections
 Coxiella burnetii,
Bartonella spp.

Rickettsiaceae

Anaplasmataceae

Phylogenetic relationships of the organisms in the order Rickettsiales, based on DNA sequences
of 16S rRNA genes [Yu X-J, Walker D. The Order Rickettsiales. The Prokaryotes: A Handbook on
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the Biology of Bacteria. Vol 5, Bukupedia; 2006. p. 493-528]
Rickettsiales
• Gram negative, α-Proteobacteria

• Obligate intracellular bacteria

• Life cycles alternate between vertebrate and

invertebrate hosts

Orientia tsutsugamushi in infected cell taken from infected animal tissue, Giemsa-stained, black
and white (x1500). [from Philip CB. Scrub Typhus, or Tsutsugamushi Disease. The Scientific
Monthly. 1949;69(5):281-9.] www.tropmedres.ac
Rickettsiaceae
SFG – R. australis, R. africae, R.
honei, R. japonica, R. helvetica,
R. slovaca, R. massiliae, R.
rhipicephali, R. aeschlimannii, R.
montanensis, R. parkeri

Comparison of the genomes of Orientia and Rickettsia spp. [SF – spotted fever, SFG – spotted
fever group, TRG – transitional group, TG – typhus group, AG – ancestral group, STG – scrub
typhus group; inferred phylogeny based on 15 proteins [Gillespie JJ et al. PloS one. 2007];
adapted from [Paris DH et al. Chapter 112 - Orientia A2. Molecular Medical Microbiology
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(Second Edition), 2015.] and [Fuxelius H-H et al. Research in Microbiology, 2007]
Epidemiology of rickettsial infections in SE Asia
Rickettsial infections in SEAsia
• Laos:
– Luang Namtha and Salavan provinces, adults and children; dengue 8%,
scrub typhus 7%, JE 6%, leptospirosis 6%, bacteraemia 2% (murine
typhus 0.5%, unspecified Rickettsia spp. 0.5%)
– Savannakhet province, adults and children; dengue 30.1%,
leptospirosis 7%, JE 3.5%, ST 2.6%, SFGR 0.9%, unspecified flavivirus
0.9%, MT 0.4%
• Malaysia:
– central Malaysia, adults and children; ST 19.3%, typhoid/paratyphoid
7.4%, flavivirus 7%, leptospirosis 6.8%, malaria 6.2% (MT 0.5%, SFGR 0.3%)
Mayxay M et al. The Lancet Global Health. 2013;1(3):e46-e54. doi: 10.1016/S2214-109X(13)70008-1.
PubMed PMID: PMC3986032.
Mayxay M et al. AMJTMH. 2015. doi: 10.4269/ajtmh.14-0772. PubMed PMID: 26149859.
Brown GW et al. AMJTMH. 1984;33(2):311-5. PubMed PMID: 6324601.
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Rickettsial infections in SEAsia
• Thailand:
– central, NE and S Thailand, adults; leptospirosis 36.9%, ST 19.9%, dengue or
influenza 10.7%, MT 2.8%, SFGR 1.3%, Q fever 1%, other bacteria 1.2%
– northern Thailand, adults; ST 22.5%, dengue 11.5%, leptospirosis 7.5%, MT
3.5%, BSI 3.5%
– northern Thailand, adults and children, seroprevalence; E. chaffeensis
36%, SFGR 30%, B. henselae 13%, A. phagocytophilum 4.5%, C. burnetii 3.5%
• Vietnam:
- Hanoi, adults and children (all admissions including fever); ST 3.5%
Suttinont C et al. Ann Trop Med Parasitol. 2006;100(4):363-70. doi: 10.1179/136485906X112158.
PubMed PMID: 16762116.
Wangrangsimakul T et al. PLoS NTD. 2018;12(5):e0006477. doi: 10.1371/journal.pntd.0006477.
Blacksell SD et al. Vector borne and zoonotic diseases. 2015;15(5):285-90. doi: 10.1089/vbz.2015.1776.
PubMed PMID: 25988437. www.tropmedres.ac
Nadjm B et al. TRSTMH. 2014;108(11):739-40. doi: 10.1093/trstmh/tru145. PubMed PMID: 25253616.
Rickettsial infections in SEAsia
• Cambodia:
– ST cases first reported from 1937
– AHC, febrile children; dengue 16.2%, ST 7.8%, BSI 6.3%, JE 5.8%, MT
2.2%, malaria 1-2%, leptospirosis 1.4%, unspecified Rickettsia spp. 0.9%
– western and eastern Cambodia, adults and children; Orientia
tsutsugamushi 3.9%, Rickettsia spp. 0.2%
– Phnom Penh and Siem Reap, children with acute meningoencephalitis;
Orientia tsutsugamushi the cause in 4.7%
– AHC, IgG seroprevalence; ST 4.2%, MT 5.3%, dengue 50.7%
Alain M, Delbove P. Bulletin de la Société de Pathologie Exotique. 1938;31(6):453-6 pp.
Chheng K et al. PloS one. 2013;8(4):e60634. doi: 10.1371/journal.pone.0060634.
Mueller TC et al. PloS one. 2014;9(4):e95868. doi: 10.1371/journal.pone.0095868.
Horwood PF et al. Emerg Microbes Infect. 2017;6(5):e35. doi: 10.1038/emi.2017.15.
Fox-Lewis A et al. AMJTMH. 2019;100(3):635-8. Epub 2019/01/25. doi: 10.4269/ajtmh.18-0865.
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Rickettsial infections in SEAsia
• Scrub typhus the most clinically important rickettsial disease

