Paulo Rabna


Rabna 2008 Rabna, Paulo. 2008. Soluble Urokinase Plasminogen Activator Receptor (suPAR) as a Marker of Tuberculosis Treatment Efficacy and Potential Prognostic marker for Survival in individuals with a TB negative diagnosis. A prospective, Longitudinal Cohort Study in Suspected Pulmonary Tuberculosis patients in Guinea-Bissau. Bandim Health Project, Statens Serum Institut. Faculty of Health Sciences, University of Copenhagen.
  Aim
The aim of this thesis was to investigate if suPAR levels are prognostic of TB treatment efficacy and to investigate whether suPAR can be used to identify aTBneg individuals with high mortality risk.

Background
Although Tuberculosis (TB) has been a curable disease for more than 50 years, it remains a global health problem of major significance in most part of the world. It is important to monitor all TB patients during treatment in order to assess the progress of individual TB patients and also to evaluate National Tuberculosis Programme (NTP) performance.

Currently, microscopy and culture are traditionally the methods used to monitor the efficacy of TB treatment recommended by the WHO and IUATLD. However, monitoring TB treatment by smear microscopy has limitations such as low sensitivity. Culturing of mycobacterium increases sensitivity but adds weeks to the process of diagnosing primary infections, as well as evaluating TB resistance and treatment effectiveness.

Use of biomarkers, such as suPAR measurements, is a developing field that has the potential to provide considerable insights for the monitoring of TB treatment response as well as HIV disease progression and for identifying individuals with a high mortality risk among individuals assumed to be TB-negative.

The problem is that TB is quite difficult to diagnose, especially in cases without presence of bacteria in direct microscopy,

Patients that are diagnosed with active TB are immediately treated with a course of medication lasting approximately 6-8 months. Prior to the end of the treatment regime, there exists very little indication of the efficacy of the particular treatment, and thus infected individuals can complete a treatment regimen without knowing if the infection has been eradicated.

Recently, a validated and CE/IVD labeled assay for measuring suPAR became available (suPARnostic®, ViroGates, Denmark).

Methods
From April 2004 to December 2006, a total of 1682 adult patients with respiratory symptoms were screened for TB during. Among these, 466 (28%) were diagnosed with active TB according to WHO guidelines and were included in the TB treatment efficacy study (paper 2). The remaining 1216 (72%) individuals were diagnosed as TB-negative according to smear and X-ray exams, and these were part of the TB-negative study (paper I and III). Among the 1216 individuals that were assumed TB negative (aTBneg), identification and follow-up was completed for 1007 individuals and these were included in the final analysis. For this purpose a cohort of 4983 age-matched healthy individuals was created from the DSS and used to compare the mortality rate of the general population with that of individuals that were aTBneg. P-suPAR and u-suPAR was measured using a commercially available ELISA (suPARnostic®, ViroGates, Denmark). Survival was analysed using Cox Regression and Kaplan-Meier analysis and ROC curves.

Results
In our TB-treatment efficacy study (paper II), we observed that there was no significant difference in survival among individuals who did or did not smear convert at 1 and 2 months. We observed a higher mortality in the higher suPAR quartiles during the 8 months of treatment compared to the lowers quartiles, the RR being 3.1 (95% CI: 1.65-6.07). An important finding of the present study was that increased suPAR after initiation of treatment carries prognostic information on mortality.

In our aTBneg study, (paper I), we observed an increased mortality rate among individuals who were aTBneg compared to the general population. This increased mortality was most profound for individuals younger than 55 years old.

The third study (paper III) examined whether urine suPAR (U-suPAR) can be used as a prognostic marker in aTBneg individuals. We found that U-suPAR carried significant prognostic information on mortality for HIV-infected subjects. For HIV-negative individuals, little or no prognostic effect was observed. However, in both HIV positives and negatives, the predictive effect of U-suPAR was found to be inferior to that of P-suPAR.

Conclusion and future perspectives
suPAR carries relevant prognostic information on mortality among aTBneg individuals independent of their HIV status. Thus, we can conclude that suPAR is not specific for any disease. However, it is specific for mortality. Hence, a high suPAR level should lead to further diagnostic testing to identify the course of increased risk of mortality. Thus, the data presented here provides a solid ground for future development of guidelines for the management of individuals that are aTBneg in order to reduce the high mortality of this group. Further studies, and preferably a randomized study, are needed to determine how suPAR can be included in a clinical decision tree for the management of aTBneg individuals. Thus, we intend to develop a proposal for a randomized study including suPAR as a decision marker in one arm.

In conclusion the plasma suPAR carries strong prognostic information on mortality in aTBneg suggesting that suPAR could be used to identify individuals with high mortality risk. Identification of individuals with high suPAR or individuals with increasing suPAR levels should lead to further clinical and diagnostic procedures in order to reduce the high mortality among these individuals.