a b s t r a c t

Background: neutrophil-to-lymphocyte ratio has been used to predict the prognosis of patients with sepsis with inconsistent results. This meta-analysis aimed to clarify the prognostic value of NLR in patients with sepsis.

Methods: A Comprehensive literature search for relevant studies, published prior to March 2019, was conducted using PubMed, Web of Science, and the China National Knowledge.

Infrastructure database. Standard mean differences (SMDs) with 95% confidence intervals (CI) were used to evaluate the NLR of patients with sepsis retrospectively. Hazard ratios (HRs) with 95% CIs were used to evaluate the prognostic value of NLR in patients with sepsis.

Results: Patients from 14 studies (n = 11,564) were selected for evaluation. Nine studies (1371 patients) analyzed the NLR in these patients. The pooled results showed significantly higher NLR in non-survivors than in survivors (random-effects model: SMD = 1.18, 95% CI; 0.42-1.94). Nine studies (10,685 patients) evaluated the prognostic value of NLR for sepsis; the pooled results showed that higher NLR was associ- ated with poor prognosis in patients with sepsis (fixed-effects model: HR = 1.75, 95% CI; 1.56-1.97). Subgroup analysis revealed that study design, cut-off NLR, or primary outcome did not affect the prog- nostic value of NLR in patients with sepsis.

Conclusion: This meta-analysis indicates that NLR may be a helpful Prognostic biomarker of patients with sepsis and that higher NLR values may indicate unfavorable prognoses in these patients.

(C) 2019

Introduction

To date, sepsis remains a major cause of morbidity and mortal- ity in both developed and Developing countries. Despite advances in sepsis treatment and critical care modalities in the past decades, the mortality rate in patients with sepsis, especially septic shock patients, remains high at approximately 30%.[1,2] This high mor- tality rate can attributed in part to low awareness, late identifica- tion, and improper management of the disease.[3] Early and accurate identification of patients with sepsis with high mortality risk is critical for appropriate management of these patients.[4] Although many clinical biomarkers have been investigated,[5-7] few are currently applied in clinical practice because of the com- plexity and heterogeneity of sepsis. Therefore, the identification of useful biomarkers is imperative to provide timely and adequate interventions to patients with sepsis.

* Corresponding author at: Department of Intensive Care Unit, First People’s Hospital of Qinzhou, Qianjin Road 47, Qinzhou 535001, China.

E-mail addresses: [email protected] (Z. Huang), [email protected] (Z. Fu), [email protected] (K. Huang).

The Neutrophil-to-lymphocyte ratio is an indicator of sys- temic inflammation based on complete blood count values. In gen- eral, blood Neutrophil count increases with the progress of inflammatory disease; however, in certain conditions like cachexia, the neutrophil count does not increase, resulting in ”false negative” condition when evaluating Disease progression. lymphocyte count reflects the immune status of a patient, and generally decreases as inflammatory disease progresses; however, this decrease is rela- tively delayed and may not reflect disease progression well.[8,9] Recently, studies have reported that the NLR is more reliable when predicting patient survival than either neutrophil count or lym- phocyte count alone.[10,11] The NLR increases with disease pro- gression, especially in inflammatory disease, and this increase is consistent with the development of some diseases.[12] Further- more, NLR is simple, inexpensive, and easily obtained. According to Forget et al., the mean NLR in Belgian adults who were non geri- atric and in good health was 1.65.[13] Similarly, data from a healthy South Korean population (n = 12,160) showed that the mean NLR across all ages was 1.65, and the mean NLR of men and women were 1.63 and 1.66, respectively.[14] These results demonstrate that the NLR may be similar among different ethnic-

https://doi.org/10.1016/j.ajem.2019.10.023

0735-6757/(C) 2019

ities, and an NLR of 1.65 might be proposed as a reference value for healthy patients.

Numerous studies have shown that a high NLR can be an inde- pendent predictor of prognosis in various clinical situations, including malignancies, cardiovascular disease, acute respiratory distress syndrome, and fibrotic liver diseases.[15-19] Although the association between NLR and mortality has been investigated in patients with sepsis, the association between NLR and clinical prognosis remains controversial.[20,21] Generally, the discrepan- cies in study results are attributed to different sample sizes or other confounding parameters that may affect the association.

