Mycobacterial infectious diseases Tuberculosis and non-tuberculous mycobacteria (NTM)

Observational studies

Mycobacterial Cohort Study (MyCoS) enables all patients with a mycobacterial infection in Radboudumc to participate in a prospective data registry and biobank study to increase our immunological, genetic and pharmacokinetic understanding.

• Procedure: MyCoS is embedded in standard care and no study-specific visits are required and blood samples are collected during routine care.
• Ethics: CMO NL2021-13231 (niet-WMO plichtig).
• Principal investigators: Arjan van Laarhoven & Wouter Hoefsloot.
• PhD candidates: Lisa Kurver, Arthur Lemson, Cynthia van Arkel and Wouter Peeters.

Tuberculin Skin Test (TST) substudy of MyCoS enrolls all patients with tuberculosis or non-tuberculous mycobacterial lung disease at the start of antituberculosis treatment to determine the relationship between tissue immune responses to a mycobacterial challenge and the clinical course of infection.

• Procedure: patients will receive the standard intradermal tuberculin skin test (normally used to diagnose latent tuberculosis) and a saline injection on the contralateral arm (visit 1). After 48 hours two 3 mm skin biopsies will be taken from the tuberculin and saline skin injection (visit 2) and patients will be followed-up by phone call at day 7.
• Ethics: CMO NL2022-13725, Toetsingonline.
• Principal investigator: Arjan van Laarhoven.
• PhD candidate: Lisa Kurver.

Skin and Soft Tissue (SSTI) substudy of MyCoS enrolls all patients with non-tuberculous (NTM) skin- and soft tissue infections (SSTI) at the start of their antimycobacterial treatment to identify clinical and immunological parameters that predict the course of disease of NTM SSTI. In addition, local and systemic pharmacokinetics are assessed to provide a systemic correlate for local pharmacokinetics.

• Procedure: Skin biopsies are collected at baseline, 2 months later, and in case of lesional worsening in a subset of patients. Blood for systemic pharmacokinetic measurements is collected after 2 months.
• Ethics: CMO NL2023-16732, ToetsingOnline.
• Principal investigator: Arjan van Laarhoven.
• PhD candidate: Wouter Peeters. 

International MAC-PD cohort enrolls MAC-LD patients starting antimycobacterial treatment into a prospective, international data-registry to assess the culture conversion rate after 6 months of antimycobacterial treatment, adverse drug reactions and treatment modifications.

• Procedure: Participant requires follow-up at the Radboudumc during the first 6 months of treatment.
• Ethics: CMO 2022-13742, ClinicalTrials.gov: NCT05906316.
• Principal investigator: Wouter Hoefsloot.
• PhD candidate: Arthur Lemson.

Clinical trials

SALINE enrolls patients with nodular-bronchiectatic M. avium complex lung disease for a randomized, controlled trial to investigate the effect of hypertonic saline inhalation on quality-of-life compared to standard supportive care. Hypertonic saline, shown to be well tolerated and in some patients sufficient to clear their NTM infection, is inhaled twice daily via a nebulizer device.

• Procedure: the trial is largely aligned with our standard-of-care and participation requires two visits to the Radboudumc with a 3-month time interval.
• Ethics: CMO NL79735.091.22, ClinicalTrials.gov: NCT05192057
• Principal investigator: Wouter Hoefsloot.

Mino-PK investigates the pharmacokinetics of minocycline in patients with M. avium complex lung disease with and without concurrent use of rifampicin.

• Procedure: two 5-day courses of minocycline (with and without concurrent use of rifampicin) are prescribed within a 6-week time interval, followed by pharmacokinetic analysis. Participation requires 3 visits to the Radboudumc, but will often partially overlap with a hospital admission to initiate NTM treatment as a whole.
• Ethics: ClinicalTrials.gov: NCT05861258.
• Principal investigator: Wouter Hoefsloot.
• PhD student: Arthur Lemson.

PORT enrolls patients with tuberculosis without major comorbidities  for optimized dose of rifampicin, to investigate the safety and tolerability of this optimized dose.

• Procedure: in this phase 3 trial, patients in the first four weeks of antibiotic treatment are randomised between standard dose and optimized dose of 1800 mg rifampin for six months.
• Ethics: CMO NL2022-13538 ClinicalTrials.gov: NCT06057519  
• Principal investigator(s): Martin Boeree and Cécile Magis-Escurra.
• Study team: Jodie Schildkraut and Iris Spelier.

