The Neutrophil-Lymphocyte Ratio as an Early Predictor of Severity and outcome of Post-Endoscopic Retrograde Cholangiopancreatography Pancreatitis

• The NLR having moderately high prognostic power in predicting the severity and outcome of PEP patients.
• At cutoff point 6.05, NLR on day 1 post-ERCP can predict sever pancreatitis with sensitivity 91.3, specificity89.6% .
• NLR at cutoff point 5.42 on day 2 post-ERCP can predict sever pancreatitis with specificity94% , sensitivity 91.3%.

DISCUSSION

The most frequent adverse consequence of ERCP is post-ERCP pancreatitis, which is iatrogenic in contrast to simple acute pancreatitis. PEP is still an imperative ERCP consequence that can negatively affect patient quality of life, morbidity, and death [15]. Although the larger part of acute pancreatitis is mild and resolves on its own, about 25% of people may experience severe cases with complications including organ failure or necrosis. There have been reports of significant death rates of up to 50% in cases with severe acute pancreatitis (SAP) [12].

Stratification by severity and early beginning of suitable treatment may be hindered by the inability to anticipate PEP's severity at an early stage [10]. Procedural features, post-procedural variables, and patient physiological characteristics and co-morbidities all have a role in the pathophysiology of PEP and can be utilized to predict the likelihood that it will manifest. In assessing the occurrence and severity of post-ERCP pancreatitis, procedure-related risk variables are just as significant as patient-related factors [16]. It's critical to understand the PEP risk variables. As research has progressed, a growing number of contributing factors have been identified, such as patient individual differences, endoscopists' expertise levels, and several clinical aspects [17].

The current study aimed to evaluate the neutrophil-lymphocyte ratio as an early predictor of the severity and outcome of post-endoscopic retrograde cholangiopancreatography pancreatitis and identify risk factors for severe pancreatitis.

In the present study, we noticed that 90 patients developed PEP, of whom 67(74.4%) exhibited mild to moderate pancreatitis, while 23(25.6%) patients showed evidence of severe pancreatitis. There were 51 males (56.7%) and 39 females (43.3%) with no discernible gender difference between patients with mild/moderate and severe pancreatitis. According to Chi et al., female sex was an independent risk factor for PEP, with 60% of the patients being female and 40% being male [18]. Furthermore, it was reported that gender differences can result in differing body structures, functions, and hormone production values, causing a higher probability of PEP in women than in men [19]. The gender-based discrepancy in the results can be explained by the different population samples used in the study, where 61.3% of the patients included in their study had evidence of choledocholithiasis, a condition that is more common in females. In this study, malignancy was detected in 32.2% of PEP patients. 

Regarding the age, the current study found that the mean age of PEP patients was 56.8 ±13.1 years with a non-significant difference between patients with mild/moderate and severe pancreatitis. Lin and his colleagues in their study on the Chinese population reported that age less than 60 was an independent risk factor for PEP [20].Studies have shown that the prevalence of PEP is significantly higher in patients younger than 60 years of age than in elderly patients, possibly due to the decrease in the exocrine function of the pancreas with increasing age. When the pancreas is mildly injured, the body is stressed, leading to a sudden increase in pancreatic juice and further aggravating pancreatic injury [20,21].

Patients with PEP were 36 (60%) diabetic patients and 25 (27.8%) hypertensive patients with a statistically non-significant difference between the two patient groups. Similarly, Chi et al. in their study have reported that DM and HTN are not significant risk factors for PEP [18].

Regarding the BMI, we noticed that 58 (64.4%) patients had a BMI ≥ 30, and 32 (35.6%) had a BMI     

In the current study, statistical analysis revealed that there was a significant difference between the two patient groups regarding the baseline (pre-ERCP) TLC where the TLC was considerably higher in patients who develop mild/moderate compared to those with severe PEP. However, NLR did not differ. Post-ERCP laboratory investigations showed that TLC was higher in a severe group than mild/moderate ones but statistically non-significant, while the mean value of NLR on days 1 and 2 was significantly higher in a severe form of acute pancreatitis. 

In addition to how the blood samples are handled, several physiological and pathological factors, such as pregnancy, stress, and hydration state, might affect the total WBC count [25]. When compared to the WBC count, the neutrophil-lymphocyte ratio (NLR) is a more accurate indicator of unfavorable outcomes in several benign, malignant conditions, or infections including hepatocellular carcinoma (HCC), colorectal cancer (CRC), esophageal cancer, and coronary heart disease (CHD) [26, 27]. The immunological response is more accurately reflected by neutrophils and lymphocytes than by the total WBC count. Specifically, research has shown that the severity of acute pancreatitis is correlated with peripheral lymphocytopenia [11].

Cumulative evidence indicates that both the innate immune system (which includes neutrophils, monocytes, and macrophages) and adaptive immune system (which is primarily made up of lymphocytes) play crucial roles in the development of the disease, though the exact pathophysiology by which local pancreatic injury triggers the systemic inflammatory response is still unclear [28, 29].

