Abstract
Objective
A positive hemoculture in acute cholangitis is serious, but a blood culture result cannot be obtained at the initial diagnosis and so cannot be used for the severity assessment and decision-making concerning urgent/early biliary drainage. Accordingly, a predictor for bacteremia at the initial diagnosis of acute cholangitis would be particularly useful. We investigated the association between neutrophil proportions in white blood cell counts (%Neutro) and bacteremic acute cholangitis.
Methods
Of 166 patients with acute cholangitis who were diagnosed with the Tokyo Guidelines 2018/2013 from April 2015 to March 2017, a total of 94 underwent blood culture assessments and were divided into those with a positive hemoculture (n=48) and a negative hemoculture (n=46) and then compared. A receiver operating characteristic curve analysis was used to evaluate the predictive ability of %Neutro and other inflammatory markers.
Results
The %Neutro values were significantly higher in the positive hemoculture group than in the negative hemoculture group (91.7±4.0% vs. 82.5±9.0%, p<0.0001). A cut-off %Neutro value of 89.7% was strongly associated with bacteremia (area under the curve 0.86, sensitivity 77.1%, specificity 80.4%). A %Neutro of ≥89.7% was a predictor of a positive hemoculture in univariate (p<0.0001) and multivariate analyses (p<0.001). Patients with a %Neutro ≥89.7% needed early biliary drainage more frequently than others (30/46, 65.2% vs. 18/48, 37.5%, p=0.0063).
Conclusion
%Neutro is an independent predictor of bacteremia in patients with acute cholangitis and may contribute to decision-making concerning early biliary drainage.
Keywords: cholangitis, acute cholangitis, bacteremia, neutrophil, neutrophil proportions in white blood cells
Introduction
Acute cholangitis requires biliary decompression at an appropriate time for recovery; however, sometimes it is a fatal disease (1). A positive hemoculture is a predictive factor for a prognosis of acute cholangitis (2-5), but a blood culture result cannot be instantly obtained upon hospital admission. Blood cultures cannot be used to assess the severity of disease or to help in the decision-making process concerning urgent or early biliary drainage. Therefore, an excellent indicator of bacteremia is needed for patients with acute cholangitis. Some biomarkers have been reported to identify bacteremia and predict prognoses in patients with acute cholangitis; for example, serum procalcitonin (PCT) levels have been reported as predictors (6-8). To our knowledge, a valid predictive biomarker for bacteremia in patients with acute cholangitis has not yet been confirmed.
In our current practice, we noticed that the neutrophil proportions of white blood cell counts (%Neutro) were frequently higher in patients with a positive hemoculture than in those with a negative hemoculture for acute cholangitis. Accordingly, we retrospectively investigated whether or not %Neutro was a useful marker in predicting bacteremia at the initial diagnosis.
Materials and Methods
This retrospective study included 166 patients diagnosed with acute cholangitis according to the updated Tokyo Guidelines for acute cholangitis and acute cholecystitis 2018/2013 (hereinafter referred to as TG18/13) (9,10) between April 2015 and March 2017 at the National Hospital Organization Kure Medical Center and Chugoku Cancer Center. We excluded 21 patients who had factors that affected the body temperature, white blood cell (WBC) count, %Neutro, and serum C-reactive protein (CRP) levels. Ninety-four of 145 patients underwent hemoculture without preadministration of antibiotics at the time of the first medical examination, and these patients were included in the study analyses (Fig. 1).
Figure 1.
Flowchart for the inclusion of patients with acute cholangitis. The diagnosis of acute cholangitis is determined based on the updated Tokyo Guidelines 2018/2013 for the severity evaluation of acute cholangitis. Twenty-one patients with factors affecting the body temperature, white blood cell (WBC) count, neutrophil percentage in the WBCs, and C-reactive protein were excluded, and the 94 patients who underwent hemoculture without pre-administration of antibiotics at the time of the first medical examination were analyzed.
This study was performed in accordance with the Declaration of Helsinki and was approved by our institution's ethics committee (Approval No. 2020-20). Patients were not required to give their informed consent to the study because the analysis used anonymous clinical data obtained after each patient agreed to receive treatment for acute cholangitis. For disclosure, the details of study are posted on some walls in the National Hospital Organization Kure Medical Center and Chugoku Cancer Center.