Meta-analysis is a quantitative statistical analysis of several separate but similar studies that is used to systematically assess the pooled data for statistical significance. Conclusions from a meta-analysis may more precisely estimate the effect of treatment or risk of disease than any individual study contributing to the Pooled analysis[22]. This approach is widely used for assessing prognostic indicators in critically ill patients. In general, the NLR increases with both the occurrence of systemic inflammatory dis- ease and the degree of inflammation. However, the exact prognos- tic value of NLR in sepsis remains to be clarified. Therefore, this study aimed to evaluate the association between NLR and the prognoses of patients with sepsis by meta-analysis.

Materials and methods

Search strategy and selection criteria

The meta-analysis was conducted in accordance with the guidelines of the Preferred Reporting Items for Systematic Review and Meta-analyses statement.[23] PubMed, Web of Science, the Chinese National Knowledge Infrastructure database (CNKI), and the Chinese Biomedical Database (SinoMed) were systematically searched to identify suitable articles published before March 2019. The search terms included: ”sepsis” or ”septic,” ”neutrophil-to-lymphocyte ratio” or ”NLR,” and ”prognosis.” We searched for articles in all languages, which were translated when necessary. The search was limited to articles on human studies. Articles were also identified using the ”related articles” function in PubMed and by manually searching the references within iden- tified articles. The search strategy used for this review is shown in the Supplementary file. The study protocol was approved by the ethics committee of the First People’s Hospital of Qinzhou.

Inclusion and exclusion criteria

The inclusion criteria were as follows: (1) studies in which patients with sepsis were selected according to the standard defi- nitions of sepsis and septic shock[24,25] and were managed according to international guidelines;[26,27] (2) studies providing NLR data of patients with sepsis or those providing NLR data for predicting sepsis from multivariate logistic regression analysis; and (3) studies providing data at the time of NLR evaluation. The exclusion criteria were as follows: (1) review articles, case reports, or case series; (2) studies involving cell lines, animals, or human xenograft experiments; and (3) studies that only provided NLR data from unadjusted univariate analysis. If the same patient pop- ulation was reported in several articles, we selected only the most comprehensive articles.

Data extraction and quality assessment of included studies

Study data were extracted independently by two reviewers. Disagreements between the reviewers were resolved by discussion and consensus. The extracted data included the following: first

author names, year of publication, sample source, study design, primary outcome, number of survivors and non-survivors, time of NLR testing, cut-off NLR value, and method of blood testing. The methodological quality of each study was assessed and scored according to the Newcastle-Ottawa Quality Assessment Scale [28]. The following items were assessed in each study: exposed cohort, ascertainment of exposure, outcome of interest, comparability of cohorts, assessment of outcome, and adequacy of follow-up. Studies with scores of 6 or higher were considered to be of high quality.

Statistical analysis

Standard mean differences (SMDs) were used to accommodate the differences in NLR measurement techniques across various studies. In this study, SMDs and corresponding 95% confidence intervals (CIs) were used to evaluate the differences in NLR among patients with sepsis. Hazard ratios (HR) with 95% CIs were used to quantitatively estimate the prognostic value of NLR in patients with sepsis. Heterogeneity among studies was evaluated using Cochran’s Q test and the I² statistic. The SMDs and HR were calcu- lated using a fixed-effects model (the Mantel-Haenszel method) in the absence of substantial study heterogeneity (I² < 50%). Other- wise, a random-effects model (the DerSimonian-Laird method) was used. Sensitivity analysis was performed by the sequential exclusion of each study to test the reliability of the overall pooled results. Subgroup analysis was performed to evaluate narrow sub- sets of the studies. To identify sources of heterogeneity, we used meta-regression to examine the effects of differences in study design, cut-off NLR value, primary outcome, and ethnicity of patients. To investigate whether publication bias affects the valid- ity of the estimates, funnel plots were constructed and assessed using Egger’s and Begg’s tests. All statistical analyses were per- formed using Stata 11.2 software (Stata Corp, College Station, TX). A two-tailed P-value < 0.05 was considered statistically significant.

