Presepsin teardown - pitfalls of biomarkers in the diagnosis and prognosis of bacterial infection in cirrhosis

Table 1 Demographic, clinical and laboratory characteristics of patients with or without bacterial infections

			Non-infected	Infected		P value
n			141	75
Gender (male/female)			77/64	41/34		NS
Age (yr)			57.3 ± 10.7	58.1 ± 9.7		NS
Child-Pugh score			6.9 ± 1.7	9.3 ± 2.2		< 0.001
Child-Pugh stage, n (%)
A			58 (41.1)	6 (8.0)		< 0.001
B			65 (46.1)	28 (37.3)
C			18 (12.8)	41 (54.7)
MELD score			12.3 ± 4.1	19.1 ± 9.1		< 0.001
Serum bilirubin (μmol/L)			41.4 ± 38.3	124.1 ± 147.4		< 0.001
Serum albumin (g/L)			35.4 ± 7.1	28.1 ± 6.5		< 0.001
INR			1.3 ± 0.2	1.6 ± 0.5		< 0.001
Serum creatinine (μmol/L)			83.8 ± 74.3	131.2 ± 129.9		< 0.001
Ascites present, n (%)			58 (41.1)	59 (78.7)		< 0.001
HCC, n (%)			4 (2.8)	11 (14.7)		0.003
Comorbidities present, n (%)			72 (51.1)	45 (60.0)		NS
Type of bacterial infections, n (%)
UTI				25 (29.4)
SBP				20 (23.5)
Pneumonia				18 (21.2)
SSTI				4 (4.7)
Miscellaneous				18 (21.2)
Multiple				9 (10.6)
Acute phase proteins, median (IQR)
Presepsin (pg/mL)	Overall		477 (332-680)	1002 (575-2149)		< 0.001
	OF absent	OF present		710 (533-1277)	2357 (1398-3666)	< 0.001
CRP (mg/L)	Overall		4.6 (1.8-8.8)	30.1 (11.3-57.4)		< 0.001
	OF absent	OF present		25 (9.6-40.5)	52.2 (23.4-84)	0.027
PCT (μmol/L)	Overall		0.1 (0.1-0.2)	0.4 (0.1-1.2)		< 0.001
	OF absent	OF present		0.2 (0.1-0.5)	1.7 (0.6-5.3)	< 0.001

Data are presented as mean ± SD or n (%) if not otherwise indicated. CRP: C-reactive protein; HCC: Hepatocellular carcinoma; IQR: Interquartile range; INR: International normalized ratio; MELD: Model for end-stage liver disease score; NS: Non-significant; PCT: Procalcitonin; SD: Standard deviation; UTI: Urinary tract infection; SBP: Spontaneous bacterial peritonitis; SSTI: Skin and soft tissue infection.

Table 2 Association of classic acute phase proteins with mortality in patients with cirrhosis

Ref.	Year	Journal	Population	n	Outcome	Measure	Value
C-reactive protein
Reuken et al[72]	2013	Liver Int	Ascites	108	90-d mortality	AUC	0.69 (0.59-0.79), P = 0.001
Moreno et al[69]	2013	Liver Int	Non-septic	95	1-yr mortality	AUC	0.71 (0.6-0.8), P < 0.001
Mortensen et al[70]	2012	Eur J Gastroenterol Hepatol	Stable alcohol cirrhosis	45	Long term mortality (about 6- yr)	HR1
							1.074 (1.001-1.153), P = 0.046
Wiese et al[74]	2014	Liver Int	Stable cirrhotic	193	1- yr survival	HR	1.18, P = 0.0483
Lim et al[68]	2014	Plos One	SBP	75	30-d mortality	AUC	0.64 (0.49-0.79), P = 0.076
						HR	ND, P = 0.064
Schwabl et al[73]	2015	Liver Int	SBP	168	30-d mortality	HR1	1.067 (1.004-1.134), P = 0.037
Ha et al[65]	2011	Korean J Intern Med	Bacteraemia	202	30-d mortality	Difference	Survivor vs non-survivor2
							37.8 vs 34.3 mg/L, P = 0.721
Cervoni et al[20]	2012	J Hepatol	CPs > 7	148	180-d mortality	AUC	0.63 (0.51-0.73), P = ND
						HR14	2.73 (1.41-5.26), P = 0.003
Di Martino et al[64]	2015	Liver Transplant	CPs > 7	109	90-d mortality	HR14	2.21 (1.03-4.76), P = 0.042
Cervoni et al[63]	2016	Eur J Gastroenterol Hepatol	CPs > 7	583	90-d mortality	HR14	1.69 (1.01-2.81), P = 0.046
Park et al[71]	2015	J Korean Med Sci	Alcoholic cirrhosis various reasons for admission	409	30-d mortality	OR	"CRP > 20 not independent predictor"
Ximenes et al[75]	2016	Am J Emerg Med	Hepatic decompensation	149	Inhospital mortality	OR	OR: ND, P > 0.100
Kwon et al[67]	2015	BMC Gastroenterol	Acute decompensation	184	30 d survival	OR	OR: ND, P = 0.122
Lazzarotto et al[19]	2013	Ann Hepatol	Acute decompensation	64	90 d survival	Difference	Survivor vs non-survivor2
							7 vs 41 mg/L, P = 0.026
Kronenberger et al[66]	2012	BMC Med	Acute decompensation + outpatients	120	Overall survival (196 ± 165 d)	HR	Univariate: 0.314 (0.141-0.702) , P = 0.005
							Multivariate: ND, P = 0.077
Procalcitonin
Lin et al[80]	2015	J Crit Care	Acute decompensation	96	Sepsis in-hospital mortality	AUC	0.692
Kotecha et al[79]	2013	Eur J Gastroenterol Hepatol	Cirrhosis + SIRS	100	In-hospital survival	OR1	0.949 (0.868-1.037), P = 0.249
Connert et al[78]	2003	Z Gastroenterol	Compensated + decompensated	100	60-d mortality	Percent died	< 0.58 vs≥ 0.58:
							9.1% vs 46.7%, P < 0.001
Al-Dorzi et al[76]	2014	Clin Lab	Septic shock	45	28-d mortality	Difference	Low PCT vs high PCT:
							80% vs 77%, P = 0.61
Berres et al[77]	2009	Liver Int	Critically ill	38	ICU mortality	Difference	NA, P = NS

