Sepsis in liver failure patients: Diagnostic challenges and recent advancements

Table 1 Prevalence of bacterial infections amongacute liver failure or acute-on-chronic liver failure patients in different countries

Ref.	Country	Patients	n	Overall infection	Remarks
Cai et al[32], 2017	China	ACLF	389	81.2%	Pneumonia 49.4%, SBP 37.3%, UTI 13.3%. Gram positive sepsis 59.8%, Gram negative 55.3%
Fernández et al[18], 2018	Europe	ACLF	407	66.1%	BI at diagnosis 37%, BI during follow-up 46%. BI was associated with higher inflammation and worse outcomes
Karvellas et al[30], 2009	Canada	ALF	206	35%	Gram positive organisms in 44% of isolates, gram negatives in 52%, and 4% was fungal
Kaur et al[8], 2024	India	ALF	143	64%	Overall infection was 77% including fungal infection in 17.3%, MDR 70%
Liu et al[33], 2021	China	ACLF	140	69.2%	SBP 36.1%, pneumonia 23.7%, and multi-site infection 22.7%. Gram-negative bacteria 68.4%, and Gram-positive 31.6%
Moreau et al[35], 2013	Europe	ACLF	303	32.6%	SBP 10.6%, Pneumonia 61%, UTI 6.1%
Mücke et al[19], 2018	Europe	ACLF	173	41%	SBP 32.4%, pneumonia 25.4%
Rolando et al[29], 1990	England	ALF	50	80%	Respiratory tract infection 47%,and gram-positive bacteria 69.8%
Shalimar et al[31], 2017	India	ALF	540	49%	BI at diagnosis 22.2%, BI during follow-up 34%
Shalimar et al[34], 2018	India	ACLF	572	66.7%	Gram negative sepsis 91.6%. Pneumonia 45%, SBP 21.1%, UTI (15.2%)
Zhai et al[43], 2020	China	ACLF	289	64%	Gram negative sepsis 58.3%, Pneumonia 55.7%, SBP 47.6%
Zhang et al[37], 2022	China	ACLF	539	58.8%	SBP 31.54%, UTI 26.53%, Pneumonia 12.9%. Gram-positive sepsis 23.76%, Gram-negative sepsis 62.87%
Zider et al[28], 2016	United States	ALF	150	41%	One site infection 60%, multi-site infection 40%. Pneumonia 64% and UTI 55%

ALF: Acute liver failure; ACLF: Acute-on-chronic liver failure; BI: Bacterial infection; MDR: Multi-drug resistance; SBP: Spontaneous bacterial peritonitis; UTI: Urinary tract infection.

Table 2 Studies on biomarkers of sepsispatients within acute liver failure or acute-on-chronic liver failure

Ref.	Country	Patients	Biomarker(s)	Results and remarks
Silvestre et al[50], 2010	Europe	ALF	CRP	CRP levels are markedly decreased in ALF, even in presence of sepsis
Igna et al[62], 2022	Europe	ACLF	Presepsin, PCT and CRP	Presepsin, CRP, and PCT levels were higher in sepsis patients. Presepsin ≥ 2300 pg/mL had excellent (AUROC 0.95) for sepsis
Rule et al[55], 2015	USA	ALF	PCT	PCT levels > 2.0 ng/mL could not differentiate ALF patients with or without BIs
Huang et al[68], 2017	China	ACLF	Prostaglandin E2	Serum Prostaglandin E2 Level 141pg/mL predicted infection with AUROC curve of 0.83
Chen et al[48], 2021	China	ACLF	sTREM-1, Presepsin, and PCT	sTREM-1 and presepsin were significantly higher in sepsis patients, with higher accuracy compared to CRP and PCT
Cavazza et al[63], 2024	United States	ALF	sCD206	sCD206, a soluble markers of macrophage activation, independently predictedinfection
Yadav et al[69], 2022	India	ACLF	IL-1Ra, IL-18, TREM1, PD-L1, and TIM3	Higher baseline and rising levels of IL-1Ra, IL-18, TREM1 soluble factors, and suppressive monocytes (PDL1+ve, TIM3+ve)predictedrisk of sepsis within 72 hours
Lin et al[57], 2020	China	ACLF	PCT, neutrophils% and CRP	The AUROC of the infection score,comprisingPCT, neutrophils% and CRP, for discriminatingBI was 0.740
Yuet al[80], 2024	China	ACLF	BTLA	BTLA levels, a member of the CD28Igsuperfamily, significantly increased in the CD4+ T cells andwere positively correlated with infection complications

