| Background: Acute-on-chronic liver failure(ACLF)is an unique clinical s yndrome with a high mortalit y rate.Effective treatment strategies for AC LF are still limited.As a candidate treatment for AC LF,the role of granuloc yte colon y-stimulating factor(G-CSF)in AC LF remains controversial,and the mechanism b y which G-CS F exerts is obscure.Monoc ytes/macrophages are regarded as the core immune cells involved in the initiation and progression of liver failure.Plasticit y of monoc ytes could be a potential therapeutic target for immune regulation in AC LF.Thus,effects of G-CS F in monoc ytes in patients with AC LF warrant further investigation.In addition,the prognosis of patients with AC LF is extremel y poor.Prompt and effective prediction of prognosis of AC LF is crucial for formulating individualized therap y strategies and improving survival.The main etiology of AC LF in China is hepatitis B virus(HBV)infection.The stud y will focus on the clinical efficac y and related immunological mechanisms of G-CS F in the treatment of HBV-related AC LF(HBV-AC LF),as well as the prognostic evaluation of HBV-AC LF.Objective: 1)To further define the treatment effects of G-CSF and the prognostic factors for HBV-AC LF.2)To explore the potential mechanisms of G-CS F in the treatment of HBV-AC LF.3)To investigate the value of COSSH-AC LF score in prognosis prediction of HBV-AC LF.Methods: 1)(1)A large randomiz ed controlled clinical trial was performed for the treatment of HBV-AC LF using G-CS F.Patients were randomized into the G-CS F group or the control group and followed up for at least 5 years.Short-term and long-term survival rates of the two groups were compared to evaluate the treatment effects of G-CS F.(2)Explore the prognostic factors for 90 ‐ da y mortalit y using multivariate Cox regression anal ysis in HBV-AC LF patients.(3)Multivariate C ox regression anal ysis were performed to explore the relationship among monoc yte counts,G-CS F treatment and the risk of death in patients with HBV-AC LF in a clinical perspective.2)The effect of G-C SF on the phenot ype and function of monoc ytes from patients with HBV-AC LF was evaluated using in vivo and in vitro experiments and flow c ytometry.3)The relationship between COSSH-AC LF score with the prognosis in patients with HBV-AC LF were evaluated with multivariate C ox regression in three models,stratified anal ysis,and survival curve comparison.ROC curves were used to assess prediction performance of COS SH-AC LF score in the prognosis of HBV-AC LF patients.Results: 1)(1)The short-term and long-term survival probabilit y of the G-CS F group were all higher than that of control group(28-da y: 94.3%vs.70.0%,P=0.0024;90-da y: 72.2% vs.53.8%,P= 0.0242;180-da y: 74.2%vs.53.8%,P=0.0152;5-year : 64.0% vs.46.1%,P=0.0251).(2)Participants tolerated G-CS F treatment well,complications in the first months were not significantl y different(P all > 0.05).(3)Age,G-CS F treatment,total bilirubin,and international normalized ratio(INR)were impact factors of 90-da y survival rates in patients with HBV-AC LF.(4)G-CS F treatment had a positive association with the short-term risk of survival in HBV-AC LF patients regardless of the gender and complications subgroup.(5)In the G-CS F-treated group,monoc yte count on da ys 0 and 7 were independentl y associated with a evaluated mortalit y risk in HBV-AC LF patients in the full y adjusted model(Model 3)[ at da y 0: hazard ratio(HR)95% confidence interval(C I): 14.24(3.35,60.52),P = 0.0003;at da y 7: HR(95%C I): 1.20(0.54,2.70),P=0.6543].A significant decrease in HR was observed in G-CS F group.2)(1)After treatment with G-CSF in HBV-ACLF patients,the expression of M1-like markers(HLA-DR and C D86)in monoc ytes decreased(HLA-DR:P = 0.0148;CD86: P = 0.0764).While the expression of Mer TK(M2-like marker)increased(P = 0.0002).(2)The secretion of TNF-α,IL-6,and IL-10 from monoc ytes decreased without lipopol ysaccharide(LP S)stimulation(TNF-α: P < 0.0001;IL-6: P= 0.0025;IL-10: P = 0.0004),or with LPS stimulation(TNF-α: P = 0.0439;P = 0.0611;IL-10: P = 0.0099).(3)Similar to effects observed in vivo,the expression of M1-like markers(H LA-DR and CD86)in monoc ytes decreased(P all < 0.01).While the expression of M2-like marker(Mer TK and CD163)increased(P all < 0.01).G-CS F promoted a decrease of TNF-α、 IL-6 secretion and an increase of IL-10 secretion in monoc ytes with LP S stimulation,although differences not statisticall y significant(P all > 0.05).(4)P hagoc ytosis of monoc ytes showed an upward trend,whereas oxidative burst showed a downward trend after G-CS F administration;however,the discrepancies were not statistically significant(P all > 0.05).3)(1)Positive correlation were observed in COSSH-ACLF score and other classical prognostic scores[CTP score:(r=0.4887),ME LD score:(r=0.7561),ME LD-Na score:(r=0.636),C LIF-S OFA score:(r=0.8247)and C LIF-C OF score:(r=0.7501),respectively;all P< 0.0001] on Spearman’s correlation anal ysis.(2)In the full y adjusted model,as a continuous variable,COSSH-AC LF score had a positive association with the short-term risk of death in HBV-AC LF patients[at 28 da ys: HR(95% C I): 1.37(1.22,1.53),P<0.001;at 90 da ys: HR(95% C I): 1.43(1.29,1.58),P< 0.001].Similar trend were detected in other models or when C OSSH-AC LF score as a categorical variable(all P < 0.05).(3)P atients were divided into several sub-groups according to sex,age,t ype of AC LF,and presence of various complications.The results showed that the 28-da y and 90-da y mortalit y risk of patients with HBV-AC LF in each sub-group increased with ever y 1-point increase in the COSSH-AC LF score,and the differences were statisticall y significant(all P <0.05)except for in female.It means the positive correlation between COSSH-AC LF score and the short-term mortalit y risk was stable in nearl y all kinds of patients with HBV-AC LF.(4)The AUR OCs of C OSSH-AC LF score for 28-da y and 90-day prognoses in patients with HBV-AC LF were 0.807 and0.792,respectivel y,indicating an ex cellent predictive accurac y.The predictive value of C OSSH-AC LF score was better than that of CTP score(at28da ys: P= 0.056;at 90 da ys: P= 0.046)and MELD score,MELD-Na score,C LIF-SOFA score and C LIF-C OF score(P all < 0.001 at 28 da ys and 90 da ys).Conclusions: 1)G-CSF therap y could improve short-term and long-term survival rates in HBV-AC LF patients.2)G-CS F can promote the anti-inflammator y/pro-restorative phenot ype(M2-like)transition of monoc ytes,which may contribute to the recover y of AC LF.3)COSSH-AC LF score,with a superior predictive accurac y compared with other classical scores,can strongl y predict short-term prognosis in patients with HBV-AC LF. |
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