Examinations on admission
The vital signs of all patients were checked, and all patients underwent abdominal computed tomography. Blood samples were obtained on admission. Blood cultures were assessed, and a differential WBC count, including the %Neutro, CRP level, PCT level, and other laboratory data were recorded. The hematology tests were performed with a Sysmex Hematology XN Modular System (Sysmex, Hyogo, Japan) (11).
The diagnosis of acute cholangitis, severity assessment, and indication for urgent or early biliary drainage
TG18/13 was used for the diagnosis and severity grading of acute cholangitis in our patients (Supplementary material 1, 2). Acute cholangitis was defined using both the suspected and definite criteria. The severity criteria involved organ dysfunction (i.e., hypotension, disturbance of consciousness, respiratory dysfunction, oliguria or serum creatinine >2.0 mg/dL, prothrombin time international normalized ratio >1.5, and platelet count <100,000/mm3). Moderate cholangitis, considered to pose a risk for severe cholangitis without early biliary drainage, was defined as the presence of ≥2 of the following 5 items: abnormal WBC count (>12,000/mm3 or <4,000/mm3), a high fever (≥39°C), age ≥75 years, hyperbilirubinemia (total bilirubin ≥5.0 mg/dL), and hypoalbuminemia (albumin <STD×0.7=2.92 at our institute; Supplementary material 2). Blood cultures were obtained twice in one session at the initial diagnosis, and one or two positive results were defined as a positive hemoculture. The presence of skin-resident bacteria was treated as a negative hemoculture. We defined the timing of biliary decompression as “urgent” if within 6 hours of admission and “early” if performed within 24 hours. We performed urgent biliary drainage for severe cholangitis and early biliary drainage for moderate cholangitis using an endoscopic retrograde cholangiopancreatography technique and/or a percutaneous transhepatic biliary drainage technique.
The analysis of characteristics of patients with acute cholangitis
We divided the 94 patients into a positive hemoculture group and negative hemoculture group and compared the WBC count, %Neutro, CRP level, PCT level, and other characteristics between the two groups. Furthermore, we compared the ability of %Neutro, PCT, and other factors associated with the severity assessment criteria in TG18/13 to predict bacteremia. Next, we divided the patients into a higher %Neutro group and a lower %Neutro group and compared several items associated with the prognosis.
Statistical analyses
Fisher's exact test and the χ2 test were used to evaluate categorical variables, and Welch's t-test was used to evaluate quantitative data, where appropriate. A logistic regression analysis was performed to identify independent predictors of a positive hemoculture. To evaluate the usefulness of the WBC count, %Neutro, CRP, and PCT values for predicting a positive hemoculture, receiver operating characteristic (ROC) curves were plotted, and areas under the curve (AUCs) were calculated with 95% confidence intervals (CIs). Statistical evaluations of the AUC curve and the differences between each biomarker were performed using a χ2 test. An ROC curve analysis was performed to evaluate the ability of WBC count, %Neutro, CRP, and PCT values to predict the presence of bacteremia and level of severity in patients with acute cholangitis. The optimal cut-off values for %Neutro on the ROC curve were determined based on the Youden index. A p value of <0.05 was regarded as significant. The odds ratios were reported together with their 95% confidence limits.
All statistical analyses of recorded data were performed using the Excel statistical software package (Ekuseru-Toukei 2015 version; Social Survey Research Information, Tokyo, Japan).
Results
Patients' characteristics
Table 1 shows the severity of acute cholangitis, frequency of urgent or early biliary drainage and positive hemoculture, drainage method, and mortality in all 94 patients. Two deaths occurred: an 84-year-old man who had hilar malignant biliary strictures and moderate cholangitis due to stent occlusion and died without biliary drainage; and an 85-year-old woman who had severe cholangitis due to choledocholithiasis and died due to multiple organ dysfunction apart from urgent biliary drainage. Their %Neutro values at the initial diagnosis were 95% and 93.8%, respectively. Forty-eight of the 94 patients had a positive hemoculture, while 46 had a negative hemoculture (Fig. 1).
Table 1.
