a b s t r a c t

Introduction: Patients with liver cirrhosis and septic shock have a significantly higher risk of mortality and mor- bidity compared with non-Cirrhotic patients. The peripheral blood lymphocyte-to-monocyte ratio (LMR) can de- termine the prognosis of cirrhotic patients. Our study aimed to investigate the usefulness of LMR as a predictive marker of mortality risk in cirrhotic patients with septic shock.

Methods: This single-center, retrospective case-control study included adult patients who visited the emergency department between January 1, 2018 and June 30, 2020 and diagnosed with liver cirrhosis and septic shock. They were divided into survivor and non-survivor groups according to their survival status at the 60-day follow-up. We used a Cox proportional hazards regression model to identify independent factors associated with mortality risk and tested the mortality discriminative ability of those factors using the area under a receiver operating char- acteristic curve.

Results: A total of 93 patients were eligible for this study. Compared with the patients in the survivor group, those in the non-survivor group had significantly higher Child-Pugh (11 +- 2 vs. 9 +- 2, p < 0.001) and MELD scores (29 +- 6 vs. 22 +- 8, p < 0.001), higher serum international normalized ratio (1.7 vs.1.4, p = 0.03), bilirubin (6.0 vs. 3.3 mg/dL, p = 0.02), lactate (5.4 vs. 2.7 mmol/L, p < 0.01), creatinine (2.2 vs. 1.6 mg/dL, p = 0.04), higher neutrophil-to-lymphocyte ratio (13.0 vs. 10.3, p = 0.02), and lower LMR (1.1 vs. 2.3, p < 0.01). The LMR (adjusted hazard ratio [aHR] = 1.54, p = 0.01) and lactate (aHR = 1.03, p < 0.01) were identified as independent predic- tive factors for mortality in the multivariate regression model. Furthermore, LMR (area under curve [AUC]: 0.87) revealed a superior discrimination ability in Mortality prediction compared with the Child-Pugh (AUC: 0.72) and MELD (AUC: 0.76) scores.

Conclusions: The LMR can be used to predict mortality risk in cirrhotic patients with septic shock.

(C) 2020

1. Introduction

Cirrhosis refers to end-stage liver disease characterized by liver structure collapse and vascular architecture distortion, resulting in por- tal hypertension and hepatic synthetic dysfunction, and is associated with a major cause of morbidity and mortality worldwide [1]. Patients with cirrhosis are in a state of immune dysfunction and excessive pro- inflammatory cytokines activation, which predispose them to bacterial

Abbreviations: qSOFA, quick Sequential Organ Failure Assessment; SIRS, Systemic Inflammatory Response Syndrome; MELD, Model for End-stage Liver Disease; ED, emer- gent department; ACLF, acute-on-chronic Liver failure; LMR, lymphocyte-to-monocyte ratio; NLR, neutrophil-to-lymphocyte ratio; ROC, receiver operating characteristic; AUC, area under curve; INR, international normalized ratio; aHR, adjusted hazard ratio.

* Corresponding author at: Department of Emergency Medicine, E-Da Hospital, No.1, Yida Road, Jiao-su Village, Kaohsiung City, Yan-chao District 82445, Taiwan.

E-mail address: [email protected] (I.-T. Tsai).

infection [2]. The progression of infection in cirrhotic patients frequently leads to acute liver function deterioration accompanied by one or more extrahepatic organ failure, further resulting in increased short-term mortality [3].

Septic shock is the most severe complication of sepsis, accounting for about 10% of intensive care unit admissions and 39% of hospital mortal- ity [4]. Compared with non-cirrhotic patients, patients with cirrhosis and septic shock have different hemodynamic and metabolic character- istics, making their Prompt diagnosis and management even more diffi- cult [5,6]. The Quick Sequential Organ Failure Assessment and Systemic Inflammatory Response Syndrome scores are widely used scoring systems for sepsis/septic shock prognosis stratification, although their validity in patients with cirrhosis revealed conflicting re- sults [7-9]. On the other hand, the Child-Pugh and model for end-stage liver disease scores were reported to be correlated with prog- nosis in cirrhotic patients with sepsis [10], although the calculation of these scores is somewhat time-consuming for clinicians.

https://doi.org/10.1016/j.ajem.2020.11.071

0735-6757/(C) 2020

Peripheral blood count-based parameters, such as neutrophils, lym- phocytes, and monocytes, have been investigated as markers of sys- temic inflammation in patients with liver disease or cirrhosis; the Neutrophil count represents ongoing inflammation, whereas the lym- phocyte and monocyte levels reflect the immune regulatory pathway [11,12]. Interestingly, the lymphocyte-to-monocyte ratio (LMR) was proposed as an outcome predictor in hospitalized cirrhotic patients, but it has never been validated in patients with septic shock [11,13- 15]. The goal of this study was to investigate whether or not peripheral blood LMR could be a prognostic marker in cirrhotic patients with septic shock.

