Clinical trial NCT02915861: Eschar Investigations in Scrub Typhus
Official title: Eschar Investigations to Improve Diagnostics, Understand Early Immune Responses and Characterize Strains for Vaccines in Scrub Typhus
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Scrub Typhus
Keywords: immune responses
vaccines
Lead sponsor: University of Oxford
Sponsor class: OTHER
Collaborators: name: Chiangrai Prachanukroh Hospital
First posted: 2016-09-27
Enrollment: 44
Sex: ALL
Minimum age (years): 7
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: EXP: Male and female patients ≥7 years old with confirmed acute scrub typhus and an eschar present on examination (N=36).

EXC: Healthy individuals ≥7 years old who normally reside in a scrub typhus endemic region, attending hospital for elective/minor surgery or treatment of minor skin injury, and preferably age and sex-matched (N=12).

Brief summary: This is an observational study of patients with scrub typhus (rapid diagnostic test/quantitative polymerase chain reaction (RDT/qPCR) positive) and an inoculation eschar present on examination, recruited from Chiangrai Prachanukroh Hospital, North of Thailand.

In this study, we aim to:

* Investigate relevant pathogen dissemination dynamics, early innate immune response, and pathogen-host interactions in scrub typhus using a minimal set of easily accessible samples; the inoculation eschar (crust or biopsy), whole blood and - where possible - a lymph node fine-needle aspiration (FNA).
* Determine the potential use of the inoculation eschar for improving early diagnostics and assessing the diversity of human pathogenic strains; by evaluating non-invasive swabs and scrapings, as well as biopsies for molecular diagnostics templates.
* Dissect the underlying patho-biology associated with the inoculation eschar and in a subgroup, including the draining lymph node; by defining the spectrum of infected cells via microscopy and double-immune labeling; by determining cytokine and RNA gene expression profiles in blood peripheral blood mononuclear cell (PBMCs) and eschar samples.

Data sharing:

No future analysis or study of legacy data/specimens including data sharing for purposes not specified in the protocol will be done without seeking further regulatory (EC/IRB) approval

* Any requests for data sharing will be considered by MORU's data sharing committee
* Any data subsequently shared will be anonymised and will not include personal identifiers

Detailed description: Scrub typhus patients will be recruited into the scrub typhus patient (EXP) arm of the study. There will be 3 sub-groups:

* EXPa (n=12) will have blood and non-invasive eschar samples collected (consent to study, declined biopsy).
* EXPb (n=12) will have blood, non-invasive eschar samples, and an eschar biopsy collected (consent to study, draining lymph node (LN) inaccessible).
* EXPc (n=12) will have blood, non-invasive eschar samples, eschar biopsy, and LN FNA collected (consent to study, draining LN accessible).

Samples will be collected at baseline (all) and 2 weeks (blood only).

Control participants will be recruited into the scrub typhus control.

- EXC (n=12) are healthy individuals, attending hospital for elective/minor surgery or treatment of minor skin injury, and normally reside in a scrub typhus endemic region. Blood and a skin sample will be collected at baseline only.

Eligibility criteria: Scrub Typhus Patients (EXP) inclusion criteria:

* Age ≥7 years old.
* Presentation to hospital with fever in ≤14 days and a clinical suspicion of typhus.
* Eschar observed on examination.
* Scrub typhus RDT positive or OT qPCR positive (if qPCR available at local site by time of study initiation).
* Willingness to participate in the study. Written informed consent obtained from the patient (≥18 years old) or, written informed assent from participant (≥7 to \<18years old) along with written informed consent from participant's parent(s)/legal guardian(s).

Scrub Typhus Controls (EXC) inclusion criteria:

* Age ≥7 years old.
* Clinically well, attending elective/minor surgery or for treatment of minor skin injury.
* Historical diagnosis of scrub typhus (RDT, serology, and/or PCR positivity) more than 2 years ago or living in an endemic area with high risk of previous exposure.
* Willingness to participate in the study. Written informed consent obtained from the patient (≥18 years old) or written informed assent from participant (≥7 to \<18years old) along with written informed consent from participant's parent(s)/legal guardian(s).

Scrub Typhus Patients (EXP) exclusion criteria:

* Current TB or TB treatment in ≤6 months (contains OT-effective antimicrobials)
* Documented HIV infection, use of steroids, chemotherapy, other immunosuppressants, or herbal remedies containing steroids, and/or pregnancy

Scrub Typhus Controls (EXC) exclusion criteria:

* Significant acute intercurrent illness at the time of admission including fever \>37.5˚C or infection (including TB) requiring antibiotics
* Documented HIV infection, use of steroids, chemotherapy, other immunosuppressants, or herbal remedies containing steroids, and/or pregnancy

Primary outcomes:
measure: Phenotypic characterisation of the major subset of Orientia tsutsugamushi (OT) infected leucocytes within eschar, lymph node, and blood during the dissemination phase of OT in vivo.
timeFrame: 2 years
measure: Characterisation of cytokine and RNA gene expression profiles within the eschar, lymph node, and blood in vivo and comparisons with profiles of uninfected target cells.
timeFrame: 2 years
Secondary outcomes:
measure: Establishing the usefulness of non-invasive eschar samples from patients with acute scrub typhus for diagnostics for OT and for genotyping +/- whole-genome sequencing.
timeFrame: 2 years
measure: Define and contrast the eschar histo-pathological findings in this study in Thailand to previous findings from Laos, where the Gilliam strain predominates.
timeFrame: 2 years
measure: Comparisons to parallel studies in the non-human primate model with emphasis on dissemination dynamics, immunomodulation, and the innate and adaptive immune responses to OT; contributing to vaccine development.
timeFrame: 2 years
Other outcomes:
Locations:
city: Chiang Rai
country: Thailand
facility: Chiangrai Prachanukroh Hospital
Study officials:
affiliation: Chiangrai Prachanukroh Hospital, Chiangrai, Thailand
name: Dr. Tri Wangrangsimakul, MD
role: PRINCIPAL_INVESTIGATOR
References: