Commercial Typhoid Tests Validation Trial
Condition: Typhoid Fever
MeSH terms: Typhoid Fever
Study type: Observational

Summary: 
      Typhoid fever (typhoid) is an enteric bacterial infection caused by Salmonella enterica
      serovar Typhi (Salmonella Typhi; S. Typhi). It is one of the most common bacterial causes of
      acute febrile illness in the developing world, with an estimated 10.9 million new cases
      worldwide and 116.8 thousand deaths in 2017. Like many febrile illnesses, typhoid presents
      with non-specific symptoms and signs, especially in its early stages. In routine healthcare
      settings in low- and middle-income countries (LMIC), typhoid fever is commonly suspected and
      treated empirically with antibiotics. This overuse of antibiotics creates a selective
      pressure for the development of antimicrobial resistance (AMR), that has resulted in the
      emergence and spread of typhoid strains that are resistant to all first-line antibiotics.
      Similarly, the low specificity of current rapid diagnostic tests (RDTs) can lead to an over
      diagnosis of typhoid fever that may result in the overuse of antibiotics and delay the proper
      treatment for underlying conditions. FIND in collaboration with international typhoid experts
      developed a target product profile outlining the ideal characteristics of point of care
      tests. As part of this activity it became apparent that no quality data are available that
      systematically compare all available commercially point of care tests against the same set of
      reference standards used in multiple populations (e.g. Africa vs Asia). This lack of
      benchmarking data significantly impedes health provider's ability to decide on the utility of
      commercial tests in different settings, ultimately restricting use and access. Further the
      lack of well characterized samples reduces the ability for targeted innovation in the typhoid
      space.

      The current study aims to benchmark different commercial typhoid tests against a defined
      reference standard applied in multiple population and simultaneously develop a sample set
      that can be used in future evaluations of emerging technologies and/or to support innovative
      test development.
    

Detailed description: 
      Typhoid is an enteric disease caused by the bacterium Salmonella Typhi; it is estimated that
      11 to 20 million people contract typhoid each year and 128 000 to 161 000 die from the
      disease; children under 5 are at higher risk of contracting the disease.

      Typhoid endemic areas are located mainly in South Asia and Sub-Saharan Africa and is
      transmitted through contaminated water and food. The disease is treatable with a specific
      antibiotics regimen, however antimicrobial resistance has been reported in several countries,
      particularly in Pakistan.Several vaccines have been developed but their uptake has been low,
      partly due to limited information on the exact burden of the disease in endemic countries.

      The symptoms of typhoid are similar to other undifferentiated febrile illnesses and typhoid
      can be mistaken with vector borne febrile illnesses such as scrub typhus.

      Blood and bone marrow cultures are considered the gold standard for the diagnosis of typhoid.
      Those methods require specific infrastructure and skilled staff that are not always available
      in LMICs and are not adequate for rapid patient management. In addition, although very
      specific, blood culture sensitivity is impacted by misuse of antibiotics that lower the
      bacterial load to undetectable levels in patients' blood.

      As a consequence, alternatives to blood culture have been used in LMIC. The Widal test is the
      most used test despite a low performance (sensitivity range: 57-34%; specificity range:
      43-83%;reported in several studies. Other options in typhoid diagnosis are rapid diagnostic
      tests; among them, three tests (Typhidot, Tubex and Test-it™ Typhoid IgM) have been evaluated
      in several studies. It has been reported a variability of tests performance in different
      studies and according to the geographical regions. Variability in the test performance
      reported so far in the literature has hampered WHO to recommend any of these rapid tests in
      the EDL. FIND in collaboration with international typhoid experts developed a target product
      profile outlining the ideal characteristics of point of care tests. As part of this activity
      it became apparent that no quality data are available that systematically compare all
      available commercially point of care tests against the same set of reference standards used
      in multiple populations (e.g. Africa vs Asia). These lack of benchmarking data significantly
      impedes health providers' ability to decide on the utility of commercial tests in different
      settings, ultimately restricting use and access. Further the lack of well characterized
      samples reduces the ability for targeted innovation in the typhoid space. A second gap that
      was identified was the lack of a simple well-performing gold standard suggesting Latent class
      modelling as a solution used for other pathogens with an imperfect gold standard.

      The current study aims to benchmark different commercial typhoid tests against a defined
      reference standard applied in multiple population and simultaneously develop a sample set
      that can be used in future evaluations of emerging technologies and/or to support innovative
      test development.
    

Intervention name(s): Rapid diagnostic tests
Intervention type(s): Diagnostic Test
Intervention description(s): To evaluate different RDTs that are commercially available internationally for detecting antigens or antibodies to Salmonella Typhi and use blood culture as standard for comparison.
Observational model: Cohort
Time perspective: Prospective
Sampling method: Probability Sample
Study population: 
        The trial population will be composed of adults and children suspected of typhoid between
        2-65 years of age. Participants will be recruited when they present to Aga Khan University
        or its collection site and 3 different hospitals at Nairobi, Kenya
      
Biospecimen description: 
      Serum samples are stored
    
Keywords: Typhoid; Enteric Fever; RDTs; Widal test