Acute cholangitis is an acute condition that manifests as biliary tract inflammation and infection, leading to significant morbidity and mortality (1–3). This condition is characterized by fever, abdominal pain, and jaundice (Charcot triad), as well as confusion and septic shock (Reynolds pentad) (1, 3). Common aetiologies of acute cholangitis include choledocholithiasis, biliary stricture, hepatolithiasis, hepatobiliary tract and pancreatic malignancy, endobiliary stent occlusion, or biliary parasites (2). Although the reported mortality rate for acute cholangitis was approximately 50% in the 1970s, this rate decreased rapidly to <7% by the 1980s, following specific advances in endoscopic drainage and appropriate antibiotic therapy (4).
Currently, approximately 80% of cases of acute cholangitis can be treated using broad-spectrum antibiotics, whereas the remaining cases require emergent drainage of the biliary system. Notably, however, severe forms of acute cholangitis can lead to life-threatening conditions such as sepsis, septic shock, multiple organ failure, and death (1, 3, 5, 6) and despite the above-mentioned advances in therapy, the mortality rates of patients with severe acute cholangitis remain as high as 8% to 10% when postoperative and malignant biliary obstruction-associated mortality are included (3, 7, 8). Nowadays, the tasks of early recognition and stratification of the risks of severe infection and sepsis development remain challenging, particularly in terms of attempts to improve the clinical outcomes of patients with acute cholangitis. To this end, recent studies that have estimated the outcomes of patients with septic conditions, including acute cholangitis, have incorporated a range of relatively simple to more complex biological laboratory markers (9).
Thus far, no widely accepted prognostic indicators can predict the severity and early intervention requirements of acute cholangitis cases with sufficient accuracy. Current trends have focused on the development of predictive severity scoring systems based on combinations of independent clinical and biochemical independent factors (10, 11). Although these scoring systems may be suitable for clinical applications, they are excessively complicated with respect to the early diagnosis of acute cholangitis, and require serial measurements for determinations of severity. Therefore, prognostic factors that can be measured rapidly and easily in emergency situations are needed when determining severity in patients with acute cholangitis.
Regarding technological advances, specific automated blood cell analysers have recently been developed to determine the delta neutrophil index (DNI), which reflects the fraction of circulating immature granulocytes (12, 13). This parameter is useful because infection, stress, and systemic inflammation will increase the immature/total granulocyte ratio or neutrophil band count, providing a measure of the presence of immature granulocytes as well as a leftward granulocytic shift (12, 13). Herein, we have evaluated the significance of the DNI as a prognostic marker of early mortality in patients with acute cholangitis. Several studies have reported associations of a higher DNI with a positive blood culture, septic shock, disseminated intravascular coagulation, and death in critical patients with suspected sepsis (12–15). To our knowledge, however, ours is the first study to evaluate the relationship between the DNI and severity of acute cholangitis in a clinical setting.
PATIENTS AND METHODS
This study was conducted between January 2010 and December 2011 at two tertiary academic hospitals with annual emergency department (ED) censuses of 65,000 and 85,000. The institutional review board of Yonsei University Health System (No 3-2016-0033) reviewed and approved the study. We retrospectively analyzed patients who were initially diagnosed with acute cholangitis at ED admission, followed by a final diagnosis. Acute cholangitis was defined according to the diagnosis criteria of the 2007 Tokyo guideline for acute cholangitis (11, 16). Septic shock was defined as sepsis with hypotension (systolic arterial blood pressure <90, or 40 mm Hg less than the patient's baseline blood pressure) despite adequate fluid resuscitation (17). The exclusion criteria were the use of antibiotics, immunosuppressive agents, or chemotherapy within 14 days before ED admission; history of previous hematologic malignancy, chronic renal failure, or human immunodeficiency virus; and comorbid conditions such as gastrointestinal bleeding, pulmonary embolism, and infections such as urinary tract infection, pneumonia, isolated cholecystitis, and liver abscess.
Demographic data (age, sex, previous medical history, and patient identifier) were collected for all patients. The DNI for each patient was determined on Day 0 (immediately at ED admission), Day 1 (24–36 h after admission), and Day 2 (48–60 h after admission). Hemodynamic instability was defined as the need for a vasopressor/inotrope.
