A three-dimensional framework for acute appendicitis integrating etiology, pathological severity, and host response

Acute appendicitis is one of the most common causes of emergency abdominal surgery, yet clinicians continue to face difficulties in predicting disease severity, interpreting laboratory biomarkers, and explaining heterogeneous clinical presentations. Current classification systems primarily rely on severity-based progression models or etiology-based disease subtypes; however, both approaches incompletely explain the frequent discordance observed between pathological severity, systemic inflammatory response, microbiological findings, and clinical course. This conceptual limitation contributes to inconsistent biomarker performance and variability in study design across the appendicitis literature. In this conceptual review, we analyze the limitations of existing severity- and etiology-based frameworks and synthesize clinicopathological, microbiological, and biomarker evidence into an integrated multidimensional model of acute appendicitis. The proposed framework conceptualizes the disease along three interacting but partially independent axes: etiologic substrate, local pathological severity, and host systemic response. The etiologic substrate describes the initiating mechanism of appendiceal inflammation, local pathological severity reflects the extent of structural tissue injury, and host systemic response determines the magnitude of inflammatory amplification and biomarker expression. Recognizing host response as an independent modulating dimension provides a biologically plausible explanation for discordant biomarker findings and heterogeneous clinical trajectories. By reframing acute appendicitis as a multidimensional disease process rather than a binary entity or simple temporal continuum, this framework offers a coherent conceptual basis for improved interpretation of biomarkers, better study design, and more precise clinicopathological correlation. Adoption of such integrative models may ultimately support improved risk stratification and biologically informed management strategies in patients with acute appendicitis.