1. Methods
   1. Study design

We performed a retrospective observational case-control study at a tertiary referral medical center located in Kaohsiung, Taiwan with ap- proximately 57,500 emergency department (ED) annual visits. All adult patients (aged >=18 years) with liver cirrhosis and septic shock who visited the ED between January 1, 2018 and June 30, 2020 were enrolled in this study. Patients with cirrhosis were identified using the ED diagnostic code (International Classification of Diseases 10th Revision, ICD-10), which was further confirmed by liver biopsy results or a combination of clinical, ultrasound, or endoscopic examination (e.g., presence of jaundice, ascites, variceal bleeding) results of each pa- tient. Septic shock was diagnosed according to the Sepsis-3 consensus: persistent hypotension requiring vasopressors to maintain a mean arte- rial pressure of >=65 mmHg, and a Serum lactate level >2 mmol/L [16]. Because lactate level can be elevated in cirrhotic patients without sepsis due to their decreased clearance [17], we identified our septic shock pa- tients by their vasopressor usage (e.g., norepinephrine, epinephrine, or vasopressin) and underwent blood culture test and antibiotics adminis- tration. Patients with concomitant hematological disease, inter-facility transfer, or a cardiac event before ED arrival were excluded. This study protocol followed the STROBE guidelines [18] and was approved by the local institutional review board, and the requirement for informed consent was waived due to the retrospective observational nature of the study.

• 1. Data collection

The eligible patients were divided into survivor and non-survivor groups based on their survival status at the 60-day follow-up. The base- line characteristics, comorbidities, microbiological data, source of sepsis, and antibiotics administration were collected from manual chart review and electronic medical records. Laboratory results (e.g., hemoglobin, leukocyte, bilirubin, etc.) were obtained within six hours of septic shock recognition. Child-Pugh score, MELD score, and presence of acute-on-chronic liver failure (ACLF) were calculated based on these laboratory results [19,20]. The Neutrophil-to-lymphocyte ratio was calculated by dividing the neutrophil count by the lymphocyte count, and LMR was calculated by dividing the lymphocyte count by the Monocyte count.

• 1. Definitions

The SIRS criteria were defined as positive if at least 2 of these criteria were met: body temperature <36 ?C or >38 ?C, heart rate >90 beats/ min, respiratory rate >20 breaths/min, white blood cells <0.4 x 10⁹/L or >1.2 x 10⁹/L, or bandemia >=10% [21]. The qSOFA score was calculated using the initial ED triage parameter: Glasgow coma score <15, respira- tory rate >=22 breaths/min, and systolic blood pressure <=100 mmHg [16]. A qSOFA score of >=2 points was used as the prognostic cutoff value based on previous studies [22]. The source of sepsis was classified as respira- tory tract infection (radiological increased infiltration combined with

clinical symptoms), urinary tract infection (urinalysis revealed pyuria and bacteriuria), Spontaneous bacterial peritonitis (paracentesis with leukocyte count of >=250 cells/uL), soft tissue infection, and others ac- cording to the corresponding discharge diagnosis of each patient. For culture-positive septic shock, the initial antibiotics was considered ap- propriate if the cultured pathogen was susceptible to it based on the re- sults of an In vitro susceptibility test. For culture-negative septic shock, the initial antibiotics was considered appropriate if the agent was con- sistent with empiric management for the disease according to the prac- tice guideline suggestions [23].

