Page 44 - Epidemiological studies on tuberculosis control and respiratory viruses

Chapter 7
this chapter was mostly by TST, as the IGRA was only recently implemented during the study period. With the increased specificity of the IGRA fewer contacts will be diagnosed with LTBI, reducing the possibility of unnecessary treatment. The ability to identify latently infected individuals at risk for developing TB would increase the clinical benefit of diagnostic tests. Previous studies have shown an association between positive IGRA results and subsequent development of TB (19) (20) (21) (22). However, these studies might have been biased as IGRA results were incorporated into the reference standard and assessments of possible TB cases were non-blinded, which could have led to relative risk estimates biased in favour of positive IGRA results (23). Indeed, Rangaka and colleagues have shown in their meta-analysis that exclusion of studies with incorporation bias resulted in only a moderate association between positive IGRA results and TB development in the included studies (23). However, these studies were all conducted in high TB incidence countries, and unbiased studies in low-incidence countries might identify increased effect measures. Nonetheless, if IGRA is to be useful as a predictive marker, studies should investigate the ability of IGRA to discriminate between individuals at risk and those who will not progress to TB, rather than demonstrating a measure of association (23). In chapter 5 we identified human biomarkers with a potential to prospectively identify individuals that develop TB. Although this study had a small sample size, was restricted to HIV- infected individuals, infection status at time of sampling was not known, and time of infection was not defined, this chapter indicated that a discriminative signature can be detected up to 6-8 months prior to clinical TB diagnosis, and these findings support the continuation of the search for predictive biomarkers. A diagnostic approach based on such biomarkers might provide the opportunity for more accurate identification of individuals with sub-clinically active M. tuberculosis replication and target them for preventive TB treatment, resulting in significant improvement to current treatment practices in low-incidence countries.
Further research
Prospective large scale studies will be necessary to establish the diagnostic accuracy of these biomarkers before they can be used as a diagnostic tool to identify high- risk individuals for preventive treatment or regular screening. It will be important to validate these markers in studies with longitudinal sampling in individuals with known M. tuberculosis infection status, in order to determine the specificity for progressive latent M. tuberculosis infection, and to determine the relevant time window preceding TB diagnosis. Since such studies are difficult to conduct, it will take
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