Transcriptomic Responses for the Identification of Pathogens

Study Overview
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Brief Summary
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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.

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

Conditions
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Enteric Fever, Acute Febrile Illness, Typhoid, Paratyphoid Fever, Fever

Intervention / Treatment
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* Diagnostic Test: 5-gene transcription signature


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Febrile Adults<br>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<br>* 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.<br>|
| Controls<br>400 afebrile, healthy adult participants (15 to 45 years old). | Diagnostic Test: 5-gene transcription signature<br>* 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.<br>|
| Febrile Children<br>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<br>* 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.<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gene Expression Profiling, RNA-Seq