1. Introduction
Acute pancreatitis is a common gastrointestinal disease caused by pancreas inflammation due to systemic inflammatory response that may lead to organ or system impairment [
1]. It is also characterized by local inflammatory reactions of the pancreas in common clinically acute and severe cases with or without functional changes of other organs. The disease is self-limiting (one week duration) in patients with mild acute pancreatitis [
2]. Moderately severe or severe acute pancreatitis (SAP) has the characteristics of rapid progress, dangerous condition, and high clinical mortality [
3]. According to revised Atlanta classification (RAC), acute pancreatitis can be either interstitial edematous pancreatitis (IEP) or acute necrotizing pancreatitis (ANP) [
4,
5,
6]. Approximately 20–30% of patients with acute pancreatitis will have necrotizing pancreatitis [
7]. According to statistics, the overall mortality of patients with acute pancreatitis is about 5–10%, and that of patients with SAP is 20–30% [
8]. While 20% patients of AP may develop SAP, there are two peaks in the course of acute pancreatitis; first stage is systemic inflammatory response syndrome with subsequent organ failure and second is infectious complication stage with related organ failure [
9,
10]. Without intensive care, SAP may progress into critical acute pancreatitis (CAP) with mortality rate of 34% [
11,
12,
13]. Predicting the risk of complications and carrying out comprehensive treatment in the early stage of acute pancreatitis is the core means to improve the prognosis of patients.
In recent studies, multiple scoring systems have been applied to the severity stratification and early prognosis prediction of patients with acute pancreatitis, but these scores have limitations [
14]. Exploring blood markers to predict the condition and complication risk of patients with acute pancreatitis has become an important research direction in recent years. Abdominal infection is an important complication in patients with acute pancreatitis, which can lead to systemic inflammatory response syndrome, multiple organ failure, and septic shock. It is one of the important causes of death in patients with acute pancreatitis [
15], but the clinical symptoms and signs of abdominal infection are not specific. However, it is difficult to obtain positive results in the early stage of the disease using imaging diagnosis and etiological examination of peritoneal puncture fluid, thus representing a significant clinical problem.
Although many studies used early infection markers to predict and diagnose abdominal infection in patients with acute pancreatitis, there is no single marker that can meet the clinical needs [
16]. It has become a consensus that combining multiple markers can improve the diagnostic effect. The cluster of differentiation 64 (CD64) antigen is considered as an important marker of bacterial infections, systemic inflammation and mortality [
17]. It is a transmembrane glycoprotein functioning as a high-affinity IgG receptor (FcγRI) [
18]. Cytokines regulate its expression and play a bridge role between humoral immunity and cellular immunity. CD64 is mainly distributed on the surface of monocytes, macrophages, and dendritic cells [
19]. Normally, CD64 expression is very low in neutrophils, but the expression is significantly induced in peripheral blood neutrophils during bacterial infection and helps in neutrophil phagocytosis and sterilization [
19,
20]. Many studies show that CD64 has high specificity in bacterial infection, which is helpful in early diagnosis of bacterial infection and the degree of infection [
21,
22].
Procalcitonin is another biomarker normally produced in thyroid C cells and enters into blood after its conversion to calcitonin when induced by glucocorticoids, glucagon, gastrin, or β-adrenergic signaling [
23]. In infection patients, it is produced by non-thyroid tissues (e.g., adipocytes) upon induction from IL-6 and TNF-α and enter bloods without being converted into calcitonin [
24]. Previously, PCT has been reported to be the most sensitive laboratory test for the detection of pancreatitis where low levels of PCT appear to be strong negative predictors of infected necrosis [
25]. C-reactive protein (CRP) is a conventional biomarker of systemic inflammatory response (SIRS) and bacterial infections. Based on this current situation, the value of neutrophil CD64 index, PCT, and CRP in predicting the incidence of acute pancreatitis complicated with abdominal infection was analyzed to provide evidence for clinical diagnosis of infectious diseases.
4. Discussion
Acute pancreatitis is one of the common emergencies of the digestive system, including mild-acute and severe-acute pancreatitis. Later is prone to septic shock and organ dysfunction. Symptoms and signs or imaging examinations are ineffective in diagnosing acute pancreatitis complicated with abdominal infection. In the clinic, a large number of patients often delay treatment and cause a bad prognosis. So, the mortality of secondary infection is as high as 36–50%. Some patients with acute pancreatitis can suffer from sequelae of pancreatitis [
30,
31,
32].
