Harald Hoffmann

Synlab (Germany)

Author Statistics

Papers

Citation

H-Index

i-10 index

Research Trends

Author Order

Document Type

Co-Authors

Sabine Hofmann-Thiel

Synlab Czech (Czechia)

Stefan Niemann

Research Center Borstel - Leibniz Lung Center

Matthias Merker

Research Center Borstel - Leibniz Lung Center

Thomas A. Kohl

Research Center Borstel - Leibniz Lung Center

Daniela María Cirillo

Vita-Salute San Raffaele University

Christian Utpatel

Research Center Borstel - Leibniz Lung Center

Christoph Lange

Research Center Borstel - Leibniz Lung Center

Emanuele Borroni

Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele

Uladzimir Antonenka

University of Edinburgh

Sara Plesnik

University of Oxford

Cooperative Institutions

Ludwig-Maximilians-Universität München

Research Center Borstel - Leibniz Lung Center

University of Oxford

German Center for Infection Research

Asklepios Fachkliniken München-Gauting

Heidelberg University

German Center for Lung Research

London School of Hygiene & Tropical Medicine

University College London

University of Cape Town

Author Statistics

Papers

Citation

H-Index

i-10 index

Research Field

DeepAMR for predicting co-occurrent resistance of Mycobacterium tuberculosis

Bioinformatics (2019)

Yang Yang A Sarah Walker A Sarah Walker Daniel J. Wilson Tim Peto

Resistance co-occurrence within first-line anti-tuberculosis (TB) drugs is a common phenomenon. Existing methods based on genetic data analysis of Mycobacterium tuberculosis (MTB) have been able to predict resistance of MTB to individual drugs, but have not considered the resistance co-occurrence and cannot capture latent structure of genomic data that corresponds to lineages.We used a large cohort of TB patients from 16 countries across six continents where whole-genome sequences for each isolate and associated phenotype to anti-TB drugs were obtained using drug susceptibility testing recommended by the World Health Organization. We then proposed an end-to-end multi-task model with deep denoising auto-encoder (DeepAMR) for multiple drug classification and developed DeepAMR_cluster, a clustering variant based on DeepAMR, for learning clusters in latent space of the data. The results showed that DeepAMR outperformed baseline model and four machine learning models with mean AUROC from 94.4% to 98.7% for predicting resistance to four first-line drugs [i.e. isoniazid (INH), ethambutol (EMB), rifampicin (RIF), pyrazinamide (PZA)], multi-drug resistant TB (MDR-TB) and pan-susceptible TB (PANS-TB: MTB that is susceptible to all four first-line anti-TB drugs). In the case of INH, EMB, PZA and MDR-TB, DeepAMR achieved its best mean sensitivity of 94.3%, 91.5%, 87.3% and 96.3%, respectively. While in the case of RIF and PANS-TB, it generated 94.2% and 92.2% sensitivity, which were lower than baseline model by 0.7% and 1.9%, respectively. t-SNE visualization shows that DeepAMR_cluster captures lineage-related clusters in the latent space.The details of source code are provided at http://www.robots.ox.ac.uk/∼davidc/code.php.Supplementary data are available at Bioinformatics online.

Pyrazinamide

Interpretability

10.1093/bioinformatics/btz067

Cite

Citations (50)

Influence of lung CT changes in chronic obstructive pulmonary disease (COPD) on the human lung microbiome

PLoS ONE (2017)

Marion Engel David Endesfelder Brigitte Schloter-Hai Susanne Kublik Michael S. Granitsiotis

Background Changes in microbial community composition in the lung of patients suffering from moderate to severe COPD have been well documented. However, knowledge about specific microbiome structures in the human lung associated with CT defined abnormalities is limited. Methods Bacterial community composition derived from brush samples from lungs of 16 patients suffering from different CT defined subtypes of COPD and 9 healthy subjects was analyzed using a cultivation independent barcoding approach applying 454-pyrosequencing of 16S rRNA gene fragment amplicons. Results We could show that bacterial community composition in patients with changes in CT (either airway or emphysema type changes, designated as severe subtypes) was different from community composition in lungs of patients without visible changes in CT as well as from healthy subjects (designated as mild COPD subtype and control group) (PC1, Padj = 0.002). Higher abundance of Prevotella in samples from patients with mild COPD subtype and from controls and of Streptococcus in the severe subtype cases mainly contributed to the separation of bacterial communities of subjects. No significant effects of treatment with inhaled glucocorticoids on bacterial community composition were detected within COPD cases with and without abnormalities in CT in PCoA. Co-occurrence analysis suggests the presence of networks of co-occurring bacteria. Four communities of positively correlated bacteria were revealed. The microbial communities can clearly be distinguished by their associations with the CT defined disease phenotype. Conclusion Our findings indicate that CT detectable structural changes in the lung of COPD patients, which we termed severe subtypes, are associated with alterations in bacterial communities, which may induce further changes in the interaction between microbes and host cells. This might result in a changed interplay with the host immune system.