Characteristics of Patients According to the Severity of Acute Cholangitis.
| Severity of acute cholangitis | Severe | Moderate | Mild | |||
|---|---|---|---|---|---|---|
| Patients’ number, n (%) | 19 (20.2) | 35 (37.2) | 40 (42.6) | |||
| Biliary drainage | ||||||
| Urgent drainage, n | 10 | 19 | 6 | |||
| Early drainage, n | 0 | 5 | 8 | |||
| Urgent or early, n (%) | 10 (52.6) | 24 (68.5) | 14 (35) | |||
| Drainage method, n | ||||||
| ENBD | 7 | 18 | 13 | |||
| ERBD | 2 | 5 | 0 | |||
| PTBD | 1 | 1 | 1 | |||
| Positive hemoculture, n (%) | 14 (73.7) | 21 (60) | 13 (32.5) | |||
| Death associated | ||||||
| with cholangitis, n (%) | 1 (5.3) | 1 (2.9) | 0 |
ENBD: endoscopic nasobiliary drainage, ERBD: endoscopic retrograde biliary drainage, PTBD: percutaneous transhepatic biliary drainage
Urgent drainage was defined as drainage within 6 hours of admission and early as within 24 hours.
The patient characteristics and the prevalence of species in a positive hemoculture are shown in Table 2 and Supplementary material 3, respectively. The mean age, body temperature, and heart rate were significantly higher in patients with a positive hemoculture than in those with a negative hemoculture. The platelet count and serum amylase levels were also lower in the patients with a positive hemoculture than in those with a negative hemoculture. The WBC count, CRP level, and PCT level did not differ significantly between the two groups. The %Neutro values were significantly higher in the positive hemoculture group than in those with a negative hemoculture (91.7±4.0% vs. 82.5±9.0%, p<0.0001). Patients diagnosed with a positive hemoculture had more moderate or severe cholangitis than those with a negative hemoculture (35/48, 72.9% vs. 17/46, 37%, p=0.0004). Urgent or early biliary drainage was performed in more patients with a positive hemoculture than in those with a negative hemoculture (31/48, 64.6% vs. 17/46, 37%, p=0.0065).
Table 2.
Characteristics at the Time of Initial Diagnosis and Outcomes According to the Result of Hemoculture.
| Positive hemoculture | Negative hemoculture | |||
|---|---|---|---|---|
| (N=48) | (N=46) | p value | ||
| Age, years | 81.5±10 | 74.5±13 | <0.01 | |
| Sex, male | 22 (45.8%) | 22 (47.8%) | 0.51 | |
| Body temperature (°C) | 38.1±1.2 | 37.1±1.0 | <0.0001 | |
| Blood pressure (systolic) (mmHg) | 123±27 | 130±28 | 0.25 | |
| Heart rate (/min) | 97±16 | 87±17 | 0.0004 | |
| Cardiovascular dysfunction | 3 (6.3%) | 1 (1.7%) | 0.32 | |
| Disturbance of consciousness | 5 (10.4%) | 0 | 0.31 | |
| Respiratory dysfunction | 2 (4.2%) | 0 | 0.26 | |
| Cause | ||||
| Benign (choledocholithiasis, etc) | 34 (70.8%) | 37 (80.4%) | 0.2 | |
| Malignant biliary obstruction (MBO) | 14 (29.2%) | 9 (19.5%) | ||
| Stent dysfunction in MBO, n/N | 12/14 (85.7%) | 8/9 (88.9%) | ||
| Comorbidities | ||||
| Cerebrovascular disease | 10 (20.8%) | 5 (10.9%) | 0.3 | |
| Heart failure or ischemic heart disease | 10 (20.8%) | 11 (23.9%) | 0.46 | |
| Emphysema or interstitial pneumonia | 3 (6.2%) | 1 (2.2%) | 0.32 | |
| Diabetes mellitus | 12 (25%) | 7 (15.2%) | 0.18 | |
| Laboratory test | ||||
| WBC count (×103/μl ) | 116±64 | 100±52 | 0.17 | |
| %Neutro | 91.7±4.0 | 82.5±9.0 | <0.0001 | |
| %Lymp | 5.0±2.9 | 11.3±7.3 | <0.0001 | |
| %Mono | 2.7±1.8 | 4.9±2.7 | <0.0001 | |
| Hemoglobin (g/dL) | 12.2±2.1 | 11.9±2.1 | 0.52 | |
| Platelet count (×104/μl) | 15.8±6.3 | 20.4±7.5 | 0.0019 | |
| AST (IU/L) | 283±276 | 235±286 | 0.41 | |
| ALT (IU/L) | 197±196 | 196±271 | 0.98 | |
| ALP (IU/L) | 908±551 | 929±646 | 0.87 | |
| Total bilirubin (mg/dL) | 2.8±1.6 | 4.3±5.9 | 0.08 | |
| Amylase (IU/L) | 70±42 | 101±83 | 0.026 | |
| Blood urea nitrogen (mg/dL) | 28±25 | 20±11 | 0.054 | |
| Creatinine (mg/dL) | 1.23±1.09 | 0.95±0.48 | 0.11 | |
| Albumin (g/dL) | 3.5±0.6 | 3.7±0.6 | 0.045 | |
| CRP (mg/dL) | 7.0±7.9 | 5.9±5.7 | 0.43 | |