• 1. Statistical analysis

Data were presented as means with standard deviation or medians with interquartile range for continuous variables, and numbers (%) for categorical variables. The two- sample t-test was used to compare con- tinuous variables, and the Mann-Whitney test was performed if they were not normally distributed. The chi-square test was used to compare categorical variables. A Cox proportional hazards regression model was used to analyze independent factors associated with 60-day mortality in cirrhotic patients with septic shock. We incorporated all variables with a p-value <0.1 in the univariate analysis into the regression model. The proportional hazards assumption was tested for each variable before being included in the final regression model. The mortality discrimina- tive ability of these independent factors was tested by using area under receiver operating characteristic curves, and the optimal cutoff point was identified using the Youden index. The Delong method was used to compare the Area under curve of the studied vari- ables [24]. The Kaplan-Meier survival analysis was used to analyze the 60-day survival differences between study groups, and the ratio was compared using the log-rank test. A two-tailed p-value <0.05 was con- sidered statistically significant. All statistical analyses were performed using the Statistical Package for the Social Sciences version 22.0 and MedCalc version 18.2.1 software.

1. Results

As shown in Fig. 1, a total of 1069 adult patients with diagnosed of liver cirrhosis visited the ED during the study period, and 108 patients had septic shock. After excluding patients with concomitant hematolog- ical disease (N = 3), a cardiac arrest event before ED visit (N = 4), and inter-facility transfer (N = 8), the remaining 93 cirrhotic patients with septic shock were finally analyzed.

• 1. Demographic and clinical characteristics

The overall 60-day in-hospital mortality rate of the patients was 66.7% (62/93). As shown in Table 1, the mean age of the patients was

56.7 +- 11.0 years, and more than three-fourth (79.6%) were male. More than half (51.6%) of the patients had cirrhosis attributed to alcohol consumption, and the majority of the studied patients had advanced cir- rhosis based on the Child-Pugh and MELD scores. A small proportion of the patients had concomitant comorbidities.

• 1. Sepsis severity and source records

As shown in Table 2, most patients (75.3%) met the SIRS criteria, whereas a small portion (31.2%) belonged to the high qSOFA group. The majority of the patients (60.2%) had bacteremia (i.e., bloodstream infection), and more than half (52.7%) had ACLF development. Only a small portion (10.8%) had culture-negative septic shock. About three- quarters of the patients (75.3%) received appropriate antibiotics admin- istration for septic shock management. Regarding the source of sepsis, spontaneous bacterial peritonitis (45.2%) accounted for the leading cause of infection, followed by respiratory (18.3%) and urinary tract in- fection (15.1%).

Fig. 1. Flowchart of patient enrollment.

• 1. Subgroup analysis

We divided patients into non-survivor and survivor groups based on their survival status at the 60-day follow-up for comparison. As shown in Table 1, patients in the non-survivor group had significantly higher Child-Pugh and MELD scores, they also had significantly higher serum

International normalized ratio , bilirubin, lactate, and Creatinine levels. Notably, patients in the non-survivor group had significantly higher NLR (13.0 vs. 10.3, p = 0.02) and lower LMR (1.1 vs. 2.3, p < 0.01) compared to the patients in the survivor group. Regarding the sepsis severity and source record, patients in the non-survivor group had a significantly higher proportion of ACLF development.

Table 1

Baseline characteristics of cirrhotic patients with septic shock (n = 93)

