Clinical Infectious Diseases
Our mission aims to improve the prevention, diagnosis and treatment of tuberculosis (especially M/XDR-TB) and respiratory diseases caused by non-tuberculous mycobacteria and to integrate scientific advances into clinical practice.
DZIF (Deutsches Zentrum für Infektionsforschung)
- DZIF Clin TB
- DZIF Biomarkerforschung
- DZIF Eastern European Study Site (EESS)
- DZIF Therapeutic Drug Monitoring
Excellenzcluster Presicion Medicine
- Individualisierte Therapie von chronischen Lungeninfektionen
EU-Projekte
- ClicTB: Novel Clinical Candidates for TB (EDCTP)
- Stool4TB (EDCTP)
- UNITE4TB: Acadamia and industry united innovation and treatment for tuberculosis
TBnet-Projekte
- TBnet study #39 - Rekrutierung und Proliferation Antigen-spezifischer T-Zellen in der Lungentuberkulose
- TBnet study #54 – Untersuchung eines neuen IGRAs bei immundefizienten Individuen
In-house Studien
- TB Datenbank
- Chronisch pulmonale Aspergillose (CPA)
Projektförderung
ledtThe clinical infrastructure (ClinTB) for tuberculosis research at the German Center for Infection Research (DZIF) has been operating since 2013 for the development and implementation of new scientific methods to improve patient care, further education and training and the development of clinical guidelines.
The University of Lübeck and the research center have been supporting the DZIF since 2014 with the establishment of the W3 professorship for Respiratory Medicine & International Health.
Our laboratory comprises approx. 100 m2 of modern infrastructure for molecular biological and immunological analysis. There is close cooperation with the national reference laboratory for mycobacteria and other scientific laboratories on our campus.
The spectrum of clinical research ranges from prevention to diagnostics and therapy. In basic scientific work, we investigate mechanisms of resistance and susceptibility to infections with Mycobacterium tuberculosis and we develop methods to improve the diagnosis of tuberculosis and to predict the response to therapy. Together with colleagues from other clinics, universities and research institutes, we are conducting national and international cohort studies to quantify the risk of developing tuberculosis in different populations and to evaluate diagnostic procedures to predict the development of active tuberculosis.
We are involved in international projects to develop new tuberculosis drugs and to identify and evaluate biomarkers that will enable therapy monitoring and, if necessary, individualized therapy duration.
In close collaboration with colleagues from other research groups at the FZB, we are developing methods for personalized medicine for tuberculosis. We translate information about mutations in the genome of Mycobacterium tuberculosis, results of differentiated antibiotic resistance determinations of the pathogens and analyses of antibiotic concentrations in the blood of patients into customized therapies. We coordinate Europe-wide observed cohort studies with the aim of improving the management of multidrug-resistant tuberculosis (MDR-TB).
In addition to the clinical aspects, we are interested in the socio-medical circumstances that lead to differences in the quality of care for tuberculosis patients and health-associated migration due to tuberculosis diseases within Europe.
In tuberculosis research, we rely on cooperation with international research networks, such as the Tuberculosis Network European Trialsgroup (TBnet), the Collaborative Group for the Meta-Analysis of Individual Patient Data in MDR-TB treatment and in EU-funded projects, currently ClickTB (EDCTP), Stool4TB (EDCTP) and the Unite4TB consortium.
With a group of experienced doctors, our team conducts around 700 documented telephone consultations (TBinfo: 04537 188 0) on all aspects of tuberculosis and infections with non-tuberculous mycobacteria every year.
Regular training and further education events include the “Clinical Tuberculosis Course”, which takes place in Borstel at the end of each spring (registration via 04537 188 7080). The course combines state-of-the-art lectures on the management of tuberculosis with an update on important new developments and includes international focus topics. Every three years, the course is held in English for an international audience.
We are regularly involved in the preparation of national and international guidelines and reviews on tuberculosis, diseases caused by non-tuberculous mycobacteria and pulmonary mycoses and are represented on advisory committees of the World Health Organization (WHO) and Médecins Sans Frontières (MSF).
There is close cooperation with the University Medical Center Hamburg Eppendorf in teaching and clinical research.
TB diagnosis is mainly based on pathogen recognition, most commonly in sputum samples from patients (Kontsevaya I. et al., 2023). Additional methods enable recognition in other matrices, particularly for patients who have difficulty producing sputum, like children. TB diagnosis can occur at different states of disease progression, from severe disease manifestation to initial development. The bacterial load, which is a key factor in infection diagnosis so far, varies accordingly. Diagnosis based on bacterial components are highly dependent on the bacterial load, making detection challenging in the early stages of disease development. Early diagnosis could potentially reduce the duration of therapy. Furthermore, alternative or additional methods to those based on pathogen recognition could include clinical factors and immunological data and lead to an early and stratified therapy approach. Several host gene expression signatures have been identified for diagnosing TB (Heyckendorf et al., 2021). However, none of the diagnostic methods based on pathogen recognition give clear information about disease severity, and on the other hand, no correlation has yet been developed between gene expression and bacterial load.
An optimised combination of simple tests should allow for the diagnosis of TB independently of the disease progression. This combination of tests should include pathogen recognition and quantification methods as well as host specific variables (clinical and intrinsic immunological parameters), enabling not only the early diagnosis of TB but also an assessment of the disease severity prior to a stratified host-directed therapy initiation, during therapy, and being able to predict relapse-free end of therapy.
Our current approaches are the following:
- Developing score models using RNA sequencing to predict individual end timepoints for antituberculosis therapies
- Analysis of epigenetic and genetic correlations with different immune responses of tuberculosis patients
- Multi-parameter characterizing of immune responses in tuberculosis patients using blood-based flow cytometry and immune assays, as well as single-cell RNA technology to investigate biomarker candidates
- Investigating mycobacterial components such as DNA in aerosols as well as both DNA and LAM in urine to monitor therapy efficacy
Diagnosing pediatric tuberculosis is highly important due to current challenges posed by nonspecific symptoms. Timely diagnosis enables prompt treatment, reducing morbidity and mortality risks. Prioritizing innovation in pediatric TB diagnostics is essential to address these factors. Tailored diagnostic tools can enhance accuracy, speed, and accessibility of TB diagnosis in children, improving their outcomes. Innovations like collecting bacilli in the breath or using stool and urine to enhance the diagnostic confirmation in children can improve detection and outcomes. Using next generation sequencing for drug susceptibility testing can help in adapting the treatment to the resistance pattern of each child. Finally, following children with TB and analyzing the changes in lung function testing before and after TB treatment can bring much needed knowledge on post TB lung disease in children.
Borstel Database Project
Prediction of response to tuberculosis treatment based on prospectively collected data from a clinical reference center in Germany
Until its closure on December 31, 2021, the Borstel Medical Clinic was both an outpatient and inpatient treatment center for people from all over the world suffering from tuberculosis. An extensive database (n = 793) was created from 2011 to 2021 as part of the clinical care of these patients. During their stay in Borstel, patients were regularly examined for the pathogen M. tuberculosis at short intervals using sputum samples, both for diagnostic purposes and during the course of treatment. The amount of microbiological data that could be generated in this way is unique worldwide. Among other things, they make it possible to analyze the time to culture positivity (TTP) during the course of therapy as well as the time to culture conversion (TTC).
The aim of the project is to describe the cohort as a whole using descriptive statistics. This is done using general data (age, gender, origin, ...), comorbidities, risk factors and data on the disease (duration of therapy, therapy outcome, pharmacological resistance, laboratory values, microbiology, ...).
The progression curves of the times to culture positivity up to the final culture conversion are to be presented and analyzed. Correlations and differences between sub-cohorts will be described. These include differences in response to therapy due to gender, pharmacological sensitivity, site of tuberculosis manifestation, time to culture positivity at the time of therapy initiation or CD4+ T-cell count.
A risk score for calculating the mortality associated with tuberculosis will be developed.
In addition, modeling will be used to develop a tool that enables physicians in clinical practice to predict the time of culture conversion of tuberculosis patients.
Detection of Mycobacterium tuberculosis
from Respiratory masks in adults with pulmonary tuberculosis
It is the aim of the aim of the study is to simplify the detection of Mycobacterium tuberculosis in adults and, if appropriate, to establish a less invasive and less costly method.
With a sensitivity of 86.5% in the original study (Williams et al. 2020), it seems promising to continue investigating face mask sampling (FMS), although this high sensitivity could not be achieved in later studies (48.1% in Hassane-Harouna et al. 2023).
In the original study, FFP2 masks with additional gelatine filters were used to detect MTB, later polyvinyl alcohol (PVA) strips proved more efficient. PVA strips were specially developed and produced at the Borstel Research Centre to ensure cost-effectiveness and comparability and can be produced locally at low cost in the future.
With an incidence of 80 new infections per 100,000 people, a third of which are MDR-TB, the Republic of Moldova is facing a major health crisis and offers an opportunity to continue our long-standing collaboration with the local health-care providers and diagnostic facilities.
In Moldova, we are working with the "Chiril Draganiuc" Lung Clinic and the National Reference Laboratory for Mycobacteria in Moldova to evaluate the efficacy of FMS in adults. Locally, 275 participants will be recruited for the study and their samples will be analysed using GeneXpert Ultra. Some of the samples will be stored in the laboratory and sent to Germany for further analysis.
UNMASK-TB (Lennard)
The aim of the UNMASK-TB research project is to develop and test modified FFP2 masks as a diagnostic test for pulmonary tuberculosis in children. Even today, tuberculosis in children can often only be diagnosed clinically, i.e. there is no reliable detection of tuberculous mycobacteria in a laboratory test. In children, failure to recognize tuberculosis is dangerous; up to 40% of children under the age of five die of tuberculosis if undiagnosed and therefore untreated.
Tongue swabs, stool, urine, and the modified masks could be promising new sample types: Obtaining these samples is less burdensome for children compared to conventional methods, such as aspirating gastric liquid. Initial studies also indicate that some of these new methods can better detect tuberculosis in children. At the Borstel Research Centre, we have therefore adapted face masks that have been successfully tested on adults for children. These contain a 3D-printed polyvinyl alcohol strip that is designed to capture bacterial DNA in exhaled breath Our method is also part of the large ‘TB GAPS’ study conducted by Baylor College of Medicine, Houston, USA, in several countries in southern Africa. The German Centre for Infection Research has repeatedly provided us with extensive support in the development of the method.
Im Rahmen des EDCTP geförderten Projekts ClicTB sollen neue Therapieregime zur Behandlung der Tuberkulose (TB), insbesondere der medikamenten-resistenten TB (MDR-TB) untersucht werden. Hierbei sollen neue Medikamentenkombinationen unter Hinzunahme von neuen Wirkstoffen klinisch erprobt werden. Dem internationalen Konsortium gehören Wissenschaftler aus Spanien und England (GSK), Südafrika (TASK, UCT), Norwegen (Uni. Tromsø) und Borstel an.
- Sanfetrinem Cilexetil ist ein sicher oral zu verabreichendes Carbapenem mit intrinsischer Stabilität gegenüber TB β-Lactamasen. Der Wirkstoff wurde bereits erfolgreich in einer Phase II Studie als Breitbandantibiotikum klinisch getestet. Dies ist die Vorrausetzung, um Sanfetrinem in einer Phase IIa „Early Bactericidal Activity“ Studie bezüglich der Bakterizidie in der TB zu testen.
- GSK3036656 ist der erste Wirkstoff einer neuen Wirkstoffklasse der selektiven mycobakteriellen LeuRS Inhibitoren. Der Wirkstoff hat die Phase I Studie erfolgreich abgeschlossen.
Die klinischen Studien werden in einem erfahrenem Studienzentrum in Südafrika (TASK) durchgeführt und beinhalten umfangreiche Biomarkeruntersuchungen (PET-CT und biologische Marker), um neue Alternativen zu den traditionellen Kultur-basierten Methoden zur Ermittlung der Bakterizidie eines Medikaments oder einer Medikamentenkombination zu ermitteln. Die biologischen Biomarker werden im Labor der Klinischen Infektiologie gemessen und analysiert. Die Untersuchungen umfassen beispielsweise Transkriptomanalysen und die Messung von transrenaler mykobakterieller DNA. Sofern die neuen Medikamente die Hoffnungen bestätigen, hat das Studienkonsortium das Ziel, die Medikamente zügig in eine Phase III Studie zu überführen, um sie den TB-Patienten zugänglich zu machen und um einen Betrag zur TB-Bekämpfung zu leisten.
Das von der EDCTP geförderte Projekt Stool4TB evaluiert eine innovative, stuhl-basierte qPCR Diagnoseplattform mit dem Ziel, die extrem große Lücke bei der Erkennung von Tuberkulose (TB) zu verringen, indem es die TB-Bestätigungsraten bei Kindern und HIV-Infizierten verbessert. Denn unter diesen Gruppen ist TB nach wie vor eine der Hauptursachen für weitere Erkrankungen und Todesfälle. Gleichzeitig ist die Tuberkulosebestätigung im Labor bei Kindern und HIV-Infizierten besonders schwierig, da es kaum möglich ist, Sputumproben zu erhalten.
Ein weiteres Ziel des Projektes ist, ein TB-Diagnose Netzwerk zwischen Ländern mit hoher Tuberkulose-Inzidenz (eSwatini, Mosambik und Uganda) zu etablieren. Dieses soll klinische Studien über neue Diagnostika und neue Arzneimittel mit dem Schwerpunkt auf Kindern und HIV-Infizierten durchführen können. Außerdem wird eine Biobank mit Vergleichsproben eingerichtet.