| Procalcitonin (ng/mL) | 21.5±50.4 | 4.3±9.1 | 0.055 | |
| PT- INR | 1.21±0.35 | 1.20±0.28 | 0.96 | |
| Severity of cholangitis | ||||
| mild : moderate : severe | 13：22：13 | 29：12：5 | 0.0019 | |
| moderate+severe | 35 (72.9%) | 17 (37%) | 0.0004 | |
| severe | 13 (27%) | 5 (10.9%) | 0.12 | |
| Duration of anitibiotics usage (day) | 8.1±5.0 | 7.1±4.0 | 0.3 | |
| Urgent/early biliary drainage | 31 (64.6%) | 17 (37%) | 0.0065 | |
| Death associated with cholangitis | 2 (4.2%) | 0 | 0.43 | |
The data of procalcitonin were obtained from 35 patients with positive hemoculture and 34 patients with negative hemoculture. Data are presented as number of patients (%). n/N shows positive number/ analyzed number. Mean values are presented as mean±SD.
WBC: white blood cells; %Neutro: proportion of neutrophils in the white blood cells; %Lymph: proportion of lymphocytes in the white blood cells; %Mono: proportion of monocytes in the white blood cells; AST: aspartate aminotransferase; ALT: alanine aminotransferase; CRP: C-reactive protein; PT-INR: prothrombin time international normalized ratio
Ability of %Neutro to predict bacteremia and severity in acute cholangitis
Fig. 2 illustrates the ROC curves for the WBC count, %Neutro, CRP, and PCT for predicting bacteremia (Fig. 2a), severe or moderate cholangitis (Fig. 2b), and severe cholangitis (Fig. 2c). %Neutro values and PCT levels were significantly associated with bacteremia (%Neutro; AUC 0.86, 95% CI: 0.77-0.95, p<0.001, PCT; AUC 0.63, 95% CI: 0.50-0.77, p=0.047), and the correlation was stronger for %Neutro than for PCT (p=0.002). The optimal cut-off value using the Youden index in the ROC curve analysis was %Neutro 89.7%, and the sensitivity and specificity of this %Neutro cut-off value for the diagnosis of bacteremia were 77.1% and 80.4%, respectively. The associations between %Neutro, CRP, and PCT and moderate or severe cholangitis were statistically significant (%Neutro; AUC 0.75, 95% CI: 0.63-0.87, p<0.001, CRP; AUC 0.67, 95% CI: 0.54-0.80, p=0.0128, PCT; AUC 0.70, 95% CI: 0.60-0.82, p=0.0023), but there was no significant difference between %Neutro and PCT (p=0.50). Regarding the predictions of severe cholangitis, %Neutro, CRP, and PCT showed good statistical power (%Neutro; AUC 0.71, 95% CI 0.56-0.86, p=0.0068, CRP; AUC 0.70, 95% CI: 0.53-0.88, p=0.0234, PCT; AUC 0.75, 95% CI 0.60-0.89, p<0.001), but there were no marked differences in the predictive ability among the three markers.
Figure 2.
The receiver operator characteristic (ROC) curve for the white blood cell (WBC) count, proportion of neutrophils in the WBCs (%Neutro), C-reactive protein (CRP), and procalcitonin (PCT) for predicting bacteremia, moderate or severe cholangitis, and severe cholangitis. (a) Bacteremic versus non-bacteremic acute cholangitis. (b) Moderate/severe versus mild acute cholangitis. (c) Severe versus mild/moderate acute cholangitis. AUC: area under the curve, CI: confidence interval
Comparing the ability to predict bacteremia with other factors
We compared the ability of %Neutro to predict bacteremia with that of PCT and other factors associated with the severity assessment of acute cholangitis in TG18/13. We set the cut-off value of %Neutro at 89.7% using the Youden index in the ROC curve. There were more patients with bacteremia in the %Neutro ≥89.7% group than in the %Neutro <89.7% group in a univariate analysis (37/48, 77.1% vs. 9/46, 19.6%, p<0.0001), and a high body temperature (≥39°C) and %Neutro ≥89.7% were selected as independent predictors of bacteremia in a multivariate analysis (Table 3). Regarding the high body temperature (≥39°C), the sensitivity for diagnosing bacteremia was 29.2%, but the specificity was 95.8%. In addition, the sensitivity and accuracy for diagnosing bacteremia in “%Neutro ≥89.7% or body temperature ≥39°C” were 87.5% and 83.0%, respectively (Table 4).