Characteristics	All		Non-survivors		Survivors	p value
	(n = 93)		(n = 62)		(n = 31)
Age, y, mean +- SD	56.7 +- 11.0		56.9 +- 11.9		56.2 +- 9.2	0.77
Male, n (%)	74 (79.6)		51 (82.3)		23 (74.2)	0.42
Etiology of cirrhosis, n (%)
Alcohol	48 (51.6)		34 (54.8)		14 (45.2)	0.39
viral hepatitis	28 (30.1)		18 (29.0)		10 (32.3)	0.81
Other	17 (18.3)		10 (16.1)		7 (22.6)	0.57
Child-Pugh score, mean +- SD	10 +- 2		11 +- 2		9 +- 2	<0.001?
MELD score, mean +- SD	27 +- 7		29 +- 6		22 +- 8	<0.001?
Comorbidities, n (%)
Diabetes mellitus	29 (31.2)		19 (30.6)		10 (32.3)	1.00
Hypertension	22 (23.7)		17 (27.4)		5 (16.1)	0.30
Malignancy	27 (29.0)		18 (29.0)		9 (29.0)	1.00
Cerebrovascular accident	12 (12.9)		8 (12.9)		4 (12.9)	1.00
obstructive lung disease	20 (21.5)		14 (22.6)		6 (19.4)	0.80
Laboratory results
Hemoglobin, g/dL, mean +- SD	10.3 +- 2.4		10.2 +- 2.6		10.5 +- 2.0	0.54
Leukocyte, x109/L, mean +- SD	11.2 +- 7.7		11.9 +- 7.7		9.8 +- 7.6	0.22
Platelet, x109/L, median(IQR) INR, median(IQR) Bilirubin, mg/dL, median(IQR)	73.0(45.5-125.5) 1.6 (1.3-2.0) 5.2 (2.4-11.9)		70.5 (44.5-131.8) 1.7 (1.4-2.1) 6.0 (3.0-13.1)		75.0 (46.0-101.0) 1.4 (1.2-1.6) 3.3 (2.0-6.9)	0.94 0.03? 0.02?
Sodium, mmol/L, mean +- SD Lactate, mmol/L, median (IQR) Creatinine, mg/dL, median(IQR)	131 +- 8 3.9 (2.3-8.4) 2.0 (1.4-2.8)		130 +- 9 5.4 (2.9-10.6) 2.2 (1.4-3.3)		132 +- 5 2.7 (1.4-4.2) 1.6 (1.2-2.2)	0.17 <0.01? 0.04?
CRP, mg/dL, median(IQR)	19.6 (2.6-78.4)		24.0 (3.8-69.8)		10.9 (1.3-100.0)	0.67
Albumin, g/dL, mean +- SD NLR, median(IQR) LMR, median(IQR)	2.7 +- 0.5 10.6 (6.5-22.5) 1.4 (0.8-3.0)		2.7 +- 0.5 13.0 (7.0-29.7) 1.1 (0.5-2.7)		2.8 +- 0.5 10.3 (5.6-14.3) 2.3 (1.3-5.0)	0.21 0.02? <0.01?

SD: standard deviation. MELD: Model for End-stage Liver Disease. IQR: interquartile range. INR: International Normalized Ratio. CRP: C-reactive protein. NLR: neutrophil-to-lymphocyte ratio. LMR: lymphocyte-to-monocyte ratio.

by dividing them into the high LMR (>0.89) and low LMR (<=0.89) groups. As shown in Fig. 3, there were significant differences in the 60-day survival probability between the two groups (log-rank p < 0.001), indicating better outcomes in the high LMR group.

Table 2 Sepsis severity and source in cirrhotic pa	tients wit	h	septic shock (n	= 93)		and lactate were 0.89 and 4.50, respectively (Table 4). We then used the Kaplan-Meier curve to further compare the prognosis of our patients
Variables	All		Non-survivors		Survivors	p
	(n = 93)		(n = 62)		(n = 31)	value
SIRS, n (%)	70 (75.3)		47 (75.8)		23 (74.2)	1.00
qSOFA score >= 2, n (%)	29 (31.2)		21 (33.9)		8 (25.8)	0.48
ACLF, n (%)	49 (52.7)		38 (61.3)		11 (35.5)	0.03?
Culture-negative?, n (%)	10 (10.8)		8 (12.9)		2 (6.5)	0.48
Bacteremia, n (%)	56 (60.2)		37 (59.7)		19 (61.3)	1.00
Infection Source, n (%)
Respiratory tract infection	17 (18.3)		13 (21.0)		4 (12.9)	0.41
Urinary tract infection	14 (15.1)		7 (11.3)		7 (22.6)	0.22
Spontaneous bacterial peritonitis	42 (45.2)		29 (46.8)		13 (41.9)	0.83
Soft tissue infection	12 (12.9)		6 (9.7)		6 (19.4)	0.21
Other	8 (8.6)		7 (11.3)		1 (3.2)	0.26
Appropriate antibiotics, n (%)	70 (75.3)		48 (77.4)		22 (71.0)	0.61
SIRS: Systemic Inflammatory Response Syndrome. qSOFA: quick Sepsis Related Organ Fail- ure Assessment. ACLF: Acute-on-chronic liver failure.

* P < 0.05.

^? septic shock without any pathogen isolated (blood, sputum, urine, ascites, wound).

There was no statistical difference (p = 0.61) in receiving appropriate antibiotics administration between the two groups.

• 1. Outcome measurement

We used Cox proportional hazard regression analysis to identify independent factors associated with 60-day mortality risk in cirrhotic patients with septic shock. To avoid collinearity, we omitted ACLF, Child-Pugh score, and MELD score from the final regression model be- cause they shared identical variables with our studied parameters (e.g., Serum bilirubin, INR). As shown in Table 3, the serum lactate, bili- rubin, NLR, and LMR were identified as significant factors by univariate analysis, and the serum lactate level (adjusted hazard ratio [aHR] = 1.03, p < 0.01) and LMR (aHR = 0.54, p = 0.01) remained independent factors in the multivariate stepwise regression analysis.

