title: Autologous mesenchymal stromal cell infusion as adjunct treatment in patients with multidrug and extensively drug-resistant tuberculosis: an open-label phase 1 safety trial.
abstract: BACKGROUND
  Novel treatment options are urgently needed for multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis, which are associated with immune dysfunction and poor treatment outcomes. Mesenchymal stromal cells (MSCs) are immunomodulatory and adjunct autologous treatment with bone marrow-derived MSCs might improve clinical outcome by transforming chronic inflammation into productive immune responses. Our aim was to assess the safety of infusion of autologous MSCs as an adjunct treatment in patients with tuberculosis.
  
  
  METHODS
  30 patients with microbiologically confirmed MDR or XDR tuberculosis were treated with single-dose autologous bone marrow-derived MSCs (aimed for 1×10(6) cells per kg), within 4 weeks of the start of antituberculosis-drug treatment in a specialist centre in Minsk, Belarus. Inclusion patients were those with pulmonary tuberculosis confirmed by sputum smear microscopy, culture, or both; MDR or XDR tuberculosis confirmed by drug-susceptibility testing to first-line and second-line drugs; age older than 21 years to 65 years or younger; and absence of lesion compatible with a malignant process or ongoing tuberculosis in organs other than the lungs and pleura. In addition to the inclusion criteria, patients were excluded if they were pregnant, coinfected with HIV, or infected with hepatitis B, C, or both. The primary endpoint was safety measured by MSC-infusion related events; any tuberculosis-related event within the 6 month observation period that related to a worsening of the underlying infectious disease, measured by conversion of Mycobacterium tuberculosis culture or microscopic examination; or any adverse event defined clinically or by changes in blood haematology and biochemistry variables, measured monthly for 6 months after MSC infusion per protocol. This study is registered with the German Clinical Trials Registry, number DRKS00000763.
  
  
  RESULTS
  The most common (grade 1 or 2) adverse events were high cholesterol levels (14 of 30 patients), nausea (11 of 30 patients), and lymphopenia or diarrhoea (ten of 30 patients). There were no serious adverse events reported. We recorded two grade 3 events that were transitory-ie, increased plasma potassium ion concentrations in one patient and a transitory grade 3 γ-glutamyltransferase elevation in another patient.
  
  
  CONCLUSIONS
  MSCs as an adjunct therapy are safe and can now be explored further for the treatment of patients with MDR or XDR tuberculosis in combination with standard drug regimens. Adjunct treatment with MSCs needs to be evaluated in controlled phase 2 trials to assess effects on immune responses and clinical and microbiological outcomes.
authors: Republican Research and Practical Centre for Pulmonology and TB, Minsk, Belarus; Department of Intensive Care, Belarussian State Medical University, Minsk, Belarus.
authors: Aliaksandr
authors: A
authors: Skrahin
authors: Swedish Institute for Infectious Disease Control (SMI), Solna, Sweden.
authors: Raija K
authors: RK
authors: Ahmed
authors: Section of Respiratory Diseases, Department of Internal Medicine, University of Perugia, Perugia, Italy.
authors: Giovanni
authors: G
authors: Ferrara
authors: Department of Microbiology, Tumour and Cell Biology, MTC, Karolinska Institutet, Stockholm, Sweden.
authors: Lalit
authors: L
authors: Rane
authors: Therapeutic Immunology (TIM), Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
authors: Thomas
authors: T
authors: Poiret
authors: Laboratory of Cellular Biotechnology and Cytotherapy, Belarussian Research Centre for Paediatric Oncology, Haematology and Immunology, Minsk, Belarus.
authors: Yanina
authors: Y
authors: Isaikina
authors: Republican Research and Practical Centre for Pulmonology and TB, Minsk, Belarus.
authors: Alena
authors: A
authors: Skrahina
authors: Division of Infection and Immunity, Centre for Clinical Microbiology, University College London, London, UK; National Institute of Health Research-Biomedical Research Centre, University College Hospitals NHS Foundation Trust, London, UK.
authors: Alimuddin
authors: A
authors: Zumla
authors: Department of Microbiology, Tumour and Cell Biology, MTC, Karolinska Institutet, Stockholm, Sweden; Therapeutic Immunology (TIM), Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden; Centre for Allogeneic Stem Cell Transplantation, CAST, Karolinska University Hospital, Stockholm, Sweden. Electronic address: markus.maeurer@ki.se.
authors: Markus J
authors: MJ
authors: Maeurer
mesh_terms: D000328:Adult; D000368:Aged; D000995:Antitubercular Agents / Q000627:therapeutic use*; D054908:Extensively Drug-Resistant Tuberculosis / Q000601:surgery; D005260:Female; D006801:Humans; D007260:Infusion Pumps; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000009:adverse effects; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D002094:Republic of Belarus; D014182:Transplantation, Autologous; D016896:Treatment Outcome; D018088:Tuberculosis, Multidrug-Resistant / Q000175:diagnosis / Q000601:surgery*; D014397:Tuberculosis, Pulmonary / Q000175:diagnosis / Q000601:surgery* / Q000628:therapy*
chemical_list: D000995:Antitubercular Agents