RIAlta enrolls both young (18-65 years) and elderly (>65 years) patients with severe pulmonary (BMI< 18) and/or extrapulmonary (meningitis) tuberculosis and comorbidities (HIV infection, renal and liver disease, DM, and/or substance abuse) to investigate the safety, tolerability and pharmakinetics and pharmacodynamics of an optimized dose of rifampin combined with a standard first line regimen.

• Procedure: in this open-label phase 2b/c international multi center trial, patients are treated with 35 mg/kg rifampin for two months +HZE (intensive phase of treatment).
• Ethics: CMO NL75346.091.20. ClinicalTrials.gov: NCT04768231.
• Principal investigator: Dr. Adrian Sanchez Montalva, Vall d'Hebron
• Research Institute, Barcelona, Spain.
• Juan Espinosa trial coordinator, VHIR.
• Local PI: Cécile Magis-Escurra.
• Local study team: Juul Altinga, Timo Hoeijmakers, Marlies de Vos and Giovanni Fumagalli.

International consortia and collaborators

International consortia

RCI members also contribute to international consortia.

Clinical trials and pharmacokinetics of tuberculosis drugs

• UNITE4TB consortium (prof. Martin Boeree, prof. Rob Aarnoutse, dr. Lindsey te Brake, prof Reinout van Crevel, dr. Cecil Magis, dr. Jakko van Ingen, dr. Elin Svensson): watch the video of UNITE4TB
• PanACEA consortium (prof. Martin Boeree, prof. Rob Aarnoutse, dr. Lindsey te Brake, dr. Elin Svensson)

Tuberculosis diagnostics 

• EUSAT-RCS consortium - (dr. Cecile Magis-Escurra) 

Prevention of diabetes-associated tuberculosis 

• PROTID consortium - (prof. Reinout van Crevel, dr. Lindsey te Brake)

Tuberculous meningitis

• Phase 3 RCT on high-dose rifampicin (HARVEST consortium on TB meningitis (prof. Rob Aarnoutse, prof. Reinout van Crevel, dr. Lindsey te Brake) 
• Multi-omics analysis on pathogenesis and survival in adults (ULTIMATE; NIH/R01-AI145781-01) and children (INTERCEPT; R01AI165721) prof. Reinout van Crevel, dr. Arjan van Laarhoven, dr Vinod Kumar.

International collaborators

• Universitas Padjadjaran (Bandung, Indonesia) 
• University of Indonesia (Jakarta, Indonesia) 
• KCMC/KCRI (Moshi, Tanzania) 
• NIMR-MMRC (Mbeya, Tanzania) 
• Makarere University (Kampala, Uganda)
• TASK (Cape Town, South Africa)  
• Nat. Instit. of Resp. Diseases and the Environment (Asunción, Paraguay) 
• University College London (London, UK) 
• University of Zaragoza (Zaragoza, Spain) 
• Forschungszentrum Borstel (Borstel, Germany) 
• Centre for Tropical Medicine and Global Health, University of Oxford, UK
• Otago University (Dunedin , New Zealand)

Our education

Where can you learn more about mycobacterial infections at Radboudumc?

• Latent tuberculosis pathophysiology (full day lecture, assignments and presentation by prof. Reinout van Crevel & dr. Arjan van Laarhoven in MED-MIN06, Minor Global Health & Infectious Diseases)
• Tuberculosis treatment and drug resistance & risk factors for non-tuberculous mycobacterial infections (a lecture by dr. Wouter Hoefsloot & dr. Jakko van Ingen in MED-MIN29, ‘Control of Infectious Diseases’)
• Global HIV and tuberculosis co-infection, TB diagnostiscs and treatment latent TB treatment (1,5 day lectures, assignment and interactive clinical puzzle by Prof. Reinout van Crevel & dr. Jakko van Ingen & dr. Mischa Huson & dr. Arjan van Laarhoven  in MED-MINK16, ‘Minor in Global Health’)
• Introduction to Tuberculosis (lecture by dr. Arjan van Laarhoven in MED-VK30-07, keuzemodule ‘Introduction to Global health')
• Central nervous system infections including tuberculous meningitis (lecture by prof. dr. van Crevel in MINK-09, ‘The Fascinating Brain’)

Read more about education at RCI

Radboudumc center of clinical expertise for tuberculosis and non-tuberculous mycobacterial infectious diseases

Radboudumc is an acknowledged center of clinical expertise for tuberculosis and non-tuberculous mycobacterial infectious diseases (NTM). Healthcare professionals, such as pulmonologists, internists and other medical specialists, municipal health physicians in tuberculosis prevention, and general practitioners are able to obtain information and advice here. The center of expertise has a TBC-unit which is technically advanced in hygiene. Here, we treats patients from across the Netherlands and sometimes from well beyond its borders.
 

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