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Assessment of neutrophil-lymphocyte ratio in ulcerative colitis: A promising marker in predicting disease severity
Clinics and Research in Hepatology and Gastroenterology (2012) 36, 491—497
Available online at
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ORIGINAL ARTICLE
Assessment of neutrophil-lymphocyte ratio in ulcerative colitis: A promising marker in predicting disease severity Serkan Torun a, Bilge Demirel Tunc a, Burak Suvak a, Hakan Yildiz a, Adnan Tas b,∗, Abdurrahim Sayilir a, Yasemin Ozin Ozderin a, Yavuz Beyazit a, Ertugrul Kayacetin a a b
Department of Gastroenterology, Turkiye Yuksek Ihtisas Training and Research Hospital, Ankara, Turkey Department of Gastroenterology, Osmaniye Public Hospital, Osmaniye, Turkey
Available online 27 July 2012
Summary Background and aim: In order to diagnosis and monitor the disease activity of ulcerative colitis (UC), serum biomarkers are generally used, but none of them are specific for intestinal inflammation. It is therefore desirable in clinical practice to be able to assess disease activity with simple, inexpensive and objective tools. The objective of the present study was to assess whether the neutrophil-lymphocyte ratio (NLR) would be useful in predicting disease severity in UC patients who had not received corticosteroid or immunosuppressive drugs within a defined period of time. Additionally, a possible relationship of NLR with other inflammatory markers in UC patients was also investigated. Methods: We designed a retrospective study examining the utility of NLR in estimating disease severity in UC patients admitted to our hospital between 2008 and 2011. In total, 119 patients with active UC and 77 patients with inactive UC were enrolled in the study group, and 59 age and gender matched healthy subjects were included as the control group. Disease activity was assessed using Truelove and Witts criteria. Results: In the active UC group, NLR values were found to be elevated compared to inactive UC patients and controls (3.22 ± 1.29, 1.84 ± 0.69 and 2.01 ± 0.64, respectively). Using ROC statistics, a cut-off value of 2.16 indicated the presence of active disease with a sensitivity of 81.8% and a specificity of 80.5% (positive predictive value [PPV] 86.8%, negative predictive value [NPV] 73.8%). NLR values were found to be correlated with WBC and ESR levels.
∗ Corresponding author. Raufbey Mahallesi, Atatürk caddesi No: 432 Sefaevler, A2 blok no:14, Osmaniye, Turkey. Tel.: +90 53 05 40 50 79; fax: +90 32 82 61 71 00. E-mail address: [email protected] (A. Tas).
2210-7401/$ – see front matter © 2012 Elsevier Masson SAS. All rights reserved. http://dx.doi.org/10.1016/j.clinre.2012.06.004
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Conclusions: The present study revealed that NLR is increased in active UC. Peripheral blood NLR can reflect disease activity and can be used as an additional marker for estimating intestinal inflammation. © 2012 Elsevier Masson SAS. All rights reserved.
Introduction Ulcerative colitis (UC) is a chronic, idiopathic, inflammatory bowel disease that causes inflammation and ulcers in the innermost layers of the large intestine (colon) and rectum. Assessment of intestinal inflammation in UC is crucial and still remains a difficult challenge for the clinician. Although endoscopic modalities with biopsy sampling seem to be the most reliable method for estimating disease severity, they are invasive and costly. Apart from endoscopic interventions, disease severity can be assessed using both laboratory studies and non-invasive imaging tests [1,2]. C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), white blood cells (WBC), acid glycoprotein, platelet count and albumin are in common use but have only modest accuracy in reflecting UC disease activity [3—5]. Therefore, adjunctive use of additional serum markers that will be more sensitive and specific for determination of disease activity and achieving diagnostic accuracy is strongly needed in daily clinical practice. A simple, inexpensive and effective marker of inflammation that has been linked with several inflammatory and neoplastic diseases is the neutrophil-lymphocyte ratio (NLR). Although the significance of systemic leukocytic alterations as an indicator of inflammatory response is relatively uncertain, the effect of total leukocytic count, differential count, or NLR on the outcome of many kinds of malignancies, including colorectal cancer, ovarian cancer, gastric cancer, intrahepatic cholangiocarcinoma, hepatocellular carcinoma and pancreatic cancer has been well demonstrated [6—13]. Moreover, it has been shown that the NLR is superior to WBC in the prediction of adverse outcomes in a variety of inflammatory and surgical conditions (i.e. pancreatitis, appendicitis, acute coronary syndrome, major vascular surgery and critical care illness) [14—18]. Recognizing the need for estimating disease severity in UC, this study was undertaken in order to investigate whether NLR levels are altered in UC patients and their correlation with clinical and laboratory parameters in conjunction with other inflammatory markers during UC activation.
Materials and methods
retrospectively reviewed, only 196 patients met study inclusion criteria, as they had a complete blood count with leukocyte differential performed before initiating any treatment and also had medical records available. The diagnosis of UC was based on standard clinical, radiological, endoscopic and histological criteria. The following data were extracted from the hospital database: age, sex, localization of the disease, disease duration, drug intake and other medical history. Complete blood count (CBC) ESR, and CRP were also recorded for each UC patient. All CBC analysis was performed in the hematology laboratory of our hospital. CBC analysis was performed with the same analyzer within 2 hours of collection of blood samples with the use of a Beckman Coulter (High Wycombe, UK) Gen-S automated analyzer. The NLR was calculated from the differential count by dividing the absolute neutrophil count by the absolute lymphocyte count. Exclusion criteria for entry into the study were defined as prior treatment with corticosteroids, hematological or neoplastic disorders, and clinical evidence of active infection, since NLR may be affected by those conditions. The study was conducted in accordance with the guidelines of the Helsinki declaration.
