Update on diagnosis and management of sepsis in cirrhosis: Current advances

Table 1 Modification of sequential organ failure assessment score for patients with cirrhosis, the chronic liver failure-sequential organ failure assessment scoring system[13,15]

Score	1	2	3	4
Respiration PaO2/FiO2 or SpO2/FiO2, mmHg	> 300 to ≤ 400 or > 357 to ≤ 512	> 200 to ≤ 300 or > 214 to ≤ 357	> 100 to ≤ 200 or 89 to ≤ 214	< 100 or ≤ 89
Liver bilirubin, mg/dL	1.2-1.9	2.0-5.9	6.0-11.9	> 12
Cardiovascular hypotension	Mean arterial pressure < 70 mmHg	Dopamine ≤ 5 or any dobutamine or terlipressin	Dopamine > 5 or noradrenaline ≤ 0.1	Dopamine > 15 or noradrenaline > 0.1
Cerebral HE grades	I	II	III	IV
Renal creatinine (mg/dL) or urine output	1.2-1.9	2.0-3.4	3.5-4.9 or use of renal replacement therapy	≥ 5.0
Coagulation - INR	≥ 1.1 to < 1.25	≥ 1.25 to < 1.5	≥ 1.5 to < 2.5	≥ 2.5 or platelet count ≤ 20000/µL

FiO₂: Fraction of inspired oxygen; HE: Hepatic encephalopathy; INR: International normalized ratio; PaO₂: Arterial oxygen pressure.

Table 2 Transcriptomics based micro assays for diagnosis of sepsis[57]

Assay name (manufacturer)	Technique/sample volume	Turn-around time	Highest noted sensitivity and specificity	Detection
SeptiFast (Roche)	Real-time PCR/1.5 mL	4 h to 6 h	83%/95%	> 16 bacteria, Candida and Aspergillus fumigatus
SeptiTest (Molzyme)	Universal PCR/1 mL	8 h to 10 h	87%/96%	> 345 bacteria and 13 fungi
SeptiCyte (ImmuneExpress)	RT-qPCR with machine learning/2.5 mL	1 h to 6 h	-/ 95% (discriminates SIRS from sepsis)	All pathogens
Iridica Plex ID (Abbott)	Multiplex broad range PCR/5 mL	6 h	83%/94%	780 bacteria and Candida
MinION (Oxford Nanopore)	Nanopore sequencing/10 ng DNA	4 h to 6 h	-/100%	Few viruses and bacteria currently
U-dHRM (UCSD, United States)	Digital PCR/1 mL	3 h	-/99.9%	37 bacteria
LAMP Tech	Loop mediated isothermal amplification/30 µL	1 h	-/100%	1 pathogen per sample
Integrated droplet digital detection tech (Velox Biosystems)	DNA-zyme base sensor droplet microencapsulation 3D particle analysis	1 h to 4 h	-	1 pathogen per sample

3D: Three-dimensional; PCR: Polymerase chain reaction; RT: Reverse transcriptase; SIRS: Systemic inflammatory response syndrome.

Table 3 The modified early warning scoring system for identification of sepsis[63]

Score	3	2	1	0	1	2	3
Respiratory rate per min		≤ 8		9-14	15-20	21-29	> 29
Heart rate per min		≤ 40	41-50	51-100	101-110	111-129	> 129
Systolic blood pressure, mmHg	≤ 70	71-80	81-100	101-199		≥ 200
Urine output, mL/(kg·h)	Nil	< 0.5
Temperature, °C		≤ 35	35.1-36	36.1-38	38.1-38.5	≥ 38.6
Neurological, subjective				Alert	Reacting to voice	Reacting to pain	Unresponsive

Table 4 Novel adjuvant therapies for management of sepsis[74-76]

