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G-CSF in acute-on-chronic liver failure – Art of ‘patient selection’ is paramount!

  • Ankur Jindal
    Correspondence
    Corresponding author. Address: Department of Hepatology, Institute of Liver and Biliary Sciences D – 1, Vasant Kunj, New Delhi 110070, India; Tel.: +91 9582670984.
    Affiliations
    Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi 110070, India
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  • Shiv K. Sarin
    Affiliations
    Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi 110070, India
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Published:August 31, 2021DOI:https://doi.org/10.1016/j.jhep.2021.08.022

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      To the Editor:
      The study by Engelmann et al. failed to show a significant beneficial effect of granulocyte-colony stimulating factor (G-CSF) in treating patients with acute-on-chronic liver failure (ACLF).
      • Engelmann C.
      • Herber A.
      • Franke A.
      • Bruns T.
      • Schiefke I.
      • Zipprich A.
      • et al.
      Granulocyte-Colony Stimulating Factor (G-CSF) to treat acute-on-chronic liver failure, a multicenter randomized trial (GRAFT study).
      The use of G-CSF neither improved 3- and 12-month transplant-free survival nor led to an improvement in model for end-stage liver disease (MELD) score or new infections. This was independent of the nature of the precipitating event, severity of ACLF or type of organ failure. We believe the negative results in this study are mainly due to limitations in patient selection, as these cohorts did not match with the pathophysiological basis of the mechanisms of action of the growth factor used, G-CSF. Several important issues need further consideration. First, previous studies have shown that G-CSF reduces MELD scores and infections and improves survival in carefully selected patients with ACLF resulting from severe alcoholic hepatitis and reactivation of hepatitis B.
      • Garg V.
      • Garg H.
      • Khan A.
      • Trehanpati N.
      • Kumar A.
      • Sharma B.C.
      • et al.
      Granulocyte colony-stimulating factor mobilizes CD34(+) cells and improves survival of patients with acute-on-chronic liver failure.
      ,
      • Duan X.Z.
      • Liu F.F.
      • Tong J.J.
      • Yang H.Z.
      • Chen J.
      • Liu X.Y.
      • et al.
      Granulocyte-colony stimulating factor therapy improves survival in patients with hepatitis B virus- associated acute-on-chronic liver failure.
      In both these disease states, intense inflammation and early immunoparesis have been documented.
      • Khanam A.
      • Trehanpati N.
      • Garg V.
      • Kumar C.
      • Garg H.
      • Sharma B.C.
      • et al.
      Altered frequencies of dendritic cells and IFN-γ-secreting T cells with granulocyte colony-stimulating factor (G-CSF) therapy in acute-on-chronic liver failure.
      The use of G-CSF ameliorated intrahepatic injury via recruitment of plasmacytoid dendritic cells and reduced interferon gamma production. In addition, it helped recruit neutrophils and monocytes from the bone marrow.
      • Kedarisetty C.K.
      • Kumar A.
      • Sarin S.K.
      Insights into the role of granulocyte colony-stimulating factor in severe alcoholic hepatitis.
      Additionally, G-CSF mobilized bone marrow and hepatic progenitor cells.
      • Arroyo V.
      • Moreau R.
      • Kamath P.S.
      • Jalan R.
      • Ginès P.
      • Nevens F.
      • et al.
      Acute-on-chronic liver failure in cirrhosis.
      In these studies, G-CSF was used in early stages of ACLF before the onset of sepsis and extrahepatic organ failures. The role of G-CSF in augmenting liver regeneration in sick ACLF patients with sepsis and organ failure is debatable. In the Engelmann study, almost 40% of patients had bacterial infection at enrollment (was reported to be 54% in the data presented at AASLD, 2019). Moreover, almost two-thirds received G-CSF when they already had hepatorenal syndrome and/or cardio-respiratory failure. This is indeed too late for any growth factor to reverse the clinical state. Further, G-CSF is helpful to prevent the development of sepsis but not to treat sepsis. One should select patients without organ failures and sepsis to test the potential benefits of G-CSF. Second, the authors tried, but failed to analyze their data based on ACLF as defined by Asian Pacific Association for the Study of Liver (APASL) criteria. APASL ACLF criteria do not include patients with extrahepatic insults. However, 50% of patients shown as belonging to the APASL ACLF cohort in the GRAFT study had bacterial infection or variceal bleed as a precipitating factor. Third, exogenous GCSF therapy enhances the production, mobilization, and function of neutrophils that will increase the host response to infection in ACLF.
      • Spiekermann K.
      • Roesler J.
      • Emmendoerffer A.
      • Elsner J.
      • Welte K.
      Functional features of neutrophils induced by G-CSF and GM-CSF treatment: differential effects and clinical implications.
      It was difficult to explain the higher incidence of spontaneous bacterial peritonitis (17 vs. 8) and lower incidence of pneumonia (9 vs. 15) in the G-CSF group compared to the control group. Fourth, the role of G-CSF in decompensated cirrhosis is limited due to the exhausted state of the bone-marrow niche.
      • Bihari C.
      • Anand L.
      • Rooge S.
      • Kumar D.
      • Saxena P.
      • Shubham S.
      • et al.
      Bone marrow stem cells and their niche components are adversely affected in advanced cirrhosis of the liver.
      In late stages of ACLF, the potential regenerative capacity of bone marrow is limited and must be evaluated before using G-CSF. A bone-marrow aspiration or biopsy should be done before starting G-CSF therapy. It is also not clear why the study was aborted when the two arms were showing comparable results. This is all the more important, as only 33% of the patients received the full 12 doses as per protocol. Importantly, in the presence of severe systemic inflammatory response syndrome and organ failures in ACLF, it is also important to rule out secondary hemophagocytic lymphohistiocytosis as in these situations, administration of G-CSF would be detrimental.
      • Kedarisetty C.K.
      • Kumar A.
      • Sarin S.K.
      Insights into the role of granulocyte colony-stimulating factor in severe alcoholic hepatitis.
      ,
      • Wang S.
      • Degar B.A.
      • Zieske A.
      • Shafi N.Q.
      • Rose M.G.
      Hemophagocytosis exacerbated by G-CSF/GM-CSF treatment in a patient with myelodysplasia.

      Financial support

      The authors received no financial support to produce this manuscript.

      Authors’ contributions

      A.J - Manuscript prepration ; S.k.S- Manuscript revision.

      Conflict of interest

      The authors declare no conflicts of interest that pertain to this work.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Supplementary data

      The following are the supplementary data to this article:

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