Disease activity The disease activity in UC patients was assessed by Truelove and Witts criteria [19]. These criteria have been validated for over 50 years and allow a simple and rapid stratification of patients with UC. Using this classification, UC patients were classified as mild, moderate or severe based on the number bloody stools per day, heart rate, hemoglobin, ESR and body temperature. Patients categorized as having moderate or severe disease were accepted as having active UC, whereas the patients in the mild group were considered to be in the remission period.
Follow-up The patients included in the present study within the activation period were reassessed 3 months after clinical remission. NLR values of the UC patients in whom clinical remission was achieved was noted.
Patients and methods Statistical analysis This retrospective study evaluated the diagnostic value of NLR for disease activity in 196 UC patients managed at the Turkiye Yuksek Ihtisas Training and Research hospital between February 2008 and July 2011. The control group consisted of 59 healthy, age and gender matched subjects (male/female: 25/34). Although 305 UC patients were
The Statistical Package for Social Sciences (SPSS) 18.0 for Windows was used to analyze the data. Continuous variables were tested for normality by the Kolmogorov—Smirnov test. Values were presented as mean ± standard deviation or, in the case of non-normally distributed data, as median
Neutrophil-lymphocyte ratio in ulcerative colitis Table 1
493
Demographic and laboratory features of ulcerative colitis patients and controls.
Age (year) Gender (F/M) Duration of disease (months) Localization of disease Distal colitis, n (%) Left sided, n (%) Pancolitis, n (%) Hemoglobin (g/dl) Platelet (/mm3 × 103 ) WBC (/mm3 × 103 ) NLR
UC Patients (n = 196)
Control group (n = 59)
P
43.3 ± 13.5 71 (36.3%)/125 (63.7%) 60 (4—300)
46.5 ± 14.2 25 (42.4%)/34 (57.6%)
NS NS
14.4 ± 1.3 270 ± 65 7.1 ± 1.5 2.01 ± 0.64
NS < 0.001 < 0.001 < 0.001
58 (29.6) 54 (27.5) 84 (42.9) 13.07 ± 2.0 359 ± 136 8.7 ± 2.9 2.67 ± 1.29
Data are presented as median (range) or mean ± SD. UC: ulcerative colitis; WBC: white blood cells; NLR: neutrophil-lymphocyte ratio; NS: non-significant.
Table 2
Comparison of NLR and other inflammation markers between active and inactive UC patients. Active UC (n = 119)
WBC (/mm3 × 103 ) NLR CRP (mg/L) ESR (mm/h) Fibrinogen (g/L)
9.6 3.22 11.7 27 3.65
± ± ± ± ±
3.3 1.29 23 15 1.02
Inactive UC (n = 77) 7.6 1.84 5.4 14 3.43
± ± ± ± ±
2.3 0.69 6.1 10 1.06
P < 0.001 < 0.001 0.008 < 0.001 NS
UC: ulcerative colitis; WBC: white blood cells; NLR: neutrophil-lymphocyte ratio; CRP: C-reactive protein; ESR: erythrocyte sedimentation rate; NS: non-significant.
and range. Comparisons of percentages between different groups of patients were carried out using the Chi2 test. All normally-distributed data were analyzed using unpaired or paired student t test. Data found to be non-normally distributed were analyzed using the Mann-Whitney U test for independent subgroups and the Wilcoxon test for dependent subgroups. Receiver operating characteristic (ROC) curve analysis was used to identify optimal cut-off values of NLR, WBC, CRP, ESR and fibrinogen with maximum sensitivity and specificity for differentiation of activation of UC from remission. Spearman’s correlation analysis was done between NLR and other inflammation markers. A P value of less than 0.05 was deemed statistically significant.
Results The demographic and laboratory characteristics of our patient population and the control group are summarized in Table 1. The mean age of the UC and control groups was 43.3 ± 13.5 years and 46.5 ± 14.2 years, respectively. There were no statistically significant differences between the ages of the study participants. The mean NLR values of UC patients and controls were 2.67 ± 1.29 and 2.01 ± 0.64, respectively (P < 0.001). Mean NLR values of active UC patients were significantly higher than those of inactive UC patients (3.22 ± 1.29 vs. 1.84 ± 0.69) (P < 0.001) (Fig. 1). Inflammatory markers, such as WBC, CRP and ESR, were found to be significantly elevated in active UC compared to inactive UC and control patients.
Figure 1 Box-plot representation of neutrophil to lymphocyte ratio (NLR) in patients with ulcerative colitis (active and inactive) and healthy controls.
Table 2 shows mean NLR values and the other inflammatory markers of study participants at the onset of the study. No significant differences were observed with respect to fibrinogen levels between study participants. Although Spearman correlation analysis indicated a significant correlation of NLR with WBC (r = 0.235, P < 0.001) and ESR (r = 0.217, P = 0.002) (Fig. 2), no correlation was found with CRP (r = 0.102, P = 0.153) and fibrinogen (r = 0.095, P = 0.187) (Table 3). In active UC patients, a
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Figure 2 The correlation between neutrophil to lymphocyte ratio (NLR) and white blood cell (WBC) (A) and erythrocyte sedimentation rate (ESR) (B) in patients with active ulcerative colitis. Lines representing the 95% confidence interval (CI) and the 95% prediction interval of the regression line are demonstrated.
further analysis was also done between patients with normal WBC levels and patients with elevated WBC levels. A total of 73 active UC patients was found to have WBC counts within the normal range. Mean NLR values of active UC patients with elevated WBC counts (n = 46) was found to be higher (3.77 ± 1.45/mm3 × 103 ) than active UC patients with normal WBC levels (2.85 ± 1.06/mm3 × 103 ). Both of these levels were significantly higher than inactive UC patients (P < 0.001) and controls (P < 0.001). ROC curve analysis suggested that the optimum NLR cut-off point for active UC was 2.16, with a sensitivity, specificity, PPV and NPV of 81.8%, 80.5%, 86.8%, and 73.8%, respectively (AUC: 0.850) (Fig. 3). The overall accuracy of NLR in determination of active UC was 81.3%. The same analysis for other inflammation markers is summarized in Table 4. Active UC patients in whom clinical remission was achieved were further analysed with respect to NLR values. NLR values were found to have decreased in this patient group (mean 2.04 ± 0.60).