• Murine typhus and SFGR also important causes of fever

• Difficulties surrounding diagnosis underpin attempts to determine the

burden of rickettsial diseases

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Clinical and diagnostic timeline
Richards AL. Worldwide detection and identification of new and old rickettisae and rickettsial diseases. FEMS Immunol
Med Microbiol 2012;64:107-110

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Scrub typhus in children
Scrub typhus in children
• Caused by Orientia tsutsugamushi

• A leading cause of treatable acute febrile illness in the tropics

• Mainly found in rural areas but cases from urban centres (Bangkok,
Seoul) reported

• Transmitted by trombiculid mites – vector and natural reservoir

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Scrub typhus in children

Life cycle of a trombiculid mite (chigger) and scrub typhus transmission.

[from Philip CB. Scrub Typhus, or Tsutsugamushi Disease. The Scientific Monthly.
1949;69(5):281-9.] www.tropmedres.ac
Photos of chiggers courtesy of Kittipong Chaisiri, Mahidol University, Thailand
Scrub typhus in children

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• Prospective observational study – 60 paediatric patients with acute fever
and +ve ST IgM RDT (InBios), 40 healthy paediatric controls
• Diagnosis confirmed by:
I. Detection of Ot-specific DNA in blood or eschar samples by PCR
II. 4-fold rise in IgM titre to ≥1:3,200 in paired plasma samples by IFA
III. Single IgM titre of ≥1:3,200 in an acute plasma sample by IFA

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• 35/60 patients (PCR +ve – 31, IFA +ve 34) were confirmed as having scrub
typhus
• All controls negative
• Patients were younger (median age/IQR – 6yrs, 3-10), mainly from hill-tribe
population (31/35, 89%) and had more contact with chickens than controls
• 33/35 (94%) were admitted from June to November

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• All patients had a fever on or during admission
• Fever days prior to admission (median, IQR) – 7 (5-10)
• Common clinical findings – eschar (60%), cough (60%), lymphadenopathy
(43%), headache (40%), rash (34%), vomiting (31%), hepatomegaly (31%)
• Eschar location – external genitalia (exclusively in boys), head, inguinal
regions
• Temp >37.5°C (89%), tachypnoea (46%), tachycardia (31%) commonly
observed on admission

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• Laboratory results (compared to controls):
– patients had low platelets, lymphocyte and eosinophil counts
– patients had elevated AST, ALT, CRP and low albumin and ALP

• CXR results – 12/21 (57%) normal, 9/21 (43%) revealed pulmonary infiltrates

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• Treatment:
– 22/35 (63%) received antibiotics prior to admission, only 4/22 (18%)
were effective for ST (chloramphenicol, doxycycline, azithromycin,
rifampicin)
– All patients received appropriate antibiotics during admission
(doxycycline 86%, chloramphenicol 40%, azithromycin 9%, rifampicin 9%)

• Complications: 14/35 (40%) developed at least 1 complication, most

common include severe hepatitis (26%), severe thrombocytopaenia (20%),
pneumonitis (14%), circulatory shock (11%), ARDS (9%)

• 1 child with multi-organ failure died (3% mortality)

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• Fever clearance time (median, IQR): 36hrs (24-53)

• Treatment failure (prolonged FCT > 72hrs): 8/35 (23%) patients, severe
hepatitis a significant predictor of treatment failure on logistic regression

