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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 5  |  Issue : 1  |  Page : 9-15

Ratios of lymphocyte and neutrophil to lymphocyte as early predictors of the severity of acute pancreatitis at different age stratifications


1 Department of General Surgery, Lu He Hospital, Capital Medical University, Tongzhou District, Beijing, China
2 Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI, USA

Date of Submission22-Nov-2019
Date of Decision13-Mar-2020
Date of Acceptance20-Mar-2020
Date of Web Publication21-Apr-2020

Correspondence Address:
Wei Han
Department of General Surgery, Lu He Hospital, Capital Medical University, No. 82, Xin-Hua South Road, Tongzhou District, Beijing
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ed.ed_35_19

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  Abstract 


Goal: To explore the values of lymphocyte ratio (LR) and neutrophil-to-lymphocyte ratio (NLR) in the early prediction of the severity of acute pancreatitis (AP) in patients of different ages.
Background and Aims: LR and NLR, as early markers, can predict the severity of disease in patients with AP according to previous studies. However, all of the studies ignored the influence of the age factor.
Study: The patients with AP from January 2012 to October 2017 were retrospectively analyzed. The patients were divided into mild acute pancreatitis (MAP) and severe acute pancreatitis (SAP) groups according to the latest Atlanta classification. In each group, the patients were further divided into the young and middle-aged group (ages ≤65), and the elderly group (ages >65). The neutrophil ratio (NR), LR and NLR were detected and collected within 24 h of disease onset. The relationship between various indicators and severity of AP was evaluated.
Results: NLR (11.15±8.20 vs. 7.83±9.17 P < 0.001) significantly increased whereas LR (10.72±6.32 vs. 16.77±9.70 P < 0.001) significantly decreased in the SAP group compared to the MAP group. LR and NLR demonstrated a significant predictive value in the young- and middle-aged group. However, LR and NLR were not significant predictors in the elderly group.
Conclusions: The LR reduction and NLR elevation in the early stages were closely related to the severity of AP. They were both important markers for predicting severity of AP, especially in the young and middle-aged patients.

Keywords: Acute pancreatitis, age, lymphocyte ratio, neutrophil ratio, neutrophil-to-lymphocyte ratio


How to cite this article:
Liu P, Feng ZD, Ji Y, Zhang ZY, Zhang TL, Bardhi R, Ji ZL, Han W. Ratios of lymphocyte and neutrophil to lymphocyte as early predictors of the severity of acute pancreatitis at different age stratifications. Environ Dis 2020;5:9-15

How to cite this URL:
Liu P, Feng ZD, Ji Y, Zhang ZY, Zhang TL, Bardhi R, Ji ZL, Han W. Ratios of lymphocyte and neutrophil to lymphocyte as early predictors of the severity of acute pancreatitis at different age stratifications. Environ Dis [serial online] 2020 [cited 2022 Oct 6];5:9-15. Available from: http://www.environmentmed.org/text.asp?2020/5/1/9/283008

Peng Liu, Zhang.Dong FengFNx01 Both authors share equal contribution to the study





  Introduction Top


Acute pancreatitis (AP) is a painful inflammatory condition of the pancreas. It is the leading cause of hospitalization among gastrointestinal diseases.[1] The annual incidence of AP globally is 13-45/100,000 persons/year. Its incidence appears to be rising. The elderly and adolescent populations have had the largest relative increase in prevalence. Gallstones and alcohol consumption are the two most common causes of AP.[2] In previous multinational epidemiological surveys of pancreatitis,]2[,[3],[4],[5],[1] the alcoholic AP was more common in males and younger people. The biliary AP was more common in females and older adults. Young- and middle-aged patients were most commonly affected. However, the mortality rate in elderly patients with AP remained significantly higher than in younger patients due to preexisting conditions and weak immune functions. Variations in gender and age distribution were observed among different geographic regions and they were related to differences in the etiology of pancreatitis.[6]