Discussion In this study, we evaluated NLR as a surrogate marker of disease activity in UC. Our findings revealed that patients with active UC have elevated NLR in comparison with healthy controls. NLR was also found to have decreased after remission
Table 3 Spearman correlation coefficients between NLR and other inflammation markers in patients with UC.
NLR rs P
CRP
WBC
ESR
fibrinogen
0.102 0.153
0.416 < 0.001
0.217 0.002
0.095 0.187
UC: ulcerative colitis; WBC: white blood cells; NLR: neutrophillymphocyte ratio; CRP: C-reactive protein; ESR: erythrocyte sedimentation rate.
Figure 3 Receiver operating characteristic (ROC) curve of neutrophil to lymphocyte ratio (NLR) vs. other inflammation markers in predicting active disease for ulcerative colitis.
of UC. Elevated levels of peripheral blood NLR was found to give high sensitivity, specificity and predictive values in patients with active UC, which suggests a superiority of NLR to total leucocyte and individual absolute neutrophil and lymphocyte counts. Moreover, elevated NLR values found in both active UC patients with normal and elevated WBC levels prove that NLR can be thought of as an independent diagnostic marker for estimating disease activity, irrespective of WBC levels in UC patients. We think that the predictive superiority of NLR that was found in our study can be attributed to its more stable nature compared to white blood cells alone and their individual subtypes. UC is a chronic inflammatory disease that primarily causes continuous inflammation of the colonic mucosa and affects the rectum and a variable extent of the colon in continuity [20]. The clinical course is characterized by remission and relapse, which may develop spontaneously or in response to medical treatment. Disease activity is
Neutrophil-lymphocyte ratio in ulcerative colitis Table 4
495
Overall accuracy and ROC analyses of NLR and other markers of inflammation to differentiate active from inactive UC.
NLR WBC CRP ESR Fibrinogen
Cut-off
AUC
Sensitivity (%)
Specificity (%)
NPV (%)
PPV (%)
OA
2.16 7.8 3.23 17.5 3.575
0.850 0.706 0.612 0.780 0.552
81.8 67.8 65.3 71.9 55.5
80.5 62.3 58.4 71.4 50.6
73.8 54.4 51.7 61.8 42.4
86.8 73.6 71.2 79.8 63.5
81.3 65.1 62.6 71.7 53.5
AUC: area under curve; OA: overall accuracy; NPV: negative predictive value; PPV: positive predictive value; UC: ulcerative colitis; WBC: white blood cells; NLR: neutrophil-lymphocyte ratio; CRP: C-reactive protein; ESR: erythrocyte sedimentation rate.
generally grouped into mild, moderate, severe and remission [20,21]. A great proportion of patients are generally mildly active and have a self-limiting disease; some will develop severe disease associated with serious complications [22]. Since effective medical therapy diminishes mortality in patients with severe UC, determination of inflammatory activity is therefore crucial for the assessment of disease activity and also for the tailoring of therapy [23]. Although clinical, histological, radiologic and endoscopic indices are used to assess disease activity in UC patients, a great number of invasive/non-invasive methods have also been investigated for UC diagnosis and determination of disease activity [22—25]. Moreover, despite the well-known role of inflammatory cells in UC pathogenesis, there is no data in the literature depicting the role of NLR as an index of disease severity. In this setting, this study was designed to evaluate the role of NLR in estimating UC activation in conjunction with other clinical and biochemical severity indices. The Truelove and Witts classification (TWC) [19] based on various clinical parameters and laboratory findings (number of bowel movements, sedimentation rate, and presence of tachycardia, anemia and fever) is one of the most widely used disease activity index in clinical practice. The major disadvantages of this index are the complexity of classifying some patients into the appropriate disease category and the changes in disease activity with time [24,26]. For this reason, endoscopic disease activity assessment is important because the complaints of the patients do not always correspond to the severity and extent of the disease. Besides the TWC, the Rachmilewitz endoscopic activity index (REI), which takes granularity, vascular pattern, and mucosal vulnerability and damage into account, can also be used to assess disease activity in UC patients. In this study, we used TWC to predict the severity of UC. Moreover, we analysed the relationship between NLR and other inflammation markers according to these severity indexes. Although there is no ideal single serum marker for predicting disease severity, white blood cell count, CRP and ESR are the most commonly used inflammatory indices in routine clinical practice for determining UC activity. These parameters can change according to the degree of the inflammatory state, but they do not adequately reflect disease activity because of their low sensitivity and specificity for intestinal inflammation [27]. In a study by Beyazit et al. [22], the overall accuracy of white blood cell count and ESR in determining disease activity was found to be 74.4% (sensitivity 70.8%) and 67.4% (sensitivity 54.2%), respectively. In this context, CRP
seems to be more promising for determining disease activity in ulcerative colitis. Although conflicting results exists in the literature, a recent study by Karoui et al. [26] showed that CRP levels are correlated with clinical and endoscopic activity in UC. It has been reported that the optimum cut-off CRP level that separates active from inactive disease was calculated to be 10 mg/l, with AUC estimated at 0.81 ± 0.04 with a sensitivity and specificity of 67.1 and 97%, respectively [26]. Prantera et al. [28] studied 60 UC patients and concluded that disease severity and the presence of signs and symptoms of toxicity seem likely to be determined by the amount of colonic tissue involved in inflammation, both in depth and in extent. Furthermore, CRP appeared to be the most reliable factor reflecting disease activity and lesion extension. In the present study, the overall accuracy of CRP for estimating active disease was 62.6% (sensitivity 65.3, specificity 58.4%). Hypercoagulable state with prothrombotic abnormalities is an important contributing factor in UC pathogenesis. In this respect, fibrinogen and d-dimer levels were shown to correlate with severity and extent of UC and also with the intensity of the acute phase response [29]. Although in our study fibrinogen