Individualised diagnosis and treatment of tuberculosis

A doctor looks at X-rays.
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Our general aim is to individualise and thereby optimize management of clinical TB by new methods and strategies.

Background

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis which results in close to 1.5 million deaths yearly. Only about 5% of those infected develop active disease which indicates effective host immune mechanisms which could be useful from a therapeutic perspective. Our results as well as others, show that such immune control includes free radicals such as nitric oxide produced by activated macrophages but also many other factors such as vitamin D-deficiency and chronic helminth infection which may attenuate important host mechanisms such as Th1-type immunity. Once TB has been diagnosed, it is essential that state-of-the art methods to assess host immunity, disease severity, bacterial load, drug exposure and minimal inhibitory concentrations are integrated to individualize and optimize treatment.

Our aim

Our general aim is to individualise and thereby optimize management of clinical TB by new methods and strategies. For this purpose, we have developed methods to evaluate host immunity to TB, drug concentration measurements, disease severity as well as culture- and whole genome sequenced based susceptibility testing in national and international collaborative projects. The research group consists of specialists in tuberculosis from different profession such as biologists, biomedical analysts, clinical microbiologists, infectious disease specialists and nurses.

Methods

In our projects we use several methods such as whole genome sequencing, MIC-determination by several methods including the EUCAST reference method, drug concentration determinations by LC-MS/MS and biological methods. There is close collaboration between the two P3 laboratories for research and clinical diagnosis of mycobacterial infections where virulent mycobacteria are studied using live-cell microscopy, in vitro studies of host immunity using cell-lines. Immunohistochemistry, flow cytometry methods, luminex are used to characterise host immunity responses. There is also expertise on methods used to diagnose active and latent tuberculosis including culture, drug susceptibility testing and interferon-gamma release assays (IGRA). The research group has long time experience in translational projects and clinical interventional studies in local, regional, national and international collaborative studies (Ethiopia, China and Guinea Bissau among others).

Funding

Funding is granted from the Swedish Heart and Lung Foundation (JP, 2021-2023; TS 2018-2021), the Swedish Research Council (TS 2017-2022, TN 2019-2022), the Reserach Council of South-East Sweden (FORSS; JP and TS), Linköping University (LiU/ALF; JP and TS).

Main research questions Show/Hide content

Individualised treatment of TB

– HIGH-SHORT RP – Is it possible to reduce the treatment duration of active TB by increased doses of rifampicin and pyrazimanid?
– Time to positive culture (TTP) as a measurement of treatment response.
– Could Ct-values replace microscopy in active TB?
– Validation of a mycobacterial growth inhibition assay (MGIA) to quantify host immunity to M. tuberculosis
– Development of a whole genome sequenced based method for resistance prediction directly on sputum
– Development of a microtiter based MIC-method for TB.

HIGH-SHORT RP: Main responsible researchers: Katarina Niward PhD, senior consultant and Jakob Paues PhD, senior consultant. David Ekqvist (consultant), Martina Sönnerbrandt (TB-nurse), Daniel Nordqvist (MD), Anna Bornefall (MD), Judith Bruchfeld (Karolinska Institutet, associate professor, senior consultant), Jan-Willem Alffenaar (Sydney University, professor, clinical pharmacology), Ulrika Simonsson (Uppsala Universitet, professor, pharmacometry).

WGS/MIC/MGIA: Michaela Jonsson Nordvall (biologist, PhD student), Blanka Andersson (biologist, Senior research associate), Jenny Welander (PhD, molecular biologist), Volda Gabro (Biomedial analyst, research associate), Claudio Köser (PhD, Cambridge, Uk), Jim Werngren and Mikael Mansjö (biologists, public health institute, Stockholm).

How is multi drug resistance developed from isoniazid monoresistance in M. tuberculosis?

What is the impact of TB drugs on host immunity?


Michaela Jonsson Nordvall (biologist, PhD student), Blanka Andersson (biologist, Senior research associate), Jenny Welander (PhD, molecular biologist), Volda Gabro (Biomedial analyst, research associate). Close collaboration with Maria Lerm (professor).

 

Diagnosis and follow up of latent TB

– How common are results in the borderline range for Quantiferon-plus and what is the clinical relevance of such results?
– What is the reason for borderline range results for Quantiferon-plus?
– How could the cascade of care for migrant screening be improved from positive IGRA results to preventive treatment in the infectious disease clinic?

QFT-plus/borderline range/LTBI follow up: Anna Wikell (MD, Karolinska Hospital). Cecilia Leitet (biomedical analyst, Kalmar County), Jerker Jonsson, (senior consultant, public health institute). Jakob Paues PhD (PI, senior consultant) and Karin Sundelin (senior consultant).

Publications Show/Hide content

Latest publications in LiU DiVA

2022

Karin Welén, Ebba Rosendal, Magnus Gisslén, Annasara Lenman, Eva Freyhult, Osvaldo Fonseca-Rodríguez, Daniel Bremell, Johan Stranne, Åse Östholm Balkhed, Katarina Niward, Johanna Repo, David Robinsson, Anna Jonsson Henningsson, Johan Styrke, Martin Angelin, Elisabeth Lindquist, Annika Allard, Miriam Becker, Stina Rudolfsson, Robert Buckland, Camilla Thellenberg Carlsson, Anders Bjartell, Anna C Nilsson, Clas Ahlm, Anne-Marie Fors Connolly, Anna K Överby, Andreas Josefsson (2022) A Phase 2 Trial of the Effect of Antiandrogen Therapy on COVID-19 Outcome: No Evidence of Benefit, Supported by Epidemiology and In Vitro Data European Urology , Vol. 81 , s. 285-293 Continue to DOI

Collaborative projects on tuberculosis Show/Hide content

How is host immunity against TB affected by chronic helminth infection?

Robert Blomgran, associate professor (PI), Giggil Pushpamithran (PhD student; TS co-supervisor), Olle Stendahl prof emeritus. Ebba Abate PhD, director of EPHI, Ethiopia; Gezahegn Beweket and Amare Kifile (PhD candidates), Gondar University, Ethiopia.

 

Individualized treatment of multidrug resistant TB

Judith Bruchfeld, associate professor (main responsible researcher), Lina Davies Forssman (PhD, consultant; post doc), Johanna Kuhlin (PhD student; TS co-supervisor).

Improved drug susceptibility testing of M. tuberculosis by phenotypic and genotypic methods

Jim Werngren and Michael Mansjö, Public Health Institute of Sweden; Claudio Köser, Cambridge, Uk.

 

The impact of TB-score for improved detection and management of active TB

Christian Wejse, associate professor, senior consultant and Frauke Rudolf (postdoc, consultant, PI); Dept of Infectious Diseases, Århus University Hospital, Denmark. Ebba Abate and Binyam Moges and Hikma Fekadu (Ethiopia); Antonio Mateus Mendes and Armando Sifna. Close collaboration between Bandim Health Project, Guinea Bissau, Gondar University Hospital, Ethiopia and Linköpings Universitet.

The research group Show/Hide content

Organisation Show/Hide content