AP is considered a pathophysiological process of self-digestion, edema, hemorrhage, and necrosis of pancreatic tissue. It is characterized by premature activation of pancreatic enzymes within pancreatic tissue due to multiple etiological factors. The exact pathogenesis of AP is not yet fully understood because of its complex etiology. Two of the three criteria must be present for diagnosis: abdominal pain consistent with pancreatitis, elevated lipase and/or amylase, or findings of AP on cross-sectional imaging.[1] The clinical manifestations of the disease are variable and include fever, abdominal tenderness, nausea, vomiting, hypotension, and respiratory distress.[1] The mild form of AP resolves within the 1st week usually.[7] However, AP can lead to local complications such pseudocysts and pancreatic necrosis.[1] The severe form of AP can result in systemic complications such as organ system failure, complex systemic inflammatory response syndrome (SIRS), or death.[1] Time is of the essence in the management of pancreatitis. If the degree of the severity of AP is not recognized early and treatment is delayed, the mortality of AP may increase from 3% in patients with mild AP (MAP) to 30% in patients with severe AP (SAP).[1] Thus, careful observation and identification of SAP in the early stages are important to improve prognosis.[1] At present, the development of modern diagnostic techniques has enabled many scoring systems that integrate symptoms and laboratory results to assess the patient's status. BISAP, Balthazar computed tomography (CT), Ranson, and APACHE II are some of the scoring systems available to assess the condition of AP.[8] However, all of the scoring systems are complicated and have a low sensitivity.[8] Most of them need to be assessed 48 hours after admission. Therefore, there is a need for a rapid, simple, and sensitive method to predict the severity of AP in patients at the time of admission.[8]

Previous studies focused on the neutrophil-to-lymphocyte ratio (NLR), lymphocyte count (LC) and platelet-to-lymphocyte ratio (PLR) as biomarkers for early severity assessment in AP. However, recent studies have shown that the early reduction of the lymphocyte ratio (LR) predicts the severity of AP more accurately.[8] Although the values of these markers in predicting SAP were confirmed in these previous studies, all of them ignored the influence of the age factor. Although the mechanisms underlying the effects of age on AP remain unclear, studies have shown that features such as dull local reactions and exaggerated systemic responses were present in elderly AP animal models.[9] Moreover, under different age stratifications, the different etiology characteristics of patients with AP would have an impact on the progression and prognosis of AP. Other characteristics such as the aging of the immune system would also have an effect. It has been established that aging influences the clinical outcomes of AP. This novel study not only explored the significance of LR and NLR as early markers but also their value in the early prediction of the severity of AP in different age stratifications.


  Materials and Methods Top


General data

This retrospective study was approved by the Ethics Committee of Beijing Luhe Hospital, Capital Medical University, China. Patients who were diagnosed with AP in the Department of General Surgery, Beijing Luhe Hospital, Capital Medical University, from January 2012 to November 2017, were included in the study. The patients were divided into MAP and SAP groups according to the 2012 Atlanta classification criteria. The MAP group included patients with no organ failure and no local or systemic complications, whereas the SAP group included those with transient or persistent organ failure (MODF), local complications (including peripancreatic fluid accumulation, pancreatic and peripancreatic tissue necrosis, pseudocysts, and enveloping necrosis), or aggravation of comorbid diseases. The exclusion criteria were as follows: (1) patients with immunological diseases; (2) those who had recently used immunosuppressants, glucocorticoids, or other drugs that affect the immune function and release of inflammatory mediators; (3) those with pancreatitis after endoscopic retrograde cholangiopancreatography and pancreatitis diagnosed during surgery; (4) those who were suspected of having infections caused by other diseases such as biliary and pancreatic malignancies and nonpancreatic infections; (5) those with the disease onset longer than 24 h; and (6) those with incomplete clinical data collection.