We further compared the mortality discriminative ability between serum lactate, LMR, Child-Pugh score, and MELD score by using ROC curves. As shown in Fig. 2, the AUC of LMR and lactate for mortality dis- crimination was 0.87 (95% confidence interval [CI] = 0.78-0.93) and

0.68 (95% CI = 0.57-0.77), respectively; the AUC of MELD and Child- Pugh score was 0.76 (95% CI = 0.66-0.84) and 0.72 (95% CI =

0.61-0.80). The area under the receiver operating characteristic of LMR was significantly higher than MELD (p = 0.04) and Child-Pugh score (p = 0.02). Using the Youden index, the cutoff values of LMR

1. Discussion

In this ED-based single-center retrospective study, we investigated the characteristics and outcomes of cirrhotic patients with septic shock. We demonstrated that bacteremia and ACLF occurred frequently in this fragile group with septic shock, resulting in a substantially high mortality rate. More importantly, we validated that peripheral blood LMR was an independent factor associated with 60-day mortality risk in cirrhotic patients with septic shock, and LMR revealed superior prog- nosis discriminative ability compared with Child-Pugh and MELD scores. To the best of our knowledge, this is the first study to provide ev- idence for a prognostic association between LMR and cirrhotic patients with septic shock.

Patients with cirrhosis frequently have bacterial infection and sepsis because of the interaction of gut microbiota alteration, pathological bac- terial translocation, and immune dysfunction [23]. Cirrhosis- associated immune dysfunction affects various types of immune systems, impairs leukocyte function, decreases complement synthesis and phagocytic ac- tivity. Infection-induced excessive circulating pro-inflammatory cyto- kines (tumor necrosis factor-? and IL-6) further predispose cirrhotic patients to serious complications that, include organ failure, shock, and mortality [2,6,23]. Unlike non-cirrhotic patients, cirrhotic patients have lower baseline Blood pressure and heart rate, lack of fever, tachypnea or elevated inflammatory markers (e.g., C-reactive protein, procalcitonin) when they have infection, making the recognition and management of sepsis/septic shock difficult and often delayed [1,5,7].

It is not surprising that the patients in the non-survivor group had significantly higher.

serum INR, bilirubin, and creatinine levels, as they are important organ parameters, and organ dysfunction is a strong prognostic predic- tor in cirrhotic patients with acute decompensation [20]. In contrast, the SIRS and qSOFA scores mainly rely on hemodynamic parameters (e.g., respiratory rate, heart rate, and consciousness level) to stratify septic patients, but their diagnostic accuracy is decreased in patients with cirrhosis due to their hyperdynamic circulatory status and medica- tion use [9,25]. In fact, SIRS was estimated to be present in 10-30% of de- compensated cirrhotic patients without infection [25], and qSOFA was

Table 3

Univariate and multivariate regression analysis of factors associated with 60-day mortality in cirrhotic patients with septic shock (n = 93)

Variables	Univariate			Multivariate
	HR (95% CI)	p value		HR (95% CI)	p value
Age (year)	1.01 (0.97-1.05)	0.57
Gender (male)	1.03 (0.64-1.65)	0.91
Child-Pugh score	1.42 (1.14-1.78)	<0.01?
MELD score	1.19 (1.09-1.30)	<0.001?
ACLF	1.60 (1.06-2.40)	0.02?
INR	2.00 (0.91-3.52)	0.11
Lactate	1.02 (1.01-1.03)	<0.01?	1.03 (1.01-1.05)		<0.01?
Bilirubin	1.07 (1.01-1.14)	0.03?	1.09 (0.99-1.20)		0.30
Creatinine	1.18 (0.90-1.55)	0.22
NLR	1.09 (1.03-1.15)	<0.01?	1.05 (0.99-1.11)		0.24
LMR	0.61 (0.44-0.83)	<0.01?	0.54 (0.34-0.87)		0.01?
Spontaneous bacterial peritonitis	1.27 (0.88-1.84)	0.28
Biliary tract infection	0.67 (0.43-1.10)	0.15

HR: hazard ratio. CI: confidence interval. MELD: Model for End-stage Liver Disease. ACLF: Acute-on-chronic liver failure. INR: International Normalized Ratio. NLR: neutrophil-to-lympho- cyte ratio. LMR: lymphocyte-to-monocyte ratio.

