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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.
In North Korea, the prevalence of hepatitis B is high due to natural factors, gaps in vaccination, and the lack of antiviral treatment. Aid projects are urgently needed, however impeded by North Korea's political and economical situation and isolation. The feasibility of a joint North Korean and German humanitarian hepatitis B prevention program was assessed. Part 1: Hepatitis B vaccination catch-up campaign. Part 2: Implementation of endoscopic ligation of esophageal varices (EVL) by trainings in Germany and North Korea. By vaccinating 7 million children between 2010 and 2012, the hepatitis B vaccination gap was closed. Coverage of 99.23% was reached. A total of 11 hepatitis B-induced liver cirrhosis patients (mean age 41.1 yr) with severe esophageal varices and previous bleedings were successfully treated by EVL without major complications. A clinical standard operating procedure, a feedback system and a follow-up plan were developed. The bi-modal preventive strategy was implemented successfully. Parts of the project can serve as an example for other low-income countries, however its general transferability is limited due to the special circumstances in North Korea.
Biomarkers play an important role in the management of infectious pulmonary diseases, even though there is only limited evidence that biomarker-guided therapies are superior to clinical strategies.Well-established indications for the use of biomarkers are the guidance of the duration of antibiotic therapy in community-acquired pneumonia (CAP) by PCT, the decision against the use of antibiotics by CRP or PCT in ambulatory settings, and the evaluation of CAP treatment by CRP or PCT kinetics.In the prognostic assessment of CAP, the standard biomarkers of acute organ dysfunction should be given priority, e. g. leukocyte and platelet counts, creatinine/urea and lactate, in combination with clinical signs and symptoms.MR-pro-ADM could enrich diagnostics in the future. Genetic transcriptome analysis is a completely new and promising concept.
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