• No relapse or re-infection during the entire follow-up period – week 2, 3

months, 1 year

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Treatment options:
• > 8yrs old – doxycycline, tetracycline, chloramphenicol, azithromycin,
rifampicin

• < 8yrs old - chloramphenicol, azithromycin, rifampicin

• Fever normally cleared within 2-3 days of treatment initiation

No effective vaccine providing long-term cross-strain protection available

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Murine typhus in children
Murine typhus in children
• Endemic typhus, caused by R. typhi, typhus group
• Worldwide prevalence
• Transmitted by fleas, scratching bitten area leads to flea faeces being
rubbed into the wound (also via inhalation, mucous membranes)
• Occurs throughout the year but usually in the warmer months
• Rats are the usual hosts

Typhus fevers, Centers for Disease Control and Prevention, National Center for Emerging and
Zoonotic Infectious Diseases (NCEZID), Division of Vector-Borne Diseases (DVBD),
https://www.cdc.gov/typhus/healthcare-providers/index.html www.tropmedres.ac
Murine typhus in children
• Common symptoms – fever, headache, anorexia, malaise/fatigue, rash,
myalgia, arthralgia, nausea/vomiting, diarrhoea, abdominal pain (no eschar)

• Common laboratory findings – elevated CRP, ESR, transaminases, LDH and

band count (immature neutrophils); low albumin, platelets and Hb

• Diagnosis – culture, PCR, serology (IFA to detect IgG or IgM), IHC; use blood,
plasma or tissue samples

Howard A, Fergie J. Pediatr Infect Dis J. 2018;37(11):1071-6. Epub 2018/02/22. doi:

10.1097/inf.0000000000001954. PubMed PMID: 29465481.
Tsioutis C et al. Acta tropica. 2017;166:16-24. doi: https://doi.org/10.1016/j.actatropica.2016.10.018. www.tropmedres.ac
Murine typhus in children
• Treatment – doxycycline for adults and children of all ages; if weight <45kg,
2.2 mg/kg given twice a day; duration until 3 days after defervescence
(usually 7-10 days)

• Rx delays lead to longer hospital stays

• Shorter FCT with tetracycline-containing regimes

• Alternative Rx – chloramphenicol, fluoroquinolones, azithromycin*,

(rifampicin and other macrolides)
Howard A, Fergie J. Pediatr Infect Dis J. 2018;37(11):1071-6. Epub 2018/02/22. doi:
10.1097/inf.0000000000001954. PubMed PMID: 29465481.
Tsioutis C et al. Acta tropica. 2017;166:16-24. doi: https://doi.org/10.1016/j.actatropica.2016.10.018. www.tropmedres.ac
Other rickettsial infections
Spotted fever group rickettsia
• R. conorii (Mediterranean SF, tick-borne) – fever, rash (maculonodular and
papular), eschar (usually single), regional lymphadenopathy, myalgia,
headache; treat with doxycycline, alternatives – chloramphenicol,
rifampicin, fluoroquinolones
• R. honei (Flinders Island SF, tick-borne) – fever, headache, myalgia, rash,
eschar in minority; treat with doxycycline, alternatives – chloramphenicol,
rifampicin, fluoroquinolones
• R. felis (flea-borne SF or cat flea typhus) – clinically and serologically similar
to murine typhus, no eschar; treat with doxycycline, alternatives –
chloramphenicol, rifampicin, fluoroquinolones

Peixoto S et al. Acta medica portuguesa. 2018;31(4):196-200. Epub 2018/06/02. doi:

10.20344/amp.9713. PubMed PMID: 29855412.
Sothmann P et al. AMJTMH. 2017;96(4):783-5. Epub 2017/01/25. doi: 10.4269/ajtmh.16-0754. www.tropmedres.ac
PubMed PMID: 28115672; PubMed Central PMCID: PMCPMC5392620.
Conclusion
• Rickettsial infections are a common cause of treatable acute febrile illness in
children in SE Asia

• Scrub typhus is the most clinically important rickettsial infection followed by

murine typhus and SFGR

• Diagnosis remains a challenge, high clinical suspicion required

• Doxycycline the mainstay of treatment (even in younger children)

Cross R et al. Revisiting doxycycline in pregnancy and early childhood - time to rebuild its
reputation? Expert Opin Drug Saf. 2015. doi: 10.1517/14740338.2016.1133584. PubMed PMID:
26680308. www.tropmedres.ac
Thank you.

Mahidol Oxford Tropical Medicine Research Unit

Faculty of Tropical Medicine | Mahidol University | 420/6 Rajvithi Road | Bangkok 10400,Thailand