Acute pancreatitis (AP) remains one of the leading causes of urgent hospitalization in gastroenterology and abdominal surgery, and is accompanied by a substantial burden of complications, necessitating timely triage. Contemporary clinical guidelines underscore the critical importance of risk stratification within the first 24–48 h to determine monitoring intensity, the need for transfer to the intensive care unit (ICU), and the selection of invasive strategies for necrotizing disease (1–4). Despite long-standing experience with composite scoring systems and laboratory indicators [C-reactive protein (CRP); procalcitonin (PCT)], their prognostic utility in the initial hours is limited by the lag to peak informativeness, need for extended variable sets, and inter-center variability in discriminative performance. Against this backdrop, there is a growing demand for simple, accessible, and reproducible biomarkers for early risk stratification, aligned with contemporary severity definitions under the revised Atlanta 2012 classification (5–7).

Updated guidance from professional societies emphasizes that early risk assessment should rely on tools that can be measured repeatedly without delay and anchored to clearly validated endpoints such as persistent organ failure (POF), infected pancreatic necrosis (IPN), and in-hospital mortality (1, 2). This creates a mandate for first-line indices of systemic inflammation that can be deployed in the emergency department.

The biological rationale for this strategy is grounded in early sterile inflammatory events in AP, including neutrophil activation, formation of neutrophil extracellular traps (NETs), microcirculatory disturbances, and the systemic effects of cytokines. Collectively, these processes drive an imbalance between an “aggressive” innate response and stress-induced immunosuppression, a framework that underpins the interpretation of indices, such as the neutrophil-to-lymphocyte ratio (NLR) and related metrics (systemic immune-inflammation index, SII; platelet-to-lymphocyte ratio, PLR). Accumulating literature, including reviews of NET cell biology and experimental studies of their pharmacologic modulation, reinforces this biological plausibility and highlights the potential of targeting NETs to mitigate inflammatory severity in AP (8–10).

At the same time, several fundamental questions remain unresolved (4, 11). First, the temporal behavior of early indicators is insufficiently characterized; the informativeness of biomarkers in AP changes materially between admission, 24 h, and 48 h. Even for widely used CRP, the discrimination of severe disease is strongly time-dependent; thus, fixed one-off thresholds that ignore trajectory are methodologically unsound (4, 12). Second, standardization of endpoints and thresholds is lacking; real-world implementation requires harmonized rule-in/rule-out cut-offs with sensitivity/specificity estimates, LR±, and AUC calculated within predefined temporal windows, accompanied by external validation. Third, etiologic stratification (e.g., biliary vs. hypertriglyceridemic) and comorbidity may modify the performance of inflammatory indices, yet available interaction data remain fragmentary. Fourth, comparisons with existing tools remain unsettled: it is unclear whether a simple first-line index improves the discrimination of validated scores or can function as a standalone, rapid primary triage test before composite scales are calculated.

In managing complications of necrotizing disease, it is crucial to distinguish markers of infection risk from indicators of overall severity. For infected pancreatic necrosis, the strongest evidence to date supports procalcitonin (PCT), particularly its dynamic changes, whereas C-reactive protein (CRP) more reliably reflects systemic inflammatory activity. Combining markers or using composite models may improve decision-making accuracy during critical time windows (13, 14). In parallel, emerging artificial intelligence algorithms for early severity prediction underscore the need for simple, yet informative variables available at admission (15).

In summary, current clinical guidelines provide clear management frameworks for AP while also highlighting an unmet need for rapid, standardized predictors to support early triage. Against the backdrop of the immunobiology of systemic inflammation and the practical constraints of the first hours of presentation, the NLR remains an attractive, readily measurable first-line index. Nevertheless, confident implementation will require concordant evidence regarding (i) associations with clinically meaningful outcomes within predefined temporal windows; (ii) test accuracy and operational thresholds; (iii) etiologic modification of effects; and (iv) the incremental value achieved when combined with scoring systems and/or other biomarkers.

Study objective: To systematically evaluate the role of the neutrophil-to-lymphocyte ratio in the early prediction of clinically meaningful outcomes in acute pancreatitis.

In accordance with PRISMA 2020 recommendations (21), 517 records were screened across databases; 92 reports underwent full-text assessment, and 72 studies (6, 22–92) were included in the qualitative synthesis (Table 1 and Figure 1). Risk of bias was evaluated using QUIPS (18) (Figures S1, S2). Overall, studies were rated as having low-to-moderate risk of bias, and none were rated as high risk.