Observation indicators and detection methods

The peripheral venous blood was collected within 24 h after the onset of the illness. The blood routine and biochemical data were collected. The main recording indicators were white cell count (WCC), neutrophil count (NC), LC, neutrophil ratio (NR), LR, and hematocrit (HCT). The NLR, BISAP, and modified Balthazar CT scores for all patients were also calculated.

Statistical analysis

Continuous data were presented as means ± standard deviation and were analyzed using the Student's t test. Categorical data were presented as proportions and were analyzed using the Chi-square or the Fisher's test, as appropriate. The diagnostic performances of LR, NR, NLR, BISAP, and CT severity index (CTSI) were assessed using receiver operating characteristic (ROC) curves, and the area under each ROC curve (area under the curve, [AUC]) was estimated. The statistical analysis was performed using SPSS 19.0 (IBM, NY, USA). The two-sided P < 0.05 were considered statistically significant.


  Results Top


A total of 535 patients with AP were included in this study. Of these, 312 patients were in the MAP group and 223 patients in the SAP group [Figure 1]. There were no statistically significant differences between the groups with respect to gender, smoking history, or drinking history (P > 0.05). The average age of patients with SAP was significantly lower than patients with MAP. The WCC, NC, NR, and NLR significantly increased in the SAP group (P < 0.05), whereas the LC and LR significantly decreased in the SAP group [Table 1]. Taking 65 years of age as a boundary, the patients were further divided into two groups: young- and middle-aged (age ≤65 years; n = 350, 149 patients with SAP, and 201 patients with MAP) and the elderly (age >65 years; n = 185 people, 74 patients with SAP, and 111 patients with MAP). The comparative analysis demonstrated that the gender composition in the elderly group was dominated by women. The probability of underlying diseases such as comorbid hypertension, diabetes, and coronary heart disease was significantly increased in the elderly group. In addition, the incidence of biliary AP was significantly higher in the elderly patients when compared to the young- and middle-aged patients. Although no significant differences were found in WCC and NC between the two groups, the LC was significantly decreased in the elderly group [Table 2].
Figure 1: Flowchart of patient enrollment. AP: Acute pancreatitis, MAP: Mild acute pancreatitis, SAP: severe acute pancreatitis

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Table 1: Baseline characteristics and clinical features of all patients with AP

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Table 2: Partial results of blood routine tests compared between the elderly and young and middle-aged groups

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In all patients with AP, the ROC curve analysis was performed on WCC, NR, LC, LR, HCT, and NLR to predict their values for SAP, and the corresponding AUCs were calculated. Although the LR [AUC, 0.698; 95% confidence interval (CI), 0.65–0.74] and NLR (AUC, 0.698; 95% CI, 0.65–0.74) were less valuable than the CTSI (AUC 0.860, 95% CI 0.826–0.893) and BISAP (AUC 0.716, 95% CI 0.67–0.76) scoring systems, they were superior to WCC (AUC, 0.673; 95% CI, 0.63–0.72) compared to other test indicators [Figure 2]. After stratifying the patients into the elderly group versus the young- and middle-aged group using >65 years as the boundary, the ROC curve of each indicator was reanalyzed.
Figure 2: Receiver operator curves and corresponding area under curve analyses demonstrating the accuracy of CTSI, BISAP, WCC, NR, LR, NC, LC, HCT, and NLR as predictors for the severity of acute pancreatitis on admission. CTSI: Computed tomography severity index, BISAP: Bedside Index for Severity in Acute Pancreatitis, HCT: Hematocrit, LC: Lymphocyte count, LR: Lymphocyte ratio, NC: Neutrophil count, NLR: Neutrophil–lymphocyte ratio, WCC: White cell count