The greater the NLR value, the more unbalanced the inflammatory state is, since it represents a balance between inflammatory regulator lymphocytes and inflammatory activator neutrophils [30, 31]. According to a study, patients with HCC who have higher pretreatment NLR may have worse outcomes. [32]. NLR is linked to AP and is more accurate than other serum indicators at predicting the severity and prognosis of AP [33]. In assessing the severity of AP, Huang et al. have shown that NLR is more sensitive and accurate than WBC [30].

In the present study, the mean value of NLR on days 1 and 2 post-ERCP significantly differed between the 2 patient groups with considerably higher values in patients with severe form of acute pancreatitis. Roc curve analysis reveals that, at cutoff point 6.05, NLR on day 1 post-ERCP can predict severe pancreatitis with sensitivity 91.3, specificity 89.6%, AUC 0.953and P value 0.00. Furthermore, NLR at cutoff point 5.42 on day 2 post-ERCP can predict severe pancreatitis with a higher AUC of 0.995 and specificity of 94%, sensitivity of 91.3%, and a P value of 0.00

The study findings are supported by Lee et al.'s documentation that the NLR can distinguish between patients with mild/moderate PEP and those who develop severe PEP. Additionally, they observed that, out of all the variables examined, NLR on day 2 post-ERCP had the strongest predictive power (AUC = 0.89) for severe PEP [10]. Additionally, Han et al. and Kong et al. reported that the NLR is associated with acute pancreatitis severity [34,35].

Given that the NLR measures the balance between neutrophilia, which indicates systemic inflammation, and lymphopenia, which represents the stress-induced cortisol response, the more elevated the NLR, the more significantly unbalanced the inflammatory status [34].

In the current study, the univariate analysis revealed BMI ≥30, history of previous pancreatitis, history of previous PEP, NLR day 1, NLR day 2, a malignant indication of ERCP, duration of procedure, difficult cannulation and pancreatic duct contrast are significant risk factors for sever pancreatitis.

Consistent with our results, Chi, et al. reported that a history of pancreatitis, pancreatic duct imaging pancreatic sphincterotomy, and difficult cannulation were significantly associated with PEP [18]. Dalma Dobszai et al found a clear correlation between overweight or obesity and the development of SAP [36]. Likewise, it was believed that fewer injections, cannulations, and minimal amount of contrast medium cause less papillary trauma making them crucial in avoiding PEP [16].

We found that univariate and multivariate analysis that NLR days 1 and 2 are significant independent risk factors for severe pancreatitis. This finding was consistent with that of Suppiah et al., who observed that the NLR within the first 48 hours is a reliable indicator of severe acute pancreatitis [12]. Likewise, a Korean study involving 490 patients found that the NLR is linked to both organ failure and severe acute pancreatitis [37].

Patients who require close observation, vigorous hydration, abdominal imaging, and potential transfer to the intensive care unit can be identified using NLR on the second day following ERCP. We observed in our study that the mean value of NLR days 1, and day 2 were significantly higher in pancreatitis patients requiring ICU admission with a p-value (0.00), and NLR day 2 with higher significant values in the severe pancreatitis group admitted to ICU with p-value (0.001) which consisted with Lee et al. and O’connell et al. studies [10] [38].

We noticed that the mean value of NLR days 1 and 2 was significantly higher in dead patients with p-values (0.00) and NLR days 1 and 2 were higher significant in dead patients of severe pancreatitis with p-values (0.050) & (0.00) respectively. According to earlier reports, the NLR has the highest prognostic value and is the most potent predictor of overall survival in AP patients [33]. Additionally, Suppiah et al. discovered a significant correlation between the risk of developing a severe form of AP and adverse outcomes and the higher NLR measured during the first 48 hours of hospitalization [12].

The prediction and early identification of PEP is challenging. PEP has the potential to dramatically raise patient mortality risk as well as healthcare-related costs [39]. Thus, a straightforward indicator that can accurately forecast the patient's prognosis within 24 hours of the disease's onset is required. The treatment of SAP patients greatly depends on early detection and prediction. The NLR's reasonably high prognostic power in predicting the severity of AP patients, along with its affordability and ease of use, gave us helpful clinical guidance that improved our ability to assess the severity of AP.

CONCLUSION

The NLR offers beneficial clinical guidance to better assess the severity of AP. It is also inexpensive, readily available, and has a moderately high prognostic power in predicting the severity, outcome, and overall survival of AP patients. Early modification of risk factors may reduce the likelihood of developing severe pancreatitis and decrease its morbidity and mortality.

Ethical approval: Each participant was informed about the study and given the chance to submit their informed consent before enrolment. The Menoufia University of Egypt's Faculty of Medicine's ethical committee gave its approval to the study (IRB: 4/2022 TROP 22).

Conflict of Interest: The authors declare that they have no competing interests.

Funding Sources: The study was fully non-funded by any organization.

Author contribution: All authors made significant contributions to the work reported. They also helped write, revise, or critically evaluate the article, gave final approval for the version to be published, and chose the journal to which the article was submitted.