DNI and other blood sample measurements
Complete blood counts, including DNI, white blood cells (WBC), haemoglobin, and platelets, were assessed using an automated blood cell analyzer (ADVIA 2120; Siemens, Forchheim, Germany). The specific automated blood cell analyzers, which are based on flow cytometric principles, comprise two independent WBC analysis methods: the MPO channel, which involves a cytochemical reaction, and the nuclear lobularity channel, which involves a light beam. The DNI was designed to use leukocyte differentials obtained from two independent channels in a specific hematologic analyzer (13). Regarding polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), which are considered immature neutrophils, the DNI values reflect MPO-reactive cells lacking nuclear lobularity as PMN-MDSCs and may detect circulating immature granulocytes as the leukocyte subfraction (14). First, the optical system based on the MPO tungsten-halogen channel measured and differentiated granulocytes, lymphocytes, and monocytes based on size and MPO content staining intensity (13). Second, the optical system based on the lobularity/nuclear density channel laser-diode calculated and classified cell types with respect to lobularity/nuclear density and size (13). DNI was then calculated by subtracting the fraction of mature PMN leukocytes from the sum of the MPO-reactive cells (12). In other words, DNI was obtained using the following formula: DNI = (neutrophil subfraction + eosinophil subfraction measured in the myeloperoxidase channel) − (polymorphonuclear subfraction measured in the nuclear lobularity channel) (12, 14, 18). Other laboratory tests of initial blood specimens collected at the time of ED admission, including determinations of the erythrocyte sedimentation rate and blood urea nitrogen, creatinine, alanine transaminase, gamma-glutamyl transpeptidase, C-reactive protein (CRP), and albumin levels, were conducted using an automated chemistry analyzer (Hitachi 7600; Hitachi, Tokyo, Japan).
Clinical outcomes were mortality and shock requiring vasopressor/inotrope at 28 days.
Demographic and clinical data are presented as medians (interquartile ranges [IQRs]), means ± standard deviations (SDs), percentages, or frequencies as appropriate. Continuous variables were compared using a two-sample t test or the Mann–Whitney U test, whereas categorical variables were compared using the χ2 test or Fisher exact test. We estimated significant differences between groups over time using a linear two-mixed model and repeated measures covariance pattern with unstructured covariance within patients. Two fixed effects were included to address the clinical effect for cholangitis (level: survival and death) and time effect (time: DNI 0, 24, and 48 h after ED admission). The areas under the curves (AUCs) of receiver operating characteristic (ROC) curves were determined to assess the ability of the DNI to predict hemodynamic instability and short-tern mortality in patients with acute cholangitis. The optimal cutoff for DNI for discriminating between survival and death or hemodynamic stability and instability was estimated using the Youden method. In addition, to investigate the diagnostic performance of DNI for discriminating acute cholangitis from other diseases with acute abdominal pain, we retrospectively analyzed patients who were initially diagnosed with acute hepatitis and cholecystitis at ED admission, followed by a final diagnosis. The AUCs were calculated to compare the diagnostic performance of each marker including DNI, WBC count, platelet, neutrophil count, segmented neutrophil, and CRP with respect to hemodynamic instability and 28-day mortality. We performed univariate analyses to evaluate relationships among demographic characteristics and clinical data. To highlight independent diagnostic indicators, we identified independent predictors of early acute cholangitis severity using a multivariate logistic regression analysis that integrated the major covariates identified in our univariate analyses (variables with a P < 0.05 in the univariate analysis). We also conducted a multivariate Cox proportional hazard regression analysis to identify promising independent factors predictive of 28-day mortality by considering time-to-event data. The results are expressed as odds ratios (ORs) or hazard ratios (HRs) and 95% confidence intervals (CIs).
Kaplan–Meier analysis survival curves were created using 28-day mortality data, and groups were compared using the log-rank test. Although previous studies estimated only cut-off values based on events alone, we estimated optimal cut-off values based on time-to-event data using the technique devised by Contal and O’Quigley. This technique was used to select the cut-off value of DNI for the dichotomization of clinical outcome variables. The optimal cut-off point was selected by maximizing the HR (19–21). Statistical analyses were performed using SAS, version 9.2 (SAS Institute Inc, Cary, NC) and MedCalc Statistical Software version 16.4.3 (MedCalc Software bvba, Ostend, Belgium). A P value <0.05 was considered significant.
Figure 1 shows the enrolment and clinical outcome data for the patients with suspected severe sepsis registered in the EGDT program. A total of 548 patients were initially diagnosed with acute cholangitis at ED admission during the study period; however, 87 patients were excluded from the analysis (Fig. 1). The baseline characteristics and clinical data of the remaining 461 (84.1%) eligible patients are presented in Table 1. The mean DNI values at admission, day 1, and day 2 differed significantly between patients with and without shock (Table 1), and were significantly higher in the survival group than in the non-survival group at admission (18.25% vs. 4.38%; P = 0.008) and day 1 (16.02% vs. 3.75%; P = 0.048; Table 1).
