Correlation Between Hysteroscopic Signs of Chronic Endometritis and CD138-Positive Endometrial Plasma Cell Density in Women Undergoing Outpatient Hysteroscopy: a Prospective, Single-Centre Observational Study

Chronic endometritis (CE) is a persistent inflammation of the endometrial mucosa associated with recurrent implantation failure (RIF) and recurrent pregnancy loss (RPL). In clinical practice, CE is assessed using two complementary methods: office hysteroscopy, which identifies visual mucosal signs according to the Cicinelli criteria (micropolyps, focal hyperemia, diffuse hyperemia, stromal edema, strawberry pattern, and hemorrhagic spots), and immunohistochemical detection of CD138-positive (syndecan-1) endometrial plasma cells, considered the histopathological reference standard.

Published evidence comparing these two methods is inconsistent: individual studies, mostly retrospective, report weak agreement between hysteroscopic findings and plasma cell counts, while pooled diagnostic accuracy estimates suggest good hysteroscopic performance. This discrepancy is plausibly related to heterogeneous and non-comparable plasma cell count thresholds across studies, the use of dichotomized analyses that discard information, and retrospective designs prone to spectrum and verification bias. No prior study has characterized the relationship between hysteroscopic appearance and plasma cell burden as a continuous phenomenon.

This is a prospective, cross-sectional, single-center, non-pharmacological, non-device, no-profit observational study correlating an index test (hysteroscopy) with a reference standard (CD138 immunohistochemistry). Both tests are performed in the same session, so the interval between index test and reference standard is zero. The proliferative phase is standardized and confirmed histologically. Hysteroscopic and histopathological assessments are performed with reciprocal blinding, and there is no verification bias, as all participants undergo both the index test and the reference standard regardless of the hysteroscopic result.

Objectives and endpoints: The primary objective is to determine whether the number of hysteroscopic signs of CE correlates with the count of CD138-positive endometrial plasma cells, specifically testing whether this correlation is not clinically relevant (equivalence relative to a pre-specified negligible-effect threshold). The primary endpoint is the Spearman correlation coefficient between the CD138-positive plasma cell count (continuous variable) and the number of positive hysteroscopic signs (0-6), evaluated as an equivalence hypothesis against a pre-specified smallest effect size of interest (SESOI) of |r| < 0.25, assessed with two one-sided tests (TOST) and complemented by a Bayes Factor quantifying the evidence in favor of the null hypothesis, together with the posterior probability that |r| is below the SESOI.

Secondary objectives are to characterize the association of each individual hysteroscopic sign with plasma cell burden; to quantify inter- and intra-observer reproducibility of hysteroscopic scoring and plasma cell counting; to describe the relationship between the indication for examination (RPL, RIF, or other) and both plasma cell burden and hysteroscopic findings; and, descriptively, to report participants' reproductive outcomes. Corresponding secondary endpoints include: the association of each hysteroscopic sign with plasma cell count; inter- and intra-observer agreement (kappa for hysteroscopy, intraclass correlation coefficient for plasma cell counting); diagnostic accuracy of hysteroscopy at conventional CD138 thresholds (≥1 and ≥5 plasma cells) as a secondary sensitivity analysis; the association between clinical indication and findings; and, descriptively, the rate of histological resolution after treatment (test-of-cure) and reproductive outcomes.