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- Heyckendorf, J, et al.
(author)
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Prediction of anti-tuberculosis treatment duration based on a 22-gene transcriptomic model
- 2021
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In: The European respiratory journal. - : European Respiratory Society (ERS). - 1399-3003 .- 0903-1936. ; 58:3
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Journal article (peer-reviewed)abstract
- The World Health Organization recommends standardised treatment durations for patients with tuberculosis (TB). We identified and validated a host-RNA signature as a biomarker for individualised therapy durations for patients with drug-susceptible (DS)- and multidrug-resistant (MDR)-TB.MethodsAdult patients with pulmonary TB were prospectively enrolled into five independent cohorts in Germany and Romania. Clinical and microbiological data and whole blood for RNA transcriptomic analysis were collected at pre-defined time points throughout therapy. Treatment outcomes were ascertained by TBnet criteria (6-month culture status/1-year follow-up). A whole-blood RNA therapy-end model was developed in a multistep process involving a machine-learning algorithm to identify hypothetical individual end-of-treatment time points.Results50 patients with DS-TB and 30 patients with MDR-TB were recruited in the German identification cohorts (DS-GIC and MDR-GIC, respectively); 28 patients with DS-TB and 32 patients with MDR-TB in the German validation cohorts (DS-GVC and MDR-GVC, respectively); and 52 patients with MDR-TB in the Romanian validation cohort (MDR-RVC). A 22-gene RNA model (TB22) that defined cure-associated end-of-therapy time points was derived from the DS- and MDR-GIC data. The TB22 model was superior to other published signatures to accurately predict clinical outcomes for patients in the DS-GVC (area under the curve 0.94, 95% CI 0.9–0.98) and suggests that cure may be achieved with shorter treatment durations for TB patients in the MDR-GIC (mean reduction 218.0 days, 34.2%; p<0.001), the MDR-GVC (mean reduction 211.0 days, 32.9%; p<0.001) and the MDR-RVC (mean reduction of 161.0 days, 23.4%; p=0.001).ConclusionBiomarker-guided management may substantially shorten the duration of therapy for many patients with MDR-TB.
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- Lange, C, et al.
(author)
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Clinical Application of Interferon-γ Release Assays for the Prevention of Tuberculosis in Countries with Low Incidence
- 2016
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In: Pathogens & immunity. - : Case Western Reserve University. - 2469-2964. ; 1:2, s. 308-329
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Journal article (peer-reviewed)abstract
- Despite global efforts to control tuberculosis (TB) the estimated number of people who developed TB worldwide increased to an all-time record of more than 10 million in 2015. The goal of the World Health Organization (WHO) to reduce the global incidence of TB to less than 100 cases per million by 2035, cannot be reached unless TB prevention is markedly improved. There is a need for an improved vaccine that better protects individuals who are exposed to Mycobacterium tuberculosis from infection and active disease compared to the current M. bovis Bacille Calmette Guérin (BCG) vaccine. In the absence of such a vaccine, prevention relies on infection control measures and preventive chemotherapy for people with latent infection with M. tuberculosis (LTBI), who have the highest risk of progression to active TB. During the past decade, interferon-γ release assays (IGRAs) have increasingly replaced the tuberculin skin test as screening tools for the diagnosis of LTBI in countries with a low incidence of TB. Despite recent WHO guidelines on the management of LTBI, the definition of groups at risk for TB remains controversial, and the role of IGRAs for TB prevention in low-incidence countries remains uncertain. We reviewed the scientific literature and provide recommendations for the use of IGRAs for LTBI diagnosis in low-incidence countries. These recommendations are based on the number of patients needing treatment in order to prevent one case of TB. As the positive predictive value of IGRAs for the development of TB is sub-optimal, research must focus on the identification of alternative biomarkers that offer better predictive ability in order to substantially reduce the number needing treatment while improving the prevention of TB and improving the effectiveness of targeted preventive chemotherapy.
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- Mandalakas, AM, et al.
(author)
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Tuberculosis prevention in children: a prospective community-based study in South Africa
- 2021
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In: The European respiratory journal. - : European Respiratory Society (ERS). - 1399-3003 .- 0903-1936. ; 57:4
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Journal article (peer-reviewed)abstract
- Tuberculosis (TB) preventive therapy reduces TB risk in children. However, the effectiveness of TB preventive therapy in children living in high TB burden settings is unclear.In a prospective observational community-based cohort study in Cape Town, South Africa, we assessed the effectiveness of routine TB preventive therapy in children ≤15 years of age in a high TB and HIV prevalence setting.Among 966 children (median (interquartile range) age 5.07 (2.52–8.72) years), 676 (70%) reported exposure to an adult with TB in the past 3 months and 240 out of 326 (74%) eligible children initiated isoniazid preventive therapy under programmatic guidelines. Prevalent (n=73) and incident (n=27) TB were diagnosed among 100 out of 966 (10%) children. Children who initiated isoniazid preventive therapy were 82% less likely to develop incident TB than children who did not (adjusted OR 0.18, 95% CI 0.06–0.52; p=0.0014). Risk of incident TB increased if children were <5 years of age, living with HIV, had a positiveMycobacterium tuberculosis-specific immune response or recent TB exposure. The risk of incident TB was not associated with sex orMycobacterium bovisbacille Calmette–Guérin vaccination status. Number needed to treat (NNT) was lowest in children living with HIV (NNT=15) and children <5 years of age (NNT=19) compared with children of all ages (NNT=82).In communities with high TB prevalence, TB preventive therapy substantially reduces the risk of TB among children who are <5 years of age or living with HIV, especially those with recent TB exposure or a positiveM. tuberculosis-specific immune response in the absence of disease.
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