Pyrosequencing

10.1371/journal.pone.0180859

Cite

Citations (36)

Stellenwert von Histologie, PCR und Kultur aus der EBUS-TBNA bei Tuberkulose der mediastinalen Lymphknoten

Pneumologie (2019)

Korkut Avsar Harald Hoffmann V Kauer Jürgen Behr Sabine Hofmann-Thiel

Hintergrund Der Befall mediastinaler Lymphknoten ist häufig, wird aber nicht immer systematisch mikrobiologisch gesichert. Wir untersuchten welchen Beitrag die EBUS-TBNA Technik leisten kann.

10.1055/s-0039-1678176

Cite

Citations (0)

Erworbene Resistenz gegenüber Chinolonen unter Behandlung einer MDR-Tuberkulose

Pneumologie (2015)

Florian Fliedner Kadir Avşar Harald Hoffmann Steffen Thiel J Behr

Wir präsentieren einen 49-jährigen türkischen Patienten mit multiresistenter (MDR), kavernöser Silikotuberkulose. Als Begleiterkrankung war ein primärer Hypoparathyreoidismus bekannt, gut substituiert mit oraler Einnahme von Kalzium und Magnesium. Der Mykobakterium tuberkulosis (MTB) Erreger zeigte sich phänotypisch resistent gegenüber Isoniazid, Rifampicin, Ethambutol, Protionamid und Streptomycin. Der Patient wurde direkt überwacht behandelt mit Moxifloxacin, Amikacin, Pyrazinamid, Terizidon und Linezolid. Zu Beginn konnte die Empfindlichkeit des Erregers gegenüber Chinolonen sowohl durch einen genetischen gyrA Hybridisierungs-Assay, als auch durch eine phänotypische Resistenztestung bestätigt werden. Aufgrund anhaltend positiver Kulturen acht Wochen nach antituberkulöser Behandlung wurde erneut eine phänotypische Resistenztestung angefordert. Hierbei zeigte sich eine Resistenz gegenüber Ofloxacin und Moxifloxacin, sowohl in der genetischen, als auch phänotypischen Resistenztestung. Dabei ergab sich eine Übereinstimmung des MTB Stamms im IS6110 fingerprint. Folglich ist von einer erworbenen Resistenz gegenüber Chinolonen trotz direkt überwachter Behandlung auszugehen. Im Verlauf wurde Moxifloxacin im Rahmen eines "compassionate use" Programms durch Bedaquilin ersetzt. Dieses Regime wurde von dem Patienten gut toleriert und der Allgemeinzustand stabilisierte sich rasch. Innerhalb von vier Wochen ergab sich eine kulturelle Sputumkonversion.

10.1055/s-0035-1544803

Cite

Citations (0)

Genetic diversity and distribution dynamics of multidrug-resistant Mycobacterium tuberculosis isolates in Nepal

Scientific Reports (2018)

Bhagwan Maharjan Chie Nakajima Norikazu Isoda Jeewan Thapa Ajay Poudel

Abstract Multidrug-resistant tuberculosis (MDR-TB) is an emerging public health problem in Nepal. Despite the implementation of a successful TB control program in Nepal, notifications of MDR-TB are increasing, yet the reasons are unknown. The objective of this study was to understand the genetic diversity and epidemiological characteristics of MDR- Mycobacterium tuberculosis (MTB) isolates in Nepal. We isolated and genotyped 498 MDR-MTB isolates collected from April 2009 to March 2013 and analyzed the patients’ background information. Our results showed that the lineage 2 (Beijing family) was the most predominant lineage (n = 241; 48.4%), followed by lineage 3 (n = 153, 30.7%). Lineage 4 was the third most prevalent (n = 73, 14.5%) followed by lineage 1 (n = 32, 6.4%). The lineages were significantly associated with geographic region, ethnic group, age and sex of patients. The Beijing genotype was found to have an important role in transmitting MDR-TB in Nepal and was significantly associated with the eastern region, mongoloid ethnic group and younger age group. We conclude that early diagnosis and treatment including molecular-epidemiological surveillance of MDR-TB cases will help to control transmission of MDR-TB in Nepal.

Lineage (genetic)

Molecular Epidemiology

Mongoloid

10.1038/s41598-018-34306-w

Cite

Citations (20)

QuantiFERON-TB Gold Plus Testing for the Detection of LTBI in Health Care Workers in the Kyrgyz Republic

Research Square (Research Square) (2021)

Caroline S. Corbett Gulmira Kalmambetova Nagira Umetalieva Sevim Ahmedov Uladzimir Antonenka