Als Projektpartner beteiligt sich das Forschungszentrum Borstel aktiv an der Einrichtung einer Biobank mit Proben für die künftige TB-Forschung. Blut wird in PAXgene- und QuantiFERON-TB Gold (QFT)-Röhrchen gesammelt, mit dem spezifischen Ziel, die TB22-Signatur (Heyckendorf et al., Eur Respir J 2021) und das Konzept der Endotypen bei TB (DiNardo et al., Eur Respir J 2022) bei Kindern zu validieren. RNAseq- und QFT-Daten aus den Proben der Studien werden verwendet, um das Potenzial von TB22 für die Diagnose von TB auch bei Kindern zu bestätigen und seine Fähigkeit zu beweisen, als Marker für die Ergebnisvorhersage bei Kindern zu dienen. Darüber hinaus soll gezeigt werden, dass TB22 als Marker für die individualisierte Therapiedauer bei Kindern dienen kann. Es werden multidimensionale Analysen in RNAseq- und QFT-Daten durchgeführt, um Endotypen bei Kindern weiter zu definieren. Die vor Ort gesammelten PAXgene-Röhrchen werden an das Forschungszentrum Borstel gesandt, wo eine transkriptomische RNA-Analyse durchgeführt wird.
Weitere Informationen zum Projekt finden Sie unter: https://www.stool4tb.org/
UNITE4TB (academia and industry united innovation and treatment for tuberculosis) is a public-private partnership consisting of academic institutions, small and medium-sized enterprises (SMEs), public organizations and pharmaceutical companies.
Over a period of seven years (2021-2028), the consortium will be active in around 40 trial sites on four continents (Europe, Asia, Africa and South America) to conduct novel phase 2 clinical trials. These are intended to help accelerate the development of new TB drugs and therapies.
With a financial volume of 180 million euros, UNITE4TB is the largest study in the history of drug development for tuberculosis in history.
The project aims to develop better tolerated drug regimens with shorter treatment duration that can be used to combat tuberculosis with different drug resistance patterns and comorbidities.
Through Professor Lange, the Research Center Borstel is represented in the 4-member steering committee of UNITE4TB. Ms. Ohanna Kirakosyan from the Clinical Infectiology Research Group coordinates the study centers of the consortium in Europe and Mr. Collins Musia is co-leader of the work package on biomarkers. Ms. Nika Zielinski and Dr. Begna Tulu are involved in data analysis and biomarker evaluation.
Further information can be found at: https://www.unite4tb.org/
TTBnet e.V. is a German non-governmental organization (NGO) with offices in Riga, Latvia and at the Research Center Borstel. TBnet promotes clinically oriented tuberculosis research in Europe through the exchange and development of ideas and research protocols. It is a European research network that brings together clinicians and researchers in the fight against tuberculosis and aims to improve the quality of care for tuberculosis patients by addressing health inequalities, conducting multicenter clinical trials and training European clinicians and scientists.
In recent years, TBnet has made important contributions to tuberculosis research in the fields of epidemiology, prevention, diagnostics and therapy. A list of TBnet publications can be found here.
TBnet currently has over 640 active members from more than 50 countries (as of May 2024). Ongoing studies focus on improving methods for diagnosis and therapy monitoring, among other things.
Specifically, this involves urinary metabolome analyses, the evaluation of a miniMDR TB test and the improvement of the diagnostic quality of the interferon-gamma release assay (IGRA) in immunosuppressed patients. More general studies are concerned with TB management in organ transplant patients or with the question of the extent to which drug levels in the blood influence specific therapy markers.
Training includes the TBnet Academy, which is aimed at young scientists and doctors to provide them with comprehensive knowledge. In recent years, the TBnet Academy has been held in Athens, Tbilisi and Riga.
TBnet member meetings take place annually on the Friday before the ERS conference, where there is an opportunity to exchange ideas, present and discuss the status of projects and initiate new research.
Membership is open to anyone who wishes to make a charitable contribution to tuberculosis research. TBnet does not charge a membership fee
One branch of TBnet is the Nontuberculous Mycobacteria Network (NTMnet). Originally, the Pediatric Tuberculosis Network (pTBnet) was also part of TBnet, but is now independent.
This network emerged in 2011 from the Clinical Infectiology Department of the Research Center Borstel. The current chair is held by Dr. Liga Kuksa from Riga in Latvia. The TBnet secretariat at the Research Center Borstel is headed by Anne Oleischeck (aoleischeck@fz-borstel.de).
Developing a REDCap (Research Electronic Data Capture) database for TBnet research projects is important in order to centralize the data collection and management process and offers customizable data entry forms, facilitating efficient and standardized data entry. Having an operational data collection and management system will provide TBnet with the opportunity of mutualizing research data from different projects and having a more powerful platform for proposals and publications.
Until recently, IGRAs were available in two commercial formats, the ELISPOT-based T-SPOT.TB and the ELISA-based QuantiFERON-TB Gold in-Tube test. Both formats are based on the detection of IFN- g production in T cells or supernatants after stimulation with specific antigens of M. tuberculosis. Among these, the RD-1-encoded proteins ESAT-6 and CFP-10 are most commonly used to identify specific immunity to M. tuberculosis. The peptides derived from these proteins mainly trigger cytokine release from CD4 T cells. Due to the use of M. tuberculosis-specific antigens, in-vitro tests show a higher specificity compared to the skin test. TBnet recently completed a large multicenter study comparing commercial IGRAs and the TST in five different groups of immunocompromised patients. This study showed that IGRAs are superior in detecting LTBI in patient groups with T-cell associated immunodeficiencies, although the positive predictive value (PPV) of IGRAs for the development of tuberculosis was no better than that of the TST. Nevertheless, the percentage of indeterminate results was higher than in non-immunocompromised controls without evidence of TB exposure. In addition, IGRA results were often negative despite the presence of risk factors for exposure to M. tuberculosis and even in patients who developed tuberculosis. However, although IGRAs appear superior to TST for the diagnosis of LTBI, a significant proportion of immunocompromised patients remain undiagnosed, and the tests do not provide a better risk estimate for future development of tuberculosis than TST. Based on the current literature and recent meta-analyses, there is an urgent need for improved in vitro tests and better biomarkers to identify immunocompromised patients with LTBI as a tool to prevent chemotherapy. In response to this need, Qiagen (Hilden, Germany) has developed a next generation ELISA that incorporates the negative and positive control tubes (Nil and Mitogen PHA, respectively) of the current version of the QuantiFERON-TB Gold in tube test (QFT). The next generation QuantiFERON-TB Gold Plus test (QFT-Plus) includes two tubes with M. tuberculosis-specific antigen cocktails (TB1 containing peptides derived from ESAT-6 and CFP-10 (similar to the previously used TB tube). Since this peptide mixture primarily induces the release of cytokines from CD4 T cells, the QFT-Plus assay includes a second M. tuberculosis-specific tube (TB2) containing not only the peptides derived from ESAT-6 and CFP-10, but also additional peptides optimized to stimulate CD8 T cells. Since many immunodeficiencies are associated with either general lymphopenia or specific depletion of CD4 T cells, this additional tube could increase the diagnostic sensitivity for LTBI and active tuberculosis in different groups of immunocompromised patients and reduce the percentage of indeterminacy.
The TBnet #54 study will evaluate the performance of this new ELISA-based QuantiFERON-TB plus in-tube test in immunocompromised populations. As in previous TBNET study described (Sester et al. AJRCCM 2014), both qualitative and quantitative test results will be determined with the degree of immunodeficiency and the presence of risk factors for prior exposure to M. tuberculosis. In addition, patients with active tuberculosis (both immunocompetent and immunocompromised individuals) will be included to assess a potential increase in susceptibility in these groups. Immunocompetent individuals at low risk of exposure will be included to assess specificity. Individuals enrolled in this study will be followed for 2 years to assess the predictive value of a positive blood test for progression to active disease longitudinally.
In some countries, patients who receive antituberculosis treatment use adjunctive medicines (“hepatoprotective drugs”) to “protect” the liver from drug injury.
We wish to evaluate and map the prevalence of the use of “hepatoprotective drugs” for patients who receive antituberculosis treatments in different countries of the WHO Europe Region.
The main aim of the study is to investigate common practices in the countries, to find out whether any study has been conducted, costs related to the use of hepatoprotective drugs and their observations on efficacy and safety, and at the end describe and analyse data received.
Die weltweite Migration hat in den letzten Jahrzehnten aufgrund von Kriegen, Konflikten, Verfolgung, Menschenrechtsverletzungen und Naturkatastrophen, aber auch aufgrund von Arbeits- oder Studienmöglichkeiten zugenommen. Das Tuberkuloserisiko von Migrantinnen und Migranten hängt von den Gründen für die Migration, dem sozioökonomischen Status, der Art der Reise und dem Tuberkuloserisiko im Transitland sowie der Gesundheitsversorgung im Herkunfts- und im Aufnahmeland ab.
Trotz Fortschritten bei der Tuberkuloseversorgung von Migrantinnen und. Migranten und neuen Behandlungsstrategien beruhen Entscheidungen über die Behandlung der Betroffenen häufig auf Expertenmeinungen und nicht auf klinischen Erkenntnissen.
Dieses Dokument fasst den aktuellen Wissensstand über TB-Diagnose, TB-Behandlungsstrategien bei Migranten, MDR-TB bei Migranten und HIV/TB-Koinfektion bei Migranten, die nach Europa kommen, zusammen. Die Studien wurden durch eine Meta-Analyse zusammengefasst, wenn dies angemessen war, ansonsten wurde eine narrative Zusammenfassung verwendet. Auf der Grundlage einer systematischen Überprüfung wurden Konsensempfehlungen von Expertinnen und Experten zu allen Aspekten der Migrantenversorgung gegeben.
Once tuberculosis has been diagnosed, anti-tuberculosis therapy is initiated and the course of treatment is monitored regularly over the next six months or more in order to detect treatment failure as early as possible. The most important proof of a treatment response is culture negation, i.e. the absence of growth of mycobacteria in microbiological culture over eight weeks. A molecular biological method for the rapid detection of Mycobacterium tuberculosis in sputum is the amplification of genomic mycobacterial DNA (e.g. GeneXpert®). However, this test system cannot distinguish between dead and viable TB bacteria, meaning that a positive result cannot reliably predict treatment failure. The determination of the expression of replicating genes in the new test system of the molecular tuberculosis bacterial load test (MBLA) has the advantage that only viable bacteria are detected.
In this prospective observational cohort study with Marit Neumann and Prof Dr Christoph Hölscher (Infection Immunology), the accuracy of TB-MBLA will be evaluated for the first time in assessing bacterial load to monitor treatment response in adults with pulmonary MDR/XDR tuberculosis. TB-MBLA results are compared with the GeneXpert method and time to culture positivity (TTP) in Mycobacterial Growth Indicator Tube (MGIT) culture.
In the 10 years from 2012 to 2021, we have treated over 800 tuberculosis patients as inpatients, of which approx. 150 patients with multidrug-resistant tuberculosis (MDR-TB) and approx. 30 patients with extensively drug-resistant tuberculosis (XDR-TB). Data necessary for the correct diagnosis and successful treatment of individual patients was routinely collected in our clinic. All patient data was documented in accordance with the legal requirements of the Data Protection Regulation.
Data from the clinical laboratory, molecular biology or microbiology were recorded at close intervals in order to characterize changes in the quantity and antibiotic sensitivity of the tuberculosis bacteria and to document the course of the tuberculosis disease and the response to therapy. This enabled us to react quickly to any changes. In addition, information about the therapy (medication, dosage, operations if necessary), any side effects and the success of the therapy was recorded. In this way, we try to identify risk factors for delayed treatment response or treatment failure, among other things.
The data collected in everyday clinical practice was compiled in a database, greatly simplifying data collection for clinical studies and enabling additional scientific evaluations. The database was used to produce case studies on individual Borstel patients, e.g. on MDR silicotuberculosis in a quarry worker and on a patient with extremely resistant XDR tuberculosis. An interim evaluation of the database showed that tuberculosis bacteria survived significantly longer in active and former smokers than in kidney smokers.
The data from the database has been used in various completed and ongoing studies, e.g.
- Long-term treatment results for MDR tuberculosis
- MDR tuberculosis treatment based on DNA sequencing
- Port infections during intravenous outpatient therapy
- Prediction of linezolid side effects
- in the DZIF Biomarker Research project
- in the DZIF Therapeutic Drug Monitoring project
- in the Cluster of Excellence Precision Medicine: Individualized therapy of chronic lung infections
- in the TBnet study Management of XDR-TB in Europe
- in a global systematic review on treatment outcomes in children and adolescents with MDR tuberculosis (BENEFIT Kids)
Carl Flügge (1847-1923) is best known for his studies on the transmission of tuberculosis and other diseases by droplet infection. Less well known is his work in various areas of applied hygiene. He emphasized the importance of the environment for the development and spread of diseases and investigated various aspects of public health care, from basic microbiological research in the laboratory to housing, nutrition, drinking water supply, sewage disposal and socio-economic and climatic conditions. Early on in his career, he promoted breastfeeding as a remedy for gastrointestinal infections, which were often fatal for infants at the time. He later recommended shielding coughs to protect against tuberculosis and other respiratory infections - advice that became particularly relevant again during and after the coronavirus pandemic.
Carl Flügge was born into a family of doctors in Hanover in 1847 and studied medicine in Göttingen together with Robert Koch. He spent the main years of his academic career at the University of Breslau before accepting the post as Director of the Berlin Institute of Hygiene in 1909. At the time of Carl Flügge's death in 1923, scientific methods and knowledge in the field of hygiene had become so complex that no single person could investigate and survey such a wide range of hygiene-related topics as Carl Flügge did in his work. Carl Flügge was the last great hygienist and founder of environmental medicine as a branch of hygiene.
To mark the 100th anniversary of the death of this great scientist and practitioner, an overview of the life and work of Carl Flügge was written in collaboration with Professor Peter R. Donald from the University of Stellenbosch (South Africa).