¹Adjusted for MELD score;

²Median values;

³Not significant in the log-rank test;

⁴CRP variation over 15 d. SBP: Spontaneous bacterial peritonitis; HR: Hazard ratio; AUC: Area under the curve; OR: Odds ratio; CPs: Child-Pugh score; ICU: Intensive care unit; SIRS: Systemic inflammatory response syndrome.

Table 3 Correlations between presepsin and different laboratory parameters or liver-orientated scores

Variable	Spearman’s rho	P value
CRP	0.63	< 0.001
PCT	0.53	< 0.001
Leucocyte count	0.27	< 0.001
Serum creatinine	0.36	< 0.001
Serum bilirubin	0.28	< 0.001
Serum albumin	-0.40	< 0.001
INR	0.15	0.032
CPs	0.42	< 0.001
MELD score	0.45	< 0.001

CRP: C-reactive protein; CPs: Child-Pugh score; INR: International normalized ratio; MELD score: Model for end-stage liver disease; PCT: Procalcitonin.

Table 4 Performance characteristics of presepsin and other acute phase proteins during bacterial infections in patients with cirrhosis in various clinical settings

	Variable	Cut-off values	Sensitivity	Specificity	PPV	NPV	LR+	LR-
INF overall	Presepsin (pg/mL)	844	60.0%	84.45	67.2%	79.9%	3.85	0.47
	PCT (μmol/L)	0.39	53.3%	93.65	81.6%	79.0%	8.36	0.50
	CRP (mg/L)	10.8	78.7%	84.4%	78.2%	88.1%	5.04	0.25
	At least one marker positive (Presepsin/CRP)		88.0%	74.5%	64.7%	92.1%	3.45	0.16
	At least one marker positive (PCT/CRP)		81.3%	84.2%	69.3%	91.1%	5.15	0.22
INF + OF	Presepsin (pg/mL)	1206	87.5%	74.5%	61.8%	92.75	3.43	0.17
	PCT (μmol/L)	0.5	79.2%	76.5%	61.3%	88.6%	3.36	0.27
	CRP (mg/L)	40.5	62.5%	76.5%	55.6%	81.2%	2.66	0.49

PPV: Positive predictive value; NPV: Negative predictive value; LR+: Positive likelihood ratio; LR-: Negative likelihood ratio; PCT: Procalcitonin; CRP: C-reactive protein; MELD: Model for end-stage liver disease; INF: Infection; OF: Organ failure.

Table 5 Performance characteristics of presepsin, procalcitonin and C-reactive protein for prediction of short-term (28-d) mortality in patients with bacterial infection (n = 75)

Variable	Cut-off values	AUC-ROC (95%CI)	Sensitivity	Specificity	PPV	NPV	LR+	LR-
Presepsin (pg/mL)	1277	0.76 (0.64-0.85)	75.0%	69.1%	46.9%	88.4%	2.43	0.36
PCT (μmol/L)	0.48	0.87 (0.77-0.93)	90.0%	74.6%	56.2%	95.3%	3.54	0.13
CRP (mg/L)	39.6	0.74 (0.63-0.84)	75.0%	74.6%	51.7%	89.1%	2.95	0.34

PPV: Positive predictive value; NPV: Negative predictive value; LR+: Positive likelihood ratio; LR-: Negative likelihood ratio; PCT: Procalcitonin; CRP: C-reactive protein; MELD: Model for end-stage liver disease.

Table 6 Association of presepsin, procalcitonin and C-reactive protein levels with short-term (28-d) mortality in patients with cirrhosis and bacterial infection

	Binary logistic regression analysis
	Univariate		Multivariate
	Unadjusted	P value	Adjusted for MELD	P value	Adjusted for leucocyte count	P value	Adjusted for MELD and leucocyte count	P value
ln(Presepsin)	3.59 (1.65-7.84)	0.001	1.9 (0.81-4.43)	0.138	2.91 (1.28-6.64)	0.011	1.61 (0.65-3.97)	0.303
ln(PCT)	2.54 (1.55-4.16)	< 0.001	1.89 (1.14-3.14)	0.014	2.33 (1.42-3.83)	0.001	1.81 (1.09-3.01)	0.022
ln(CRP)	2.17 (1.23-3.81)	0.007	1.73 (0.93-3.21)	0.081	1.84 (1.03-3.31)	0.040	1.56 (0.81-2.99)	0.180

Associations are expressed as odds ratios and 95%CI per 1 loge-unit increase. MELD: Model for end-stage liver disease; PCT: Procalcitonin; CRP: C-reactive protein.