| Aims: To investigate the prevalence of bacterial infection in patients with HBV-related decompensated cirrhosis and explore its clinical,immunological characteristics with comparisons to HBV flare for their effects on precipitating organ failure and acute-onchronic liver failure(ACLF)and finally,clinical outcome.To further characterize microbiological pattern and to determine the prevalence of multidrug-resistant bacteria and the impact of empirical antibiotics therapy on clinical outcome.Methods: Retrospective cohort study were carried out in two tertiary medical academic hospital in Shanghai with inclusion of all the patients with HBV-related decompensated cirrhosis between 2005 and 2010 to investigated the prevalence and characteristics of bacterial infection and its impact on clinical outcome followed by a prospective validation with patients enrolled between 2016 and 2018.Twenty-one cytokines were measured through electrochemiluminescence and enzyme-linked immunosorbent assay to characterize the immunological features of patients with bacterial infection and/or HBV flare.Survival analyses in this study were performed with competing risk analysis considering liver transplantation as a competing event for death.Results: The overall prevalence of bacterial infection was 28.1% in 1281 patients with HBV-related decompensated cirrhosis in the retrospective cohort.Health-care system and hospital were the main source of infection accounting for 35% and 45.5% of all episodes of infection,respective.The most common type of infection was pneumonia(40.3%),followed by spontaneous bacterial peritonitis(20.4%),urinary tract infection(9.4%),bacteremia(5.9%),skin/soft tissue infection(2.8%)and other types or infection without identifiable site(21.2%).The presence of bacterial infection increased the rate of liver,coagulation,kidney,brain,circulation,and respiration failure by 2.4-,2.4-,3.8-,3.7-,4.2-and 4.2-fold,respectively.The overall prevalence of ACLF was significantly higher in patients with bacterial infection than those without(60% vs 21.7%,p <0.001).Accordingly,patients with bacterial infection had significantly lower overall in-hospital survival,90-day transplantation-free survival and 5-year post-discharge transplantation-free survival(Gray test,p <0.001).The prevalence of bacterial infection,source of acquisition and type of infection were similar in the prospective cohort and the negative impact of infection on clinical outcome was validated.The prevalence of multi-drug resistance(MDR)in 155 episodes of infection occurred in the prospective cohort was 38.8%,including 14.5% of extended-spectrum beta-lactamases positive enterobacteriaceae,7.2% of carbapenemresistant bacteria,1.4% of methicillin-resistant staphylococcus aureus and 5.8% of enterococcus(all of them were susceptible to vancomycin)and 1.4% of stenotrophomonas maltophilia.Patients with MDR infection had significantly lower clinical efficacy than those without(26.3% vs 70.4%,p <0.01).Accordingly,the incidence of ACLF was significantly higher(60% vs 12.5%,p <0.01)and 28-(57.9% vs 92.6%,p <0.05)or 90-day transplantfree survival(33.3% vs 84.6%,p <0.01)was significantly lower in patients with MDR infection than those without.There is no difference of clinical efficacy nor clinical outcome between patients whose empirical antibiotic treatment was adherent or non-adherent to the national or international clinical practice guideline.It was the clinical efficacy of empirical antibiotic treatment(sub-distributional hazard ratio(s HR),95% confidence interval(CI):0.09,0.02-0.36,p <0.001),sepsis(s HR,95%CI: 4.65,2.41-8.99,p <0.001)and ACLF at infection(s HR,95%CI: 5.06,2.57-9.97,p <0.001)independently affected 28-day mortality.In addition to bacterial infection,HBV flare is another important precipitant of ACLF in patients with HBV-related decompensated cirrhosis as observed in 360 patients with bacterial infection from the retrospective cohort,the rate of liver(93.3% vs 48.8%,p <0.001)and coagulation failure(64% vs 48.8%,p <0.001)were significantly higher than those without.The overall prevalence of ACLF(85.3% vs 53.3%,p <0.001),especially ACLF grade 3(52% vs 27%,p <0.001)was significantly higher and accordingly,the 90-day transplant-free survival was significantly lower in patients with bacterial infection than those without(Gray test,p <0.001).These results were subsequently validated in the prospective cohort.Furthermore,either patients with bacterial infection or with HBV flare,their levels of blood cytokines were significantly higher than those in patients without both bacterial infection and HBV flare.However,the signature of cytokines between the two populations was different.Patiens with HBV flare alone had significantly higher level of cell death biomarkers(K18 and c K18)and monocyte chemotactic protein 1(p <0.01),macrophage inflammatory proteins-3?(p <0.01),interferon-inducible protein 10(p <0.01)and interleukin-8(p <0.01)comparing to those in patients with bacterial infection alone.Patients with bacterial infection had significantly higher level of interleukin-6(p <0.05)and interleukin-17A(p <0.01)comparing to those in patients with bacterial infection alone.Most of the cytokines were significantly higher in patients with both bacterial infection and HBV flare than those in patients with single event.The blood immune cells including leukocyte counts,neutrophil counts,monocyte counts and two-thirds of the 21 cytokines were significantly higher in patients with ACLF than patients with traditional acute decompensated cirrhosis.Among these immunological parameters,the baseline leukocyte counts,neutrophil counts,monocyte counts,interleukin-6,interleukin-10,and soluble CD163 were independent predictors of 28-day mortality in patients with ACLF.Conclusions: Around one-thirds of the patients with HBV-related decompensated cirrhosis had bacterial infection;among them,MDR infection is highly prevalent with 38.8% in the prospective cohort.The clinical efficacy of empirical antibiotic treatment is a strong and independent protective factor of 28-day mortality.The short-term survival would significantly increase if the empirical antibiotic treatment was clinically efficient.HBV flare also occurred frequently in patients with HBV-related decompensated cirrhosis.Either bacterial infection or HBV flare could independently precipitate ACLF.The risk of ACLF development and progression significantly increased when bacterial infection and HBV flare occur together in an individual patient.Both bacterial infection and HBV flare induced significantly increased level of blood immune cells and cytokines,but might through different pathway.There was also significantly different type of organ failure between patiens with bacterial infection and with HBV flare.The measurements of immunological biomarkers could help evaluate the severity of systemic inflammation in patients with ACLF and several specific biomarkers could help predict poor outcome of ACLF.Future studies should further establish multi-center prospective cohort to generate data for the improvement of clinical practice.Basic immunological studies are also needed to further explore the detailed mechanism involved in the precipitation of ACLF by bacterial infection or HBV flare. |
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