The treatment of tuberculosis is becoming increasingly difficult due to increasing antibiotic resistance. The WHO defines MDR (multidrug-resistant) tuberculosis as resistance to rifampicin and isoniazid. XDR (extensively drug-resistant) tuberculosis occurs when there is also resistance to a fluoroquinolone and one of the injectable second-line antibiotics.
As the therapy lasts several months, intravenous therapy must be continued in an outpatient setting. A port is inserted and the patient is trained to administer the medication independently. Prolonged outpatient intravenous therapy by the patient carries risks. The aim of this study is to detect adverse side effects/events, in particular port infection, in this outpatient therapy. Furthermore, the therapy outcome and the therapy costs were included in the evaluation of the therapy success. Patients with MDR, pre-XDR and XDR tuberculosis were included in the study who continued i.v. medication on an outpatient basis and obtained their medication from the Aposan pharmacy. The duration of medication administration and the doses administered until the occurrence of any side effects and port infections as well as the therapy outcome were analyzed.
The data was collected retrospectively. A total of 73 patients whose therapy began between 01/2015 and 12/2020 were included.
Patients whose intravenous therapy ended after discharge were excluded. Furthermore, supply by another pharmacy (e.g. due to moving abroad, etc.) led to exclusion.
Drug-resistant (DR) tuberculosis (TB) cases pose a challenge in the care for TB patients and remain a significant epidemiological issue. Globally, rifampicin- and multidrug-resistant (RR/MDR) cases caused an estimated 160 000 deaths in 2022. In low-incidence countries and regions, foreign-born individuals are often more commonly affected by DR TB.
Ukraine is one of the countries in the European region with the highest incidence of tuberculosis (TB) and is also globally one of the countries with the highest burden of drug-resistant TB (1 - 3). Further, Ukraine has recently been affected by two unprecedented challenges to the national healthcare system with the COVID-19 pandemic and the outbreak of an armed conflict. The annually reported notification rates for infections caused by Mycobacterium tuberculosis across the European Union and the European Economic Area (EU/EEA) have been gradually declining in the last decades. In 2022, both the total TB notification rates (49.3 versus 8.0/ 100 000) and the proportion of DR TB among bacteriologically confirmed pulmonary cases (4.9% versus 28.3%) in the EU/EEA were substantially lower than the level reported in Ukraine. As of December 2023, about 5 million displaced Ukrainians had received temporary protection status in the countries of the EU/EEA. As a result of this substantial population size increase, the total number of notified TB cases in Ukrainians in the region rose almost four-fold in 2022. The proportion of the DR TB cases of Ukrainian origin amounted to almost 20% of all DR TB cases in the region and over 30% of the laboratory confirmed Ukrainian TB cases were affected by DR TB . In this context we aim to explore the DR TB epidemiology in Ukrainian and other foreign-born TB cases notified in the EU/EEA.
In the "OPAT-TB" project, we are investigating the benefits, safety and treatment outcomes of self-administered outpatient parenteral antimicrobial therapy (sOPAT) for the treatment of tuberculosis. sOPAT enables patients to receive their treatment at home. This reduces exposure to hospital germs, lowers treatment costs and improves patient satisfaction and adherence to treatment.
The treatment of patients with drug-resistant tuberculosis is characterized by the number and type of antibiotics and the long duration of therapy, which influence the diversity and composition of the human microbiota. Second-line anti-TB treatment includes several broad-spectrum antibiotics, in particular the injectable aminoglycosides and carbapenems.
In this study, in collaboration with Dr. Mathias Hauptmann from the Cellular Microbiology Research Group, we are investigating how different second-line anti-TB treatment regimens affect the diversity of the human microbiota in the lung and gut in patients with varying degrees of drug-resistant TB.
The Xpert MTB/RIF Ultra is a rapid molecular assay in cartridge format, first introduced in 2017 as an upgrade of the Xpert MTB/RIF assay for diagnosing tuberculosis. While trace-positive results may represent detection of residual DNA from prior TB, sample cross-contamination, or laboratory error, they may also represent opportunities to detect active TB disease at an early stage. Stool is a clinical sample recommended by the WHO for the diagnosis of TB in children and gaining increasing evidence for adults. We are analyzing trace results from stool in a case-control study of TB patients paired with healthy controls.
A transcriptome model has been developed at the Borstel Research Centre to monitor treatment response in patients with pulmonary tuberculosis. The model uses the response of the human body to an infection with tuberculous mycobacteria to determine whether someone is infected. It could also be used to determine very precisely when someone has been treated with antibiotics long enough to be cured. This means that treatment durations could one day be adapted to each patient and overall shortened.
The model, which is based on 22 genes (TB22 for short), can also be used for diagnostics. This is particularly interesting for children, as many laboratory methods fail to detect tuberculosis in children. There is then no clear evidence of M. tuberculosis, so the diagnosis can only be made clinically. The aim of this research project is to test whether the TB22 model can help in the diagnosis of children or people with HIV infection. In close collaboration with Baylor College of Medicine, Houston, USA, we have been able to obtain RNA samples from children with tuberculosis in Eswatini in southern Africa. The first samples are currently on their way to Borstel and we are starting the measurements for the TB22 transcriptome model.
Background (149)
National TB Drug Resistance Surveys conducted in Eswatini in 2009/2010 and 2018 revealed transmission of a rifampicin resistant (RR) Mycobacterium tuberculosis complex (Mtbc) strain harboring the rpoB I491F mutation. This strain increased in prevalence from 30 % in the 2009/2010 survey to 58% in the 2018 survey. Current commercial molecular rapid diagnostics (MRD) and phenotypic drug susceptibility testing (pDST) by MGIT do not detect RR caused by this mutation, leading to a diagnostic gap and suboptimal TB treatment. In response, the Eswatini National Tuberculosis Program in collaboration with the Baylor College of Medicine Global TB Program and other key partners implemented a pilot project, utilizing targeted next generation sequencing (tNGS) for molecular drug susceptibility testing (mDST) of clinical Mtb strains from November 2021 to December 2022. A Clinical Advisory Committee (CAC) with clinical, laboratory and public health expertise was formed to guide optimization of treatment for patients with additional tNGS results.
Preliminary results (64)
During the period of November 2021-December 2022, a total of 85 samples were sequenced and 61 RR strains were identified. Out of these, 38(62%) had rpoB I491F mutation with 29 (76%) of the rpoB I491F strains having an additional resistance to Bedaquiline and Clofazimine. From these results, 40 patients were followed up and their clinical reports were submitted to the CAC for treatment guidance.
Conclusion
Without using tNGS in DR-TB diagnosis in Eswatini, 38/61(62%) of MDR/RR-TB with rpoB I491F mutation and 29/38(76%) with additional Bdq and Cfz resistance would be missed. Based on tNGS results and CAC recommendations, 14/40(35%) of the patients benefitted from optimized treatment regimens. With treatment adaptation, 10/14(71%) of patients with worsening clinical condition on initial regimen (“treatment failure”) achieved successful treatment outcomes.
Recommendation
Detection of the I491F rpoB mutation and drug resistance mutations for new and repurposed drugs should be considered when developing MRDs. Newer medicines are needed, as bedaquiline resistance is becoming more common.
For more information, please contact the Eswatini Health Laboratory services Chief Laboratory Technologist, Mrs. Sindisiwe Dlamini at sindydlamini36@yahoo.com
The Baylor College of Medicine Global TB Program’s collaborative HIV/AIDS training program, Siyakhula (meaning “we are growing” in siSwati): Growing HIV/TB Research Knowledge for Growing Healthy Kids in Eswatini, seeks to bolster research capacity in Eswatini focused on HIV/AIDS and TB in pediatric populations. We seek to accomplish this goal by:
- Capitalizing on existing pediatric HIV expertise to enhance the investigation of children and adolescents impacted by HIV/TB and to provide long-term training that will produce independent Swazi investigators skilled in the most recent advances in the fields of epidemiology; biostatistics and bioinformatics; behavioral science and health promotion; and health systems management and policy.
- Providing intensive in-country training in Child Health Applied Research Training (CHART) to well-qualified Siyakhula scholars from partner institutions in Eswatini.
- Supporting local research infrastructure and the existing research community while enriching the environment and capacity to lead educational research opportunities for future health professionals.
Siyakhula is a blended binational approach, primarily driven by Eswatini-based learning forums, which are augmented by strategic U.S.-based learning opportunities. Two supplemental projects expand the program's rigor by integrating expertise on the intersection of climate change and public health, and the impact of premature ageing caused by HIV/TB and associated co-morbidities.
Two of the three doctoral scholars (independent investigators) are progressing successfully through their PhD programs, having completed two years of study. The third doctoral candidate will begin their studies in August 2024.
Siyakhula trained the first cohort of 15 CHART scholars in 2022 and continues to promote their growth and education through unique eSwatini-based learning activities, including supporting eight scholars to design, implement, and analyze independently developed research projects. Siyakhula is currently training its second cohort of 25 scholars. Under the leadership of Dr. Anna Mandalakas, the project PI, a robust group of multinational lecturers and mentos including partners from Research Center Borstal provide a rich collection of lectures.
For more information, please contact the Siyakhula Program Director, Dr. Debrah Vambe at debrah.vambe@bcm.edu.
The Integrated Network of Scholars in Global Health Research Training (INSIGHT) consortium comprises four U.S. academic institutions (Baylor College of Medicine’s Global TB Program, University of Alabama at Birmingham, University of Maryland Baltimore, University of Pittsburgh) and their affiliated international institutions in Africa, Asia, and the Americas. The program is sponsored by the Fogarty International Center (FIC) and several collaborating Institutes and Centers at the U.S. National Institutes of Health (NIH) and is one of the seven consortia in the NIH Fogarty Launching Future Leaders in Global Health (LAUNCH) Research Training Program. INSIGHT aims to:
- Create collaborative, multidisciplinary global health research that integrates cross institutional pairing of mentors
- Provide one year of mentored research training for 105 scholars
- Promote and support diversity, equity, and inclusion in global health research training
- Support the transition of scholars into successful and sustainable research careers
This opportunity supports mentored research training in global health for eligible U.S. doctoral candidates and U.S. and LMIC postdoctoral (MD, MD/PhD, ScD or equivalent degree) fellows. Successful applicants spend 12 months abroad at one of 27 affiliated institutions across 20 countries, where they gain experience conducting research in international settings. LMIC postdocs have short-term training at the affiliated U.S. institution. Trainee research projects are supported by experienced and dedicated mentors with expertise in clinical, public health, laboratory, and implementation research.
More information on the INSIGHT training program can be found on the INSIGHT website.
Tuberculosis (TB) is the world’s leading infectious cause of mortality and responsible for one third of deaths in people living with human immunodeficiency virus (HIV). Children and adolescents living with HIV are disproportionately affected due to inadequate preventive services, large case detection gaps, treatment and adherence challenges, and knowledge gaps. The TB GAPS project, funded by the U.S. Centers for Disease Control and Prevention (CDC) and implemented by Baylor College of Medicine’s Global TB Program, in collaboration with partners such as Research Center Borstel, is generating evidence to inform interventions targeting several of these weaknesses in the TB/HIV cascade of care through:
- Assessing the performance of novel TB screening and diagnostic algorithms among children, adolescents, and adults living with HIV and presenting for routine care across a network of family-centered HIV clinics in five sub-Saharan African countries as compared to the current WHO recommended symptom based screening and diagnostic strategy.
- Comparing the proportion of people living with HIV (PLHIV) who initiate and complete TB preventive therapy (TPT) with different regimens within the context of a patient centered differentiated service delivery model allowing selection of TPT regimen and randomly providing enhanced adherence support versus the standard of care for TPT and adherence support.
- Evaluating the cost-effectiveness of successful TB screening and diagnostic strategies and TPT regimens among children, adolescents, and adults living with HIV.
- Disseminating and promoting uptake of evidence based best practices in TB prevention, detection, and treatment.
Under the direction of Dr. Mandalaks, project PI, The TB GAPS study began enrolling clients in July 2023 in Eswatini followed by Lesotho in October 2023, Malawi in January 2024, and Uganda in February 2024. The implementation team is in the process of initiating enrollment in Tanzania. The study is expected to run through early 2026.
More information about TB GAPS can be found at www.tbgaps.org.
In cooperation with the Clinical Pharmacology working group at the University of Hamburg and the Department of Pharmaceutical Biosciences at Uppsala University, we are developing an innovative tool for optimizing tuberculosis treatment with second-line drugs in the "AccessTDMetrics" project. The aim is to provide an easily accessible tool for pharmacokinetic modeling of the drugs
By measuring the concentration of antibiotics in patients' blood (Therapeutic Drug Monitoring, TDM), the dosage of medication can be adapted to the resistance of bacteria and the risk of side effects. This allows second-line drugs to be used more effectively and side effects to be avoided. However, there is currently no easily accessible tool that can interpret the measured concentrations using pharmacokinetic models and help doctors make dosing decisions.
With generous support from the “Schleswig-Holsteinische Gesellschaft zur Verhütung und Bekämpfung der Tuberkulose und der Lungenkrankheiten e.V.”, we can generate pharmacokinetic cohort data as part of the project and validate existing pharmacokinetic models using the data. The best models will then be integrated into the web application TDMx.eu at the University of Hamburg in order to support doctors more effectively in the dosing of tuberculosis drugs.
At the Research Center Borstel, a new biomarker (TB22) was identified that enables the individualization of the duration of tuberculosis therapy. For this purpose, a signature was identified from RNA sequences in the peripheral blood of patients. For further validation, access to blood samples from very well characterized tuberculosis patients from Mozambique, Uganda and eSwatini is available through participation in an EU project.
The TB22 signature will be applied to transcriptome data to determine whether it can accurately diagnose tuberculosis in African children and PLHIV at the start of treatment. In addition, the dynamics of TB22 during treatment will be assessed to determine if the model can accurately predict the time at which the patient has achieved a relapse-free cure.
