Transcriptomic Responses for the Identification of Pathogens (TRiP)

A Multisite Evaluation of Functional Genomic Signatures for the Improved Diagnosis of Acute Undifferentiated Febrile Infections

Acute undifferentiated febrile infection (AUFI) is a common presenting syndrome in low-resource settings and better diagnostics are urgently needed to improve patient management and guide disease prevention interventions. Assessment of the host gene expression response to infection in endemic populations has demonstrated significant promise as a new approach to identifying patients with enteric fever and for potential in differentiating between other causes of AUFI. Signatures identified through new data analytic techniques could be developed into a point-of-care test for use in endemic settings.

In this multisite diagnostic evaluation study we will collect prospective clinical, laboratory and diagnostic data from two endemic settings to evaluate host gene expression signatures for detecting enteric fever and for determining the cause of AUFI in LMIC settings.

Study Overview

• Status: Recruiting
• Conditions: Fever; Typhoid; Paratyphoid Fever; Acute Febrile Illness; Enteric Fever
• Intervention / Treatment: Diagnostic test: 5-gene transcription signature

• Study Type: Observational
• Enrollment (Anticipated): 2000

Contacts and Locations

• Study Contact: Name: Farah Shahi; Phone Number: 01142159522; Email: f.shahi@sheffield.ac.uk
• Study Contact Backup: Name: Thomas Darton; Email: t.darton@sheffield.ac.uk

Study Locations

• India
  • Vellore, India
    • Recruiting
    • Christian Medical Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 45 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

We will recruit adults aged 15 to 45 years presenting to hospital with fever at 2 sites in Asia where enteric fever is endemic. All included febrile participants will have a documented tympanic/rectal temperature of ≥ 38°C or an axillary/oral temperature of ≥ 37.8°C on presentation and will report a history of fever lasting 3 to 14 days. In parallel, healthy community control participants will be recruited from each site catchment area during the course of the study with enrolment designed to result in an even representation of age groups and seasonal variation. Identified signatures of infection will be explored in a cohort of febrile children aged 2 to 14 years at each site. 600 febrile adults, 200 febrile children and 200 afebrile adult controls will be recruited at each site.

Description

FEBRILE ADULTS- INCLUSION CRITERIA

• Age greater than or equal to 15 years and less than or equal to 45 years
• Participant is willing and they and/or an appropriate guardian/relative/representative is able to give informed consent for participation in the study and a follow-up (telephone) discussion at 14 days

• Febrile illness without localising features (see 'exclusion criteria' and 'screening' sections) where fever is defined as:

  • documented tympanic/rectal temperature of ≥ 38°C or an axillary/oral temperature of ≥ 37.8°C and
  • Reported duration of fever 3-14 days
• They may have had recent exposure to antimicrobials.

FEBRILE ADULTS- EXCLUSION CRITERIA

• The participant may not enter the study if ANY of the following apply:
• Unable to provide informed consent and no next of kin is willing and able to provide informed consent.

• Any history or clinical suspicion of:

  • Rheumatological or connective tissue disorder (e.g. Rheumatoid arthritis)
  • Autoimmune condition (e.g. Autoimmune Hepatitis)
  • Malignancy
  • Active treatment with immunomodulating medications, or for tuberculosis (pulmonary or extrapulmonary) or any other chronic infection.
• Pregnancy (breast feeding mothers will NOT be excluded)
• Hospitalisation within 4 weeks prior to current admission
• Vaccination within 4 weeks prior to current admission
• They live outside of the normal/local catchment area for each hospital site
• Localising signs or symptoms of infection sufficient to diagnose the likely cause of acute febrile illness and thus prevent it from being 'undifferentiated' (see Section 8.4 'Screening and Eligibility').

CONTROLS- INCLUSION CRITERIA

• Participant is willing and they are (and in 15-18 year olds, a guardian is) able to give informed consent for participation in the study
• Age greater than or equal to 15 years and less than or equal to 45 years
• They live outside of the normal/local catchment area for each hospital site
• Afebrile (as defined by no reported fever and temperature ≤ 38°C or an axillary/oral temperature of ≤ 37.8°C).

CONTROLS- EXCLUSION CRITERIA

• The participant may not enter the study if ANY of the following apply:
• Unable to provide informed consent and no next of kin (or parent/guardian in the case of a minor) is willing and able to provide informed consent.

