title: Epidemiologic analysis of histologic cervical inflammation: relationship to human papillomavirus infections.
abstract: Infections with carcinogenic human papillomaviruses, the causal agents of cervical intraepithelial neoplasia and cancer, as well as infections with noncarcinogenic human papillomaviruses, are common but typically resolve spontaneously. Effective cell-mediated immune responses are critical for human papillomavirus clearance; however, data relating cervical inflammation to the outcome of human papillomavirus infection are lacking. To investigate this topic, we performed a masked parallel review of inflammation in the stroma and epithelium of cervical biopsies (n = 564) collected from a retrospectively defined subcohort of women systematically followed up in the Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesion Triage Study. Women in our analysis had undergone colposcopically directed enrollment biopsies diagnosed as negative or cervical intraepithelial neoplasia 1 and had corresponding human papillomavirus polymerase chain reaction test results of negative (n = 250), positive for a single carcinogenic (n = 237), or noncarcinogenic (n = 81) type. Inflammation in cervical stroma varied with cofactors for human papillomavirus progression: current smokers showed less inflammation (odds ratio, 0.55; 95% confidence interval, 0.31-0.97), whereas current oral contraceptive users had increased inflammation (odds ratio, 1.7; 95% confidence interval, 0.92-3.0) as did those with a self-reported 2-year history of a sexually transmitted disease (odds ratio, 1.9; 95% confidence interval, 1.0-3.5). Biopsies of women with carcinogenic human papillomaviruses had greater inflammation within the epithelium (odds ratio, 1.6; 95% confidence interval, 1.1-2.3) compared with human papillomavirus-negative women. Associations with human papillomavirus type-specific persistence or progression to histologic cervical intraepithelial neoplasia 3 were diminished among women with moderate or marked inflammation in stroma (odds ratio, 0.49; 95% confidence interval, 0.25-0.99) or within epithelium (odds ratio, 0.51; 95% confidence interval, 0.26-0.97). These data suggest that cervical inflammation varies with human papillomavirus cofactors, type of human papillomavirus infection, and risk of persistence and progression. Additional studies are needed to confirm and extend these findings.
authors.affiliation: Institute for Personalized and Predictive Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA. melinda.butsch.kovacic@cchmc.org
authors.forename: Melinda Butsch
authors.initials: MB
authors.lastname: Kovacic
authors.forename: Hormuzd A
authors.initials: HA
authors.lastname: Katki
authors.forename: Aimee R
authors.initials: AR
authors.lastname: Kreimer
authors.forename: Mark E
authors.initials: ME
authors.lastname: Sherman
mesh_terms: D015331:Cohort Studies; D005260:Female; D006801:Humans; D008396:Maryland / Q000453:epidemiology; D016017:Odds Ratio; D027383:Papillomaviridae / Q000302:isolation & purification* / Q000502:physiology; D030361:Papillomavirus Infections / Q000453:epidemiology* / Q000473:pathology / Q000821:virology; D012189:Retrospective Studies; D002583:Uterine Cervical Neoplasms / Q000453:epidemiology* / Q000473:pathology / Q000821:virology; D002575:Uterine Cervicitis / Q000453:epidemiology* / Q000473:pathology / Q000821:virology; D002578:Uterine Cervical Dysplasia / Q000453:epidemiology* / Q000473:pathology / Q000821:virology