To the Editor: Twenty-eight-day mortality rates in patients with acute-on-chronic liver failure (ACLF) grades 1, 2, and 3, as per the European Association for the Study of the Liver-Chronic Liver Failure (EASL-CLIF) classification, are 22%, 32%, and 73%, respectively.[1] The 30-day mortality rates in cirrhosis with grade 3–4 hepatic encephalopathy (HE) and ≥2 extra-hepatic organ failures (OFs), and one OF are 70% and 44%, respectively.[2] It suggests that the prognosis in cirrhotic patients with ACLF and grades 3–4 HE is usually poor, which can be effectively treated by liver transplantation (LT) with good post-LT survival rates.[3,4] Hepatitis B virus (HBV) is the main cirrhotic etiology in China.[5] Currently, there is limited data available regarding LT for HBV-related ACLF patients with grade 3–4 HE (hereinafter referred to as ACLF with grade 3–4 HE). Our aim was to investigate the peri-LT complications, pre-LT prognostic scorings, survival, and quality of life assessed by the Karnofsky performance status (KPS) scores at post-LT 1 year in ACLF with grade 3–4 HE, when compared with other three transplanted groups (ACLF with grade 1–2 HE, ACLF with no HE, and cirrhosis with no ACLF and HE). There were 411 patients transplanted for HBV-related end-stage benign cirrhosis in Shulan (Hangzhou) Hospital between January 2016 and June 2021. Inclusion and exclusion criteria are presented in Supplementary Figure 1, https://links.lww.com/CM9/B922. Perioperative management; various definitions such as HBV infection, ACLF, HE, multi-drug resistant (MDR), and extensively drug resistant (XDR); and statistical analysis are available in the Supplementary Materials and Methods, https://links.lww.com/CM9/B922. The KPS scores were divided into three groups: 0–40% (requirement of hospital care, or deteriorating or dead), 50–70% (able to live at home and requires varying assistance), and 80–100% (able to carry on normal activity or work and no assistance required).[6] Minimum follow-ups were post-LT 12 months. The Ethics Committee of Shulan (Hangzhou) Hospital had approved this study (No. KY2022074). In comparison with pre-LT complications in the other three transplanted groups [Supplementary Table 1, https://links.lww.com/CM9/B922], ACLF with grade 3–4 HE had significantly higher occurrence rates of history of shock, renal failure, circulation failure, endotracheal intubation, hemodialysis, bacteremia, and pneumonia; and much higher proportions of ACLF grade 3 (91.2%, 83/91), model for end-stage liver disease (MELD) ≥30 (61.5%, 56/91), MELD ≥40 (30.8%, 28/91), and chronic liver failure consortium ACLF score (CLIF-C-ACLFs) ≥64 (29.7%, 27/91). When compared to post-LT complications in the other three transplanted groups [Supplementary Table 2, https://links.lww.com/CM9/B922], ACLF with grade 3–4 HE possessed significantly higher incidences of prolonged endotracheal intubation (≥72 h), tracheostomy, hemodialysis, bacteremia, pneumonia, bacteremia and pneumonia caused by MDR bacteria and XDR bacteria, and futile LT. ACLF patients, whether or not in whom HE existed, had observably higher incidences of early allograft dysfunction (EAD), when compared with cirrhosis with no ACLF and HE (P <0.001, Supplementary Table 2, https://links.lww.com/CM9/B922). Of all 98 bacteremic episodes in the first 6 months after LT, Gram-negative bacilli (GNB) were responsible for 76.5%. The most frequent GNB was Klebsiella pneumonia (K. pneumoniae) accounting for 48.0% [Supplementary Table 3, https://links.lww.com/CM9/B922]. The isolated rates of MDR and XDR among K. pneumoniae bacteremic episodes were 95.7% and 87.2%, respectively. Totally, 194 (94.2%) of 206 pneumonic isolates in the first 6 months post-LT were GNB, which were mainly constituted by K. pneumoniae (31.4%), followed by Acinetobacter baumannii (A. baumannii) (23.7%) and Pseudomonas aeruginosa (P. aeruginosa, 12.9%). The incidences of pneumonic episodes caused by MDR K. pneumoniae, A. baumannii, and P. aeruginosa were 91.8%, 93.4%, and 60.0%, respectively; their corresponding XDR isolates were 80.3%, 69.6%, and 20.0%, respectively. About 70 (72.9%) of the 96 isolates among 81 abdominal infectious patients in the first 6 months post-LT were GNB, of which K. pneumoniae (36.5%) was primary GNB, and its isolated rates of MDR and XDR were 94.3% and 85.7%, respectively. Post-LT 1-year survival rate in ACLF with grade 3–4 HE was 68.1%, which was markedly lower than that of the other three transplanted groups (P <0.0001, Supplementary Figure 2, https://links.lww.com/CM9/B922). Futile LTs occurred predominantly in ACLF with grade 3–4 HE, accounting for 60.5% (26/43). Among all 51 post-LT death cases in the first 6 months, 52.9% occured in ACLF with grade 3–4 HE. The chief cause for death was MDR or XDR isolates–related sepsis with multi-OFs (82.4%, 42/51). At post-LT 1-year, 59.3% (54/91) of ACLF with grade 3–4 HE achieved KPS ≥80, which was lower than that in the other three groups (P <0.001, Figure 1). The univariate analyses [Supplementary Table 4, https://links.lww.com/CM9/B922] and multivariate analyses for the first post-LT 6-month mortalities in ACLF with grade 3–4 HE were