Transcriptome data may also enable the discovery of new RNA signatures that are not yet known, such as signatures to predict disease progression, detect active tuberculosis, distinguish between tuberculosis and non-tuberculous lung disease, monitor response to treatment, or predict tuberculosis relapse in early stages.
In a longitudinal cohort, samples were taken at various points during treatment to obtain DNA and epigenetic data, and clinical data on disease severity in the form of culture data and imaging procedures, treatment results, medication and any side effects were collected. These data will be used to determine whether and which TB-relevant RNA expressions identified in previous studies can be attributed to DNA mutations or epigenetic disorders in order to draw conclusions about supplementary epigenetic or immunomodulatory therapy. In addition, it will be investigated whether there is a correlation between epigenetic disorders and the clinical manifestations, therapy results and immune cell activity or with existing concepts of personalized TB therapy (e.g. endotypes). Furthermore, it will be investigated whether the epigenetic profile is altered by certain drugs used in TB therapy.
Antibiotic resistance is making the treatment of tuberculosis increasingly difficult. Cultural methods to determine antibiotic resistance are complex and time-consuming. It usually takes several months between the diagnosis of tuberculosis and the receipt of an antibiogram. New methods of gene sequencing allow rapid and comprehensive information on mutations in the genome of tuberculosis bacteria that are associated with antibiotic resistance. These molecular predictions of antibiotic resistance using targeted sequencing technologies (t-NGS) have been officially recommended by the WHO since summer 2023 for the prediction of antibiotic resistance and the composition of treatment regimens. The Research Center Borstel is significantly involved in this process and the preparation of the WHO recommendations.
Whether the treatment results of patients affected by multidrug-resistant tuberculosis (MDR-TB) can actually be improved by using the new technologies is plausible, but has never been proven in a clinical study.
The Research Center Borstel has entered into a strategic partnership with the University of Cape Town, South Africa, to jointly address these and other questions. Our research group is supporting colleagues from the University of Cape Town (Prof. Dr. Keertan Dheda, MD PhD) in the T3 Study 2024, which is investigating the impact of tNGS technology on treatment outcomes of patients with MDR-TB in South Africa. The first patients were enrolled in spring 2024.
The overall endpoint of the study is to determine the impact of t-NGS information-based treatment regimens on treatment outcomes of patients with MDR-TB.
Phase 1 primary endpoint:
proportion of patients initiated on treatment with ≥4 likely effective drugs within 14 days of diagnosis of rifampicin-resistant TB in each group (n=120).
Phase 2 primary endpoint:
rate of unfavorable outcomes 6 months after treatment initiation in each group (n=240 including phase 1 patients)
Phase 3 primary endpoint:
rate of unfavorable outcomes in each group 12 months after treatment initiation (n=300 including phase 2 patients).
EU-Projekte
- anTBiotic (EU-H2020)
- CARE: COMMON ACTION AGAINST HIV/TB/HCV ACROSS THE REGIONS OF EUROPE (EU-H2020)
Internationale Universitäts- und Krankenhauspartnerschaften
- DAAD PAGEL „BREATHE“
New tuberculosis treatments are needed to address drug resistance, lengthy treatment duration and adverse reactions of available agents. GSK3036656 (ganfeborole) is a first-in-class benzoxaborole inhibiting the Mycobacterium tuberculosis leucyl-tRNA synthetase. Here, in this phase 2a, single-center, open-label, randomized trial, we assessed early bactericidal activity (primary objective) and safety and pharmacokinetics (secondary objectives) of ganfeborole in participants with untreated, rifampicin-susceptible pulmonary tuberculosis. Overall, 75 males were treated with ganfeborole (1/5/15/30 mg) or standard of care (Rifafour e-275 or generic alternative) once daily for 14 days. We observed numerical reductions in daily sputum-derived colony-forming units from baseline in participants receiving 5, 15 and 30 mg once daily but not those receiving 1 mg ganfeborole. Adverse event rates were comparable across groups; all events were grade 1 or 2. In a participant subset, post hoc exploratory computational analysis of 18F-fluorodeoxyglucose positron emission tomography/computed tomography findings showed measurable treatment responses across several lesion types in those receiving ganfeborole 30 mg at day 14. Analysis of whole-blood transcriptional treatment response to ganfeborole 30 mg at day 14 revealed a strong association with neutrophil-dominated transcriptional modules. The demonstrated bactericidal activity and acceptable safety profile suggest that ganfeborole is a potential candidate for combination treatment of pulmonary tuberculosis.
doi: 10.1038/s41591-024-02829-7.
Objectives:
To describe long-term treatment outcomes in patients with multi-drug-resistant/rifampicin resistant tuberculosis (MDR/RR-TB) and validate established outcome definitions for MDR/RR-TB treatment.
Methods:
Among patients with MDR/RR-TB admitted to a German MDR/RR-TB referral centre from 1 September 2002 to 29 February 2020, we compared long-term treatment outcomes derived from individual patient follow-up with treatment outcomes defined by WHO-2013, WHO-2021 and the Tuberculosis Network European Trials Group-2016.
Results:
In a total of 163 patients (mean age, 35 years; standard deviation, 13 years; 14/163 [8.6%] living with HIV; 109/163 [66.9%] men, 149/163 [91.4%] migrating to Germany within 5 years), the treatment of culture-confirmed MDR/RR-TB was initiated. Additional drug resistance to a fluoroquinolone or a second-line injectable agent was present in 15 of the 163 (9.2%) Mycobacterium tuberculosis strains; resistance against both the drug classes was present in 29 of the 163 (17.8%) strains. The median duration of MDR/RR-TB treatment was 20 months (interquartile range, 19.3-21.6 months), with a medium of five active drugs included. The median follow-up time was 4 years (47.7 months; interquartile range, 21.7 65.8 months). Among the 163 patients, cure was achieved in 25 (15.3%), 82 (50.3%) and 95 (58.3%) patients according to the outcome definitions of WHO-2013, WHO-2021, and the Tuberculosis Network European Trials Group-2016, respectively. The lost to follow-up rate was 17 of 163 (10.4%). Death was more likely in patients living with HIV (hazard ratio, 4.28; 95% confidence interval, 1.26e12.86) and older patients (hazard ratio, 1.08; 95% confidence interval, 1.05e1.12; increment of 1 year). Overall, 101/163 (62.0%) patients experienced long-term, relapse-free cure; of those, 101/122 (82.8%) patients with a known status (not lost to-follow-up or transferred out) at follow-up.
Conclusion:
Under optimal management conditions leveraging individualized treatment regimens, long-term, relapse-free cure from MDR/RR-TB is substantially higher than cure rates defined by current treatment outcome definitions.
The tuberculosis notification rate in Ukraine is around six times higher than the overall notification rate in the European Union (EU) and the European Economic Area (EEA). Ukraine is also a high priority country for the World Health Organization in terms of antibiotic-resistant tuberculosis. According to Eurostat, around 5 million Ukrainians have been displaced to EU and EEA countries since the beginning of the war between Russia and Ukraine.
In close collaboration with the European Center for Disease Prevention and Control (ECDC), we assessed the epidemiology of tuberculosis in cases of Ukrainian origin reported in the EU/EEA from 2019 to 2022 using routinely collected data.
Our results showed that the number of reported tuberculosis cases among Ukrainians in the region almost quadrupled in 2022 (n = 780, compared to an average of n = 201 in the three previous years). However, cases of Ukrainian origin continued to account for only a small proportion (2.2% in 2022) of all cases reported in the EU/EEA. In addition, notification rates among Ukrainian citizens in the EU/EEA were lower than those reported in Ukraine and remained below 20 per 100,000. The proportion of antibiotic-resistant forms of tuberculosis among cases of Ukrainian origin in the EU/EEA was high, reflecting the high proportion of resistant cases in Ukraine. In 2022, almost one in five antibiotic-resistant TB cases in the EU/EEA was of Ukrainian origin.
These results underline the importance of migrant-sensitive and patient-centered healthcare to ensure early presentation, initiation and continuation of treatment. Due to the high rate of antibiotic-resistant cases, pathogen detection and susceptibility testing in TB patients from Ukraine is crucial.
Tuberculosis (TB) remains the foremost cause of death by an infectious disease globally. Multidrug-resistant or rifampicin-resistant TB (MDR/RR-TB; resistance to rifampicin and isoniazid, or rifampicin alone) is a burgeoning public health challenge in several parts of the world, and especially Eastern Europe, Russia, Asia and sub-Saharan Africa. Pre-extensively drug-resistant TB (pre-XDR-TB) refers to MDR/RR-TB that is also resistant to a fluoroquinolone, and extensively drug-resistant TB (XDR-TB) isolates are additionally resistant to other key drugs such as bedaquiline and/or linezolid. Collectively, these subgroups are referred to as drug-resistant TB (DR-TB). All forms of DR-TB can be as transmissible as rifampicin-susceptible TB; however, it is more difficult to diagnose, is associated with higher mortality and morbidity, and higher rates of post-TB lung damage. The various forms of DR-TB often consume >50% of national TB budgets despite comprising <5-10% of the total TB case-load. The past decade has seen a dramatic change in the DR-TB treatment landscape with the introduction of new diagnostics and therapeutic agents. However, there is limited guidance on understanding and managing various aspects of this complex entity, including the pathogenesis, transmission, diagnosis, management and prevention of MDR-TB and XDR-TB, especially at the primary care physician level.
DOI: 10.1038/s41572-024-00504-2
Background:
European-specific policies for tuberculosis (TB) elimination require identification of key populations that benefit from TB screening.
Aim:
We aimed to identify groups of foreign-born individuals residing in European countries that benefit most from targeted TB prevention screening.
Methods:
The Tuberculosis Network European Trials group collected, by cross-sectional survey, numbers of foreign-born TB patients residing in European Union (EU) countries, Iceland, Norway, Switzerland and the United Kingdom (UK) in 2020 from the 10 highest ranked countries of origin in terms of TB cases in each country of residence. Tuberculosis incidence rates (IRs) in countries of residence were compared with countries of origin.
Results:
Data on 9,116 foreign-born TB patients in 30 countries of residence were collected. Main countries of origin were Eritrea, India, Pakistan, Morocco, Romania and Somalia. Tuberculosis IRs were highest in patients of Eritrean and Somali origin in Greece and Malta (both > 1,000/100,000) and lowest among Ukrainian patients in Poland (3.6/100,000). They were mainly lower in countries of residence than countries of origin. However, IRs among Eritreans and Somalis in Greece and Malta were five times higher than in Eritrea and Somalia. Similarly, IRs among Eritreans in Germany, the Netherlands and the UK were four times higher than in Eritrea.
Conclusions:
Country of origin TB IR is an insufficient indicator when targeting foreign-born populations for active case finding or TB prevention policies in the countries covered here. Elimination strategies should be informed by regularly collected country-specific data to address rapidly changing epidemiology and associated risks.
doi: 10.2807/1560-7917.ES.2023.28.42.2300051
Background:
Despite increasing availability of rapid molecular tests for the diagnosis of tuberculosis in high-burden settings, many people with tuberculosis are undiagnosed. Reliance on sputum as the primary specimen for tuberculosis diagnostics contributes to this diagnostic gap. We evaluated the diagnostic accuracy and additive yield of a novel stool quantitative PCR (qPCR) assay for the diagnosis of tuberculosis in three countries in Africa with high tuberculosis burdens.
Methods:
We undertook a prospective diagnostic accuracy study in Eswatini, Mozambique, and Tanzania from Sept 21, 2020, to Feb 2, 2023, to compare the diagnostic accuracy for tuberculosis of a novel stool qPCR test with the current diagnostic standard for Mycobacterium tuberculosis DNA detection from sputum and stool, Xpert-MTB/RIF Ultra (Xpert Ultra). Sputum, stool, and urine samples were provided by a cohort of participants, aged 10 years or older, diagnosed with tuberculosis. Participants with tuberculosis (cases) were enrolled within 72 h of treatment initiation for tuberculosis diagnosed clinically or following laboratory confirmation. Participants without tuberculosis (controls) consisted of household contacts of the cases who did not develop tuberculosis during a 6-month follow-up. The performance was compared with a robust composite microbiological reference standard (CMRS).
Findings:
The cohort of adolescents and adults (n=408) included 268 participants with confirmed or clinical tuberculosis (cases), 147 (55%) of whom were living with HIV, and 140 participants (controls) without tuberculosis. The sensitivity of the novel stool qPCR was 93·7% (95% CI 87·4-97·4) compared with participants with detectable growth on M tuberculosis culture, and 88·1% (81·3-93·0) compared with sputum Xpert Ultra. The stool qPCR had an equivalent sensitivity as sputum Xpert Ultra (94·8%, 89·1-98·1) compared with culture. Compared with the CMRS, the sensitivity of the stool qPCR was higher than the current standard for tuberculosis diagnostics on stool, Xpert Ultra (80·4%, 73·4-86·2 vs 73·5%, 66·0-80·1; p=0·025 on paired comparison). The qPCR also identified 17-21% additional tuberculosis cases compared to sputum Xpert Ultra or sputum culture. In controls without tuberculosis, the specificity of the stool qPCR was 96·9% (92·2-99·1).
Interpretation:
In this study, a novel qPCR for the diagnosis of tuberculosis from stool specimens had a higher accuracy in adolescents and adults than the current diagnostic PCR gold standard on stool, Xpert-MTB/RIF Ultra, and equivalent sensitivity to Xpert-MTB/RIF Ultra on sputum.
Funding:
National Institutes of Health (NIH) Allergy and Infectious Diseases, and NIH Fogarty International Center.
DOI: 10.1016/S2666-5247(23)00391-9
Effectiveness of preventive antibiotic treatment depending on age, tuberculosis prevalence and Mycobacterium tuberculosis infection status.
Tuberculosis is a preventable disease. However, there is debate regarding which individuals would benefit most from tuberculosis preventive treatment and whether these benefits vary in settings with a high burden and low burden of tuberculosis. We aimed to compare the effectiveness of tuberculosis preventive treatment in exposed individuals of differing ages and Mycobacterium tuberculosis infection status while considering tuberculosis burden of
the settings.