ALF: Acute liver failure; ACLF: Acute-on-chronic liver failure; AUROC: Area under receiver operating characteristic curve; BI: Bacterial infection; CRP: C-reactive protein; PCT: Procalcitonin; IL-1Ra: Interleukin-1 receptor antagonist; IL-18: Interleukin-18; TREM1: Triggering receptor expressed on myeloid cells 1; PD-L1: Programmed death ligand 1; TIM3: T-cell immunoglobulin and mucin domain-containing protein 3; BTLA: B- and T-lymphocyte attenuator.

Table 3 Summary of the performance, advantages, and limitations of various traditional and novel biomarkers of sepsis

Biomarkers	Overall performance for sepsis	Advantages	Limitations
CRP	Pooled sensitivity 80% and pooled specificity 61% for BI in general[49]	Wide availability. Low cost	Low specificity for BI. Falsely low levels in liver failure. Lag time: 12-24 hours. False positive in inflammation
PCT	Pooled sensitivity 77% and pooled specificity of 79% in general[53]	Easily available. Validated across multiple studies. Rapid elevation, 3–4 hours after BI	Modest to poor discriminatory role in liver failure patients. Varying cut-off levels. False positive in inflammation. Poor performance in renal failure and immunocompromised patients
IL-6	Pooled sensitivity 85% and specificity 91% for BI in cirrhosis[58]	Estimation is accurate, fast, and simple	It is a non-specific pro-inflammatory cytokine. Needs further studies in liver failure patients
HDL-C	HDL-C has an inverse correlation with BI[65,66]	Simple test. Low-cost. Widely available	Inverse correlation also exists between HDL-C and liver disease per se. Needs further studies as a biomarker for sepsis
Presepsin	Overall diagnostic sensitivity 83% and specificity 78%[59]	Better performance in liver failure patients than CRP and PCT[48]. Specific association with gram negative sepsis-Detectable within 2 hours of BI	Limited availability. Expensive test. More effective as an adjunct biomarker than when used alone. Requires further validation studies
sTREM-1	Pooled sensitivity 85% andspecificity 79% for differentiating sepsis from SIRS[61]	Early detection, < 2 hours after BI. Short half-life, making it useful for treatment response	Not routinely available. Varying cut-off levels. Requires further validation studies. Only modest performance when used alone
Bacterial DNA testing	Next-Generation Sequencing methodenables the identification of all bacteria in the blood and body fluid[70,71]	Quick and wide-ranging detection of bacteria	Not routinely available. Primer cross-reactivity with human DNA. Limited specificityand inconsistent results. DNA without a live pathogen compromises interpretation
sCD206	Significant association with infection (AUROC 71%) and mortality in ALF (AUROC 81%)[63]	It is among few novel biomarker evaluated in ALF patients	Not routinely available for use. Levels also increases in fungal and viral infection.Requires further validation studies

CRP: C-reactive protein; BI: Bacterial infection; PCT: Procalcitonin; IL: Interleukin; HDL: High density lipoprotein; sTREM-1: Soluble triggering receptor expressed on myeloid cell-1; SIRS: Systemic inflammatory response syndrome; AUROC: Area under receiver operating characteristics; ALF: Acute liver failure.