IL-17C is a driver of damaging inflammation during Neisseria gonorrhoeae infection of human Fallopian tube.

The human pathogen Neisseria gonorrhoeae ascends into the upper female reproductive tract to cause damaging inflammation within the Fallopian tubes and pelvic inflammatory disease (PID), increasing the risk of infertility and ectopic pregnancy. The loss of ciliated cells from the epithelium is thought to be both a consequence of inflammation and a cause of adverse sequelae. However, the links between infection, inflammation, and ciliated cell extrusion remain unresolved. With the use of ex vivo cultures of human Fallopian tube paired with RNA sequencing we defined the tissue response to gonococcal challenge, identifying cytokine, chemokine, cell adhesion, and apoptosis related transcripts not previously recognized as potentiators of gonococcal PID. Unexpectedly, IL-17C was one of the most highly induced genes. Yet, this cytokine has no previous association with gonococcal infection nor pelvic inflammatory disease and thus it was selected for further characterization. We show that human Fallopian tubes express the IL-17C receptor on the epithelial surface and that treatment with purified IL-17C induces pro-inflammatory cytokine secretion in addition to sloughing of the epithelium and generalized tissue damage. These results demonstrate a previously unrecognized but critical role of IL-17C in the damaging inflammation induced by gonococci in a human explant model of PID.

Mycoplasma Genitalium: A Lesser-Known Cause of Pelvic Inflammatory Disease.

Mycoplasma genitalium (MG) is a bacterium that can be spread through sexual contact with another person who is infected. If misdiagnosed and left untreated, this newer, emerging sexually transmitted infection (STI) can cause complications such as urethritis and pelvic inflammatory disease (PID) in both men and women. In males, MG can be asymptomatic and undetectable. In females, MG may present with nonspecific symptoms, such as dysuria, vaginal discharge, and/or pelvic pain. In addition to chlamydia and gonorrhea, MG may result in PID. Due to the complications of MG, health care providers in the emergency department setting need to consider this as a differential diagnosis when performing STI and vaginitis screenings on sexually active patients who may present with urinary or vaginal complaints. As patients with pelvic pain are frequently seen in the emergency department, providers need to be aware of the role that MG may play in STIs and the subsequent sequelae if not treated properly.

Functional interferon-epsilon gene polymorphisms and sexually transmitted infections of the endometrium.

PROBLEM: Interferon-epsilon (IFNε) is the only type I IFN constitutively expressed in the female reproductive tract and fluctuates across the menstrual cycle in humans. Mouse models show that IFNε protects against Chlamydia trachomatis, Herpes Simplex Virus, HIV, and Zika in mice, but human studies are limited. Bacterial sexually transmitted infections (STI) can ascend to the upper genital tract and cause pelvic inflammatory disease (PID) and subsequent infertility. However, the host immunological mechanisms that play a role in the ascension and infection of the endometrium in individuals with clinically suspected PID are not elucidated. METHOD OF STUDY: This pilot investigation determined if IFNε gene variants are associated with bacterial vaginosis (BV) and endometrial infection with C. trachomatis, Neisseria gonorrhoeae, and Mycoplasma genitalium using biospecimens from 154 self-report Black individuals who participated in the PID Evaluation and Clinical Health (PEACH) study. RESULTS: The T allele for rs2039381 was associated with endometrial STI infection (OR 2.7, 95% CI: 1.0-7.1) and the C allele for rs1125488 was inversely associated with BV (OR: .2, 95% CI: .05-.8). CONCLUSIONS: Few studies have examined IFNε gene variants, our study raises the possibility that IFNε gene variants may be a potential host contributor to STI pathogenesis.

Update on the Epidemiology, Screening, and Management of Chlamydia trachomatis Infection.

Chlamydia trachomatis infection ("chlamydia") is the most commonly diagnosed bacterial sexually transmitted infection globally, occurring in the genitals (urethra or vagina/cervix), rectum, or pharynx. If left untreated in women, genital chlamydia can ascend into the upper genital tract causing pelvic inflammatory disease, increasing their risk for ectopic pregnancy, infertility, and chronic pelvic pain. In men, chlamydia can cause epididymitis and proctitis. However, chlamydia is asymptomatic in over 80% of cases. This article provides an update on the epidemiology, natural history, and clinical manifestations of chlamydia in adults and discusses the current approaches to its management and control policy.

Identification and Treatment of Acute Pelvic Inflammatory Disease and Associated Sequelae.

Pelvic inflammatory disease (PID) is an ascending polymicrobial infection of the upper female genital tract. The presentation of PID varies from asymptomatic cases to severe sepsis. The diagnosis of PID is often one of exclusion. Primary treatment for PID includes broad-spectrum antibiotics with coverage against gonorrhea, chlamydia, and common anaerobic and aerobic bacteria. If not clinically improved by antibiotics, percutaneous drain placement can promote efficient source control, as is often the case with large tubo-ovarian abscesses. Ultimately, even with treatment, PID can result in long-term morbidity, including chronic pelvic pain, infertility, and ectopic pregnancy.

Pelvic inflammatory disease in the adolescent and young adult: An update.

Pelvic inflammatory disease (PID) is an infection of the female upper genital tract that is typically polymicrobial with classic core involvement of Neisseria gonorrhoeae and/or Chlamydia trachomatis, though other endogenous flora from the vagino-cervical areas can be involved as well. It is often a sexually transmitted disease but other etiologic routes are also noted. A variety of risk factors have been identified including adolescence, young adulthood, adolescent cervical ectropion, multiple sexual partners, immature immune system, history of previous PID, risky contraceptive practices and others. An early diagnosis and prompt treatment are necessary to reduce risks of PID complications such as chronic pelvic pain, ectopic pregnancy and infertility. Current management principles of PID are also reviewed. It is important for clinicians to screen sexually active females for common sexually transmitted infections such as Chlamydia trachomatis and provide safer sex education to their adolescent and young adult patients. Clinicians should provide comprehensive management to persons with PID and utilize established guidelines such as those from the US Centers for Disease Control and Prevention (CDC).