Table 3.
Analysis to Identify Predictors of Bacteremia.
| Positive hemoculture | Negative hemoculture | Univariate analysis | Multivariate analysis | |
|---|---|---|---|---|
| (N=48) | (N=46) | p value | p value | |
| HR (95%CI) | ||||
| Age ≥75 years old | 35 (72.9%) | 27 (58.7%) | 0.045 | 0.59 1.4 (0.38-5.29) |
| Body temperature ≥39°C | 14 (29.2%) | 2 (4.3%) | 0.0012 | 0.01 13.1 (1.85-92.65) |
| WBC count ≥12, <4×103/μL | 25 (52%) | 10 (21.7%) | 0.0022 | 0.48 1.6 (0.45-5.40) |
| %Neutro ≥89.7％ | 39 (81.3%) | 11 (23.9%) | <0.0001 | <0.001 12.7 (3.71-43.78) |
| Platelet count <10×104/μL | 9 (18.8%) | 1 (2.2%) | 0.009 | 0.12 7.3 (0.61-86.79) |
| Total bilirubin ≥5.0 mg/dL | 7 (14.6%) | 11 (23.9%) | 0.19 | |
| Creatinine >2.0 mg/dL | 4 (8.3%) | 0 | 0.06 | |
| Albumin <2.92 g/dL | 13 (27%) | 6 (13%) | 0.08 | |
| Procalcitonin ≥2.0 ng/mL | 17 (35.4%) | 11 (23.9%) | 0.13 | |
| Procalcitonin ≥0.5 ng/mL | 26 (54.1%) | 18 (39.1%) | 0.06 | |
| PT-INR ≥1.5 | 3 (6.3%) | 2 (4.3%) | 0.52 | |
| Severe or moderate cholangitis | 35 (72.9%) | 17 (37.0%) | 0.00044 | 1.00 1.0 (0.28-3.62) |
The data of procalcitonin were obtained from 35 patients with positive hemoculture and 34 patients with negative hemoculture. Data are presented as number of patients (%). Mean values are presented as mean±SD.
WBC: white blood cells; %Neutro: proportion of neutrophils in the white blood cells, PT-INR: prothrombin time international normalized ratio
Table 4.
Predictive Ability to Diagnose of Positive Hemoculture in Patients with Acute Cholangitis.
| Sensitivity | Specificity | Accuracy | ||||
|---|---|---|---|---|---|---|
| Positive hemoculture | ||||||
| %Neutro ≥89.7% | 0.771 | 0.804 | 0.787 | |||
| BT ≥39°C | 0.292 | 0.958 | 0.625 | |||
| %Neutro ≥89.7% or BT ≥39°C | 0.875 | 0.783 | 0.830 |
%Neutro: proportion of neutrophils in the white blood cells, BT: body temperature
The prognosis according to %Neutro
We divided the 94 patients into a %Neutro ≥89.7% group (n=46) and a %Neutro <89.7% group (n=48) and compared several items associated with the prognoses in both groups (Table 5). The %Neutro ≥89.7% group included more patients with moderate or severe cholangitis than the %Neutro <89.7% group (34/46, 73.9%, vs. 20/48, 37.5%, p=0.0015), and the frequency of urgent or early biliary decompression (within 24 hours) was higher than in the %Neutro <89.7% group (30/46, 65.2% vs. 18/48, 37.5%, p=0.0063). Furthermore, hospital days were longer in the %Neutro ≥89.7% group than in the %Neutro <89.7% group (median: 18 days vs. 14 days, p=0.04).
Table 5.
