Clinical effectiveness of cell therapies in patients with chronic liver disease and acute-on-chronic liver failure: a systematic review protocol.
BACKGROUND
Chronic liver disease (CLD) is a major health burden worldwide. Liver cirrhosis, a form of CLD is the fifth most common cause of death in the UK. Acute-on-chronic liver failure (ACLF) is the result of an acute insult superimposed on patients with liver cirrhosis as a result of precipitating events such as infection or bleeding. ACLF has a high associated mortality as a result of multi-organ failure. The only effective treatment for CLD is liver transplantation, but the treatment is limited by shortage of donor organs. As a result, alternative treatments such as cell therapies have been studied in patients with liver diseases. This study will systematically review the evidence on clinical effectiveness of cell therapies in patients.


METHODS
All types of study design that investigate the effectiveness of cell therapies (haematopoietic, mesenchymal and unsorted cell types) of autologous or allogeneic origin and/or the use of granulocyte colony-stimulating factor in patients with CLD including ACLF will be included (except case reports). Both autologous and allogenic cell types will be included. The primary outcomes of interest are survival, model for end-stage liver disease score, quality of life and adverse events. Secondary outcomes include liver function tests, Child-Pugh score and events of liver decompensation. A literature search will be conducted in the following databases: MEDLINE, MEDLINE in Process, EMBASE and Cochrane Library (CENTRAL, CDSR, DARE, HTA databases). Trial registers will be searched for ongoing trials, as will conference proceedings. Reference lists of relevant articles and systematic reviews will be screened. Randomised controlled trial (RCT) evidence is likely to be scant; therefore, controlled trials and concurrently controlled observational studies will be primarily analysed and uncontrolled observational studies will be analysed where primary outcomes are not reported in the control studies or where uncontrolled studies have longer follow-up. Initial screening of studies will be carried by one reviewer with a proportion checked by another reviewer. Full-text selection will be performed by two reviewers independently against the pre-defined selection criteria. The data collection and the risk of bias assessment will be completed by one reviewer and counter checked by another reviewer for all selected studies. Where appropriate, data will be meta-analysed for each study design, therapy and outcome. Data specifically on ACLF will be treated as a subgroup.


CONCLUSIONS
This systematic review will identify the available evidence on the effectiveness of cell therapies in patients with CLD and in ACLF subgroup. The findings will aid decision-making by clinicians and health service leaders.


BACKGROUND
PROSPERO CRD42016016104.
National Institute for Health Research (NIHR) Birmingham Liver Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.
Nwe Ni
NN
Than
Birmingham Clinical Trials Unit, Institute of Applied Health Research, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.
Claire L
CL
Tomlinson
National Institute for Health Research (NIHR) Birmingham Liver Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.
Debashis
D
Haldar
National Institute for Health Research (NIHR) Birmingham Liver Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.
Andrew L
AL
King
Institute of Applied Health Research, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.
David
D
Moore
National Institute for Health Research (NIHR) Birmingham Liver Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK. p.n.newsome@bham.ac.uk.
Philip N
PN
Newsome
D065290:Acute-On-Chronic Liver Failure / Q000628:therapy*; D064987:Cell- and Tissue-Based Therapy / Q000379:methods; D002908:Chronic Disease; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D008103:Liver Cirrhosis / Q000628:therapy*; D008107:Liver Diseases / Q000628:therapy; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D000078202:Systematic Reviews as Topic; D014182:Transplantation, Autologous; D014184:Transplantation, Homologous; D016896:Treatment Outcome
Acute on chronic liver failure; Cell therapy; Chronic liver disease; Granulocyte colony-stimulating factor; Model for end-stage liver disease; Quality of life; Survival