Therapy	Mechanism	Systemic effect in sepsis
Eritoran; resatorvid	Toll-like receptor 4 antagonist; Eritoran is structurally similar to lipopolysaccharide – A of Gram-negative bacteria. Resatorvid is a direct antagonist of toll like receptor 4	Anti-inflammatory; Immunomodulation
Polymixin B fibre column; CytoSorb	Hemoperfusion; CytoSorb has hemadsorption properties	Removal of circulating endotoxin and bacterial components
Plasma exchange; Whole blood exchange; Coupled plasma filtration adsorption; Hemofiltration	Exchange of plasma or blood with or without sorbent adsorption; either continuous or intermittent; low or high volume	Removal of endotoxins and circulating cytokines
Macrolides	Nuclear factor kB and AP-1 signalling suppression, inhibition of ERK-1 and 2 pathways	Anti-inflammatory and immunomodulating properties
Interferon-gamma	Increase in monocyte HLA-DR expression	Restores immune regulation, abolishes immunoparalysis by restoring monocyte function
Immunoglobulins	Increase in IgA and IgM levels	Boosts humoral immunity
Granulocyte macrophage colony stimulating factor	Promotes maturation and differentiation of neutrophils, monocytes, macrophages, dendritic cells, T lymphocytes and plasma cells	Improves immune regulation, reduces immunoparalysis
Anti-MIF	Antagonizes macrophage migration inhibition factor	Immunomodulation through boosting activity of endogenous glucocorticoids
Super-Antigen-Antagonist	Suppression of pro-inflammatory gene expression by inhibition of T cell activation	Th1 blockade and prevention of lethal shock
Heparin and its analogues	Anti-thrombotic, immunomodulation	Prevents early disseminated intravascular coagulation, prevents early organ failures due to diffuse system microvascular thrombosis
Naloxone	Opioid receptor antagonism	Improves hemodynamic instability
Pentoxifylline	Decreases erythrocyte aggregation and deformability, anti TNF-alpha effect	Improvement in arterial oxygen tension by improving fractionated oxygen exchange
GTS-21	Selective alpha-7-nicotinic acetylcholine receptor agonist, blocks nuclear factor – kB and cytokines downstream	Activates cholinergic anti-inflammatory pathway
Interleukin 7 and 2	Pro-inflammatory cytokines	Prevents immunoparalysis
Programmed cell death-1 (PD-1) and ligand (PD-L1) antagonist	Prevention of lymphocyte depletion, improvement in pro-inflammatory mediators and increased bacterial clearance	Immune modulation
B and T cell lymphocyte attenuator antagonism (BTLA)	Increases activity and proliferation of T cells	Increases resistance to endotoxin and prevention of endotoxin mediated shock
Antagonism of cytotoxic T lymphocyte antigen 4 (CTLA-4)	Increased activity and proliferation of T cells	Abolishes endotoxemia and associated toxic shock
Methylthiouracil	Suppresses high mobility group box – 1 (HMGB-1)	Anti-inflammatory
Structurally nanoengineered antimicrobial peptide polymers; Ceria – zirconia nanoparticles; Piceatannol-loaded albumin nanoparticles; Sialic-acid decorated nanoparticles; Exsosomes loaded with MFGE8, miR-223; Red blood cells and macrophage coated nanoparticles; Liposomes tagged to antimicrobials; Opsonin bound magnetic nanobeads	Nanoparticle technology (pre-clinical studies)	Antibacterial; Antioxidant; Anti-inflammatory; Endotoxin antagonist; Extracorporeal blood cleansing; Clearance of apoptotic cells

AP: Activator protein; BTLA: B and T lymphocyte associated; CTLA-4: Cytotoxic T-lymphocyte-associated protein 4; ERK: Extracellular signal-regulated kinases; HLA-DR: Human leukocyte antigen – DR isotype; HMGB: High-mobility group box; Ig: Immunoglobulins; MFGE8: Milk fat globule epidermal growth factor 8 protein; MIF: Macrophage migration inhibitory factor; miR: Micro-RNA; PD-L: Programmed death receptor ligand; TNF: Tumour necrosis factor.