levels in active UC patients were seem to be higher than inactive UC patients, this was not statistically significant. NLR is a simple and inexpensive index of systemic inflammatory burden that correlates with prognosis in distinct disease states. It has been generally investigated in inflammatory and neoplastic diseases, such as acute pancreatitis, colorectal cancer, hepatocellular, ovarian, nasopharyngeal, and metastatic renal cell carcinoma, as a prognostic index [6—13,16—18]. Moreover, recent data also suggests that NLR is useful for predicting survival following coronary interventions [30] and non-ST-segment elevation myocardial infarction [31]. Our data revealed a significant association between NLR and disease activity as reflected by TWC. Moreover, based on the findings of our study, we believe that a standardized cut-off value for NLR in estimating disease severity is crucial for initial evaluation. Because of the need for starting an optimal treatment as soon as possible, elevated NLR levels can give a significant clue to the clinician for estimating disease severity. In UC, the neutrophil granulocyte is one of the most important infiltrating leukocytes and has been proposed to contribute significantly to the development of tissue injury and inflammation seen in this disease [32,33]. Neutrophil accumulation in the intestinal mucosa may have been a consequence of increased recruitment of neutrophils and from
496 defective apoptosis [34]. Several chemotactic molecules play a significant role in the recruitment of neutrophils from the blood into inflamed tissue. The neutrophil is the key cell responsible for the active nonspecific inflammatory response and is closely tied to the destructive tissue cascades by secretion of interleukin-1, interleukin-6, myeloperoxidase, and elastase. On the other hand, previous studies in patients with inflammatory bowel disease have strongly revealed that their lymphocyte function is abnormal at both the peripheral and mucosal level [35]. For example, a reduction in lymphocyte responsiveness to the mitogen phytohemagglutinin has been reported with peripheral lymphocytes from both Crohn’s disease and ulcerative colitis [36]. Although in the present study the mean peripheral lymphocyte levels of UC patients was slightly lower than healthy controls, this was not statistically significant. In conclusion, the present study for the first time has demonstrated that NLR levels are significantly elevated in active UC patients and are correlated with clinical and laboratory indices. NLR in conjunction with other inflammatory markers may estimate disease activity. If our data can be confirmed with further trials, we believe that a standardized cut-off value for NLR would facilitate the diagnosis of UC activation. We therefore suggest that NLR, as an inexpensive and easily applicable test, is a valuable tool for a rapid assessment of disease activity in UC.
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
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epithelial ovarian cancer and predicts survival after treatment. Cancer Immunol Immunother 2009;58:15—23. Gomez D, Morris-Stiff G, Toogood GJ, Lodge JP, Prasad KR. Impact of systemic inflammation on outcome following resection for intrahepatic cholangiocarcinoma. J Surg Oncol 2008;97:513—8. Gomez D, Farid S, Malik HZ, Young AL, Toogood GJ, Lodge JP, et al. Preoperative neutrophil to lymphocyte ratio as a prognostic predictor after curative resection for hepatocellular carcinoma. World J Surg 2008;32:1757—62. Halazun KJ, Hardy MA, Rana AA, Woodland 4th DC, Luyten EJ, Mahadev S, et al. Negative impact of neutrophil-lymphocyte ratio on outcome after liver transplantation for hepatocellular carcinoma. Ann Surg 2009;250:141—51. An X, Ding PR, Li YH, Wang FH, Shi YX, Wang ZQ, et al. Elevated neutrophil to lymphocyte ratio predicts survival in advanced pancreatic cancer. Biomarkers 2010;15:516—22. Zahorec R. Ratio of neutrophil to lymphocyte counts — rapid and simple parameter of systemic inflammation and stress in critically ill. Bratisl Lek Listy 2001;102:5—14. Goodman DA, Goodman CB, Monk JS. Use of the neutrophil:lymphocyte ratio in the diagnosis of appendicitis. Am Surg 1995;61:257—9. Tamhane UU, Aneja S, Montgomery D, Rogers EK, Eagle KA, Gurm HS. Association between admission neutrophil to lymphocyte ratio and outcomes in patients with acute coronary syndrome. Am J Cardiol 2008;102:653—7. Bhutta H, Agha R, Wong J, Tang TY, Wilson YG, Walsh SR. Neutrophil-lymphocyte ratio predicts medium-term survival following elective major vascular surgery: a cross-sectional study. Vasc Endovascular Surg 2011;45:227—31. Azab B, Jaglall N, Atallah JP, Lamet A, Raja-Surya V, Farah B, et al. Neutrophil-lymphocyte ratio as a predictor of adverse outcomes of acute pancreatitis. Pancreatology 2011;11:445—52. Truelove SC, Witts LJ. Cortisone in ulcerative colitis; final report on a therapeutic trial. Br Med J 1955;2:1041—8. Stange EF, Travis SP, Vermeire S, Reinisch W, Geboes K, Barakauskiene A, et al. European evidence-based consensus on the diagnosis and management of ulcerative colitis: definitions and diagnosis. J Crohn Colitis 2008;2:1—23. Cima RR, Pemberton JH. Medical and surgical management of chronic ulcerative colitis. Arch Surg 2005;140:300—10. Beyazit Y, Koklu S, Tas A, Purnak T, Sayilir A, Kurt M, et al. Serum adenosine deaminase activity as a predictor of disease severity in ulcerative colitis. J Crohns Colitis 2012;6: 102—7. Travis SP. Review article: the management of mild to severe acute ulcerative colitis. Aliment Pharmacol Ther 2004;20(Suppl. 4):88—92. Naber AH, de Jong DJ. Assessment of disease activity in inflammatory bowel disease; relevance for clinical trials. Neth J Med 2003;61:105—10. Bruining DH, Loftus EV. Current and future diagnostic approaches: from serologies to imaging. Curr Gastroenterol Rep 2007;9:489—96. Karoui S, Laz S, Serghini M, Bibani N, Boubaker J, Filali A. Correlation of C-reactive protein with clinical and endoscopic activity in patients with ulcerative colitis. Dig Dis Sci 2011;56:1801—5. Khan K, Schwarzenberg SJ, Sharp H, Greenwood D, WeisdorfSchindele S. Role of serology and routine laboratory tests in childhood inflammatory bowel disease. Inflamm Bowel Dis 2002;8:325—9. Prantera C, Davoli M, Lorenzetti R, Pallone F, Marcheggiano A, Iannoni C, et al. Clinical and laboratory indicators of extent of ulcerative colitis. Serum C-reactive protein helps the most. J Clin Gastroenterol 1988;10:41—5.