In this systematic review and individual-participant meta-analysis, we investigated the development of incident tuberculosis in people closely exposed to individuals with tuberculosis. We searched for studies published between Jan 1, 1998, and April 6, 2018, in MEDLINE, Web of Science, BIOSIS, and Embase. We restricted our search to cohort studies; case-control studies and outbreak reports were excluded. Two reviewers evaluated titles, abstracts, and full text articles for eligibility. At each stage, two reviewers discussed discrepancies and re-evaluated articles until a consensus was reached. Individual-participant data and a pre-specified list of variables, including characteristics of the exposed contact, the index patient, and environmental characteristics, were requested from authors of all eligible
studies; contacts exposed to a drug-resistant tuberculosis index patient were excluded. The primary study outcome was incident tuberculosis. We estimated adjusted hazard ratios (aHRs) for incident tuberculosis with mixed-effects Cox regression models with a study-level random effect. We estimated the number-needed-to-treat (NNT) to prevent one person developing tuberculosis. Propensity score matching procedures were used in all analyses. This study is registered with PROSPERO (CRD42018087022).
After screening 25 358 records for eligibility, 439 644 participants from 32 cohort studies were included in the individual-participant data meta-analysis. Participants were followed for 1 396 413 person-years (median of 2·7 years [IQR 1·3–4.4]), during which 2496 people were diagnosed with incident tuberculosis. Overall, effectiveness of preventive treatment was 49% (aHR 0·51 [95% CI 0·44–0·60]). Participants with a positive tuberculin-skin-test (TST) or IFNγ release assay (IGRA) result at baseline benefitted from greater protection, regardless of age (0·09 [0·05–0·17] in children younger than 5 years, 0·20 [0·15–0·28] in individuals aged 5–17 years, and 0·17 [0·13–0·22] in adults aged 18 years and older). The effectiveness of preventive treatment was greater in high-burden (0·31 [0·23–0·40]) versus low-burden (0·58 [0·47–0·72]) settings. The NNT ranged from 9 to 34 depending on age among participants with a positive TST or IGRA in both high-burden and low-burden settings; among all contacts (regardless of TST or IGRA test result), the NNT ranged from 29 to 43 in high-burden settings and 213 to 455 in low-burden settings.
Our findings suggest that a risk-targeted strategy prioritising contacts with evidence of M tuberculosis infection might be indicated in low-burden settings, and a broad approach including all contacts should be considered in high-burden settings. Preventive treatment was similarly effective among contacts of all ages.
doi.org/10.1016/S2213-2600(24)00083-3
Background:
Comprehensive and reliable drug susceptibility testing (DST) is urgently needed to provide adequate treatment regimens for patients with multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB). We determined whether next-generation sequencing (NGS) analysis of Mycobacterium tuberculosis complex isolates and genes implicated in drug resistance can guide the design of effective MDR/RR-TB treatment regimens.
Methods:
NGS-based genomic DST predictions of M. tuberculosis complex isolates from MDR/RR-TB patients admitted to a TB reference center in Germany between 1 January 2015 and 30 April 2019 were compared with phenotypic DST results of mycobacteria growth indicator tubes (MGIT). Standardized treatment algorithms were applied to design individualized therapies based on either genomic or phenotypic DST results, and discrepancies were further evaluated by determination of minimal inhibitory drug concentrations (MICs) using Sensititre MYCOTBI and UKMYC microtiter plates.
Results:
In 70 patients with MDR/RR-TB, agreement among 1048 pairwise comparisons of genomic and phenotypic DST was 86.3%; 76 (7.2%) results were discordant, and 68 (6.5%) could not be evaluated due to the presence of polymorphisms with yet unknown implications for drug resistance. Importantly, 549 of 561 (97.9%) predictions of drug susceptibility were phenotypically confirmed in MGIT, and 27 of 64 (42.2%) false-positive results were linked to previously described mutations mediating a low or moderate MIC increase. Virtually all drugs (99.0%) used in combination therapies that were inferred from genomic DST were confirmed to be susceptible by phenotypic DST.
Conclusions:
NGS-based genomic DST can reliably guide the design of effective MDR/RR-TB treatment regimens.
doi: 10.1093/cid/ciab359. PMID: 33900387
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.
Trial registration: ClinicalTrials.gov NCT02597621.
doi: 10.1183/13993003.03492-2020.
International consensus document on molecular prediction of drug resistance
Drug-resistant tuberculosis is a substantial health-care concern worldwide. Despite culture-based methods being considered the gold standard for drug susceptibility testing, molecular methods provide rapid information about the Mycobacterium tuberculosis mutations associated with resistance to anti-tuberculosis drugs. This consensus document was developed on the basis of a comprehensive literature search, by the TBnet and RESIST-TB networks, about reporting standards for the clinical use of molecular drug susceptibility testing. Review and the search for evidence included hand-searching journals and searching electronic databases. The panel identified studies that linked mutations in genomic regions of M tuberculosis with treatment outcome data. Implementation of molecular testing for the prediction of drug resistance in M tuberculosis is key. Detection of mutations in clinical isolates has implications for the clinical management of patients with multidrug-resistant or rifampicin-resistant tuberculosis, especially in situations when phenotypic drug susceptibility testing is not available. A multidisciplinary team including clinicians, microbiologists, and laboratory scientists reached a consensus on key questions relevant to molecular prediction of drug susceptibility or resistance to M tuberculosis, and their implications for clinical practice. This consensus document should help clinicians in the management of patients with tuberculosis, providing guidance for the design of treatment regimens and optimising outcomes
doi: 10.1016/S1473-3099(22)00875-1
Adverse events can make the treatment of tuberculosis more difficult and can be associated with a reduction in the patient's quality of life. The underlying mechanisms are not yet known for all drugs, meaning that adverse events cannot be completely prevented to date.
The aim of this project is therefore to identify and validate gene signatures using machine-learning algorithms to predict severe adverse events before the start of tuberculosis treatment. Transcriptome-based signatures are particularly suitable here. In addition, possible explanatory approaches for the development of severe adverse events are to be generated by identification and biological interpretation of genes and pathways. This would be a possible foundation for further research aimed at gaining a better understanding of the mechanisms and, if necessary, taking preventive countermeasures.
With the help of this work, it will hopefully be possible in the near future to identify an increased risk of serious adverse events before exposure to medication and thus make a contribution to personalised medicine in tuberculosis treatment.
Background:
Evaluation of novel anti-tuberculosis (TB) drugs for the treatment of multidrug-resistant (MDR)-TB continues to be of high interest on the TB research agenda. We assessed treatment outcomes in patients with pulmonary MDR-TB who received bedaquiline-containing treatment regimens in the Republic of Moldova, a high-burden MDR-TB country.
Methods:
We systematically analysed the SIMETB national electronic TB database and performed a retrospective propensity score-matched comparison of treatment outcomes in a cohort of patients with MDR-TB who started treatment during 2016-2018 with a bedaquiline-containing regimen (bedaquiline cohort) and a cohort of patients treated without bedaquiline (non-bedaquiline cohort).
Results:
Following propensity score matching, 114 patients were assigned to each cohort of MDR-TB patients. Patients in the bedaquiline cohort had a higher 6-month sputum culture conversion rate than those in the non-bedaquiline cohort (66.7% versus 40.3%; p<0.001). Patients under bedaquiline-containing regimens had a higher cure rate assessed by both World Health Organization (WHO) and TBnet definitions (55.3% versus 24.6%; p=0.001 and 43.5% versus 19.6%; p=0.004, respectively), as well as a lower mortality rate (8.8% versus 20.2%; p<0.001 and 10.9% versus 25.2%; p=0.01, respectively). In patients who previously failed on MDR-TB treatment, >40% of patients achieved a cure with a bedaquiline-containing regimen.
Conclusions:
Bedaquiline-based MDR-TB treatment regimens result in better disease resolution when compared with bedaquiline-sparing MDR-TB treatment regimens under programmatic conditions in a country with a high burden of MDR-TB.
doi: 10.1183/13993003.02544-2020
Tumor necrosis factor (TNF) antagonists and Janus kinase (JAK) inhibitors are important treatment options for chronic inflammatory diseases such as rheumatoid arthritis. There is currently uncertainty about how to manage patients with prior or current tuberculosis who require treatment with TNF antagonists or JAK inhibitors for underlying inflammatory conditions. As part of a systematic review, we searched the medical literature for corresponding reports and identified 368 patients who were treated with TNF antagonists during or after tuberculosis. Only 14 of these patients (3.8 %) had a recurrence of tuberculosis. Of the eleven patients who received a JAK inhibitor during or after tuberculosis, only one patient (9.1 %) had a recurrence of tuberculosis. These low numbers suggest that the use of TNF antagonists and JAK inhibitors may be relatively safe in patients with current or previous TB and the need for further treatment of underlying diseases.
Background:
In vitro, animal model and clinical evidence suggests that tuberculosis is not a monomorphic disease, and that host response to tuberculosis is protean with multiple distinct molecular pathways and pathologies (endotypes). We applied unbiased clustering to identify separate tuberculosis endotypes with classifiable gene expression patterns and clinical outcomes.
Methods:
A cohort comprised of microarray gene expression data from microbiologically confirmed tuberculosis patients was used to identify putative endotypes. One microarray cohort with longitudinal clinical outcomes was reserved for validation, as were two RNA-sequencing (seq) cohorts. Finally, a separate cohort of tuberculosis patients with functional immune responses was evaluated to clarify stimulated from unstimulated immune responses.
Results:
A discovery cohort, including 435 tuberculosis patients and 533 asymptomatic controls, identified two tuberculosis endotypes. Endotype A is characterised by increased expression of genes related to inflammation and immunity and decreased metabolism and proliferation; in contrast, endotype B has increased activity of metabolism and proliferation pathways. An independent RNA-seq validation cohort, including 118 tuberculosis patients and 179 controls, validated the discovery results. Gene expression signatures for treatment failure were elevated in endotype A in the discovery cohort, and a separate validation cohort confirmed that endotype A patients had slower time to culture conversion, and a reduced cure rate. These observations suggest that endotypes reflect functional immunity, supported by the observation that tuberculosis patients with a hyperinflammatory endotype have less responsive cytokine production upon stimulation.
Conclusion:
These findings provide evidence that metabolic and immune profiling could inform optimisation of endotype-specific host-directed therapies for tuberculosis.
doi: 10.1183/13993003.02263-2021
Consensus management recommendations for less common non-tuberculous mycobacterial pulmonary diseases
The 2020 clinical practice guideline for the treatment of non-tuberculous mycobacterial pulmonary disease (NTM-PD) by the American Thoracic Society, European Respiratory Society, European Society of Clinical Microbiology and Infectious Diseases, and Infectious Diseases Society of America; and the 2017 management guideline by the British Thoracic Society covered pulmonary diseases in adults caused by Mycobacterium avium complex, Mycobacterium kansasii, Mycobacterium xenopi, and Mycobacterium abscessus. In order to provide evidence-based recommendations for the treatment of less common non-tuberculous mycobacterial (NTM) species in adult patients without cystic fibrosis or HIV infection, our expert panel group performed systematic literature searches to provide management guidance for pulmonary diseases caused by seven additional organisms: Mycobacterium chelonae, Mycobacterium fortuitum, Mycobacterium genavense, Mycobacterium gordonae, Mycobacterium malmoense, Mycobacterium simiae, and Mycobacterium szulgai. Treatment recommendations were developed by a structured consensus process. The evidence from the scientific literature published in English for treatment recommendations for pulmonary diseases caused by other NTM species was of very low quality, with the exception of M malmoense, and based on the evaluation of case reports and case series. For M malmoense, results from two randomised controlled trials and three retrospective cohort studies provided a better evidence base for treatment recommendations, although the evidence was still of low quality.
doi: 10.1016/S1473-3099(21)00586-7
Development of a tuberculosis therapeutic drug monitoring platform
The treatment of drug-resistant Mycobacterium tuberculosis relies on complex antibiotic therapy. Inadequate antibiotic exposure can lead to treatment failure, acquired drug resistance, and an increased risk of adverse events. Therapeutic drug monitoring (TDM) can be used to optimize the antibiotic exposure. Therefore, we aimed to develop a single-run multiplex assay using high-performance liquid chromatography-mass spectrometry (HPLC-MS) for TDM of patients with multidrug-resistant, pre-extensively drug-resistant and extensively drug-resistant tuberculosis. A target profile for sufficient performance, based on the intended clinical application, was established and the assay was developed accordingly. Antibiotics were analyzed on a zwitterionic hydrophilic interaction liquid chromatography column and a triple quadrupole mass spectrometer using stable isotope-labeled internal standards. The assay was sufficiently sensitive to monitor drug concentrations over five half-lives for rifampicin, rifabutin, levofloxacin, moxifloxacin, bedaquiline, linezolid, clofazimine, terizidone/cycloserine, ethambutol, delamanid, pyrazinamide, meropenem, prothionamide, and para-amino salicylic acid (PAS). Accuracy and precision were sufficient to support clinical decision making (≤±15% in clinical samples and ±20-25% in spiked samples, with 80% of future measured concentrations predicted to fall within ±40% of nominal concentrations). The method was applied in the TDM of two patients with complex drug-resistant tuberculosis. All relevant antibiotics from their regimens could be quantified and high-dose therapy was initiated, followed by microbiological conversion. In conclusion, we developed a multiplex assay that enables TDM of the relevant first- and second-line anti-tuberculosis medicines in a single run and was able to show its applicability in TDM of two drug-resistant tuberculosis patients.