Results

Identification of relevant studies

The initial literature search retrieved 68 potentially eligible studies based on the predefined selection criteria. We excluded 30 studies after screening the titles and abstracts. After a detailed evaluation of the full texts, 24 studies were excluded, including 10 with insufficient data, eight that were case series, four that were reviews, and two that were irrelevant to the present analysis. Thus,

14 studies [20,21,29-40] comprising 11,564 patients, including 9455 survivors and 2109 non-survivors, were included in this meta-analysis. Fig. 1 shows a flow chart summarizing the Selection process.

Study characteristics and quality assessment

Among the 14 included studies, patients with sepsis from 4 studies[20,21,29,30] were of Caucasian ethnicity. Four studies [20,21,29,31] had prospective designs; nine studies[20,32,33,35- 40] provided NLR data for both survivors and non-survivors, whereas nine studies[21,29-31,33-35,38,39] provided NLR data for predicting sepsis from multivariate logistic regression analysis. Only one study[31] used NLR measured on day two after admis- sion. Nine studies[21,31,32,34-38,40] used 28-day mortality as the primary outcome; other primary outcomes included in- hospital mortality or intensive care unit mortality. The quality of

Fig. 1. Flowchart of the study selection process.

the studies was high, with scores ranging from 7 to 9. The demo- graphic data of the patients in each study are listed in Table 1.

Comparison of NLR between survivors and non-survivors

Nine of 14 studies, [20,32,33,35-40] comprising 1371 patients with sepsis, compared NLR between survivors and non-survivors. After analysis, our results showed that NLR was significantly higher in non-survivors than in survivors (random-effects model: SMD = 1.18, 95% CI; 0.42-1.94, p = 0.002). However, significant heterogeneity was observed across the studies (I² = 96.8%, p < 0.01; Fig. 2). Sensitivity analysis showed results similar to the overall results. No significant publication bias was found among these studies (Egger’s test: p = 0.223; Begg’s test: p = 0.118; Fig. 3).

Association of NLR with prognosis in patients with sepsis

Nine studies,[21,29-31,33-35,38,39] comprising 10,685 patients, evaluated the prognostic value of NLR in patients with sepsis. The pooled results showed that higher NLR were associated with poor prognosis in patients with sepsis (fixed-effects model: HR = 1.75, 95% CI; 1.56-1.97, p < 0.01). No significant heterogeneity was observed among the studies (I² = 47.3%, p = 0.056; Fig. 4).

Sensitivity analysis showed results similar to the overall results, suggesting the robustness of the overall results. The analysis for publication bias indicated no significant publication bias among the studies (Egger’s test: p = 0.051; Begg’s test: p = 0.076; Fig. 5).

Subgroup analysis of prognosis in patients with sepsis

To identify other parameters that could affect the prognostic value of NLR in patients with sepsis, a subgroup analysis was per- formed based on several confounders, including study design (prospective or retrospective), cut-off NLR value (>10 or < 10), and primary outcome (28-day mortality or other mortality). The results of subgroup and meta-regression analyses showed that the study design, cut-off NLR value, primary outcome, and ethnic- ity of the patients did not affect the prognostic value of NLR in patients with sepsis (Table 2).

Discussion

The present meta-analysis of 14 studies, including 11,564 patients with sepsis, showed that the NLR was significantly higher in non-survivors than in survivors and that higher NLR was associ- ated with prognosis in patients with sepsis. Furthermore, analysis

Table 1

Characteristics of the included studies.