Prognosis According to %Neutro.
| %Neutro ≥89.7% | %Neutro <89.7% | |||||
|---|---|---|---|---|---|---|
| (N=46) | (N=48) | p value | ||||
| Severe cholangitis | 13 (28.3%) | 6 (12.5%) | 0.049 | |||
| Moderate or severe cholangitis | 34 (73.9%) | 20 (41.7%) | 0.0015 | |||
| Urgent or early biliary drainage | 30 (65.2%) | 18 (37.5%) | 0.0063 | |||
| Duration of antibiotics (day) | 7 (3-33) | 7 (2-20) | 0.96 | |||
| Hospital days (day) | 18 (7-56) | 14 (3-119) | 0.04 | |||
| Death associated with cholangitis | 2 (4.3%) | 0 | 0.24 |
Data except duration of antibiotics and hospital days are presented as number of patients (%).
Duration of antibiotics and hospital days are presented as median values (range).
Discussion
Patients with bacteremic cholangitis (2-4) have a serious condition and may require urgent/early biliary drainage. A blood culture result, however, cannot be obtained at the initial diagnosis and so cannot be used for making decisions concerning urgent/early biliary drainage. An effective biomarker for the prediction of bacteremic cholangitis would therefore be useful for managing acute cholangitis.
To our knowledge, this study is the first to show the usefulness of %Neutro for predicting bacteremia in patients with acute cholangitis. %Neutro showed an excellent independent diagnostic ability for bacteremia in an ROC curve analysis (AUC 0.86, diagnostic sensitivity 77.1%, and specificity 80.4% for %Neutro ≥89.7%), and there were more patients with moderate and severe cholangitis and more patients requiring urgent or early biliary drainages in the high %Neutro group than in the low %Neutro group. Based on these results, %Neutro is suggested to be an excellent predictor of not only bacteremia but also the prognosis of cholangitis. Furthermore, the measurement of %Neutro is easy, quick, and inexpensive. A %Neutro assessment may therefore be useful when caring for patients with acute cholangitis, especially in terms of decisions to perform early biliary drainage.
Factors associated with prognoses of acute cholangitis (mortality and/or need for early biliary decompression) have been reported to be the WBC count, hyperbilirubinemia, hypoalbuminemia, acute renal failure, shock, thrombocytopenia, endotoxemia, a high fever, comorbidities, advanced age, malignant disease, extension of prolonged prothrombin time, a smoking history, and bacteremia (2,8,12-16). Some researchers have developed scoring systems using various prognostic factors with good results (2,13,17,18). TG13 (9) also assesses severity using several prognostic factors. TG13 is an easy and effective scoring system, the usefulness of which has been confirmed, and it was modified in the updated Tokyo Guidelines for acute cholangitis and cholecystitis in 2018 (10,19). Furthermore, PCT (6-8), endotoxin activity (20,21), NF-κB (22), IL-7 (23), the delta-neutrophil index (24), and presepsin (25) have been reported as independent biomarkers for the prognosis of acute cholangitis, and PCT (6,23), endotoxin activity (20), and IL-7 (23) are factors for predicting bacteremia.
In our clinical practice, we have observed that patients with bacteremia and/or severe cholangitis often have a high %Neutro value (e.g. ≥90%). Currently, at any hospital in Japan, the neutrophil, lymphocyte, eosinophil, and monocyte counts among WBCs are measured automatically and quickly with an easy method, and the results are extremely accurate (11). In bacterial and fungal infections, the number of mature neutrophils increases in the blood, and the neutrophil count (number of mature and young neutrophils), %Neutro, and WBC count are all up-regulated (26,27). If inflammation becomes severe, as in sepsis, younger neutrophils are released into the peripheral blood, resulting in a neutrophil left shift. WBC and neutrophil counts are thought to be the earliest and most sensitive inflammatory markers and useful for evaluating treatment effects (26,27). Therefore, we studied the association between bacteremia and the %Neutro values and found that the %Neutro values were excellent diagnostic factors for a positive hemoculture.
Some studies have reported that %Neutro is a useful marker for bacteremia in infections. Fukui et al. (28) stated that %Neutro >80% was an independent risk factor for a positive hemoculture. In the present study, we assessed the correlation between bacteremia and %Neutro focusing on only acute cholangitis. Another previous study (29) concluded that a high neutrophil-to-lymphocyte ratio (NLR) was a very good independent predictor of lethal outcomes in critically ill patients with secondary sepsis and/or trauma. We presume that NLR values are nearly equal to %Neutro values. The neutrophil left shift is used for diagnosing sepsis and is a possible predictive factor for bacteremia. Kim et al. reported the efficacy of measuring the delta-neutrophil index (DNI) as a parameter of a neutrophil left shift for predicting the prognosis in patients with acute cholangitis (24). However, measuring the DNI can be difficult, and it is challenging to obtain a blood smear for all patients. Based on the present findings, the up-regulation of %Neutro may indicate an increasing necessity for neutrophil and neutrophil left shift assessments.