doi: 10.3390/pharmaceutics15112543
DZIF – Germany Center for Infection Research
- Clin TB
- Sponsor: DZIF
- Project leader in the research group: Prof. C. Lange
- Project partners: DZIF
- Duration: 2020-2025
- DZIF Personalized Medicine
- Sponsor: DZIF
- Project leader in the research group: Prof. C. Lange
- Project partners:
Dr. C. Geldmacher (Munich)
Dr. M. Hoelscher (Munich)
Dr. v Both (Munich)
Dr. A. Rachow (Munich)
Prof. Dr. U. Schaible (RCB)
Dr. D. Schwudke (RCB) - Duration: 2021-2025
- Detection of Mycobacterium tuberculosis from respiratory masks in adults with pulmonary tuberculosis
- Sponsor: DZIF MD Stipend
- Project leader in the research group: Dariusz Wölk
- Project partner: Lungclinic “Chiril Draganiuc”, Chisinau, Moldova
- Duration: 2024-2025
- Support: 20.0000 Euro
- Prediction of response to tuberculosis treatment based on prospectively collected data from a clinical reference center in Germany
- Sponsor: DZIF MD Stipend
- Project leader in the research group: Laura Böttcher
- Project partner: -
- Duration: 2023-2024
- Support: 18.0000 Euro
EU-Projekte
- ClickTB
- Sponsor: EU - EDCTP
- Project leader in the research group: Prof. C. Lange
- Project partner:
GSK, Tres Cantos Spanien
Prof. A. Diacon, TASK, RSA
Prof. C. Barry, Capetown, RSA - Duration: 2019-2025
- Stool4TB
- Sponsor: EU - EDCTP
- Project leader in the research group: Prof. C. Lange
- Project partner:
ISGlobal
Baylor College of Medicine Children’s Foundation, Eswatini
Manhiça Health Research Center
Makerere University
The Amsterdam Institute for Global Health and Development
Baylor College of Medicine - Duration: 2020-2024
- UNITE4TB
- Sponsor: EU-IMI
- Project leader in the research group: Prof. C. Lange
- Project partner: 27 international project partners
- Duration: 2021-2027
S-H Gesellschaft zur Verhütung & Bekämpfung d. Tuberkulose & Lungenkrankheiten e.V
- Access TDMetrics
- Sponsor: S-H Gesellschaft zur Verhütung & Bekämpfung d. Tuberkulose & Lungenkrankheiten e.V.
- Project leader in the research group: Niklas Köhler
- Project partner:
University of Hamburg, Institute for Clinical Pharmacy
Uppsala University - Duration: 2023-2024
- Funding amount: 70.000 Euro
- Epigenetic & genetic evaluation of treatment outcome in patients with multidrug-resistent and drug-sensitive tuberculosis
- Sponsor: S-H Gesellschaft zur Verhütung & Bekämpfung d. Tuberkulose & Lungenkrankheiten e.V.
- Project leader in the research group Dr. Maja Reimann
- Project partners:
Prof. Dr. Markus Weckmann (UKSH Lübeck)
Prof. Dr. Folke Brinkmann (UKSH Lübeck) - Duration: 2023-2024
- Validation of a new biomarker (TB22) for the diagnosis and therapy monitoring of tuberculosis
- Sponsor: S-H Gesellschaft zur Verhütung & Bekämpfung d. Tuberkulose & Lungenkrankheiten e.V.
- Project leader in the research group: Dr. Maja Reimann
- Project partners:
- Duration: 2023-2024
- Funding amount: 60.000 Euro
- Impact of sputum-based and sequence-guided individualized therapy on treatment outcomes in drug-resistant TB (T3 study)
- Sponsor: S-H Gesellschaft zur Verhütung & Bekämpfung d. Tuberkulose & Lungenkrankheiten e.V.
- Projec leader in the research group: Prof. Dr. Christoph Lange
- Project partner: Prof. Dr. Keertan Dheda (Kapstadt, South Africa)
- Duratation: 2023-2024
EXE PMI
- Individualized Antibiotic Therapy of Chronic Lung Infections
- Sponsor: Exzellenzcluster Precision Medicine in Chronic Inflammation (PMI)
- Project leader in the research group: Prof. C. Lange
- Project partners:
Prof. K. F. Rabe (Großhansdorf)
Prof. H. Schulenburg (Kiel)
Prof. S. Niemann (FZB) - Duration: 2019-2025
Bronchoscopic techniques for the diagnosis of pulmonary infections
- Bronchoalveolar lavages (BAL) for the preparation of cell suspensions (Endoscopy)
Cell biological methods
- Preparation of BAL for cytospins and BAL fluids (Immune Cell Analytics)
- Preparation of peripheral mononuclear cells (PBMNC)
- Elutriation for the preparation of monocytes (Immune Cell Analytics)
- In vitro infection of BAL cell suspensions with M. tuberculosis (Immune Cell Analytics, Microbial Inflammation Research)
- FACS-analysis for the detection of intracellular cytokines (Immune Cell Analytics)
- ELISPOT for the detection of IFN-g producing T-cells (Immune Cell Analytics)
- ELISA for the quantification of cytokines
- Multiplex-Analysis for the detection of max. 27 cytokines
- Quantitative RT-PCR for the detection of cytokine expression in BAL or PBMNC
- Immunohistochemistry for the intracellular detection of CXCL4 (PF4) (Pathology)
Molekularbiologische Methoden
- Quantitative RT-PCR zum Gennachweis zum Beispiel der Zytokin-Expression in BAL oder PBMC und mykobakterieller DNA
- Transkriptomanalysen aus dem peripheren Blut mittels Array-Technik oder RNAseq (in Kooperation mit FG Goldmann und FG Niemann)
Therapeutisches Drug Monitoring
- HPLC-MS²-basierte Konzentrationsbestimmung von Amikacin, Amoxicillin, Bedaquilin, Capreomycin, Clavulansäure, Clofazimin, Cycloserin, Delamanid, Ethambutol, Isoniazid, Kanamycin, Levofloxacin, Linezolid, Meropenem, Moxifloxacin, PAS, Prothionamid, Pyrazinamid, Rifabutin, Rifampicin, Streptomycin, Terizidon aus humanem Plasma. (Methode in Entwicklung).
Translational studies
- Design, organization, coordination and analysis of international studies in collaboration with the TBNET
Öffentlichkeitsarbeit und Beratungstätigkeit
- Konsiliarische klinische Beratung (TBinfo 045371880)
- M/XDR-TB consilium
- Kursus Klinische Tuberkulose
- European Advanced Course for Clinical Tuberculosis
- TBnet-Academy
- TBnet Postgraduate Course
- Deutsch-Dänisches TB Forum
2024
Abhimanyu, Longlax, SC, Nishiguchi, T, Ladki, M, Sheikh, D, Martinez, AL, Mace, EM, Grimm, SL, Caldwell, T & Portillo Varela, A et al. 2024, 'TCA metabolism regulates DNA hypermethylation in LPS and Mycobacterium tuberculosis-induced immune tolerance', PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Jg. 121, Nr. 41, S. e2404841121. https://doi.org/10.1073/pnas.2404841121
Argel, M, Conde, M, Vieira, M, Lange, C, Magis-Escurra, C & Duarte, R 2024, 'Screening of refugees from Ukraine for TB: a TBnet survey', INTERNATIONAL JOURNAL OF TUBERCULOSIS AND LUNG DISEASE, Jg. 28, Nr. 4, S. 202-203. https://doi.org/10.5588/ijtld.23.0447
Brehm, TT, Reimann, M, Köhler, N & Lange, C 2024, '(Re-)introduction of TNF antagonists and JAK inhibitors in patients with previous tuberculosis: a systematic review', CLINICAL MICROBIOLOGY AND INFECTION , Jg. 30, Nr. 8, S. 989-998. https://doi.org/10.1016/j.cmi.2024.04.011
Brehm, TT, Shijaku, F, Krumkamp, R, Jochum, J, Hoffmann, A, Ramharter, M & Kreuels, B 2024, 'Influenza in travelers from Germany returning from abroad: a retrospective case-control study', BMC INFECTIOUS DISEASES , Jg. 24, Nr. 1, S. 1107. https://doi.org/10.1186/s12879-024-10008-9
Carow, B, Muliadi, V, Skålén, K, Yokota, C, Kathamuthu, GR, Setiabudiawan, TP, Lange, C, Scheu, K, Gaede, KI & Goldmann, T et al. 2024, 'Immune mapping of human tuberculosis and sarcoidosis lung granulomas', FRONTIERS IN IMMUNOLOGY, Jg. 14, S. 1332733. https://doi.org/10.3389/fimmu.2023.1332733
Carratala-Castro, L, Ssengooba, W, Kay, A, Acácio, S, Ehrlich, J, DiNardo, AR, Shiba, N, Nsubuga, JK, Munguambe, S & Saavedra-Cervera, B et al. 2024, 'A stool based qPCR for the diagnosis of TB in children and people living with HIV in Uganda, Eswatini and Mozambique (Stool4TB): a protocol for a multicenter diagnostic evaluation', BMC INFECTIOUS DISEASES , Jg. 24, Nr. 1, S. 233. https://doi.org/10.1186/s12879-023-08708-9
Cirillo, D, Anthony, R, Gagneux, S, Horsburgh, CR, Hasan, R, Darboe, S, Laniado-Laborin, R, Probandari, A, Tukvadze, N & Arcêncio, RA et al. 2024, 'A successful UN High-Level Meeting on antimicrobial resistance must build on the 2023 UN High-Level Meeting on tuberculosis', The Lancet. Global health, Jg. 12, Nr. 8, S. e1225-e1226. https://doi.org/10.1016/S2214-109X(24)00229-8
Dheda, K & Lange, C 2024, 'Towards shorter, safer, flexible, and more effective treatment regimens for drug-resistant tuberculosis', Lancet Respiratory Medicine. https://doi.org/10.1016/S2213-2600(24)00300-X
Dheda, K, Mirzayev, F, Cirillo, DM, Udwadia, Z, Dooley, KE, Chang, K-C, Omar, SV, Reuter, A, Perumal, T & Horsburgh, CR et al. 2024, 'Multidrug-resistant tuberculosis', Nature reviews. Disease primers, Jg. 10, Nr. 1, S. 22. https://doi.org/10.1038/s41572-024-00504-2
Diacon, AH, Barry, CE, Carlton, A, Chen, RY, Davies, M, de Jager, V, Fletcher, K, Koh, GCKW, Kontsevaya, I & Heyckendorf, J et al. 2024, 'A first-in-class leucyl-tRNA synthetase inhibitor, ganfeborole, for rifampicin-susceptible tuberculosis: a phase 2a open-label, randomized trial', NATURE MEDICINE , Jg. 30, Nr. 3, S. 896-904. https://doi.org/10.1038/s41591-024-02829-7
Donald, PR, Kaufmann, SHE, Schaub, D, Thee, S & Lange, C 2024, 'Carl Flügge, one of the last holistic hygienists and discoverer of droplet transmission of infectious diseases', MEDICAL MICROBIOLOGY AND IMMUNOLOGY, Jg. 213, Nr. 1, S. 17. https://doi.org/10.1007/s00430-024-00801-3
Eggeling, J, Kalsdorf, B, Schaub, D, Schierholz, S, Hammerl, P, Nowak, D & Lange, C 2024, 'Alles unter Kontrolle?', Pneumologie (Stuttgart, Germany). https://doi.org/10.1055/a-2313-4137
Eggeling, J, Ramharter, M, Wichmann, D & Schmiedel, S 2024, 'Schwere komplizierte Malaria durch Plasmodium falciparum bei einer Reiserückkehrerin aus Sansibar', Deutsche medizinische Wochenschrift (1946), Jg. 149, Nr. 18, S. 1090-1093. https://doi.org/10.1055/a-2359-7083
Gillespie, SH, DiNardo, AR, Georghiou, SB, Sabiiti, W, Kohli, M, Panzner, U, Kontsevaya, I, Hittel, N, Stuyver, LJ & Tan, JB et al. 2024, 'Developing biomarker assays to accelerate tuberculosis drug development: defining target product profiles', The Lancet. Microbe, Jg. 5, Nr. 9, S. 100869. https://doi.org/10.1016/S2666-5247(24)00085-5
Günther, G, Guglielmetti, L, Kherabi, Y, Duarte, R, Lange, C & Tuberculosis Network European Trials group 2024, 'Availability of drugs and resistance testing for bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaL(M)) regimen for rifampicin-resistant tuberculosis in Europe', CLINICAL MICROBIOLOGY AND INFECTION , Jg. 30, Nr. 9, S. 1197.e1-1197.e4. https://doi.org/10.1016/j.cmi.2024.03.009
Hauptmann, M, Kalsdorf, B, Akoh-Arrey, JE, Lange, C & Schaible, UE 2024, 'Microbiota alterations in patients treated for susceptible or drug-resistant TB', IJTLD open, Jg. 1, Nr. 8, S. 355-361. https://doi.org/10.5588/ijtldopen.24.0325
Hoelscher, M, Barros-Aguirre, D, Dara, M, Heinrich, N, Sun, E, Lange, C, Tiberi, S & Wells, C 2024, 'Candidate anti-tuberculosis medicines and regimens under clinical evaluation', CLINICAL MICROBIOLOGY AND INFECTION , Jg. 30, Nr. 9, S. 1131-1138. https://doi.org/10.1016/j.cmi.2024.06.016