Abstract Background: Health care workers (HCW) are at increased risk of TB infection due to their close contact with infected patients with active TB. The objectives of the study were (1) to assess the prevalence of LTBI among HCW in major TB hospitals of the Northern Kyrgyz Republic, and (2) to determine the association of LTBI with certain job positions, hospital units, or hospitals. Methods: HCWs from 4 TB hospitals in the Northern Kyrgyz Republic were tested with the interferon-gamma release assay (IGRA) Quantiferon-TB Gold plus (QFT) for the detection of an immune response to TB as marker of TB infection. Age was controlled for as a confounder. Univariate and multivariable analysis were performed using logistic regression to assess the association of the risk factors (age, job position, and hospital unit) with having a QTF positive result. Firth’s penalized-likelihood estimates were used for determining the odd’s of QFT positivity to account for the small-sample size. Pairwise comparisons using the Bonferroni correction (conservative) and comparisons without adjusting for multiple comparisons (unadjusted) were used to identify the categories where differences occurred. Results: QFT yielded valid results for 404 HCW, with 189 (47%) that had a positive test. In the National Tuberculosis Center, there was an increased odds to have a positive QFT test for the position of physician (OR=8.7, 95%, CI=1.2-60.5, p=0.03) and laboratory staff (OR=19.8, 95% CI=2.9-135.4, p<0.01) when administration staff was used as the baseline and controlling for age. No job position was found to have a significantly higher odds of positivity following a pairwise analysis controlling for multiple comparisons. Fifteen of the 49 HCW with follow-up tests converted from negative to positive at follow-up testing. Conclusions: This is the first report on prevalence and risk factors of LTBI for HCW in the Kyrgyz republic, and results indicate an increased risk for LTBI among physicians and laboratory personnel.

10.21203/rs.3.rs-366339/v1

Cite

Citations (0)

Consensus Not Yet Reached on Key Drugs for Extensively Drug‐Resistant Tuberculosis Treatment

Clinical Infectious Diseases (2009)

Giovanni Battista Migliori Giovanni Sotgiu M. D’Arcy Richardson Rosella Centis Gunar Guenther

To the Editor — Multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant TB (XDR-TB) are increasing in frequency globally and are difficult to treat. Although treatment successes have been reported, there are no definitive clinical studies available that show which classes or combinations of available drugs are most effective in yielding positive treatment outcomes. In the 1 March 2009 issue of Clinical Infectious Diseases , Chan et al . reported that MDR-TB due to strains resistant to fluoroquinolones (FQNs) and streptomycin (STM) but susceptible to second-line injectables ( n =12 ) has a significantly better prognosis than does XDR-TB ( n =10).

Extensively drug-resistant tuberculosis

10.1086/600060

Cite

Citations (5)

Delamanid and Bedaquiline Resistance in Mycobacterium tuberculosis Ancestral Beijing Genotype Causing Extensively Drug-Resistant Tuberculosis in a Tibetan Refugee

American Journal of Respiratory and Critical Care Medicine (2016)

Harald Hoffmann Thomas A. Kohl Sabine Hofmann-Thiel Matthias Merker Patrick Beckert

Bedaquiline

Drug resistant tuberculosis

Extensively drug-resistant tuberculosis

10.1164/rccm.201502-0372le

Cite

Citations (126)

Mechanisms of heteroresistance to isoniazid and rifampin ofMycobacterium tuberculosisin Tashkent, Uzbekistan

European Respiratory Journal (2008)

Sabine Hofmann-Thiel Jakko van Ingen K. Feldmann Laziz Turaev G Uzakova

Heteroresistance of Mycobacterium tuberculosis (MTB) is defined as the coexistence of susceptible and resistant organisms to anti-tuberculosis (TB) drugs in the same patient. Heteroresistance of MTB is considered a preliminary stage to full resistance. To date, no mechanism causing heteroresistance of MTB has been proven. Clinical specimens and cultures from 35 TB patients from Tashkent, Uzbekistan, were analysed using the Genotype MTBDR assay (Hain Lifescience, Nehren, Germany), which is designed to detect genetic mutations associated with resistance to rifampin and isoniazid. Cases of heteroresistance were further subjected to genotyping using mycobacterial interspersed repetitive unit-variable-number tandem repeat typing, spoligotyping and IS 6110 fingerprinting. Heteroresistance to rifampin and/or isoniazid was found in seven cases (20%). In five of them, heteroresistance was caused by two different strains and in two by a single strain of the Beijing genotype. The latter cases had a history of relapse of their TB. For the first time, two different mechanisms of heteroresistance in tuberculosis have been proven using a stepwise molecular-biological approach: 1) superinfection with two different strains, which is of interest for clinical infection control practitioners; and 2) splitting of a single strain into susceptible and resistant organisms. The latter mechanism is most likely to be related to poor treatment quality and could serve as a quality marker for tuberculosis therapy programmes in the future.

10.1183/09031936.00089808

Cite

Citations (121)

iLED – ein Leuchtdiodenmikroskop revolutioniert die Tuberkulose Diagnostik in Hochprävalenzländern

Pneumologie (2010)

Harald Hoffmann Pamela Nabeta Dietzel Ha Joy Sarojini Fiorella Krapp

10.1055/s-0030-1251375

Cite

Citations (0)