Neutrophil-lymphocyte ratio in ulcerative colitis [29] Zezos P, Papaioannou G, Nikolaidis N, Patsiaoura K, Vassiliadis T, Mpoumponaris A, et al. Elevated markers of thrombin generation and fibrinolysis in patients with active and quiescent ulcerative colitis. Med Sci Monit 2009;15:CR563—72. [30] Duffy BK, Gurm HS, Rajagopal V, Gupta R, Ellis SG, Bhatt DL. Usefulness of an elevated neutrophil to lymphocyte ratio in predicting long term mortality after percutaneous coronary intervention. Am J Cardiol 2006;97:993—6. [31] Azab B, Zaher M, Weiserbs KF, Torbey E, Lacossiere K, Gaddam S, et al. Usefulness of neutrophil to lymphocyte ratio in predicting short and long term mortality after non-ST-elevation myocardial infarction. Am J Cardiol 2010;106:470—6. [32] Nixon J, Riddell R. Histopathology in ulcerative colitis. In: Allan R, Keighley M, Alexander-Williams C, Hawkins C, editors. Inflammatory bowel disease. Edinburgh: Churchill Livingstone; 1990. p. 247—85.
497 [33] Hermanowicz A, Gibson PR, Jewell DP. The role of phagocytes in inflammatory bowel disease. Clin Sci (Lond) 1985;69: 241—9. [34] Brannigan AE, O’Connell PR, Hurley H, O’Neill A, Brady HR, Fitzpatrick JM, et al. Neutrophil apoptosis is delayed in patients with inflammatory bowel disease. Shock 2000;13:361—6. [35] Roche JK, Watkins MH, Cook SL. Inflammatory bowel disease: prevalence and level of activation of circulating T-lymphocyte subpopulations mediating suppressor/cytotoxic and helper function as defined by monoclonal antibodies. Clin Immunol Immunopathol 1982;25:362—73. [36] Sachar DB, Taub RN, Brown SM, Present DH, Korelitz BI, Janowitz HD. Imparied lymphocyte responsiveness in inflammatory bowel disease. Gastroenterology 1973;64: 203—9.
Available online at
www.sciencedirect.com
ORIGINAL ARTICLE
Assessment of neutrophil-lymphocyte ratio in ulcerative colitis: A promising marker in predicting disease severity Serkan Torun a, Bilge Demirel Tunc a, Burak Suvak a, Hakan Yildiz a, Adnan Tas b,∗, Abdurrahim Sayilir a, Yasemin Ozin Ozderin a, Yavuz Beyazit a, Ertugrul Kayacetin a a b
Department of Gastroenterology, Turkiye Yuksek Ihtisas Training and Research Hospital, Ankara, Turkey Department of Gastroenterology, Osmaniye Public Hospital, Osmaniye, Turkey
Available online 27 July 2012
Summary Background and aim: In order to diagnosis and monitor the disease activity of ulcerative colitis (UC), serum biomarkers are generally used, but none of them are specific for intestinal inflammation. It is therefore desirable in clinical practice to be able to assess disease activity with simple, inexpensive and objective tools. The objective of the present study was to assess whether the neutrophil-lymphocyte ratio (NLR) would be useful in predicting disease severity in UC patients who had not received corticosteroid or immunosuppressive drugs within a defined period of time. Additionally, a possible relationship of NLR with other inflammatory markers in UC patients was also investigated. Methods: We designed a retrospective study examining the utility of NLR in estimating disease severity in UC patients admitted to our hospital between 2008 and 2011. In total, 119 patients with active UC and 77 patients with inactive UC were enrolled in the study group, and 59 age and gender matched healthy subjects were included as the control group. Disease activity was assessed using Truelove and Witts criteria. Results: In the active UC group, NLR values were found to be elevated compared to inactive UC patients and controls (3.22 ± 1.29, 1.84 ± 0.69 and 2.01 ± 0.64, respectively). Using ROC statistics, a cut-off value of 2.16 indicated the presence of active disease with a sensitivity of 81.8% and a specificity of 80.5% (positive predictive value [PPV] 86.8%, negative predictive value [NPV] 73.8%). NLR values were found to be correlated with WBC and ESR levels.
∗ Corresponding author. Raufbey Mahallesi, Atatürk caddesi No: 432 Sefaevler, A2 blok no:14, Osmaniye, Turkey. Tel.: +90 53 05 40 50 79; fax: +90 32 82 61 71 00. E-mail address: [email protected] (A. Tas).
2210-7401/$ – see front matter © 2012 Elsevier Masson SAS. All rights reserved. http://dx.doi.org/10.1016/j.clinre.2012.06.004
492
S. Torun et al.
Conclusions: The present study revealed that NLR is increased in active UC. Peripheral blood NLR can reflect disease activity and can be used as an additional marker for estimating intestinal inflammation. © 2012 Elsevier Masson SAS. All rights reserved.