James, LP, Klaassen, F, Sweeney, S, Furin, J, Franke, MF, Yaesoubi, R, Chesov, D, Ciobanu, N, Codreanu, A & Crudu, V et al. 2024, 'Impact and cost-effectiveness of the 6-month BPaLM regimen for rifampicin-resistant tuberculosis in Moldova: A mathematical modeling analysis', PLoS medicine, Jg. 21, Nr. 5, S. e1004401. https://doi.org/10.1371/journal.pmed.1004401
Kay, A, Lukhele, B, Dlamini, S, Seeger, A, Dlamini, P, Ndabezitha, S, Mthethwa, N, Steffy, T, Komba, L & Amuge, P et al. 2024, 'Predicting mortality within 1 year of ART initiation in children and adolescents living with HIV in sub-Saharan Africa: a retrospective observational cohort study', The Lancet. Global health, Jg. 12, Nr. 6, S. e929-e937. https://doi.org/10.1016/S2214-109X(24)00091-3
Kay, A, Vasiliu, A, Carratala-Castro, L, Mtafya, B, Mendez Reyes, JE, Maphalala, N, Munguambe, S, Mulengwa, D, Ness, T & Saavedra, B et al. 2024, 'Performance of a stool-based quantitative PCR assay for the diagnosis of tuberculosis in adolescents and adults: a multinational, prospective diagnostic accuracy study', The Lancet. Microbe, Jg. 5, Nr. 5, S. e433-e441. https://doi.org/10.1016/S2666-5247(23)00391-9
Lange, C, Kherabi, Y, Guglielmetti, L, Duarte, R, Günther, G & Tuberculosis Network European Trials group 2024, 'Availability of drugs and resistance testing for bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaL(M)) regimen for rifampicin-resistant tuberculosis in Europe: author's response', CLINICAL MICROBIOLOGY AND INFECTION , Jg. 30, Nr. 9, S. 1207-1208. https://doi.org/10.1016/j.cmi.2024.06.009
Lienhardt, C, Dooley, KE, Nahid, P, Wells, C, Ryckman, TS, Kendall, EA, Davies, G, Brigden, G, Churchyard, G & Cirillo, DM et al. 2024, 'Target regimen profiles for tuberculosis treatment', Bulletin of the World Health Organization, Jg. 102, Nr. 8, S. 600-607. https://doi.org/10.2471/BLT.24.291881
Loebinger, MR, Aliberti, S, Haworth, C, Jankovic Makek, M, Lange, C, Lorent, N, Papavasileiou, A, Polverino, E, Rohde, G & Veziris, N et al. 2024, 'Patients at risk of nontuberculous mycobacterial pulmonary disease who need testing evaluated using a modified Delphi process by European experts', ERJ Open Research, Jg. 10, Nr. 5. https://doi.org/10.1183/23120541.00791-2023
Martinez, L, Seddon, JA, Horsburgh, CR, Lange, C, Mandalakas, AM & TB Contact Studies Consortium 2024, 'Effectiveness of preventive treatment among different age groups and Mycobacterium tuberculosis infection status: a systematic review and individual-participant data meta-analysis of contact tracing studies', Lancet Respiratory Medicine, Jg. 12, Nr. 8, S. 633-641. https://doi.org/10.1016/S2213-2600(24)00083-3
Meiwes, L, Kontsevaya, I, Chesov, D, Kulciţkaia, S, Dreyer, V, Hillemann, D, Dlamini, Q, Williams, C, Barer, M & Brinkmann, F et al. 2024, 'Whispers in the wind: Face mask sampling for Mycobacterium tuberculosis detection in children with pulmonary tuberculosis', JOURNAL OF INFECTIOUS DISEASES. https://doi.org/10.1093/infdis/jiae282
Neuböck, MJ, and for CPAnet#, Günther, G, Barac, A, Davidsen, JR, Laursen, CB, Agarwal, R, Sehgal, IS, Lange, C & Salzer, HJF 2024, 'Chronic Pulmonary Aspergillosis as a Considerable Complication in Post-Tuberculosis Lung Disease', Seminars in respiratory and critical care medicine, Jg. 45, Nr. 1, S. 102-113. https://doi.org/10.1055/s-0043-1776913
Nieuwenhuizen, NE, Nouailles, G, Sutherland, JS, Zyla, J, Pasternack, AH, Heyckendorf, J, Frye, BC, Höhne, K, Zedler, U & Bandermann, S et al. 2024, 'Activin A levels are raised during human tuberculosis and blockade of the activin signaling axis influences murine responses to M. tuberculosis infection', mBio, Jg. 15, Nr. 3, S. e0340823. https://doi.org/10.1128/mbio.03408-23
Otto-Knapp, R, Bauer, T, Brinkmann, F, Feiterna-Sperling, C, Friesen, I, Geerdes-Fenge, H, Hartmann, P, Häcker, B, Heyckendorf, J & Kuhns, M et al. 2024, 'Treatment of MDR, Pre-XDR, XDR, and Rifampicin-Resistant Tuberculosis or in Case of Intolerance to at Least Rifampicin in Austria, Germany, and Switzerland', RESPIRATION, Jg. 103, Nr. 9, S. 593-600. https://doi.org/10.1159/000539410
Rosenheim, J, Abebe, M, Belay, M, Tulu, B, Tayachew, D, Tegegn, M, Younis, S, Jolliffe, DA, Aseffa, A & Ameni, G et al. 2024, 'Detection of M. tuberculosis DNA in TB contacts' PBMC does not associate with blood RNA signatures for incipient tuberculosis', The European respiratory journal. https://doi.org/10.1183/13993003.00479-2024
Salzer, HJF & Lange, C 2024, 'Aspergillus-specific IgG antibodies for diagnosing chronic pulmonary aspergillosis compared with the reference standard-author's reply: Aspergillus-specific IgG antibodies for diagnosing chronic pulmonary aspergillosis compared with the reference standard-author's reply', CLINICAL MICROBIOLOGY AND INFECTION , Jg. 30, Nr. 5, S. 696-697. https://doi.org/10.1016/j.cmi.2024.02.010
Schönfeld, N, Barkane, L, Davoliene, I, Danilovits, M, Miliauskas, S, Ader, F, Kon, OM, Lange, C, Duvignaud, A & Heiss-Neumann, M et al. 2024, 'Real-life use of delamanid: results from the European post-authorisation safety study', IJTLD open, Jg. 1, Nr. 6, S. 274-278. https://doi.org/10.5588/ijtldopen.24.0113
Shaw, ES, Stoker, NG, Potter, JL, Claassen, H, Leslie, A, Tweed, CD, Chiang, C-Y, Conradie, F, Esmail, H & Lange, C et al. 2024, 'Bedaquiline: what might the future hold?', The Lancet. Microbe, S. 100909. https://doi.org/10.1016/S2666-5247(24)00149-6
Stoycheva, K, Cristea, V, Ködmön, C, Rosales-Klintz, S, Zenner, D, Vasiliu, A, van der Werf, M & Lange, C 2024, 'Tuberculosis in people of Ukrainian origin in the European Union and the European Economic Area, 2019 to 2022', Eurosurveillance, Jg. 29, Nr. 12, 2400094. https://doi.org/10.2807/1560-7917.ES.2024.29.12.2400094
Sutter, JP, Kocheise, L, Kempski, J, Christner, M, Wichmann, D, Pinnschmidt, H, Schmiedel, S, Lohse, AW, Huber, S & Brehm, TT 2024, 'Gentamicin combination treatment is associated with lower mortality in patients with invasive listeriosis: a retrospective analysis', Infection, Jg. 52, Nr. 4, S. 1601-1606. https://doi.org/10.1007/s15010-024-02330-w
Wetzstein, N, Dahl, VN, Lillebaek, T & Lange, C 2024, 'Clinical spectrum and relevance of Mycobacterium malmoense: Systematic review and meta-analysis of 859 patients', Journal of infection, Jg. 89, Nr. 2, S. 106203. https://doi.org/10.1016/j.jinf.2024.106203
Zielinski, N, Baiceanu, D, Dragomir, A, Heyckendorf, J, Ibraim, E, Köhler, N, Leschczyk, C, Popa, C, Rachow, A & Sachsenweger, J et al. 2024, 'A Transcriptomic Biomarker Predicting Linezolid-Associated Neuropathy During Treatment of Drug-Resistant Tuberculosis', Pathogens and Immunity, Jg. 9, Nr. 2, S. 25-42. https://doi.org/10.20411/pai.v9i2.705
2023
Brehm, TT, Köhler, N, Schmiedel, S, Terhalle, E, Martensen, J, Kalsdorf, B, Kandulla, J, Heyckendorf, J, Kuhns, M, Friesen, I & Lange, C 2023, 'Therapie der Tuberkulose: Was gibt es Neues?', Innere Medizin (Heidelberg, Germany), Jg. 64, Nr. 7, S. 701-707. https://doi.org/10.1007/s00108-023-01523-z
Butov, D, Feshchenko, Y, Chesov, D, Myasoedov, V, Kuzhko, M, Dudnyk, A, Reimann, M, Hryshchuk, L, Yareshko, A, Tkachenko, A, Tarleeva, Y, Konstantynovska, O, Butova, T & Lange, C 2023, 'National survey on the impact of the war in Ukraine on TB diagnostics and treatment services in 2022', INTERNATIONAL JOURNAL OF TUBERCULOSIS AND LUNG DISEASE, Jg. 27, Nr. 1, S. 86-88. https://doi.org/10.5588/ijtld.22.0563
European Tuberculosis Network TBNET, Günther, G, Guglielmetti, L, Leu, C, Lange, C & van Leth, F 2023, 'Availability and costs of medicines for the treatment of tuberculosis in Europe', CLINICAL MICROBIOLOGY AND INFECTION , Jg. 29, Nr. 1, S. 77-84. https://doi.org/10.1016/j.cmi.2022.07.026
Günther, G, Guglielmetti, L, Leu, C, van Leth, F & Lange, C 2023, 'Relative cost of multidrug-resistant TB medicines in Europe', INTERNATIONAL JOURNAL OF TUBERCULOSIS AND LUNG DISEASE, Jg. 27, Nr. 5, S. 341-344. https://doi.org/10.5588/ijtld.23.0026
Hamada, Y, Gupta, RK, Quartagno, M, Izzard, A, Acuna-Villaorduna, C, Altet, N, Diel, R, Dominguez, J, Floyd, S, Gupta, A, Huerga, H, Jones-López, EC, Kinikar, A, Lange, C, van Leth, F, Liu, Q, Lu, W, Lu, P, Rueda, IL, Martinez, L, Mbandi, SK, Muñoz, L, Padilla, ES, Paradkar, M, Scriba, T, Sester, M, Shanaube, K, Sharma, SK, Sloot, R, Sotgiu, G, Thiruvengadam, K, Vashishtha, R, Abubakar, I & Rangaka, MX 2023, 'Predictive performance of interferon-gamma release assays and the tuberculin skin test for incident tuberculosis: an individual participant data meta-analysis', EClinicalMedicine, Jg. 56, S. 101815. https://doi.org/10.1016/j.eclinm.2022.101815
Hamada, Y, Kontsevaya, I, Surkova, E, Wang, TT, Wan-Hsin, L, Matveev, A, Ziganshina, LE, Denkinger, CM, Korobitsyn, A, Ismail, N, Abubakar, I & Rangaka, MX 2023, 'A Systematic Review on the Safety of Mycobacterium tuberculosis-Specific Antigen-Based Skin Tests for Tuberculosis Infection Compared With Tuberculin Skin Tests', Open forum infectious diseases, Jg. 10, Nr. 5, S. ofad228. https://doi.org/10.1093/ofid/ofad228
Ivanova, O, Hoffmann, VS, Lange, C, Hoelscher, M & Rachow, A 2023, 'Post-tuberculosis lung impairment: systematic review and meta-analysis of spirometry data from 14 621 people', European Respiratory Review, Jg. 32, Nr. 168, S. 220221. https://doi.org/10.1183/16000617.0221-2022
Koehler, N, Andres, S, Merker, M, Dreyer, V, John, A, Kuhns, M, Krieger, D, Choong, E, Verougstraete, N, Zur Wiesch, PA, Wicha, SG, König, C, Kalsdorf, B, Sanchez Carballo, PM, Schaub, D, Werngren, J, Schön, T, Peloquin, CA, Schönfeld, N, Verstraete, AG, Decosterd, LA, Aarnoutse, R, Niemann, S, Maurer, FP & Lange, C 2023, 'Pretomanid-Resistant Tuberculosis', Journal of infection, Jg. 86, Nr. 5, S. 520-524. https://doi.org/10.1016/j.jinf.2023.01.039
Kontsevaya, I, Cabibbe, AM, Cirillo, DM, DiNardo, AR, Frahm, N, Gillespie, SH, Holtzman, D, Meiwes, L, Petruccioli, E, Reimann, M, Ruhwald, M, Sabiiti, W, Saluzzo, F, Tagliani, E & Goletti, D 2023, 'Update on the diagnosis of tuberculosis', CLINICAL MICROBIOLOGY AND INFECTION . https://doi.org/10.1016/j.cmi.2023.07.014
Lange, C 2023, 'Mission (im)possible: elimination of tuberculosis', CLINICAL MICROBIOLOGY AND INFECTION . https://doi.org/10.1016/j.cmi.2023.07.033
Lange, C, Köhler, N & Günther, G 2023, 'Regimens for Drug-Resistant Tuberculosis', New England Journal of Medicine, Jg. 388, Nr. 2, S. 189-191. https://doi.org/10.1056/NEJMc2213970
Maier, C, Chesov, D, Schaub, D, Kalsdorf, B, Andres, S, Friesen, I, Reimann, M & Lange, C 2023, 'Long-term treatment outcomes in patients with multidrug-resistant tuberculosis', CLINICAL MICROBIOLOGY AND INFECTION , Jg. 29, Nr. 6, S. 751-757. https://doi.org/10.1016/j.cmi.2023.02.013