Study	Country/ year	Study design	Disease severity	Mean Age (yrs)	Survival/ Death	Primary outcome	Test time	Cut-off value	Test Method	Quality Score*
Park KS	Korea	R	Septic shock	64.8	92/10	In-hospital mortality	day 1	16.9	NA	8
Hwang SY	/2018 Korea	P	severe sepsis,	65	1397/211	28-day mortality	day 2	31.0	NA	8
Liu JJ	/2017 China	R	septic shock severe sepsis,	62.35	53/63	30-day mortality	day 1	16.97	Beckman hematology analyzer	8
Xu JY	/2016 China	R	septic shock Sepsis, severe sepsis	52.7	47/25	28-day mortality	day 1	15.7	Beckman hematology analyzer	8
Cheng YC	/2017 China	R	septic shock Sepsis, severe sepsis	10-14	168/34	28-day mortality	day 1	4.36	Beckman hematology analyzer	8
Feng C	/2016 China	R	septic shock Sepsis	61	21/117	28-day mortality	day 1	16.89	Beckman hematology analyzer	8
Salciccioli JD	/2015 UK	P	Sepsis	65	4797/966	28-day mortality	day 1	8.9	NA	8
	/2015
Terradas R	Espana	R	Sepsis	67.7	2056/ 255	15-day mortality	day 1	7	Sysmex XT-1800i	8
Akilli NB	/2012 Turkey	P	Sepsis	74	209/164	In-hospital mortality	day 1	11.9	SIEMENS hematology analyzer	9
Chen J	/2014 China	R	Sepsis, severe sepsis,	52.5	167/59	28-day mortality	day 1	14.4	Beckman hematology analyzer	7
Liu X	/2017 China	R	septic shock Sepsis, severe sepsis	70.26	253/80	28-day mortality	day 1	23.8	Beckman hematology analyzer	8
	/2016		septic shock
Riche F	France	P	Septic shock	72.7	76/54	ICU mortality	day 1	NA	NA	8
Sun WW	/2015 China	R	Sepsis, severe sepsis	68.5	69/25	28-day mortality	day 1	11.9	Beckman hematology analyzer	8
Yu Z	/2015 China	R	Septic shock Sepsis, severe sepsis	69.9	50/46	28-day mortality	day 1	NA	Beckman hematology analyzer	8
	/2014		Septic shock

P: prospective; R: retrospective; NA: not available; * The Newcastle-Ottawa Quality Assessment Scale

Fig. 2. Forest plot diagrams of neutrophil-to-lymphocyte ratios (NLR) in survivors and non-survivors among patients with sepsis. The squares and horizontal lines correspond to study-specific standard mean differences (SMDs) and 95% confidence intervals (CIs).

of the combined data of nine studies, after adjusting for potential confounders, showed that patients with sepsis and increased NLR had poor prognoses, suggesting that the NLR can serve as an inde- pendent predictive indicator in patients with sepsis. After sensitiv- ity analysis, the overall results did not significantly change after the sequential exclusion of each study. Subgroup analysis based on confounders failed to show that the study design, cut-off NLR value, or primary outcome affected the prognostic value of NLR in patients with sepsis. These results indicate that higher NLR are independently associated with unfavorable clinical prognosis in patients with sepsis.

Sepsis occurs when an infection leads to widespread immune activation, causing diffuse circulatory abnormalities and multiple

Fig. 3. Funnel plot for NLR in survivors and non-survivors among patients with sepsis.

organ failures. It is a complex pathophysiological process in which large quantities of pro-inflammatory cytokines are released, triggering inflammatory responses throughout the body and lead- ing to sepsis progression.[41] In addition, the various anti- inflammatory cytokines released into the bloodstream can induce immunosuppression, subsequently leading to apoptosis of a large number of lymphocytes.[11,42] During the process of sepsis, neu- trophils and lymphocytes rapidly respond to microbial infection, but the changes observed in neutrophils and lymphocytes are different. The neutrophil count increases dramatically, and these neutrophils then migrate to the affected area; however, the lym- phocyte count decreases due to the aforementioned immunosup- pression. Although neutrophil count alone is associated with the overall severity of the infection/inflammation, neutrophil apopto-

Fig. 4. Forest plot diagrams of hazard ratios of NLR for predicting prognosis in patients with sepsis.

Fig. 5. Funnel plot for the predictive value of higher NLR for mortality in patients with sepsis.

sis is delayed in complicated sepsis cases.[9] This suggests that the neutrophil count has limited predictive value for prognosis in some sepsis cases.

NLR is a readily available biomarker in clinical practice. Com- pared with other prognostic biomarkers, NLR measurement is con- venient and cost-effective, which makes it an attractive biomarker in the clinical setting. Changes in NLR indicate the balance between neutrophil and lymphocyte counts, and NLR is an indicator of sys- temic inflammation.[43,44] Although several conditions can influ- ence NLR values, including medications and comorbidities that affect the neutrophil and lymphocyte counts, NLR has been con- firmed as a useful indicator for the prognosis of several diseases.