Fig. 2. Receiver operating characteristic curves for 60-day mortality prediction of LMR, serum lactate, Child-Pugh score and MELD score in cirrhotic patients with septic shock.

reported to have limited adverse outcome predicting ability in patients with cirrhosis in recent studies [9,26].

Compared with SIRS and qSOFA scores, the Child-Pugh and MELD scores have been widely used as prognostic predictors in cirrhotic

patients under various conditions, including sepsis [19]. Since both scores adopted parameters that reflect the functional status of vital or- gans, which are important in outcome stratification in patients with cir- rhosis, it is reasonable that both scores revealed moderate mortality discriminative ability in our study (Fig. 2). Nevertheless, the calculation of Child-Pugh score may be influenced by drug use and clinicians’ judg- ment for the severity estimation of ascites and Hepatic encephalopathy, and the MELD score may be affected by laboratory measurement varia- tions [27,28], making their applications limited in some situations.

The novel finding in our study was to validate the prognostic signifi- cance of peripheral blood LMR in cirrhotic patients with septic shock. Monocytes are central mediators in the immune system and are activated by inflammatory responses and endotoxin stimuli, resulting in multiple pro-inflammatory cytokines released into the circulatory system. Endotoxin-driven monocyte activation is a key factor of SIRS and organ failure in patients with HBV cirrhosis [12,29]. Furthermore, patients with cirrhosis have monocytes with decreased human leukocyte antigen-DR expression, and are associated with immune dissonance and high bacterial infection complications [29]. Lymphocytes are the basic components of the host immune system, and the disruption of immunity in cirrhosis re- sults in lymphopenia [30]. Taken together, low LMR (i.e., decreased lym- phocytes and increased monocytes) reflects the severity and liver injury progression as well as the immune system disarrangement in patients with cirrhosis. LMR was recognized as a mortality predictor in patients with HBV cirrhosis or Hepatocellular carcinoma who underwent surgical resection [12,29-32]. In our study, LMR was a much easier and readily available clinical parameter and revealed better mortality discriminative ability compared with the Child-Pugh and MELD scores (Fig. 2).

Our study also identified serum lactate as an independent mortality risk predictor in cirrhotic patients with septic shock. Lactate has been recognized as a marker of tissue hypoxia and systemic hypoperfusion

Table 4

Area under curve (AUC), cutoff value, sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio of LMR and lactate

Variables	AUC	Cutoff value	Sensitivity	Specificity	Positive likelihood ratio	Negative likelihood ratio
LMR	0.87	0.89	0.59	0.98	28.95	0.42
lactate	0.68	4.5	0.64	0.71	2.23	0.51

LMR: lymphocyte-to-monocyte ratio.

Fig. 3. The Kaplan-Meier survival analysis for a 60-day cumulative survival probability stratified by LMR in cirrhotic patients with septic shock.

and was proposed as a routine examination in patients with sepsis/sep- tic shock in a recent updated guideline [33]; however, other conditions, including severe trauma, medication use (e.g., metformin, cyanide, sa- licylates), and Chronic liver disease may also affect lactate levels, com- plicating the interpretation of these situations [34]. Notably, although hyperlactatemia is common in patients with chronic liver disease due to decreased Lactate clearance, its initial and follow-up measurement level still correlated well with disease severity and organ failure, further associated with short-term mortality in critically ill patients with cirrho- sis in several large cohort studies [17,35]. Our study confirmed the prog- nostic value of lactate; therefore clinicians can utilize both LMR and lactate for outcome prediction in cirrhotic patients with septic shock.

There were several limitations to our study. First, this was a single- center retrospective study, which made the recall and selection bias in- evitable. Second, the mechanism between the LMR and progression of sepsis and septic shock (such as tumor necrosis factor-? and IL-6) in cir- rhotic patients was not investigated. Finally, the relatively small sample size of this study limited the generalization of these results to other in- stitutions. Future larger multicenter prospective studies are warranted to validate these findings.

1. Conclusions

In conclusion, this study demonstrated the prognostic value of pe- ripheral blood LMR in cirrhotic patients with septic shock. The LMR is a simple, rapid, and easily calculated from the differential white blood cells in a daily routine measurement. Clinicians could use this parameter as a prognostic marker to stratify patients with cirrhosis and septic shock more rapidly, to initiate prompt treatment in high-risk patients.