Bacteriological culture results and drug sensitivity tests are the gold standards for diagnosing bacterial infection and guiding antibiotic treatment. Still, their positive rate is low, and the isolation time of pathogens is long, which cannot provide the basis for early diagnosis in time. Therefore, finding a rapid and accurate method to evaluate a bacterial infection is particularly important.
In recent years, the application of flow cytometry to detect the expression of CD64 on the surface of peripheral blood neutrophils has attracted extensive attention in the diagnosis of bacterial infection. CD64 mRNA in neutrophils began to express 1~3 h after infection, and CD64 on the cell surface could be detected up-regulated 3~6 h after infection, which has the ability to detect infection early [
33]. Rogina et al. also showed that the differentiation of CD64 index and CD64 positive rate in each group of acute pancreatitis was higher. The CD64 index, CD64 positive rate, and PCT in the infected group were significantly higher than those in the uninfected group (all
p < 0.05), but there was no significant difference in CRP between the two groups (
p > 0.05). It may be that CRP primarily reflects the acute stress state in vivo, and the basic CRP in patients with acute pancreatitis is higher. The increase was not obvious during infection. Previously, CRP shows low specificity and limited correlation with the disease activity in comparison to other infection indexes [
34].
Some studies pointed out that Gram-negative bacteria infection in patients with acute pancreatitis with abdominal infection was significantly higher than that of Gram-positive bacteria [
35]. Therefore, this study compared the differences of various indexes between the two types of bacterial infections. The results showed that the PCT of Gram-negative bacterial infections was significantly higher than that of Gram-positive bacterial infections (
p < 0.05), but there was no significant difference in CD64 index, CD64 positive rate, and CRP between the two groups (all
p > 0.05). PCT is an important biomarker commonly used to predict bacterial infections in clinics. It can also guide the diagnosis and treatment of infectious diseases. Its sensitivity and specificity are higher than traditional markers such as WBC and CRP. CRP test is controversial in term of limitation sensitivity and specificity [
36]. PCT may be better than CD64 index in the early diagnosis of bacterial infection [
37] but CD64 index is still preferable and a method of choice in diagnosing severe and complicated bacterial infection in term of sensitivity and specificity [
38,
39]. When the body is infected or invaded by endotoxins, neutrophil CD64 can increase 4~6 h after stimulation and 0~24 h after sepsis. This study confirmed by the bacterial culture that the peripheral blood CD64 index of acute pancreatitis (AP) patients can be significantly increased within 24 h after concurrent bacterial infection, which is expected to become a new biomarker for the early diagnosis of sepsis.
Ye Z et al. reported that the sensitivity of CD64 on the surface of neutrophils for the diagnosis of bacterial infection is ≥90%, and the specificity can reach 90~100%, which is significantly better than PCT, CRP, and other indicators. However, there are many ways to express the test results, including CD64 MFI, CD64 positive rate, and CD64 index, and the calculation formula of CD64 index is not unified. The calculation formula of the CD64 index for diagnosing infection obtained by various laboratories is quite different from the cut-off value, and the comparability is poor [
40].
Because CD64 is expressed in various cells; in monocytes, these are produced in large amounts in physiological and infectious states, while lymphocytes have low expression of CD64 [
41]. Considering this expression pattern, this study used (MFI_PMN CD64/MFI_LYM CD64)/(MFI_MO CD64/MFI_PMN CD64) to express the CD64 index, which not only quantified the expression level of CD64, but could also reduce the operation error to make the CD64 index more objective. The results showed that the efficacy of CD64 index in the diagnosis of acute pancreatitis with abdominal infection was better than other indexes, but the specificity was lower than PCT. The Youden index (0.781) was the largest in the diagnosis of sepsis, while the AUC of PCT (0.897) was the highest. The sensitivity of the CD64 index was higher than that of PCT, but the specificity was lower than that of PCT. Previously, the sensitivity and specificity of neutrophil CD64 was found to be more than 80% [
42].
When the CD64 index was combined with PCT, the sensitivity and Youden index increased, but the specificity decreased. It is suggested that combined diagnosis is helpful to improve the diagnostic efficiency of acute pancreatitis with abdominal infection and sepsis.