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In the young- and middle-aged group, the values of LR (AUC, 0.747; 95% CI, 0.70–0.80) and NLR (AUC, 0.748; 95% CI, 0.70–0.80) were more obvious in the early prediction of the severity of AP (AUC >0.7) compared with that of WCC (AUC, 0.680; 95% CI, 0.63–0.74) [Figure 3].
Figure 3:Receiver operator curves and corresponding area under curve analyses demonstrating the accuracy of CTSI, BISAP, WCC, NR, LR, NC, LC, HCT, and NLR as predictors for the severity of acute pancreatitis in the young- and middle-aged group. CTSI: Computed tomography severity index, BISAP: Bedside Index for Severity in Acute Pancreatitis, HCT: Hematocrit, LC: Lymphocyte count, LR: Lymphocyte ratio, NC: Neutrophil count, NLR: Neutrophil–lymphocyte ratio, WCC: White cell count

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In the elderly group, however, LR (AUC, 0.629; 95% CI, 0.55–0.71) and NLR (AUC, 0.629; 95% CI, 0.55–0.71) were not superior predictors to WCC (AUC, 0.628; 95% CI, 0.55–0.71) [Figure 4].
Figure 4: Receiver operator curves (ROC) and corresponding area under curve (AUC) analyses demonstrating the accuracy of CTSI, BISAP, WCC, NR, LR, NC, LC, HCT, NLR as predictors for the severity of acute pancreatitis in the elderly group. CTSI: Computed tomography severity index, BISAP: Bedside Index for Severity in Acute Pancreatitis, HCT: Hematocrit, LC: Lymphocyte count, LR: Lymphocyte ratio, NC: Neutrophil count, NLR: Neutrophil–lymphocyte ratio, WCC: White cell count

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The cutoff values of LR and NLR in the early prediction of SAP were obtained by analyzing the ROC curves and the corresponding AUCs. The sensitivity and specificity of LR were superior to those of NLR, and under the age stratification, the cutoff value was different [Table 3].
Table 3: Sensitivity, specificity, +LR and -LR of optimal Cut-off value for LR and NLR defined by our study

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  Discussion Top


AP is an inflammatory disease that starts with the activation of trypsinogen and causes damage to the pancreatic acinar cells. WBCs (neutrophils and lymphocytes), endothelial cells, and macrophages within the pancreatic acinar cells are the main effector cells that cause pancreatic acinar cell injury.[10] During the subsequent development of pancreatitis, innate immune cells (neutrophils, monocytes, macrophages), and adaptive immune cells (CD4+, CD8+ T, and CD19+ B lymphocytes) in the peripheral circulating blood also have an important effect, and may lead to SIRS development associated with SAP-induced multiple organ failure.[11]

The neutrophils and lymphocytes in the aforementioned cells are both constituent cells of WBCs. The WCC is a common index parameter appearing in various AP scoring systems. However, previous studies placed more emphasis upon the WBC components because they were susceptible to many internal and external factors. As an important component of WBC, lymphocytes participate mainly in the adaptive immunity of the body. In the previous studies of pancreatitis, the focus of attention was placed on the role of innate immune cells and related inflammatory mediators, whereas lymphocytes were less studied.[7] The absolute lymphocyte count was first proposed by Christophi in 1985 as an indicator[12] to monitor the prognosis of AP, but it was not widely explored for a long time. In recent years, the effect of peripheral circulating lymphocytes has gained importance in the pathogenesis of AP. One consensus in the previous studies was that circulating lymphocytes in patients with AP, especially SAP, were severely depleted.[13] In this study, the LC was also found to be significantly decreased in the elderly group. This is believed to be due to activated lymphocytes migrating to sites of inflammation, reaching the pancreas and other sites such as the lungs and kidneys, and undergoing apoptosis.[14] Compared with LC, LR was more stable. Xiuzhong et al. explored the early reduction of LR as a predictor of SAP for the first time in their study. An optimal LR cutoff value of ≤0.081 was used to identify a poor outcome in AP. It was concluded that early LR reduction could predict the severity of AP at an early stage and was associated with clinical outcomes in AP.[8] However, the effects of gender, etiology, and functional changes in the immune system on the results were ignored in different age stratifications. Moreover, the sample size was small.