Motta, I, Boeree, M, Chesov, D, Dheda, K, Günther, G, Horsburgh, CR, Kherabi, Y, Lange, C, Lienhardt, C, McIlleron, HM, Paton, NI, Stagg, HR, Thwaites, G, Udwadia, Z, Van Crevel, R, Velásquez, GE, Wilkinson, RJ & Guglielmetti, L 2023, 'Recent advances in the treatment of tuberculosis', CLINICAL MICROBIOLOGY AND INFECTION . https://doi.org/10.1016/j.cmi.2023.07.013
Ness, T, Van, LH, Petermane, I, Duarte, R, Lange, C, Menzies, D & Cirillo, DM 2023, 'Rolling out new anti-tuberculosis drugs without diagnostic capacity', Breathe, Jg. 19, Nr. 2, S. 230084. https://doi.org/10.1183/20734735.0084-2023
Ness, TE, Meiwes, L, Kay, A, Mejia, R, Lange, C, Farhat, M, Mandalakas, A & DiNardo, A 2023, 'Optimizing DNA Extraction from Pediatric Stool for Diagnosis of Tuberculosis and Use in Next-Generation Sequencing Applications', Microbiology spectrum, Jg. 11, Nr. 1, S. e0226922. https://doi.org/10.1128/spectrum.02269-22
Pedersen, OS, Holmgaard, FB, Mikkelsen, MKD, Lange, C, Sotgiu, G, Lillebaek, T, Andersen, AB, Wejse, CM & Dahl, VN 2023, 'Global treatment outcomes of extensively drug-resistant tuberculosis in adults: A systematic review and meta-analysis', Journal of infection, Jg. 87, Nr. 3, S. 177-189. https://doi.org/10.1016/j.jinf.2023.06.014
Sandoval, M, Mtetwa, G, Devezin, T, Vambe, D, Sibanda, J, Dube, GS, Dlamini-Simelane, T, Lukhele, B, Mandalakas, AM & Kay, A 2023, 'Community-based tuberculosis contact management: Caregiver experience and factors promoting adherence to preventive therapy', PLOS global public health, Jg. 3, Nr. 7, S. e0001920. https://doi.org/10.1371/journal.pgph.0001920
TBNET and RESIST-TB networks, Domínguez, J, Boeree, MJ, Cambau, E, Chesov, D, Conradie, F, Cox, V, Dheda, K, Dudnyk, A, Farhat, MR, Gagneux, S, Grobusch, MP, Gröschel, MI, Guglielmetti, L, Kontsevaya, I, Lange, B, van Leth, F, Lienhardt, C, Mandalakas, AM, Maurer, FP, Merker, M, Miotto, P, Molina-Moya, B, Morel, F, Niemann, S, Veziris, N, Whitelaw, A, Horsburgh, CR & Lange, C 2023, 'Clinical implications of molecular drug resistance testing for Mycobacterium tuberculosis: a 2023 TBnet/RESIST-TB consensus statement', Lancet Infectious Diseases, Jg. 23, Nr. 4, S. e122-e137. https://doi.org/10.1016/S1473-3099(22)00875-1
UNITE4TB Consortium 2023, 'Implementing molecular tuberculosis diagnostic methods in limited-resource and high-burden countries', Breathe, Jg. 18, Nr. 4, S. 220226. https://doi.org/10.1183/20734735.0226-2022
UNITE4TB Consortium 2023, 'Tuberculosis: current challenges and beyond', Breathe, Jg. 19, Nr. 1, S. 220166. https://doi.org/10.1183/20734735.0166-2022
2022
Akkerman, OW, Duarte, R, Tiberi, S, Schaaf, HS, Lange, C, Alffenaar, JWC, Denholm, J, Carvalho, ACC, Bolhuis, MS, Borisov, S, Bruchfeld, J, Cabibbe, AM, Caminero, JA, Carvalho, I, Chakaya, J, Centis, R, Dalcomo, MP, D Ambrosio, L, Dedicoat, M, Dheda, K, Dooley, KE, Furin, J, García-García, J-M, van Hest, NAH, de Jong, BC, Kurhasani, X, Märtson, AG, Mpagama, S, Torrico, MM, Nunes, E, Ong, CWM, Palmero, DJ, Ruslami, R, Saktiawati, AMI, Semuto, C, Silva, DR, Singla, R, Solovic, I, Srivastava, S, de Steenwinkel, JEM, Story, A, Sturkenboom, MGG, Tadolini, M, Udwadia, ZF, Verhage, AR, Zellweger, JP & Migliori, GB 2022, 'Clinical standards for drug-susceptible pulmonary TB', INTERNATIONAL JOURNAL OF TUBERCULOSIS AND LUNG DISEASE, Jg. 26, Nr. 7, S. 592-604. https://doi.org/10.5588/ijtld.22.0228
Brandenburg, J, Heyckendorf, J, Marwitz, F, Zehethofer, N, Linnemann, L, Gisch, N, Karaköse, H, Reimann, M, Kranzer, K, Kalsdorf, B, Sanchez-Carballo, P, Weinkauf, M, Scholz, V, Malm, S, Homolka, S, Gaede, KI, Herzmann, C, Schaible, UE, Hölscher, C, Reiling, N & Schwudke, D 2022, 'Tuberculostearic Acid-Containing Phosphatidylinositols as Markers of Bacterial Burden in Tuberculosis', ACS infectious diseases, Jg. 8, Nr. 7, S. 1303-1315. https://doi.org/10.1021/acsinfecdis.2c00075
Chesov, E, Chesov, D, Maurer, FP, Andres, S, Utpatel, C, Barilar, I, Donica, A, Reimann, M, Niemann, S, Lange, C, Crudu, V, Heyckendorf, J & Merker, M 2022, 'Emergence of bedaquiline resistance in a high tuberculosis burden country', The European respiratory journal, Jg. 59, Nr. 3, 2100621. https://doi.org/10.1183/13993003.00621-2021
COVICAT study group, Aachen Study (COVAS) 2022, 'Detailed stratified GWAS analysis for severe COVID-19 in four European populations', HUMAN MOLECULAR GENETICS , Jg. 31, Nr. 23, S. 3945-3966. https://doi.org/10.1093/hmg/ddac158
Donald, P, Kaufmann, S, Thee, S, Mandalakas, AM & Lange, C 2022, 'Pathogenesis of tuberculosis: the 1930 Lübeck disaster revisited', European Respiratory Review, Jg. 31, Nr. 164, 220046. https://doi.org/10.1183/16000617.0046-2022
DZIF-TB cohort study group 2022, 'Gene expression signatures identify biologically and clinically distinct tuberculosis endotypes', The European respiratory journal, Jg. 60, Nr. 3. https://doi.org/10.1183/13993003.02263-2021
European Conference on Infections in Leukaemia group 2022, 'Mycobacterial infections in adults with haematological malignancies and haematopoietic stem cell transplants: guidelines from the 8th European Conference on Infections in Leukaemia', Lancet Infectious Diseases, Jg. 22, Nr. 12, S. e359-e369. https://doi.org/10.1016/S1473-3099(22)00227-4
expert panel group for management recommendations in non-tuberculous mycobacterial pulmonary diseases 2022, 'Consensus management recommendations for less common non-tuberculous mycobacterial pulmonary diseases', Lancet Infectious Diseases, Jg. 22, Nr. 7, S. e178-e190. https://doi.org/10.1016/S1473-3099(21)00586-7
Günther, G, Saathoff, E, Rachow, A, Ekandjo, H, Diergaardt, A, Marais, N, Lange, C & Nepolo, E 2022, 'Clinical Evaluation of a Line-Probe Assay for Tuberculosis Detection and Drug-Resistance Prediction in Namibia', Microbiology spectrum, Jg. 10, Nr. 3, S. e0025922. https://doi.org/10.1128/spectrum.00259-22
Gutowski, J-P, Sachsenweger, J, May, K, Lange, C & Heyckendorf, J 2022, 'Eine unerwartete Komplikation: Kontralateraler Spannungspneumothorax nach transbronchialer Zangenbiopsie', Pneumologie (Stuttgart, Germany), Jg. 76, Nr. 9, S. 622-625. https://doi.org/10.1055/a-1775-5693
Lange, C, Aaby, P, Behr, MA, Donald, PR, Kaufmann, SHE, Netea, MG & Mandalakas, AM 2022, '100 years of Mycobacterium bovis bacille Calmette-Guérin', Lancet Infectious Diseases, Jg. 22, Nr. 1, S. e2-e12. https://doi.org/10.1016/S1473-3099(21)00403-5
Lange, C, Kay, A & Mandalakas, AM 2022, 'The need for effective drugs for TB prevention: set your goals high, and don´t stop till you get there', INTERNATIONAL JOURNAL OF TUBERCULOSIS AND LUNG DISEASE, Jg. 26, Nr. 2, S. 85-88. https://doi.org/10.5588/ijtld.21.0736
Martinez, L, Cords, O, Liu, Q, Acuna-Villaorduna, C, Bonnet, M, Fox, GJ, Carvalho, ACC, Chan, P-C, Croda, J, Hill, PC, Lopez-Varela, E, Donkor, S, Fielding, K, Graham, SM, Espinal, MA, Kampmann, B, Reingold, A, Huerga, H, Villalba, JA, Grandjean, L, Sotgiu, G, Egere, U, Singh, S, Zhu, L, Lienhardt, C, Denholm, JT, Seddon, JA, Whalen, CC, García-Basteiro, AL, Triasih, R, Chen, C, Singh, J, Huang, L-M, Sharma, S, Hannoun, D, Del Corral, H, Mandalakas, AM, Malone, LL, Ling, D-L, Kritski, A, Stein, CM, Vashishtha, R, Boulahbal, F, Fang, C-T, Boom, WH, Netto, EM, Lemos, AC, Hesseling, AC, Kay, A, Jones-López, EC, Horsburgh, CR, Lange, C & Andrews, JR 2022, 'Infant BCG vaccination and risk of pulmonary and extrapulmonary tuberculosis throughout the life course: a systematic review and individual participant data meta-analysis', The Lancet. Global health, Jg. 10, Nr. 9, S. e1307-e1316. https://doi.org/10.1016/S2214-109X(22)00283-2
Mercier, T, Desfontaine, V, Cruchon, S, Da Silva Pereira Clara, JA, Briki, M, Mazza-Stalder, J, Kajkus, A, Burger, R, Suttels, V, Buclin, T, Opota, O, Koehler, N, Sanchez Carballo, PM, Lange, C, André, P, Decosterd, LA & Choong, E 2022, 'A battery of tandem mass spectrometry assays with stable isotope-dilution for the quantification of 15 anti-tuberculosis drugs and two metabolites in patients with susceptible-, multidrug-resistant- and extensively drug-resistant tuberculosis', JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES, Jg. 1211, S. 123456. https://doi.org/10.1016/j.jchromb.2022.123456
Rachow, A, Saathoff, E, Mindru, R, Popescu, O, Lugoji, D, Mahler, B, Merker, M, Niemann, S, Olaru, ID, Kastner, S, Hoelscher, M, Lange, C & Ibraim, E 2022, 'Diagnostic performance of the AID line probe assay in the detection of Mycobacterium tuberculosis and drug resistance in Romanian patients with presumed TB', PLOS ONE, Jg. 17, Nr. 8, S. e0271297. https://doi.org/10.1371/journal.pone.0271297
Schaberg, T, Brinkmann, F, Feiterna-Sperling, C, Geerdes-Fenge, H, Hartmann, P, Häcker, B, Hauer, B, Haas, W, Heyckendorf, J, Lange, C, Maurer, FP, Nienhaus, A, Otto-Knapp, R, Priwitzer, M, Richter, E, Salzer, HJF, Schoch, O, Schönfeld, N, Stahlmann, R & Bauer, T 2022, 'Tuberkulose im Erwachsenenalter', Pneumologie (Stuttgart, Germany), Jg. 76, Nr. 11, S. 727-819. https://doi.org/10.1055/a-1934-8303
Sibandze, DB, Kay, A, Dreyer, V, Sikhondze, W, Dlamini, Q, DiNardo, A, Mtetwa, G, Lukhele, B, Vambe, D, Lange, C, Glenn Dlamini, M, Ness, T, Mejia, R, Kalsdorf, B, Heyckendorf, J, Kuhns, M, Maurer, FP, Dlamini, S, Maphalala, G, Niemann, S & Mandalakas, A 2022, 'Rapid molecular diagnostics of tuberculosis resistance by targeted stool sequencing', Genome medicine, Jg. 14, Nr. 1, S. 52. https://doi.org/10.1186/s13073-022-01054-6
Study Group on Mycobacteria of the European Society of Microbiology and Infectious Diseases (ESGMYC), European Society of Mycobacteriology (ESM), European Respiratory Society (ERS) and 2022, 'Rifapentine access in Europe: growing concerns over key tuberculosis treatment component', The European respiratory journal, Jg. 59, Nr. 5, S. 2200388. https://doi.org/10.1183/13993003.00388-2022
TBnet, The ESGMYC, and The French MDR-TB Group 2022, 'Co-administration of treatment for rifampicin-resistant TB and chronic HCV infection: a TBnet and ESGMYC study', Journal of infection, Jg. 84, Nr. 6, S. 834-872. https://doi.org/10.1016/j.jinf.2022.03.004
Tran, F, Harris, DMM, Scharmacher, A, Graßhoff, H, Sterner, K, Schinke, S, Käding, N, Humrich, JY, Cabral-Marques, O, Bernardes, JP, Mishra, N, Bahmer, T, Franzenburg, J, Hoyer, BF, Glück, A, Guggeis, M, Ossysek, A, Küller, A, Frank, D, Lange, C, Rupp, J, Heyckendorf, J, Gaede, KI, Amital, H, Rosenstiel, P, Shoenfeld, Y, Halpert, G, Rosenberg, AZ, Schulze-Forster, K, Heidecke, H, Riemekasten, G & Schreiber, S 2022, 'Increased protease-activated receptor 1 autoantibodies are associated with severe COVID-19', ERJ Open Research, Jg. 8, Nr. 4. https://doi.org/10.1183/23120541.00379-2022
UNITE4TB Consortium 2022, 'Tuberculosis Treatment Monitoring and Outcome Measures: New Interest and New Strategies', Clinical microbiology reviews, Jg. 35, Nr. 3, S. e0022721. https://doi.org/10.1128/cmr.00227-21
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