Introduction Ulcerative colitis (UC) is a chronic, idiopathic, inflammatory bowel disease that causes inflammation and ulcers in the innermost layers of the large intestine (colon) and rectum. Assessment of intestinal inflammation in UC is crucial and still remains a difficult challenge for the clinician. Although endoscopic modalities with biopsy sampling seem to be the most reliable method for estimating disease severity, they are invasive and costly. Apart from endoscopic interventions, disease severity can be assessed using both laboratory studies and non-invasive imaging tests [1,2]. C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), white blood cells (WBC), acid glycoprotein, platelet count and albumin are in common use but have only modest accuracy in reflecting UC disease activity [3—5]. Therefore, adjunctive use of additional serum markers that will be more sensitive and specific for determination of disease activity and achieving diagnostic accuracy is strongly needed in daily clinical practice. A simple, inexpensive and effective marker of inflammation that has been linked with several inflammatory and neoplastic diseases is the neutrophil-lymphocyte ratio (NLR). Although the significance of systemic leukocytic alterations as an indicator of inflammatory response is relatively uncertain, the effect of total leukocytic count, differential count, or NLR on the outcome of many kinds of malignancies, including colorectal cancer, ovarian cancer, gastric cancer, intrahepatic cholangiocarcinoma, hepatocellular carcinoma and pancreatic cancer has been well demonstrated [6—13]. Moreover, it has been shown that the NLR is superior to WBC in the prediction of adverse outcomes in a variety of inflammatory and surgical conditions (i.e. pancreatitis, appendicitis, acute coronary syndrome, major vascular surgery and critical care illness) [14—18]. Recognizing the need for estimating disease severity in UC, this study was undertaken in order to investigate whether NLR levels are altered in UC patients and their correlation with clinical and laboratory parameters in conjunction with other inflammatory markers during UC activation.
Materials and methods
retrospectively reviewed, only 196 patients met study inclusion criteria, as they had a complete blood count with leukocyte differential performed before initiating any treatment and also had medical records available. The diagnosis of UC was based on standard clinical, radiological, endoscopic and histological criteria. The following data were extracted from the hospital database: age, sex, localization of the disease, disease duration, drug intake and other medical history. Complete blood count (CBC) ESR, and CRP were also recorded for each UC patient. All CBC analysis was performed in the hematology laboratory of our hospital. CBC analysis was performed with the same analyzer within 2 hours of collection of blood samples with the use of a Beckman Coulter (High Wycombe, UK) Gen-S automated analyzer. The NLR was calculated from the differential count by dividing the absolute neutrophil count by the absolute lymphocyte count. Exclusion criteria for entry into the study were defined as prior treatment with corticosteroids, hematological or neoplastic disorders, and clinical evidence of active infection, since NLR may be affected by those conditions. The study was conducted in accordance with the guidelines of the Helsinki declaration.
Disease activity The disease activity in UC patients was assessed by Truelove and Witts criteria [19]. These criteria have been validated for over 50 years and allow a simple and rapid stratification of patients with UC. Using this classification, UC patients were classified as mild, moderate or severe based on the number bloody stools per day, heart rate, hemoglobin, ESR and body temperature. Patients categorized as having moderate or severe disease were accepted as having active UC, whereas the patients in the mild group were considered to be in the remission period.
Follow-up The patients included in the present study within the activation period were reassessed 3 months after clinical remission. NLR values of the UC patients in whom clinical remission was achieved was noted.
Patients and methods Statistical analysis This retrospective study evaluated the diagnostic value of NLR for disease activity in 196 UC patients managed at the Turkiye Yuksek Ihtisas Training and Research hospital between February 2008 and July 2011. The control group consisted of 59 healthy, age and gender matched subjects (male/female: 25/34). Although 305 UC patients were
The Statistical Package for Social Sciences (SPSS) 18.0 for Windows was used to analyze the data. Continuous variables were tested for normality by the Kolmogorov—Smirnov test. Values were presented as mean ± standard deviation or, in the case of non-normally distributed data, as median
Neutrophil-lymphocyte ratio in ulcerative colitis Table 1
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Demographic and laboratory features of ulcerative colitis patients and controls.
Age (year) Gender (F/M) Duration of disease (months) Localization of disease Distal colitis, n (%) Left sided, n (%) Pancolitis, n (%) Hemoglobin (g/dl) Platelet (/mm3 × 103 ) WBC (/mm3 × 103 ) NLR
UC Patients (n = 196)
Control group (n = 59)
P
43.3 ± 13.5 71 (36.3%)/125 (63.7%) 60 (4—300)
46.5 ± 14.2 25 (42.4%)/34 (57.6%)
NS NS
14.4 ± 1.3 270 ± 65 7.1 ± 1.5 2.01 ± 0.64
NS < 0.001 < 0.001 < 0.001
58 (29.6) 54 (27.5) 84 (42.9) 13.07 ± 2.0 359 ± 136 8.7 ± 2.9 2.67 ± 1.29
Data are presented as median (range) or mean ± SD. UC: ulcerative colitis; WBC: white blood cells; NLR: neutrophil-lymphocyte ratio; NS: non-significant.