• Current treatment for or prior history, or clinical suspicion of:

  • Rheumatological or connective tissue disorder
  • Autoimmune condition
  • Malignancy
  • Active treatment for tuberculosis (pulmonary or extrapulmonary) or clinical suspicion of active tuberculosis. Previous completed treatment is not a reason for exclusion.
  • Active treatment with immunomodulating medications or any other chronic infection.
• Pregnant (breast feeding mothers will NOT be excluded)
• Hospitalisation within 4 weeks of recruitment
• Vaccination within 4 weeks prior to recruitment
• Antimicrobial use within 4 weeks of recruitment
• They live outside of the normal/local catchment area for each hospital site
• Participant reports feeling more unwell than usual on the day of enrolment.

EXPLORATORY AIMS- PAEDIATRIC CRITERIA; INCLUSION CRITERIA

• Age greater than or equal to 2 years and less than 15 years
• As above for adult participants.

EXPLORATORY AIMS- PAEDIATRIC CRITERIA; EXCLUSION CRITERIA

• Parent/guardian is unwilling, and/or patient aged 8 to 14 years is unwilling to assent to provide informed consent.
• As above for adult participants.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Febrile Adults; 1200 adult participants (15 to 45 years old) with a febrile illness without localising features and reported duration of 3-14 days.	Diagnostic test: 5-gene transcription signature; This is a prospective multisite diagnostic evaluation study to assess a novel approach to the diagnosis of enteric fever. The index test of host gene transcription responses by a 5 gene-signature will be compared to the reference test of blood culture confirmation for a diagnosis of enteric fever in patients with AUFI.
Controls; 400 afebrile, healthy adult participants (15 to 45 years old).	Diagnostic test: 5-gene transcription signature; This is a prospective multisite diagnostic evaluation study to assess a novel approach to the diagnosis of enteric fever. The index test of host gene transcription responses by a 5 gene-signature will be compared to the reference test of blood culture confirmation for a diagnosis of enteric fever in patients with AUFI.
Febrile Children; 400 child participants (2 to 14 years old) with a febrile illness without localising features and reported duration of 3-14 days. This is an exploratory arm of the study.	Diagnostic test: 5-gene transcription signature; This is a prospective multisite diagnostic evaluation study to assess a novel approach to the diagnosis of enteric fever. The index test of host gene transcription responses by a 5 gene-signature will be compared to the reference test of blood culture confirmation for a diagnosis of enteric fever in patients with AUFI.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sensitivity and specificity (AUROC) of a diagnostic score derived from transcriptional responses by a 5-gene transcription signature (STAT1, SLAMF8, PSME2, WARS, ALDH1A1) in classifying patients with blood culture-confirmed enteric fever.	Evaluate the performance of a host gene transcription signature for detecting enteric fever in adults presenting with acute undifferentiated fever (AUFI)	2.5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with diagnosis confirmed by laboratory testing.	Determine the frequency of other common causes of AUFI at each site.	2.5 years
Number of participants presenting with mild, moderate or severe illness by clinical diagnosis according to validated prognostic scores such as sepsis scoring systems.	Assess the relationship between markers of clinical illness severity, likely infection cause and level of molecular perturbation.	2.5 years

Collaborators and Investigators

• Sponsor: University of Sheffield
• Collaborators: Christian Medical College, Vellore, India
• Investigators: Study Director: Thomas Darton, University of Sheffield

Study record dates

Study Major Dates

• Study Start (Actual): May 2, 2022
• Primary Completion (Anticipated): January 1, 2024
• Study Completion (Anticipated): June 1, 2024

Study Registration Dates

• First Submitted: January 20, 2021
• First Submitted That Met QC Criteria: May 5, 2021
• First Posted (Actual): May 7, 2021

Study Record Updates

• Last Update Posted (Actual): June 22, 2022
• Last Update Submitted That Met QC Criteria: June 15, 2022
• Last Verified: June 1, 2022

More Information

Terms related to this study

• Keywords: Gene Expression Profiling; RNA-Seq
• Additional Relevant MeSH Terms: Infections; Wounds and Injuries; Gram-Negative Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Body Temperature Changes; Heat Stress Disorders; Enterobacteriaceae Infections; Salmonella Infections; Hyperthermia; Fever; Typhoid Fever; Paratyphoid Fever
• Other Study ID Numbers: 157365

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No