[15-18] Despite the inconsistent results reported by existing stud- ies, NLR has been used in critical care medicine and may prove to be a valuable Prognostic tool for patients with sepsis. This is con- sistent with our results that the mean NLR value was significantly higher in non-survivors than in survivors and that NLR was an independent predictor of prognosis in patients with sepsis. These results suggest that NLR can be used as a reliable predictor for prognosis in patients with sepsis.

NLR has been proposed as an additional infection marker, and it is an interesting potential parameter for predicting bacteremia.[45] Previous studies have shown that the prognostic impact of NLR was affected by sepsis severity.[32,46] Although different cut-off NLR have been published for predicting the prognosis of sepsis, the ideal cut-off remains controversial. In the present study, the cut-off value varied considerably across the included studies, rang- ing from 4.36 to 23.8. Interestingly, the cut-off value varied greatly even with the use of the same detecting method, such as the Beck- man hematology analyzer. Therefore, the present study did not find an ideal cut-off NLR for the prognosis of sepsis.

To our knowledge, this meta-analysis is the most extensive study investigating the associations and prognostic value of NLR in patients with sepsis. In addition, our study combined the data of several studies that were adjusted for potential confounders, which are more reliable than the data of single studies. Further- more, results of the sensitivity and subgroup analyses were consis- tent with the overall results, indicating the robustness of the results. Considering the inconsistency between the results of previ- ous studies, our results may be of great help to clinicians for iden- tifying high-risk patients with sepsis to provide proper treatment, which will consequently increase the survival rate of these patients.

However, this meta-analysis has several limitations. First, we observed significant heterogeneity across the studies, which decreases the robustness of the conclusions despite the use of the random-effects model. Second, some of the included studies had retrospective designs; therefore, selection bias, recall bias, and other biases should be considered. Third, although no signifi- cant publication bias was detected in this study, some latent pub- lication bias is inevitable in meta-analysis because most original studies publish positive results. Fourth, sepsis shows high immune variability in patient populations of different ethnicities and sexes;

[47] however, most of the studies included in this meta-analysis were from Asian countries, and thus, the association of NLR with prognosis in sepsis needs to be validated in populations of other ethnicities and sexes. Finally, the cause of sepsis varied across the included studies, which might induce selection bias. Therefore, these results should be interpreted with caution.

Conclusions

This meta-analysis demonstrates that initial NLR may be a help- ful prognostic biomarker for sepsis and that high NLR may indicate unfavorable prognoses in patients with sepsis. However, these

Table 2

Subgroup analysis of the prognosis in septic patients.

	Subgroup	Study	HR(95%)	P subgroup I2 P heterogeneity P regression
Study design	Retrospective	6	1.86 (1.44-2.41)	<0.01	58.6%	0.034	0.434
	Prospective	3	1.84 (1.45-2.35)	<0.01	34.1%	0.233
Cut-off value	>10	6	1.90 (1.46-2.49)	<0.01	64.1%	0.016	0.130
	<10	3	1.75 (1.45-2.11)	<0.01	0	0.536
Primary outcome	Other mortality	3	2.76 (1.25-6.07)	<0.01	0	0.580	0.098
	28-day mortality	6	1.99 (1.47-3.02)	<0.01	50.7%	0.071
Ethnicity	Asian	6	1.93 (1.26-2.95)	0.002	66.4%	0.011	0.232
	Caucasian	3	2.95(1.29-6.78)	0.011	0	0.975

findings should be interpreted with caution due to the aforemen- tioned limitations.

Contributors

FZY and HKG conceived and designed the study; HZW and HWJ performed the research; HZW, FZY and HKG performed the statis- tical analysis; HZW and HKG wrote the manuscript; all authors read and approved the final manuscript.

Funding

This work was supported by grants from the Scientific and Technology Development Project of Qinzhou (201614505; 201616814). The funders had no role in study design, data collec- tion and analysis, decision to publish, or preparation of the manuscript.

Patient consent

Not required.

Consent for publication

Not required.

Data sharing statement

No additional data are available.

Declaration of Competing Interest

The authors do not have any conflicts of interest in relation to this manuscript.

Appendix A. Supplementary material

Supplementary data to this article can be found online at https://doi.org/10.1016/j.ajem.2019.10.023.

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