In this systematic review and meta-analysis, NLR measured within the first two days of hospitalization provided time-dependent prognostic information in acute pancreatitis. At admission, NLR provided moderate discrimination for severe disease and good discrimination for mortality, whereas performance for infection-related outcomes, driven largely by infected pancreatic necrosis, was only moderate. Importantly, the association-based synthesis for infected pancreatic necrosis (odds ratios) was not robust, reflecting extreme heterogeneity and the small number of available studies. Overall, the evidence supports NLR as a rapid adjunct for early triage and follow-up assessment, rather than a standalone decision rule.

Several included cohorts directly compared NLR with established multivariable scores for predicting severe acute pancreatitis (Table S11), helping to contextualize NLR within routine risk stratification. Across these head-to-head comparisons, admission-based analyses more often favored multivariable scores (e.g., BISAP and APACHE II) for predicting severe disease in multiple cohorts (35, 37, 70). Findings for mortality and organ failure were less consistent: some cohorts reported better discrimination for mortality with NLR than with BISAP (37), whereas others showed the opposite (35). For organ failure, Junare et al. reported slightly better performance for NLR than for BISAP and APACHE II (51). When dynamic testing was available, NLR reassessed at approximately 48 h sometimes matched or exceeded BISAP/APACHE II for both severe disease and mortality (53, 87). However, these comparisons derive from a limited set of heterogeneous studies with variable endpoints and sampling windows and therefore do not justify firm claims of superiority. Taken together, NLR is best interpreted as a universally available complement to established prognostic scores, with its main value in rapid early screening and short-interval reassessment during the first forty-eight hours.

Biologically, NLR captures two early processes in acute pancreatitis: neutrophil-driven innate activation (DAMP/cytokine/NET-mediated injury) and relative lymphopenia reflecting stress-related immune dysregulation. This dual signal supports its use as an early, readily available marker during the first days of illness (93) and aligns with evidence linking neutrophils/NETs to systemic complications in AP (8–10, 94). Overall, NLR condenses the early inflammatory–immune balance into a simple, readily repeatable metric, making 0–48-h trends clinically informative. This is consistent with guideline emphasis on early stratification aimed at predicting persistent organ failure, infected pancreatic necrosis, and mortality (1, 2). Across diverse conditions, higher NLR is associated with worse outcomes, reflecting the broader prognostic relevance of neutrophilia with relative lymphopenia (95). In AP, many cohorts report higher NLR in patients who progress to organ dysfunction, infection, and death; however, thresholds and sampling windows vary, reinforcing the need for dynamic, context-aware interpretation rather than reliance on a single universal cut-off (1, 2).

To address this variability, we performed a prespecified systematic review using two complementary lenses: (i) association measures (OR/RR) and (ii) prognostic accuracy (ROC/HSROC). This approach allowed us to assess both the direction of risk and the practical discriminatory value of NLR across clinically relevant early time windows. Consistent with the evolving inflammatory response, NLR measured at ~24 h generally showed improved discrimination compared with admission. For day-1 reassessment, many cohorts support a pragmatic working threshold near ~8, best used for serial monitoring rather than as a standalone decision rule. By ~48 h, reported thresholds tend to shift lower (often around ~7, commonly within 6–8), supporting continued serial reassessment. Lower or declining values in clinically stable patients may help justify de-escalation, whereas persistently elevated or rising values should prompt evaluation for evolving organ dysfunction or complications.

Similarly, emergency-department cohorts suggest that an admission NLR of approximately 9–10 can aid early identification of patients unlikely to develop a severe course and may outperform single routine laboratory measures (e.g., CRP, creatinine, BUN) in the first hours—supporting a rule-out–oriented role rather than definitive rule-in (28, 96). In multivariable models incorporating routine hemogram parameters, NLR often remains among the strongest contributors to ICU admission and organ failure, supporting its relevance for predicting persistent organ failure rather than only binary severity classification (28, 51).

Etiology may modify performance. In biliary AP, admission NLR tends to show higher sensitivity than specificity, suggesting stronger rule-out than rule-in utility, and limited data in hypertriglyceridemic AP suggest that practical admission thresholds often fall toward the upper end of the ~9–11 range. Across etiologies, confounding by comorbidities, medications, resuscitation intensity, and antibiotic strategies remains important, yet few studies have formally quantified clinical utility (e.g., via decision-curve analysis). Importantly, etiology-specific evidence, particularly for alcohol-induced acute pancreatitis, remains scarce. None of the included studies were specifically designed to evaluate NLR in alcoholic AP, nor did they report sufficiently detailed, etiology-stratified diagnostic/performance metrics to enable a separate quantitative synthesis. At present, only a single dedicated report has addressed NLR/PLR in alcoholic AP (97), which precludes meta-analysis and underscores the need for well-designed prospective studies with standardized etiology-stratified reporting.

