Cervicitis is an inflammatory condition of the cervix, characterized by infiltration of neutrophils, friability, and production of mucopus. Cervicitis can often be attributed to a sexually transmitted infection (STI); however 40% or more cases have no STI identified. Women with non-specific cervicitis (e.g. cervicitis with no identified STI) may not respond to antimicrobial therapy, suggesting viral involvement. Cytomegalovirus (CMV) is the most plausible viral candidate suspected of contributing to NS cervicitis. CMV reactivates frequently in the cervix in response to STIs or hormonal changes and induces a florid inflammatory response, specifically enhancing production of cytokines involved in cervicitis (IL-1?, IL-6, IL-8). Two cross- sectional studies reported increased CMV shedding during cervicitis, and several case reports have found CMV inclusion bodies during cervicitis. Many investigators have speculated that CMV could be a cause of NS cervicitis. An alternative hypothesis is that CMV could function as a co-pathogen for cervicitis, reactivating coincidentally to STIs, and further augmenting inflammation. The purpose of the study is to gather strong evidence to either support or refute a role for CMV in the risk of cervicitis. The proposed study will utilize data and specimens from an existing cohort of HIV-negative Kenyan sexworkers followed since 2010 (Mombasa Cohort), who have detailed monthly serial assessment for cervicitis, STI (gonorrhea, chlamydia, trichomonas), BV, and sexual risk factors. Vaginal swabs are collected monthly, and are available for use. This is an ideal population in which to address this study question: Longitudinal sampling of 710 women over 5 years will enable detailed ascertainment of CMV, STI, cytokine, and cervicitis interactions. Together, 180 women contributed 320 cases of cervicitis, and 105 women had recurrent disease. STI incidence and CMV seroprevalence are high. Swabs will be used to measure CMV DNA loads and test for additional STIs. A novel multiplex immunoassay will be used to measure a panel of inflammatory cytokines to assess differences in cervicitis pathogenesis by type, and to mechanistically connect STIs, CMV, and cervicitis.
Aim 1 will compare the relative risk of cervicitis between women with and without genital CMV reactivation. We hypothesize CMV reactivation will be associated with NS cervicitis, and CMV will synergistically increase the relative risk of cervicitis in women with STIs.
Aim 2 will define correlates of cervicitis recurrence and persistent inflammation.
Aim 3 will assess inflammatory cytokines as mediators of the association between CMV reactivation and cervicitis to better understand the pathogenesis of cervicitis, and its relationship to CMV. Together, these data are expected to strengthen the case for, or against, CMV as a causative agent of cervicitis. If CMV is found to predict cervicitis, we will conduct a small, randomized trial of CMV suppression, with eligibility criteria, endpoints, and study design guided by our results.
Cervicitis can cause infertility, pelvic inflammatory disease and adverse birth outcomes. Successful treatment requires accurate diagnosis; however cervicitis is a syndrome with many potential causes, 40% of cases cannot be attributed to known pathogens, and many women do not respond to conventional treatment. This study will systematically determine whether cytomegalovirus (CMV), which has been previously associated with cervicitis in a small number of observational studies and case reports, may be a cause of cervicitis; data gathered here will determine whether a randomized trial of CMV suppression is warranted and feasible.