done, which were independently associated with EAD (Hazard ratio [HR]: 3.29, 95% CI: 1.28–8.43, P = 0.011), XDR isolates–related bacteremia (HR: 4.50, 95% CI: 2.24–9.05, P <0.001), XDR isolates–related pneumonia (HR: 13.11, 95% CI: 2.70–63.57, P = 0.002), and abdominal MDR bacterial infections (HR: 3.57, 95% CI: 1.48–8.62, P <0.001).Figure 1: One-year survival rate and KPS scores after liver transplantation in ACLF patients with grade 3-4 HE (ACLF with grade 3-4 HE), ACLF with grade 1-2 HE, ACLF with no HE, and cirrhosis with no ACLF and HE. ACLF: Acute-on-chronic liver failure; HE: Hepatic encephalopathy; KPS: Karnofsky performance status.This was a rare report regarding LT on the survival and quality of life in ACLF with grade 3–4 HE. Our post-LT 1-year overall survival of all ACLF cases was 81.9%, which was analogous to the reported data ranging from 65.0% to 84.3%.[3,4,7] ACLF grade 3, MELD ≥25, and chronic liver failure consortium ACLF (CLIF-C ACLFs) scoring ≥64 among ACLF with grade 3–4 HE accounted for 90.2%, 80.2%, and 29.7%, respectively. The 90-day post-LT survival among patients with CLIF-C ACLFs >64 is 52.4%[3] and 1-year post-LT survival of patients with MELD scorings >25 and grade 3–4 HE is 79.2%.[7] We highlight that the post-LT 1-year survival rate (68.1%) in ACLF with grade 3–4 HE is acceptable. At post-LT 1-year, there is 59.3% of ACLF with grade 3–4 HE achieving a KPS >80, which is similar to 60–64% patients transplanted with 3–4 OFs diagnosed by sequential OF assessment (CLIF-SOFA).[6] It suggests that the LT benefits for ACLF with grade 3–4 HE are noticeable. LT is considered a rescue treatment for ACLF patients who cannot get well by conservative treatment alone. Therefore, we suggest that LT for ACLF with grade 3–4 HE should be done in time when conditions permit. Our study and reported data[4] indicate that post-LT acquired bacteremia and pneumonia predominantly occur in ACLF with grade 3–4 HE. Sepsis with multi-OFs resulting mainly from post-LT bacteremia, pneumonia, or abdominal infections caused by MDR or XDR GNB serves as a chief post-LT death cause in our study and the reported reports.[3,4,7] More severe pre-LT HE is associated with more perioperative complications and higher post-LT infection-related mortalities.[7] This suggests that the severe susceptibility of ACLF with grade 3–4 HE to GNB infections is a serious threat to LT[1,7]; the indispensable systematic screening of pre-LT infections in these critically ill patients is important. Contradictorily, clinical deterioration of ACLF with grade 3–4 HE can sometimes evolve rapidly, and pre-LT evaluation process must be quick. Our study suggests that post-LT XDR bacteria–related bacteremia and pneumonia, and MDR isolates–related abdominal infections are independently associated with the post-LT mortality of ACLF with grade 3–4 HE. Post-LT acquired bacteremia, pneumonia, and abdominal infections are predominantly caused by MDR/XDR GNB such as K. pneumoniae, A. baumannii, and P. aeruginosa, which have been the main causes of bloodstream infections in LT recipients over the past two decades[8] They are the major threats to LT successes as a result of their high infections-related mortalities.[8,9] Mortality rates in carbapenemases-producing K. pneumoniae infections reach 50%, and go up often to 75%.[9] The higher carbapenem resistance rates for A. baumannii in bacteremic solid organ transplant and LT recipients are 72.7% and 92.8%, respectively.[8] The in-hospital mortality rate in solid organ transplant patients with bacteremia caused by MDR or XDR non-lactose-fermenting GNB is over 50%, whereas in patients with septic shock, the rate sharply increases to 95%.[10]P. aeruginosa is known for the high mortality, which exceeds 30% and may be doubled in nosocomial infections due to MDR P. aeruginosa.[10] As for treatment of MDR/XDR GNB-related infections, antibiotics selections should take into account pre-LT critical illness, antibiotic exposures in the past 30 days, the likely infectious source, and local antibiotics-susceptibility.[11] The Infectious Diseases Society of America has provided antibiotic therapy guidelines for infections caused by extended-spectrum β-lactamase–producing Enterobacterales, carbapenem-resistant Enterobacterales, and P. aeruginosa with difficult-to-treat resistance, and has recommended the preferred antibiotics and alternatives based on in vitro susceptibility.[11] Eravacycline and cefiderocol have activity against carbapenem-resistant strains of A. baumannii and Stenotrophomonas maltophilia.[11] In addition, the reported data have indicated that EAD, as an independent risk factor for post-LT 6-month mortality in ACLF with grade 3–4 HE, is associated with markedly inferior allograft and patient survivals. In summary, ACLF with grade 3–4 HE presents the most severe illness. LTs for them have an acceptable post-LT 1-year survival rate, and overall physical and mental status. Post-LT death causes are sepsis with multi-OFs. The evaluation process of LT must be quick to avoid a higher risk of mortality. Funding None. Conflicts of interest None.
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