For fatal outcomes, pooling the available ROC estimates in our meta-analysis yielded a summary AUC = 0.80 at admission and a weighted mean = 0.79–0.80, which we deem sufficient to use the NLR as an early risk “signal,” with subsequent confirmation by more complex scores and specialized biomarkers. For IPN, the OR-based association meta-analysis was non-robust (imprecise pooled estimate with extreme heterogeneity across only four studies). Therefore, NLR should not be interpreted as a consistent prognostic factor for IPN; its role in infection-related endpoints is best viewed as adjunctive and interpreted within diagnostic accuracy metrics and dynamic clinical assessment. Accordingly, it should complement (not replace) PCT/CRP and imaging.

We emphasize that for early detection of a severe course, cytokine markers, particularly IL-6, demonstrate the highest diagnostic informativeness among single tests (Se = 87% and Sp = 88% at a threshold >50 pg/ml in the first hours), whereas procalcitonin performs best for infected necrosis (dynamic high LR+), and CRP is more useful as a background indicator of systemic inflammatory activity (13, 98). Therefore, after 72 h and thereafter, and particularly in clinically unstable patients, it is rational to rely on PCT-based algorithms, using the NLR as a low-cost indicator of trend. Where available, early IL-6 may outperform NLR for confirming severe disease; however, it is less accessible in routine practice. In this context, NLR can serve as an immediate first-line screen, complemented by PCT/CRP, composite scores, and imaging, consistent with professional society recommendations (1, 2).

Clinical translation of NLR is best framed as serial assessment (Box 1). At admission, a higher NLR can flag patients who warrant closer monitoring, whereas a low NLR, alongside clinical stability, argues against immediate escalation. Repeat testing at ~24–48 h adds context: falling values support de-escalation, while persistently high or rising values should prompt reassessment for organ dysfunction and complications and consideration of additional biomarkers when available.

The present findings should be interpreted in light of several methodological and clinical constraints. Substantial between-study heterogeneity persists; differences in study design, cohort composition, etiologic spectrum of acute pancreatitis, timing of blood sampling, and analytical platform characteristics inevitably influence the accuracy and reproducibility of the metric. Variability in threshold values reflects not only the statistical methods used to derive them, but also the clinical context of application—event prevalence, initial treatment strategies, criteria for severity and complications, and divergent operational definitions of endpoints. Additional risks of bias include incomplete primary data, selective reporting, lack of prespecified analytical protocols, and the limited number of prospective studies using standardized measurement procedures. Residual confounding inherent to observational research remains a major challenge, encompassing comorbidities, concomitant pharmacotherapy, the intensity of fluid resuscitation, and antibacterial prophylaxis. Finally, most studies do not provide access to individual patient data and rarely evaluate clinical utility (e.g., decision-curve analysis), which constrains interpretability, external validity, and translation of results into real-world care pathways.

Prospective multicenter validation should be prioritized, with uniform endpoint definitions, harmonized protocols for sample collection and processing, and pre-specified clinical thresholds that allow local recalibration. Systematic evaluation of early marker dynamics—within the first hours and days—as triggers for intensified monitoring and treatment is a promising direction, as is integration into multimodal prognostic models that combine clinical features, routine biomarkers, and imaging with modern analytical tools. Traditional diagnostic metrics should be complemented by assessments of net clinical benefit, effects on decision-making, resource requirements, and cost-effectiveness across diverse healthcare systems. Priorities also include open reporting, replication in independent cohorts, adoption of transparent standards for the development and validation of prognostic tools, and implementation studies that test readiness for routine practice while ensuring equitable access to innovative approaches across diverse clinical settings.

This systematic review and meta-analysis suggest that the neutrophil-to-lymphocyte ratio measured within the first 48 h of hospitalization may provide clinically useful, low-cost prognostic information in acute pancreatitis when used as an adjunct to established scores and routine assessment (Box 1). Across the included studies, NLR showed moderate-to-good discrimination for severe disease at presentation (pooled AUC ~0.77), with commonly reported thresholds shifting over time (approximately ~9 at admission, ~8 at 24 h, and ~7 at 48 h), reflecting the evolving inflammatory response. However, substantial between-study heterogeneity, variable endpoint definitions, and differences in patient mix and sampling windows limit the generalizability of any single cut-off. Therefore, NLR should not be used as a stand-alone criterion; rather, it may support early screening and serial reassessment within 0–48 h, with mandatory local calibration and integration with validated clinical scores, other laboratory markers, and imaging, where appropriate. Prospective multicenter studies with standardized time windows and prespecified thresholds are needed to determine net clinical benefit and to guide implementation pathways.