Table 2
Comparison of NLR and other inflammation markers between active and inactive UC patients. Active UC (n = 119)
WBC (/mm3 × 103 ) NLR CRP (mg/L) ESR (mm/h) Fibrinogen (g/L)
9.6 3.22 11.7 27 3.65
± ± ± ± ±
3.3 1.29 23 15 1.02
Inactive UC (n = 77) 7.6 1.84 5.4 14 3.43
± ± ± ± ±
2.3 0.69 6.1 10 1.06
P < 0.001 < 0.001 0.008 < 0.001 NS
UC: ulcerative colitis; WBC: white blood cells; NLR: neutrophil-lymphocyte ratio; CRP: C-reactive protein; ESR: erythrocyte sedimentation rate; NS: non-significant.
and range. Comparisons of percentages between different groups of patients were carried out using the Chi2 test. All normally-distributed data were analyzed using unpaired or paired student t test. Data found to be non-normally distributed were analyzed using the Mann-Whitney U test for independent subgroups and the Wilcoxon test for dependent subgroups. Receiver operating characteristic (ROC) curve analysis was used to identify optimal cut-off values of NLR, WBC, CRP, ESR and fibrinogen with maximum sensitivity and specificity for differentiation of activation of UC from remission. Spearman’s correlation analysis was done between NLR and other inflammation markers. A P value of less than 0.05 was deemed statistically significant.
Results The demographic and laboratory characteristics of our patient population and the control group are summarized in Table 1. The mean age of the UC and control groups was 43.3 ± 13.5 years and 46.5 ± 14.2 years, respectively. There were no statistically significant differences between the ages of the study participants. The mean NLR values of UC patients and controls were 2.67 ± 1.29 and 2.01 ± 0.64, respectively (P < 0.001). Mean NLR values of active UC patients were significantly higher than those of inactive UC patients (3.22 ± 1.29 vs. 1.84 ± 0.69) (P < 0.001) (Fig. 1). Inflammatory markers, such as WBC, CRP and ESR, were found to be significantly elevated in active UC compared to inactive UC and control patients.
Figure 1 Box-plot representation of neutrophil to lymphocyte ratio (NLR) in patients with ulcerative colitis (active and inactive) and healthy controls.
Table 2 shows mean NLR values and the other inflammatory markers of study participants at the onset of the study. No significant differences were observed with respect to fibrinogen levels between study participants. Although Spearman correlation analysis indicated a significant correlation of NLR with WBC (r = 0.235, P < 0.001) and ESR (r = 0.217, P = 0.002) (Fig. 2), no correlation was found with CRP (r = 0.102, P = 0.153) and fibrinogen (r = 0.095, P = 0.187) (Table 3). In active UC patients, a
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Figure 2 The correlation between neutrophil to lymphocyte ratio (NLR) and white blood cell (WBC) (A) and erythrocyte sedimentation rate (ESR) (B) in patients with active ulcerative colitis. Lines representing the 95% confidence interval (CI) and the 95% prediction interval of the regression line are demonstrated.
further analysis was also done between patients with normal WBC levels and patients with elevated WBC levels. A total of 73 active UC patients was found to have WBC counts within the normal range. Mean NLR values of active UC patients with elevated WBC counts (n = 46) was found to be higher (3.77 ± 1.45/mm3 × 103 ) than active UC patients with normal WBC levels (2.85 ± 1.06/mm3 × 103 ). Both of these levels were significantly higher than inactive UC patients (P < 0.001) and controls (P < 0.001). ROC curve analysis suggested that the optimum NLR cut-off point for active UC was 2.16, with a sensitivity, specificity, PPV and NPV of 81.8%, 80.5%, 86.8%, and 73.8%, respectively (AUC: 0.850) (Fig. 3). The overall accuracy of NLR in determination of active UC was 81.3%. The same analysis for other inflammation markers is summarized in Table 4. Active UC patients in whom clinical remission was achieved were further analysed with respect to NLR values. NLR values were found to have decreased in this patient group (mean 2.04 ± 0.60).
Discussion In this study, we evaluated NLR as a surrogate marker of disease activity in UC. Our findings revealed that patients with active UC have elevated NLR in comparison with healthy controls. NLR was also found to have decreased after remission
Table 3 Spearman correlation coefficients between NLR and other inflammation markers in patients with UC.
NLR rs P
CRP
WBC
ESR
fibrinogen
0.102 0.153
0.416 < 0.001
0.217 0.002
0.095 0.187
UC: ulcerative colitis; WBC: white blood cells; NLR: neutrophillymphocyte ratio; CRP: C-reactive protein; ESR: erythrocyte sedimentation rate.
Figure 3 Receiver operating characteristic (ROC) curve of neutrophil to lymphocyte ratio (NLR) vs. other inflammation markers in predicting active disease for ulcerative colitis.
of UC. Elevated levels of peripheral blood NLR was found to give high sensitivity, specificity and predictive values in patients with active UC, which suggests a superiority of NLR to total leucocyte and individual absolute neutrophil and lymphocyte counts. Moreover, elevated NLR values found in both active UC patients with normal and elevated WBC levels prove that NLR can be thought of as an independent diagnostic marker for estimating disease activity, irrespective of WBC levels in UC patients. We think that the predictive superiority of NLR that was found in our study can be attributed to its more stable nature compared to white blood cells alone and their individual subtypes. UC is a chronic inflammatory disease that primarily causes continuous inflammation of the colonic mucosa and affects the rectum and a variable extent of the colon in continuity [20]. The clinical course is characterized by remission and relapse, which may develop spontaneously or in response to medical treatment. Disease activity is
Neutrophil-lymphocyte ratio in ulcerative colitis Table 4
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Overall accuracy and ROC analyses of NLR and other markers of inflammation to differentiate active from inactive UC.