Ethics approval and consent to participate

This observational study was approved by the Institutional Review Board of E-Da hospital (EMRP-108-144). Informed consent was waived due to the retrospective observational nature of the study.

Consent for publication

Not applicable.

Availability of data and materials

The datasets used and/or analyzed during the present study are available from the corresponding author upon reasonable request.

Funding

Not applicable.

Credit author statement

Yin-Chou Hsu: conceived and designed the study, drafted the manu- script, conducted the data extraction and manual chart review.

Yong-Ye Yang: conducted the data extraction and manual chart review, performed data analysis.

I-Ting Tsai: performed data analysis, critically revised the manu- script and final approval.

Disclosure statement

None declared.

Declaration of Competing Interest

The authors declare that they have no competing interest.

Acknowledgments

Not applicable.

References

1. Tsochatzis EA, Bosch J, Burroughs AK. Liver cirrhosis. Lancet. 2014;383(9930): 1749-61.
2. Bunchorntavakul C, Chamroonkul N, Chavalitdhamrong D. Bacterial infections in cir- rhosis: a critical review and practical guidance. World J Hepatol. 2016;8(6):307.
3. Jalan R, Yurdaydin C, Bajaj JS, Acharya SK, Arroyo V, Lin H-C, et al. Toward an im- proved definition of acute-on-chronic liver failure. Gastroenterology. 2014;147(1): 4-10.
4. Vincent J-L, Jones G, David S, Olariu E, Cadwell KK. Frequency and mortality of septic shock in Europe and North America: a systematic review and meta-analysis. Crit Care. 2019;23(1):1-11.
5. Moreau R, Hadengue A, Soupison T, Kirstetter P, Mamzer M-F, Vanjak D, et al. Septic shock in patients with cirrhosis: hemodynamic and metabolic characteristics and in- tensive care unit outcome. Crit Care Med. 1992;20(6):746-50.
6. Gustot T, Durand F, Lebrec D, Vincent JL, Moreau R. Severe sepsis in cirrhosis. Hepatology. 2009;50(6):2022-33.
7. Piano S, Bartoletti M, Tonon M, Baldassarre M, Chies G, Romano A, et al. Assessment of Sepsis-3 criteria and quick SOFA in patients with cirrhosis and bacterial infections. Gut. 2018;67(10):1892-9.
8. Patidar KR, Shaw J, Acharya C, Thacker LR, White MB, Ganapathy D, et al. No associ- ation between quick sequential organ failure assessment and outcomes of patients with cirrhosis and infections. Clin Gastroenterol Hepatol. 2017;15(11):1803-4.
9. Son J, Choi S, Huh JW, Lim C-M, Koh Y, Kim KM, et al. The quick sepsis-related organ failure score has limited value for predicting adverse outcomes in sepsis patients with liver cirrhosis. Korean J Intern Med. 2020;35(4):861.
10. Lim L-G, Tan X-XE, Woo S-J, Dan Y-Y, Lee Y-M, Lai V, et al. Risk factors for mortality in cirrhotic patients with sepsis. Hepatol Int. 2011;5(3):800-7.
11. Kwon JH, Jang JW, Kim YW, Lee SW, Nam SW, Jaegal D, et al. The usefulness of C- reactive protein and neutrophil-to-lymphocyte ratio for predicting the outcome in hospitalized patients with liver cirrhosis. BMC Gastroenterol. 2015;15(1):1-7.
12. Jamil Z, Durrani AA. Assessing the outcome of patients with liver cirrhosis during hospital stay: a comparison of lymphocyte/monocyte ratio with MELD and child- Pugh scores. Turk J Gastroenterol. 2018;29(3):308.
13. Biyik M, Ucar R, Solak Y, Gungor G, Polat I, Gaipov A, et al. Blood neutrophil-to- lymphocyte ratio independently predicts survival in patients with liver cirrhosis. Eur J Gastroenterol Hepatol. 2013;25(4):435-41.
14. Rice J, Dodge JL, Bambha KM, Bajaj JS, Reddy KR, Gralla J, et al. Neutrophil-to-Lym- phocyte ratio associates independently with mortality in hospitalized patients with cirrhosis. Clin Gastroenterol Hepatol. 2018;16(11):1786-91 e1.
15. Zhu S, Waili Y, Qi X, Chen Y, Lou Y. Lymphocyte-monocyte ratio at admission pre- dicts possible outcomes in patients with acute-on-chronic liver failure. Eur J Gastroenterol Hepatol. 2017;29(1):31-5.
16. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA. 2016;315(8):801-10.
17. Drolz A, Horvatits T, Rutter K, Landahl F, Roedl K, Meersseman P, et al. Lactate im- proves prediction of short-term mortality in critically ill patients with cirrhosis: a multinational study. Hepatology. 2019;69(1):258-69.
18. Von Elm E, Altman DG, Egger M, Pocock SJ, Gotzsche PC, Vandenbroucke JP. The strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting observational studies. Ann Intern Med. 2007; 147(8):573-7.
19. Peng Y, Qi X, Guo X. Child-Pugh versus MELD score for the assessment of prognosis in liver cirrhosis: a systematic review and meta-analysis of observational studies. Medicine. 2016;95(8):e2877.
20. Moreau R, Jalan R, Gines P, Pavesi M, Angeli P, Cordoba J, et al. Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis. Gastroenterology. 2013;144(7):1426-37 e9.
21. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and sep- tic shock, 2012. Intensive Care Med. 2013;39(2):165-228.
22. Jiang J, Yang J, Mei J, Jin Y, Lu Y. Head-to-head comparison of qSOFA and SIRS criteria in predicting the mortality of infected patients in the emergency department: a meta-analysis. Scand J Trauma Resus Emer Med. 2018;26(1):56.
23. Jalan R, Fernandez J, Wiest R, Schnabl B, Moreau R, Angeli P, et al. Bacterial infections in cirrhosis: a position statement based on the EASL special conference 2013. J Hepatol. 2014;60(6):1310-24.
24. DeLong ER, DeLong DM, Clarke-Pearson DL. Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. Bio- metrics. 1988:837-45.
25. Fernandez J, Gustot T. Management of bacterial infections in cirrhosis. J Hepatol. 2012;56:S1-S12.
26. Muller M, Schefold JC, Leichtle AB, Srivastava D, Lindner G, Exadaktylos A, et al. qSOFA score not predictive of in-hospital mortality in emergency patients with de- compensated liver cirrhosis. Medizinische Klinik-Intensivmedizin und Notfallmedizin. 2019;114(8):724-32.
27. Trotter JF, Brimhall B, Arjal R, Phillips C. Specific laboratory methodologies achieve higher model for endstage liver disease (MELD) scores for patients listed for liver transplantation. Liver Transpl. 2004;10(8):995-1000.
28. Cholongitas E, Marelli L, Kerry A, Senzolo M, Goodier DW, Nair D, et al. Different methods of creatinine measurement significantly affect MELD scores. Liver Transpl. 2007;13(4):523-9.
29. Zhang J, Feng G, Zhao Y, Zhang J, Feng L, Yang J. Association between lymphocyte-to- monocyte ratio (LMR) and the mortality of HBV-related liver cirrhosis: a retrospec- tive cohort study. BMJ Open. 2015;5(8).
30. Lin Z-X, Ruan D-Y, Li Y, Wu D-H, Ma X-K, Chen J, et al. Lymphocyte-to-monocyte ratio predicts survival of patients with hepatocellular carcinoma after curative resec- tion. World J Gastroenterol: WJG. 2015;21(38):10898.
31. Yang Y-T, Jiang J-H, Yang H-J, Wu Z-j, Xiao Z-M, Xiang B-D. The lymphocyte-to- monocyte ratio is a superior predictor of overall survival compared to established biomarkers in HCC patients undergoing liver resection. Sci Rep. 2018;8(1):1-7.
32. Piotrowski D, Saczewska-Piotrowska A, Jaroszewicz J, Boron-Kaczmarska A. Lym- phocyte-to-monocyte ratio as the best simple predictor of bacterial infection in pa- tients with liver cirrhosis. Int J Environ Res Public Health. 2020;17(5):1727.
33. Levy MM, Evans LE, Rhodes A. The surviving sepsis campaign bundle: 2018 update. Intensive Care Med. 2018;44(6):925-8.
34. Kraut JA, Madias NE. Lactic acidosis. N Engl J Med. 2014;371(24):2309-19.
35. Sun D-Q, Zheng C-F, Lu F-B, Van Poucke S, Chen X-M, Chen Y-P, et al. Serum lactate level accurately predicts mortality in critically ill patients with cirrhosis with acute kidney injury. Eur J Gastroenterol Hepatol. 2018;30(11):1361-7.