The univariate analysis and multivariate logistic regression model revealed significant differences in DNI values at admission, day 1, and day 2 between patients who did and did not require vasopressor/inotrope therapy. In addition, higher DNIs at all three time points were strong independent factors predictive of septic shock (Table 2, Appendix 1, http://links.lww.com/SHK/A467). Both the univariate analysis and multivariate logistic regression model revealed that the mean DNI values of the survival and non-survival groups differed significantly on days 0, 1, and 2 (Table 2). In addition, the multivariate logistic regression model demonstrated that higher DNI values at admission, day 1, and day 2 were strong independent factors predictive of 28-day mortality (Table 2). Regarding the time-to-event analysis, the multivariate Cox regression model also found that higher DNI values at admission, day 1, and day 2 were strong independent factors predictive of 28-day mortality (Table 3). A two-mixed model revealed significant differences in DNI values between patients grouped according to hemodynamic instability and 28-day mortality (P < 0.001 for all; Fig. 2, A and B). To assess diagnostic performance of DNI, we analyzed the total of 826 patients with acute hepatitis at the time of ED admission during the same study period. The mean DNI values at admission differed significantly between patients with acute hepatitis and cholangitis (1.612 ± 3.393% vs. 4.892 ± 7.889%; P < 0.001). Again, the AUCs of ROC curves were determined to assess the ability of the DNI to discriminate between acute cholangitis and hepatitis. The AUCs of DNI value on admission for predicting acute cholangitis were 0.69 (0.664–0.716; P < 0.001), and the optimal DNI cutoff at ED admission was 1.3% (sensitivity, 66.16% and specificity, 67.68%) (Appendix 2, http://links.lww.com/SHK/A467). In clinical outcomes of acute cholangitis, the AUCs of DNI values on day 0, 1, and 2 were 0.783, 0.751, and 0.722, respectively, for shock prediction (P < 0.001 for all) and 0.75, 0.843, and 0.845, respectively, for 28-day mortality prediction (P < 0.01 for all; Fig. 3). Regarding 28-day mortality, the optimal DNI cutoffs at ED admission, day 1, and day 2 were 4.7%, 3%, and 2.4%; in other words, a DNI > 4.7% at ED admission, > 3% on day 1, and/or > 2.4% on day 2 was associated with an increased risk of 28-day mortality among patients with acute cholangitis (Table 4). Figure 4 shows the accuracy of DNI for discriminating hemodynamic instability (P < 0.001) and 28-day mortality (P < 0.001) was superior to those of other laboratory markers. Table 4 also presents data concerning the AUCs of DNI for shock predictions, such as the optimal DNI cutoffs and increased predicted risk respective to these optimal cutoffs. The multivariate Cox proportional hazard model further confirmed the associations of increased DNI values on days 0, 1, and 2 with an increased risk of 28-day mortality among patients with acute cholangitis (Table 3); specifically, an increased risk of 28-day mortality was observed among patients with an increased DNI at the time of ED admission.
To estimate the optimal cut-off values based on the time-to-event, Kaplan–Meier curves of 28-day mortality were generated from the DNI values at admission, day 1, and day 2, and results of a log-rank test demonstrated that these DNI values were also independent factors predictive of clinical outcomes at 28 days after cholangitis. In a slight contrast to the results described above, the log-rank test indicated that the optimal DNI cut-off values for 28-day mortality predictions were 4.9% (P < 0.001) at admission (P < 0.001), 4.9% (P < 0.001) on day 1 (P < 0.001), and 2.5% (P = 0.004) on day 2 (P < 0.001). Further analysis of these cut-off values using the Contal and O’Quigley technique indicated that a DNI > 4.9% at ED admission, > 4.9% on day 1, and > 2.5% on day 2 were associated with an increased risk of 28-day mortality among patients with acute cholangitis (Fig. 5).
Acute bacterial cholangitis exists on a wide spectrum, ranging from a self-limiting condition to life-threatening disease requiring specialized treatment (22). However, rapid progression to severe sepsis or septic shock is frequently observed with acute cholangitis (16). Accordingly, prompt clinical recognition and accurate diagnosis are the most critical factors associated with the treatment of cholangitis (22). Accurate assessments of severity are also a necessary component of appropriate medical therapy in addition to intensive care, which includes organ support and urgent biliary drainage (16). Our study results indicate that DNI could be a promising predictor of septic shock requiring vasopressor/inotrope as well as 28-day mortality in patients with early-phase acute cholangitis. Specifically, we found that DNI values > 4.3% and > 4.9% at ED admission could predict septic shock requiring vasopressor/inotrope and 28-day mortality, respectively, in patients with acute cholangitis. We propose that these DNI values can be determined rapidly, simply, and inexpensively for the assessment of acute cholangitis severity in patients admitted to the ED.
