Sampling Extension, Chronic Infiltrates, and Eosinophils: Support for the Evaluation of Histological Healing in Inflammatory Bowel Disease with Endoscopic Remission

<b>Background/Objectives:</b> Histological healing, primarily assessed by the absence of neutrophils in mucosal biopsies, is increasingly used to evaluate treatment efficacy in inflammatory bowel disease (IBD) and may identify residual inflammation despite endoscopic mucosal healing. We aimed to quantify histological parameters commonly linked to active disease in patients with endoscopic healing and to explore their association with neutrophil-defined histologic activity in endoscopically healed mucosa. <b>Methods:</b> We assessed 371 colonoscopies from IBD patients with an endoscopic report of mucosal healing at a reference center. For each procedure, we recorded the number of biopsy samples obtained and histologic features according to ECCO consensus/position statements, including neutrophil infiltration, lymphoplasmacytic infiltrate, eosinophil infiltrate, and mucosal lesions. <b>Results:</b> Histologic activity was found in 21/98 (21.4%) procedures with one to three biopsy samples and in 89/273 (32.6%) procedures with more than three samples (<i>p</i> = 0.04). Neutrophils were absent in 207/212 (97.6%) procedures with normal lymphoplasmacytic infiltrate versus 55/159 (34.6%) with increased lymphoplasmacytic infiltrate (<i>p</i> < 0.00001). Eosinophils were below cut-off values in 122/168 (72.6%) procedures with normal lymphoplasmacytic infiltrate versus 90/203 (44.3%) with increased lymphoplasmacytic infiltrate (<i>p</i> < 0.00001). Eosinophils were below cut-off in 148/168 (88.1%) procedures without neutrophils and in 114/203 (56.2%) with neutrophils in the lamina propria (<i>p</i> < 0.00001). <b>Conclusions:</b> In IBD patients with endoscopic healing, the extent of biopsy sampling is associated with the detection of histologic activity. Lymphoplasmacytic and eosinophil infiltrates are strongly associated with neutrophil presence and are associated with neutrophil-defined activity and may serve as supportive indicators prompting closer pathological assessment in endoscopically healed mucosa.