NLR WBC CRP ESR Fibrinogen
Cut-off
AUC
Sensitivity (%)
Specificity (%)
NPV (%)
PPV (%)
OA
2.16 7.8 3.23 17.5 3.575
0.850 0.706 0.612 0.780 0.552
81.8 67.8 65.3 71.9 55.5
80.5 62.3 58.4 71.4 50.6
73.8 54.4 51.7 61.8 42.4
86.8 73.6 71.2 79.8 63.5
81.3 65.1 62.6 71.7 53.5
AUC: area under curve; OA: overall accuracy; NPV: negative predictive value; PPV: positive predictive value; UC: ulcerative colitis; WBC: white blood cells; NLR: neutrophil-lymphocyte ratio; CRP: C-reactive protein; ESR: erythrocyte sedimentation rate.
generally grouped into mild, moderate, severe and remission [20,21]. A great proportion of patients are generally mildly active and have a self-limiting disease; some will develop severe disease associated with serious complications [22]. Since effective medical therapy diminishes mortality in patients with severe UC, determination of inflammatory activity is therefore crucial for the assessment of disease activity and also for the tailoring of therapy [23]. Although clinical, histological, radiologic and endoscopic indices are used to assess disease activity in UC patients, a great number of invasive/non-invasive methods have also been investigated for UC diagnosis and determination of disease activity [22—25]. Moreover, despite the well-known role of inflammatory cells in UC pathogenesis, there is no data in the literature depicting the role of NLR as an index of disease severity. In this setting, this study was designed to evaluate the role of NLR in estimating UC activation in conjunction with other clinical and biochemical severity indices. The Truelove and Witts classification (TWC) [19] based on various clinical parameters and laboratory findings (number of bowel movements, sedimentation rate, and presence of tachycardia, anemia and fever) is one of the most widely used disease activity index in clinical practice. The major disadvantages of this index are the complexity of classifying some patients into the appropriate disease category and the changes in disease activity with time [24,26]. For this reason, endoscopic disease activity assessment is important because the complaints of the patients do not always correspond to the severity and extent of the disease. Besides the TWC, the Rachmilewitz endoscopic activity index (REI), which takes granularity, vascular pattern, and mucosal vulnerability and damage into account, can also be used to assess disease activity in UC patients. In this study, we used TWC to predict the severity of UC. Moreover, we analysed the relationship between NLR and other inflammation markers according to these severity indexes. Although there is no ideal single serum marker for predicting disease severity, white blood cell count, CRP and ESR are the most commonly used inflammatory indices in routine clinical practice for determining UC activity. These parameters can change according to the degree of the inflammatory state, but they do not adequately reflect disease activity because of their low sensitivity and specificity for intestinal inflammation [27]. In a study by Beyazit et al. [22], the overall accuracy of white blood cell count and ESR in determining disease activity was found to be 74.4% (sensitivity 70.8%) and 67.4% (sensitivity 54.2%), respectively. In this context, CRP
seems to be more promising for determining disease activity in ulcerative colitis. Although conflicting results exists in the literature, a recent study by Karoui et al. [26] showed that CRP levels are correlated with clinical and endoscopic activity in UC. It has been reported that the optimum cut-off CRP level that separates active from inactive disease was calculated to be 10 mg/l, with AUC estimated at 0.81 ± 0.04 with a sensitivity and specificity of 67.1 and 97%, respectively [26]. Prantera et al. [28] studied 60 UC patients and concluded that disease severity and the presence of signs and symptoms of toxicity seem likely to be determined by the amount of colonic tissue involved in inflammation, both in depth and in extent. Furthermore, CRP appeared to be the most reliable factor reflecting disease activity and lesion extension. In the present study, the overall accuracy of CRP for estimating active disease was 62.6% (sensitivity 65.3, specificity 58.4%). Hypercoagulable state with prothrombotic abnormalities is an important contributing factor in UC pathogenesis. In this respect, fibrinogen and d-dimer levels were shown to correlate with severity and extent of UC and also with the intensity of the acute phase response [29]. Although in our study fibrinogen levels in active UC patients were seem to be higher than inactive UC patients, this was not statistically significant. NLR is a simple and inexpensive index of systemic inflammatory burden that correlates with prognosis in distinct disease states. It has been generally investigated in inflammatory and neoplastic diseases, such as acute pancreatitis, colorectal cancer, hepatocellular, ovarian, nasopharyngeal, and metastatic renal cell carcinoma, as a prognostic index [6—13,16—18]. Moreover, recent data also suggests that NLR is useful for predicting survival following coronary interventions [30] and non-ST-segment elevation myocardial infarction [31]. Our data revealed a significant association between NLR and disease activity as reflected by TWC. Moreover, based on the findings of our study, we believe that a standardized cut-off value for NLR in estimating disease severity is crucial for initial evaluation. Because of the need for starting an optimal treatment as soon as possible, elevated NLR levels can give a significant clue to the clinician for estimating disease severity. In UC, the neutrophil granulocyte is one of the most important infiltrating leukocytes and has been proposed to contribute significantly to the development of tissue injury and inflammation seen in this disease [32,33]. Neutrophil accumulation in the intestinal mucosa may have been a consequence of increased recruitment of neutrophils and from
496 defective apoptosis [34]. Several chemotactic molecules play a significant role in the recruitment of neutrophils from the blood into inflamed tissue. The neutrophil is the key cell responsible for the active nonspecific inflammatory response and is closely tied to the destructive tissue cascades by secretion of interleukin-1, interleukin-6, myeloperoxidase, and elastase. On the other hand, previous studies in patients with inflammatory bowel disease have strongly revealed that their lymphocyte function is abnormal at both the peripheral and mucosal level [35]. For example, a reduction in lymphocyte responsiveness to the mitogen phytohemagglutinin has been reported with peripheral lymphocytes from both Crohn’s disease and ulcerative colitis [36]. Although in the present study the mean peripheral lymphocyte levels of UC patients was slightly lower than healthy controls, this was not statistically significant. In conclusion, the present study for the first time has demonstrated that NLR levels are significantly elevated in active UC patients and are correlated with clinical and laboratory indices. NLR in conjunction with other inflammatory markers may estimate disease activity. If our data can be confirmed with further trials, we believe that a standardized cut-off value for NLR would facilitate the diagnosis of UC activation. We therefore suggest that NLR, as an inexpensive and easily applicable test, is a valuable tool for a rapid assessment of disease activity in UC.
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
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