The Charcot triad criteria, fever, biliary tract pain, and jaundice have traditionally been considered an important diagnostic tool for acute cholangitis. However, these criteria have a very low sensitivity and little power to predict the severity of disease (16, 23). Although the principal benefit of a scoring systems is the ability to grade disease severity (16), the 2006 International Consensus Meeting for the management of Acute Cholecystitis and Cholangitis in Tokyo did not include the APACHE II system for severity assessments of acute cholangitis because the advantages of this system were not satisfactorily validated and its disadvantages were difficult to calculate (16). Following the initial publication of the Tokyo guidelines for the management of acute cholangitis (TG 07), a new guideline with a different severity grading system was published in 2013 (TG 13) in an attempt to improve practicality and the quality of care (8). However, the severity assessment criteria, which include cardiovascular, nervous, respiratory, renal, hepatic, and hematologic dysfunction, require complex items such as baseline characteristics (age), vital signs (fever, disturbance of consciousness, and hypotension), and laboratory results (WBC, platelets, creatinine, PT-INR, hyperbilirubinemia, hypoalbuminemia, and PaO2/FiO2) accompanied with diagnostic criteria for acute cholangitis (fever, evidence of inflammatory response, jaundice, abnormal liver function and biliary dilatation, and aetiology from imaging study findings); accordingly, this guideline was not easily applicable to an emergency setting (8).
Most physicians in EDs require rapid, simple, and serially measureable predictors to discriminate severity in patients with acute cholangitis. As procalcitonin (PCT) and CRP have been widely used as critical care biomarkers (20), Shinya et al. (24) investigated the usefulness of these markers, as well as the WBC, as biomarkers of inflammation in patients with acute cholangitis at the time of admission. In that study, both PCT and CRP levels were significantly higher in patients with severe cholangitis, although PCT yielded a significantly higher AUC value for predicting severe cholangitis (24). In contrast to CRP, PCT levels increase in the context of a bacterial infection, and thus PCT is a sensitive marker for detecting early sepsis with bile duct inflammation (24). Although the PCT test can be used routinely at the time of ED admission and results can be obtained in approximately 30 min (24), it is expensive and therefore difficult to obtain serial measurements of both PCT and CRP (20).
Neutrophils are a well-known and crucial component of innate immunity during sepsis (25). Because immature neutrophils enter the circulation during infection, stress, or systemic inflammation, systemic inflammatory response syndrome (SIRS) criteria include an increase in the number of immature granulocytes in circulation (19, 20). Therefore, an elevated immature/total granulocyte ratio is a well-known marker of infection or systemic inflammation, including SIRS (13). Several researchers have proposed mechanisms to explain this rapid and early release of immature neutrophils. For example, immune responses to infection induce a rapid expansion of circulating neutrophils to compensate for a loss of active neutrophils due to the massive consumption and destruction of mature cells under conditions of severe sepsis (19, 25, 26). In addition, dysregulated neutrophil function during severe sepsis, or neutrophil paralysis, results in impaired migration to the infection site, inappropriate antimicrobial responses, and neutrophil sequestration in remote organs (25, 26). Furthermore, Alves-Filho et al. (26) suggested that chemotaxis and adhesion interactions between neutrophils and endothelium are rapidly suppressed by the overproduction of nitric oxide, chemokines, and cytokines. We suggest that DNI is representative of immature granulocytes and also reflects neutrophilic dysfunction. The immature neutrophil population might be increased by compensating for the overconsumption and dysfunction of active neutrophils. However, other haematological indicators, including WBC count, neutrophil count, and segmented neutrophil fraction, are reported simply as arithmetical increases or decreases without considering the functional activities of neutrophils. Consequently, the accuracy of DNI for predicting the severity of acute cholangitis was superior to that of WBC count, neutrophil count, and segmented neutrophil values. The present study demonstrated that a higher DNI could predict both shock requiring vasopressor/inotrope treatment and short-term mortality in patients with acute cholangitis. Despite the importance of neutrophils in sepsis, manual counting, which involves only a 200-cell manual differential count of a blood smear and is difficult to perform rapidly for manual measurement after staining, might be inaccurate when compared with DNI, which uses a 30,000-cell differential count (12, 14). Therefore, it remains difficult to determine the number of immature granulocytes in clinical practice. Recently developed automated blood cell analyzer can determine the fraction of circulating immature neutrophils, thus yielding the DNI (14, 27). Before implementing DNI, our institution also measured immature granulocytes by manual counting. Recently, DNI has been substituted for manual measurement except in special cases; in other words, we only analyzed manual band measurements for 133 of 461 cases. Despite the partial data analysis, the present study also indicates a strong correlation between DNI and manual measurement values (r = 0.769, P < 0.001). We further analyzed the ability of manual band measurements to predict short-term mortality in patients with acute cholangitis using ROC curves. The AUCs of DNI and band values on ED admission were 0.842 (0.74–0.937) and 0.704 (0.602–0.807), respectively, for 28-day mortality prediction (P < 0.001). The accuracy of DNI for predicting 28-day mortality was superior to that of manual band measurement (Appendix 3, http://links.lww.com/SHK/A467). In addition, we made efforts to discriminate acute cholangitis from other clinically similar diseases with acute abdominal pain. Although it is not easy to discriminate acute cholangitis and other diseases with different aetiologies using DNI values alone, our results suggest that the DNI value facilitates the additional diagnosis of cholangitis in patients with acute hepatitis.