By clinical observation of a relatively large sample size at a single center, this study found that the early reduction in LR was closely related to the severity of AP. Moreover, by analyzing the ROC curves for various detection indicators and scoring systems and calculating the corresponding AUCs, it was noted that the value of LR (AUC, 0.698; 95% CI, 0.65–0.74) was more accurate than WCC (AUC, 0.673; 95% CI, 0.63–0.72) in the early prediction of the severity of AP, although it was less accurate than both CTSI (AUC, 0.860; 95% CI, 0.826–0.893) and BISAP (AUC, 0.716; 95% CI, 0.67–0.76) [Figure 2]. When the patients were stratified by age using >65 years as the boundary, the value of LR (AUC, 0.747; 95% CI, 0.70–0.80) was found to be almost equivalent to that of BISAP (AUC, 0.762; 95% CI, 0.71–0.82) in the young- and middle-aged group. The AUC was not less than 0.7, which represented a clear advantage for predicting SAP. In the elderly group, the value of LR (AUC, 0.629; 95% CI, 0.55–0.71) was relatively low, and was comparable to that of WCC (AUC, 0.628; 95% CI 0.55–0.71); the advantage of LR for predicting SAP was not obvious.

This study showed that the optimal cut-off value of LR in the early prediction of SAP was < 14.65 (sensitivity, 79.2%; specificity, 60.2%; +LR, 1.990; −LR, 0.346) in the young- and middle-aged group. The optimal cutoff value of LR was <9.9 (sensitivity, 67.6%; specificity, 59.5%; +LR, 1.667; −LR, 0.576) in the elderly group. Ling et al.[15] found that human B-cells and NK cells did not show significant fluctuations with aging in a study that evaluated circulating lymphocyte subsets in healthy Chinese adults. The total number of T lymphocytes, however, decreased from 1,403 ± 414 cells/μl to 1,198 ± 399 cells/μl, indicating a decline in immune function with age. They also discovered that immature lymphocytes decreased, while memory cells increased with age. This may be one of the reasons that the LR had a relatively good value in predicting AP severity in the young and middle-aged patients. Further studies are required to verify this hypothesis. Thus, the changes in the optimal cutoff value of LR for predicting the severity of AP as well as the differences in sensitivity and specificity seen in the two groups were related to the aging of the immune system and the age-dependent decrease in the number of lymphocytes.

Neutrophils, representing the majority of white blood cells, are crucial both in infectious inflammation and in the immune regulation of aseptic inflammation. Neutrophils phagocytose and release reactive oxygen species, lysosomal enzymes, and extracellular traps. New evidence suggests that therapeutic interventions targeting neutrophils in AP can significantly reduce tissue damage and prevent the occurrence of severe pancreatitis.[16] The NLR, which is obtained by calculating the ratio of NC to LC, has been a quick and simple indicator for evaluating the systemic inflammation and stress response in patients with SAP.[17] Azab et al.[18] reported for the first time that the value of NLR in predicting a poor prognosis in patients with AP was superior to the value of WCC. In this study, the early increase in the NLR was also closely related to the severity of AP. From the ROC curves and calculations of the corresponding AUCs, it was further found that NLR and LR had similar values in predicting the severity of AP at an early stage. Although they were less accurate than the BISAP and CTSI scoring systems, they were still more accurate than the WCC. Moreover, compared with the NLR (AUC, 0.629; 95% CI, 0.55–0.71) in the elderly group, the NLR (AUC, 0.748; 95% CI, 0.70–0.80) in the young- and middle-aged group was more obvious in predicting the severity of AP. The AUC was >0.7, which was close to the predictive values of BISAP and CTSI scoring systems. Tae JooJeon et al., in a study of 490 patients with AP, also discovered that the NLR, as a simple indicator, had a relatively good value in the early prediction of poor prognosis and degree of severity in patients with AP.[19] Moreover, they concluded that the optimal cutoff value of >4.76 could predict SAP, which was the same as the optimal cutoff value suggested in Azab's study. It was also similar to the optimal cutoff value, which was >5.27 (sensitivity, 79.2%; specificity, 60.2%; +LR, 1.990; −LR, 0.346), of NLR in the young- and middle-aged group obtained in the present study. In addition, in this study, the NLR had very good sensitivity and specificity, comparable with the optimal cutoff value of LR. This also indirectly proved that lymphocytes and neutrophils are vital effector cells in the development of AP. The underlying mechanisms need to be further studied in detail.

