Prediction of anti-tuberculosis treatment duration based on a 22-gene transcriptomic model.

BACKGROUND: 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. METHODS: Adult 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. RESULTS: 50 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). CONCLUSION: Biomarker-guided management may substantially shorten the duration of therapy for many patients with MDR-TB.

Personalized Medicine for Chronic Respiratory Infectious Diseases: Tuberculosis, Nontuberculous Mycobacterial Pulmonary Diseases, and Chronic Pulmonary Aspergillosis.

Chronic respiratory infectious diseases are causing high rates of morbidity and mortality worldwide. Tuberculosis, a major cause of chronic pulmonary infection, is currently responsible for approximately 1.5 million deaths per year. Although important advances in the fight against tuberculosis have been made, the progress towards eradication of this disease is being challenged by the dramatic increase in multidrug-resistant bacilli. Nontuberculous mycobacteria causing pulmonary disease and chronic pulmonary aspergillosis are emerging infectious diseases. In contrast to other infectious diseases, chronic respiratory infections share the trait of having highly variable treatment outcomes despite longstanding antimicrobial therapy. Recent scientific progress indicates that medicine is presently at a transition stage from programmatic to personalized management. We explain current state-of-the-art management concepts of chronic pulmonary infectious diseases as well as the underlying methods for therapeutic decisions and their implications for personalized medicine. Furthermore, we describe promising biomarkers and techniques with the potential to serve future individual treatment concepts in this field of difficult-to-treat patients. These include candidate markers to improve individual risk assessment for disease development, the design of tailor-made drug therapy regimens, and individualized biomarker-guided therapy duration to achieve relapse-free cure. In addition, the use of therapeutic drug monitoring to reach optimal drug dosing with the smallest rate of adverse events as well as candidate agents for future host-directed therapies are described. Taken together, personalized medicine will provide opportunities to substantially improve the management and treatment outcome of difficult-to-treat patients with chronic respiratory infections.

'Tree-in-bud': thinking beyond infectious causes.

High-resolution computed tomography is an important diagnostic instrument in pneumology. The 'tree-in-bud' sign is a common finding in HRCT scans. The list of the most frequent differential diagnoses for 'tree-in-bud' sign includes infections with Mycobacterium tuberculosis, nontuberculous mycobacteria, and other bacterial, fungal, or viral pathogens. Other causes could be immunological, congenital, and idiopathic disorders as well as aspiration or inhalation of toxic agents. Rare differential diagnoses are malignant conditions. We present a case with 'tree-in-bud' pulmonary infiltrates of chronic lymphatic leukemia which was only diagnosed by transbronchial biopsies, and discuss other differential diagnoses.

[Extrapulmonary tuberculosis]. / Extrapulmonale Tuberkulose.

Extrapulmonary tuberculosis (TB) presents unique diagnostic and therapeutic challenges. The site of involvement can vary widely, with common sites including the lymph nodes, pleura, skin, ear, nose and throat, genitourinary system, pericardium, gastrointestinal tract, bones and joints, and central nervous system. Clinical manifestations of extrapulmonary TB are diverse and often non-specific. Diagnosis is based on a combination of clinical suspicion, imaging, histopathology, and microbiology. Treatment of extrapulmonary TB generally follows similar principles to pulmonary TB, but the duration of treatment depends on the site of involvement and the extent of the disease. Increased awareness among healthcare providers is essential for the timely recognition and effective management of extrapulmonary TB cases.

[Treatment of tuberculosis: what is new?] / Therapie der Tuberkulose: Was gibt es Neues?

Never before have so many people around the world been simultaneously affected by tuberculosis. Tuberculosis is the leading cause of death from a bacterial infectious disease worldwide. The World Health Organization's ambitious goal from 2014 of achieving global elimination of tuberculosis does not seem realistic, but on current trends, tuberculosis could be eliminated in the European Union by 2040. Since the beginning of 2022, there have been more innovations for the treatment of tuberculosis than in no other comparable time period before. One month of rifapentine and isoniazid is effective in treating latent tuberculosis infection. However, rifapentine is licensed in the USA but not in the EU and must be imported for individual cases. The duration of the standard treatment for tuberculosis can be shortened to four months but this treatment regimen is also based on rifapentine, in addition to isoniazid, pyrazinamide, and moxifloxacin. The approval of rifapentine in Europe is a much-needed step towards shortening the treatment of tuberculosis. With new drugs an even shorter standard treatment of only 2 months is possible. The treatment of multidrug-resistant/rifampicin-resistant tuberculosis (MDR-/RR-TB) has been shortened to six months, the same length as the standard treatment available in Germany. The combination of bedaquiline, pretomanid, linezolid ± moxifloxacin, cured around 90% of affected patients were cured in studies with a treatment duration of six months. With 19 drugs in clinical trials, the treatment of tuberculosis is expected to continue to improve rapidly in the coming years.

[New developments in outpatient parenteral antibiotic therapy (OPAT)]. / Neue Entwicklungen in der ambulanten parenteralen Antibiotikatherapie (APAT).

Long term intravenous antibiotic therapy is required for the treatment of selected infections. Outpatient parenteral antibiotic therapy (OPAT) allows patients who require intravenous treatment to be treated outside of the hospital with equal efficacy and safety as in-hospital; prolonged intravenous antibiotic therapy is required for the treatment of selected infections. OPAT is particularly beneficial for patients. Staying at home and resuming everyday life lead to significantly higher patient satisfaction and quality of life. Furthermore, the risk of nosocomial infections can be reduced, especially through multi-resistant pathogens. Outpatient prescriptions shorten the inpatient length of stay and costs can be saved. Additionally the reception capacities of hospitals will be increased.