WBC counts are the most common inflammatory biomarker, and many authors have reported the usefulness of WBC counts as predictors of severe acute cholangitis. However, our study and several others (6,7) have concluded that WBC counts are not independently useful for determining the prognosis and predicting bacteremia in acute cholangitis. One reason for this may be that the reaction of the WBC count in response to bacterial or fungal infections differs among patients, especially in the elderly. Another reason is that the WBC count may change from high to low over the course of treatment in severe cases with severe inflammation.
Many authors have suggested that serum PCT levels are a superior predictor of the presence of severe acute inflammation to conventional markers, such as WBC counts and serum CRP levels (30). In the present study, PCT showed a good and equivalent ability for assessing severity compared with %Neutro in an ROC curve analysis, but the diagnostic ability for bacteremia was weaker than that of %Neutro. In general, in most diseases, bacteremia occurs with extensive and prolonged inflammation, but bacteremia in acute cholangitis occurs early and easily with the onset of obstruction of the bile duct because the cause of bacteremia is cholangio-venous reflux due to up-regulation of the pressure in the bile duct. Therefore, in acute cholangitis, it is important to identify infection in the early phase after the onset. Although PCT is readily produced within 6-12 hours, and serum PCT levels increase (30), we suspect that the earliest biomarker for bacteremic cholangitis is not the WBC count, CRP level, or PCT level but rather the %Neutro.
In the present study, we reconfirmed the importance of a high fever (body temperature ≥39°C) for a diagnosis of bacteremia in acute cholangitis. Regarding body temperature (≥39°C), the sensitivity for diagnosing bacteremia was not high, but the specificity was surprisingly high (95.8%). In addition, the diagnostic sensitivity and accuracy for bacteremia in “body temperature (≥39°C) or %Neutro ≥89.7%” increased to 87.5% and 83.0%, respectively. Given these results, we might be able to utilize the body temperature and %Neutro for diagnosing bacteremia in acute cholangitis.
Several limitations associated with the present study warrant mention. First, this was a retrospective analysis of medical records at a single hospital. There were some patients with acute cholangitis who did not have a blood culture test, and there were no criteria on which to base the decision to obtain a blood culture. Patients who underwent a blood culture test had acute cholangitis with suspicion of bacteremia and severe cholangitis, and as such, our analysis using this population was relatively reasonable. Second, we lacked some data concerning serum PCT levels; therefore, this analysis may not have provided a completely correct assessment of the association between %Neutro and PCT. Third, in our study, patients with acute pancreatitis and usage of an anticancer drug were excluded, as these conditions can affect the WBC count, %Neutro, and CRP values. In acute pancreatitis, not only the severity assessment but also the diagnosis of cholangitis is difficult, and %Neutro values are relatively high in acute pancreatitis. Thus, predicting bacteremia in patients with acute pancreatitis is challenging. Anticancer drugs used to treat pancreato-biliary cancer, such as gemcitabine, S-1, nab-paclitaxel, and cisplatin, do not induce severe bone marrow suppression compared with drugs for other cancers. As such, there is often a high %Neutro value with a normal or low WBC count in patients with bacteremic acute cholangitis (data not shown). We believe that a high %Neutro value is an important factor to consider when bacteremia is suspected in a patient taking an anticancer drug.
Conclusion
%Neutro, which can be easily measured in clinical practice, is a useful marker for predicting the severity of acute cholangitis at the diagnosis. Therefore, patients with high %Neutro values and a high fever should be considered for early biliary drainage in anticipation of bacteremia.
The authors state that they have no Conflict of Interest (COI).
Supplementary Material
TG18/13 diagnostic criteria for acute cholangitis
TG18/13 severity criteria for acute cholangitis
Results of blood cultures in patients with acute cholangitis
Acknowledgement
We thank all clinical technologists and our colleagues at the Kure Medical Center and Chugoku Cancer Center. We are also grateful to Tomoyuki Akita for the direction and review of the statistical analyses and Kanami Okino for helping collect the data and conduct the literature search.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
TG18/13 diagnostic criteria for acute cholangitis
TG18/13 severity criteria for acute cholangitis
Results of blood cultures in patients with acute cholangitis