This study found that after age stratification, the gender composition in the elderly group was dominated by females. Furthermore, the probability of underlying diseases, such as comorbid hypertension, diabetes, and coronary heart disease, significantly increased in the elderly. In addition, the proportion of biliary AP was significantly higher in the elderly patients compared with the young- and middle-aged patients. Although no significant differences were found in WCC and NC between the two groups, the LC significantly decreased in the elderly group [Table 2]. Moreover, the values of LR and NLR in the early prediction of SAP were significantly different due to age stratification. These differences may be attributed to the complex changes caused by age. Aging manifests not only in the degenerative changes of physiological structures, but it also significantly increases the probability of comorbidities, such as hypertension, diabetes, and coronary heart disease. It also leads to the decline in physiological functions, called immunosenescence when it occurs in the immune system. Immunosenescence is caused by the age-related changes in the innate immune system and decreased function of adaptive immune cells, which is a process strictly controlled by genes. The main features are a decrease in the cell-mediated immune function and a reduction in humoral immune response.[20] Studies have shown that the effects of immunosenescence on neutrophils were mainly in their ability to migrate, phagocytose, and produce reactive oxygen species. Intracellular killing and degranulation were also disrupted. However, in the peripheral blood circulation, the number of neutrophils did not change.[21] The effects of immune system aging on the lymphocytes reflected not only in the reduction of the overall number but also in the proportion of functional cells.[15]

Differences were found in the gender and etiology of patients with AP with increasing age.[22] In the elderly group of this study, the proportion of women was higher and the incidence of biliary AP was also significantly higher. Whereas in the young and middle-aged group, the proportion of male patients was higher and the proportion of nonbiliary pancreatitis was relatively large [Table 2]. Some studies have shown that early intervention of the biliary obstruction in patients with biliary AP can effectively reduce the occurrence of complications and the reoccurrence of AP.[23],[24] Influenced by many factors, the LR and NLR were more valuable for the early prediction of the AP severity in the young- and middle-aged group compared with the elderly group.

This study had some limitations. First, the number of cases included in the study was still relatively small and could not classify a more refined age group. Second, the retrospective nature of the study limited the extension of the study. Therefore, to verify the conclusions, prospective studies with a larger scale will be necessary. Despite these limitations, this study also had some advantages. This was the first retrospective study that included age stratification in the assessment of NLR and LR in predicting the severity of AP, and notable differences were obtained. In addition, all laboratory test items were obtained within 24 hours of disease onset, which minimized the changes in drug-induced test indicators.


  Conclusion Top


The early reduction in LR and increase in NLR were closely related to the severity of disease in patients with AP. They were of great value in predicting the severity of AP in the early stages; the value was more significant in the young- and middle-aged group. Large-scale prospective studies are still needed to confirm the optimal cut off values of LR and NLR for different age groups. The age stratification should be refined. The values of LR and NLR in the early prediction of the severity of AP should be further evaluated in the refined age stratification. In addition, more studies should confirm if LR and NLR should be included in the current AP prognosis scoring system.

Financial support and sponsorship

The study received support from the Scientific Research Common Program of Beijing Municipal Commission of Education (#KM201810025030).

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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