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BackgroundThe World Health Organization recommends standardised treatment durations for patients with tuberculosis. 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)-tuberculosis.MethodsAdult patients with pulmonary tuberculosis were prospectively enrolled into 5 independent cohorts in Germany and Romania. Clinical and microbiological data, and whole-blood for RNA transcriptomic analysis were collected at pre-defined timepoints throughout therapy. Treatment outcomes were ascertained Treatment outcomes were ascertained by TBNET criteria (6-month culture status/one-year follow-up). A whole-blood RNA therapy end model was developed in a multi-step process involving a machine-learning algorithm to identify hypothetical individual end-of-treatment timepoints.ResultsFifty patients with drug-susceptible (DS)-tuberculosis and 30 patients with MDR-tuberculosis were recruited in the German identification cohorts (DS- and MDR-GIC), 28 patients with DS-tuberculosis and 32 patients with MDR-tuberculosis in the German validation cohorts (DS- and MDR-GVC), and 52 patients with MDR-tuberculosis in the Romanian validation cohort (MDR-RVC). A 22-gene RNA model that defined cure-associated end-of-therapy timepoints was derived from the DS- and MDR-GIC data. The model was superior to other published signatures to accurately predict clinical outcomes for patients in the DS-GVC (AUC=0.94 [95%CI:0.9–0.98]) and suggests that cure may be achieved with shorter treatment durations for tuberculosis 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-tuberculosis.
Background: To diagnose Pneumocystis jirovecii pneumonia (PCP), PCR testing in bronchoalveolar lavage (BAL) fluid has recently become an alternative to immunofluorescence testing (IFT); however, its diagnostic accuracy is less clear. Objective: To analyze the diagnostic value of a new semiquantitative real-time PCR (RT-PCR) in BAL in a real-life clinical setting. Methods: Retrospective analysis of all RT-PCR results [semiquantitative: negative, weakly positive, and strongly positive; measured in cycle thresholds (Ct)] in BAL in the period between 2010 and 2014. The diagnosis of PCP was defined by clinical, radiological, and laboratory signs and by treatment initiation. Any positive PCR was compared with subsequent IFT. Results: Of 128 patient samples, 32 had PCP. There is a relevant correlation of high significance between positive PCR Ct and IFT (r = -0.7781, p < 0.001), which amounts to about 60% of the variance. Sensitivity, specificity, and positive predictive values (PPV) of any positive RT-PCR were 100, 80, and 63%, respectively. No patient with negative RT-PCR had PCP. Specificity and PPV are 100% in strongly positive RT-PCR, whereas they decrease to 80 and 21% in weakly positive RT-PCR. Conclusion: A negative RT-PCR (Ct >45) rules out PCP. A strongly positive PCR (Ct <31.5) confirms PCP. In these cases, the diagnostic value of the new method is at least equal to the IFT. A weakly positive PCR probably represents pneumocystis colonization and can occur under PCP treatment.
Emerging multidrug-resistant tuberculosis is a major global health challenge. The World Health Organization currently recommends treatment durations of 9-18 months or more for patients with multidrug-resistant tuberculosis. We identified and validated a host-RNA signature to serve as a biomarker for individualized therapy durations for patients with multidrug-resistant tuberculosis. Adult patients with pulmonary tuberculosis were prospectively enrolled into 5 independent cohorts in Germany and Romania. Clinical and microbiological data, and whole-blood for RNA transcriptomic analysis were collected at pre-defined timepoints throughout therapy. Treatment outcomes were ascertained one year after end-of-therapy. A whole-blood RNA therapy end model was developed in a multi-step process involving a machine-learning algorithm to identify hypothetical individual end-of-treatment timepoints. Fifty patients with drug-susceptible tuberculosis and 30 patients with multidrug-resistant tuberculosis were recruited in the German identification cohorts (DS- and MDR-GIC), 28 patients with drug-susceptible tuberculosis and 32 patients with multidrug-resistant tuberculosis in the German validation cohorts (DS- and MDR-GVC), and 52 patients with multidrug-resistant tuberculosis in the Romanian validation cohort (MDR-RVC). A 22-gene RNA model that defined cure-associated end-of-therapy timepoints was derived from the DS- and MDR-GIC data. The model accurately predicted clinical outcomes for patients in the DS-GVC (AUC=0.937 [95%CI:0.899-0.976]) and suggested that cure may be achieved with shorter treatment durations for tuberculosis 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). Biomarker-guided management may substantially shorten the duration of therapy for many patients with multidrug-resistant tuberculosis.
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