Several studies based on this new concept have demonstrated the usefulness of DNI as a prognostic factor in patients with local infection or sepsis/septic shock (12–14). Previously, Park et al. (13) demonstrated that a DNI > 6.5% was a promising diagnostic marker of severe sepsis and septic shock within the first 24 h after admission to an intensive care unit. In that study, however, elevated DNI values were present up to 12 h before the onset of organ/circulatory failure (13). An increase in DNI of > 12% at 72 h after ED admission predicted mortality in patients with neonatal sepsis (28). In a recent study, Kim et al. (29) investigated the usefulness of DNI as an early predictor of acute complicated appendicitis in children, and observed a significantly higher median DNI in patients with acute complicated appendicitis (2.2%), compared with those with non-complicated appendicitis (0%; P < 0.001) (29). Furthermore, a DNI cut-off value of 5.7% was used to determine 30-day mortality at the time of diagnosis of spontaneous bacterial peritonitis (30). In addition, whole-body ischaemia/reperfusion after cardiac arrest can activate a severe systemic inflammatory response associated with sterile insult; in this context, Yune et al. (20) demonstrated that a DNI > 8.4% on day 1 (HR, 3.227; 95% CI, 1.485–6.967; P = 0.001) and > 10.5% on day 2 (HR, 3.292; 95% CI, 1.662–6.519; P < 0.001) were associated with increased 30-day mortality in patients with out-of hospital cardiac arrest. Notably, Yune et al. (20) revealed an increase in DNI during the early post-resuscitation phase, as well as associations of a higher DNI with worse neurologic outcomes and increased 30-day mortality. These findings suggest that sterile inflammation may cause a higher DNI and could support the usefulness of DNI in patients with severe trauma or haemorrhagic shock. Further studies are required to validate whether DNI is a useful marker of sterile inflammation and prognostic markers of severity in patients with severe trauma or haemorrhagic shock.
The present study further demonstrated that increased DNI values were independent risk factors for the development of shock as a parameter of organ dysfunction, as well as 28-day mortality in patients with acute cholangitis. DNI can be determined rapidly, simply, and inexpensively, and could therefore become a useful tool for assessing the occurrence and severity of sepsis in patients with acute cholangitis. Furthermore, DNI is serially measurable and therefore able to assess changes in severity over time in this patient population. Based on these benefits, DNI could be applied to the assessment of responses to initial medical treatment and appropriate time points for urgent biliary system drainage.
Although this study was conducted at two tertiary academic hospitals, it involved relative small patient populations and the usual limitations of a retrospective study; therefore, this study is inherently susceptible to certain biases associated with a single-center investigation. Second, although our study demonstrated that the DNI during the acute phase of acute cholangitis was associated with 28-day mortality, we could not assess the long-term clinical outcomes in patients with cholangitis. Finally, although the two affiliated hospitals attempted to standardize their treatment processes, the prognoses might have varied because of the administration of different antibiotics to patients with different primary infections and different time points at which urgent biliary system drainage was required.
DNI values can be rapidly, simply, and inexpensively measured after ED admission. Higher DNI levels are predictive markers of hemodynamic instability and 28-day mortality in patients with acute cholangitis. The accuracy of DNI for predicting 28-day mortality is superior to that of other parameters. In the future, prospective multicentre studies involving larger numbers of patients will be needed to validate the usefulness of DNI as a promising predictor of severity for acute cholangitis.
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