Clinical evaluation of new diagnostic tests and development of testing strategies for tuberculosis diagnosis in Africa

Rachow-Walkowitz, Andrea (2018): Clinical evaluation of new diagnostic tests and development of testing strategies for tuberculosis diagnosis in Africa. Habilitationsschrift, LMU München: Medizinische Fakultät

Abstract

Tuberculosis (TB) continues to kill more than 1.5 Mio people every year and causes a significant morbidity burden in the about 9 Mio patients who survived this infectious disease. Rapid and accurate TB diagnosis is considered one cornerstone of the global fight against TB. The “End TB Strategy” of the World Health Organization (WHO) is enforcing the need to develop new TB diagnostic tests, which are addressing the shortcomings of standard diagnostic tests that are currently used in TB epidemic and resource constrained settings like sub-Saharan Africa. In addition, to improved diagnostic tests, innovate testing strategies are needed to detect TB and control TB transmissions within specific risk groups such as prisoners, children and also TB contacts. In the frame of the presented habilitation project, three new diagnostic tests, namely the new Xpert MTB/RIF assay, which was endorsed by WHO in 2010, and two urine- based LAM tests, were evaluated in various clinical diagnostic studies in Tanzania. Further, a cross-sectional TB prevalence study was conducted in 13 Ethiopian prisons to study risk factors for TB in inmates and how successful currently implemented diagnostics algorithms are to detect TB in detention facilities. Finally, the isolated TB strains from these research studies were further analyzed using genotyping techniques in order to analyse mechanisms of TB transmission, spread of drug resistance and pathogenicity of TB strains in different high TB risk populations in Africa. For the Xpert MTB/RIF evaluation, the studies included adult and pediatric cohorts of patients with suspicion of TB. Further, the Xpert MTB/RIF assay was evaluated in a study with household contacts of smear-positive TB patients. Finally, the assay´s capacity to monitor TB treatment was assessed in TB patients who were enrolled in a therapeutic drug trial. The results of these studies contributed relevant information on the diagnostic accuracy of the assay and are also reflected by the current Xpert MTB/RIF policy recommendations from WHO. The most relevant findings were that Xpert MTB/RIF had a significant higher sensitivity compared to smear microscopy and detected up to 60% of smear negative, culture positive adult and paediatric TB cases. Xpert MTB/RIF performs equally well in HIV-positive and HIV-negative TB suspects and only one test in adults is sufficient to reach almost maximal sensitivity. Due to easy handling, rapid availability of test results and good performance in field conditions, the Xpert MTB/RIF test should be considered as the preferred test in contact tracing scenarios in Tanzania. However, due to sustained positive Xpert MTB/RIF results until the end of antimicrobial therapy in up to 27% of smear-positive TB patients, this assay is not useful to monitor microbiological response to TB treatment. The diagnostic capacity of the two LAM-assays was evaluated in a cohort of children with presumed TB. This study showed that LAM-sensitivity was highest, with maximal 70%, in HIV positive TB cases but had poor sensitivity, 28%, in HIV-negative TB suspects. Importantly, those groups of children suffering most from (co-) morbidities and high mortality were more likely to be LAM-positive. Therefore, specifically HIV-positive children with presumed active TB infection and advanced morbidity might benefit most from urine LAM-testing. This is in line with current WHO recommendations on the use of urine-based LAM tests. However, further scientific evidence is needed for a final evaluation of the use of LAM tests for the diagnosis of TB in clinical routine in Africa. The prison studies revealed that TB prevalence with about 450 TB cases among 100.000 convicts was twice as large as in the standard Ethiopian population. About 30% of existing TB cases were not detected by the prison health staff, whereby half on these were smear negative. Risk factors for TB in prisons were related to subject characteristics and behavior (e.g. alcohol drinking and TB contact at home) as well as to prison capacities (e.g. windows in prison cells). Genotypic analyses revealed that TB strains from prisoners were forming joint clusters with TB strains isolated from the Ethiopian standard population. These findings support the concept of interrelated TB epidemics among populations inside and outside prisons. Both sides need to be addressed in TB control programmes, and e.g. systematic and comprehensive TB screenings among new prisoners at entry as well as long-term prisoners might be an important strategy in order to end TB in high risk populations in Africa.

• Dokumententyp: Habilitationsschriften
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften ; 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Fakultäten: Medizinische Fakultät
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 2018