Chlamydia trachomatis and Mycoplasma genitalium prevalence and associated factors among women presenting to a pregnancy termination and contraception clinic, 2009-2019.

BACKGROUND: Risk of pelvic inflammatory disease associated with Chlamydia trachomatis and Mycoplasma genitalium is increased after termination of pregnancy (TOP) and may be increased after insertion of intrauterine devices (IUDs). Screening prior to these procedures is recommended only for C. trachomatis. We examined C. trachomatis and M. genitalium prevalence and associated factors among women presenting to a pregnancy termination and contraception service over 10 years. METHODS: Retrospective analysis of clinical data collected from 17 573 women aged 15-45 years in 2009-2019 and for 266 M. genitalium positive women tested for macrolide resistance-associated mutations in 2016-2019. RESULTS: C. trachomatis and M. genitalium prevalence was 3.7% and 3.4%, respectively. In multivariable analyses, shared risk factors were younger age (p<0.001, for both C. trachomatis and M. genitalium), socioeconomic disadvantage (p=0.045 and p=0.008, respectively) and coinfection (p<0.001, for both sexually transmitted infections), with 10.1% of C. trachomatis positive women also positive for M. genitalium. Additional risk factors were earlier year of visit (p=0.001) for C. trachomatis and for M. genitalium residing outside a major city (p=0.013). The proportion of M. genitalium infections tested between 2016 and 2019 with macrolide resistance-associated mutations was 32.7%. CONCLUSIONS: Given the high level of antimicrobial resistance and the prevalence of coinfection, testing C. trachomatis positive women for M. genitalium could be considered in this setting to prevent further spread of resistant infections. Further research is required into the causal link between M. genitalium and pelvic inflammatory disease in women undergoing TOP and IUD insertion.

Characteristics of Vaginal Microbiome in Women with Pelvic Inflammatory Disease in Korea.

Human vaginal microorganisms play an important role in maintaining good health throughout the human life cycle. An imbalance in the vaginal microbiota is associated with an increased risk of pelvic inflammatory disease (PID). This study aimed to characterize and compare vaginal microbial profiles of premenopausal Korean women with and without PID. 74 Korean premenopausal female vaginal samples were obtained; 33 were from healthy women (a control group) and 41 from PID patients. Vaginal fluid samples were collected from the vaginal wall and posterior cervix and then analyzed by 16S ribosomal ribonucleic acid (rRNA) gene-based amplicon sequencing. Results showed a significant difference between the vaginal microbial communities of the two groups (Jensen-Shannon, p = 0.014; Bray-Curtis, p = 0.009; Generalized UniFrac, p = 0.007; UniFrac, p = 0.008). Lactobacillus accounted for the highest percentage (61.0%) of the control group but was significantly decreased (34.9%) in PID patients; this was the most significant difference among all bacterial communities (p = 0.028, LDA effect size = 5.129). In addition, in the PID patient group, species diversity significantly increased (Simpson, p = 0.07) as the proportion of various pathogens increased evenly, resulting in a polymicrobial infection. Similarly, lactate, which constituted the highest percentage of the organic acids in the control group, was significantly decreased in the PID patient group (p = 0.04). The present study's findings will help understand PID from the microbiome perspective and are expected to contribute to the development of more efficient PID diagnosis and treatment modalities.

Pelvic inflammatory disease and causative pathogens in older women in a medical center in eastern Taiwan: A retrospective cross-sectional study.

OBJECTIVES: Most research into the management of pelvic inflammatory disease (PID) is in younger women and focuses on sexually transmitted pathogens such as N. gonorrhoeae or C. trachomatis. Non-sexually transmitted bacterial pathogens and PID in older women are rarely examined. The objective of this study is to explore cervical culture pathogens in women of different age groups in a medical center in eastern Taiwan. METHODS: We enrolled patients whose medical records were diagnosed with PID (ICD-9-CM 614.0 [N70.01-03], 614.1[N70.11-13], 614.9 [N73.5, N73.9]) at our hospital from October 2014 to March 2020. Patients were divided into three groups according to age: the age <25 years, age 25-44 years, and the ≥ 45 years group. Chi-square test, ANOVA and logistic regression were used for statistical analysis. In subgroup analysis, endocervical pathogens were further stratified into vaginal, respiratory, enteric, skin, oral, and other. RESULTS: A total of 96 patients were included in the study. There were 31 patients in the age ≥ 45 years group, 52 patients in the age 25-44 years group, and 13 patients in the age <25 years group. Vagina and enteric pathogens were the most common pathogens among all groups. The isolated respiratory and other pathogens were more in the age ≥ 45 years group than in the other two groups. Prevotella bivia was more common in the age <25 years and 25-44 years groups. CONCLUSIONS: This may be due to different pathogeneses of PID in the age ≥ 45 years patients. Our study can be used as a reference for antibiotic choice of non-sexually transmitted PID and to prevent long-term sequelae of PID.

A Review of the Challenges and Complexities in the Diagnosis, Etiology, Epidemiology, and Pathogenesis of Pelvic Inflammatory Disease.

Pelvic inflammatory disease (PID) is a syndrome that causes substantial morbidity, including chronic pelvic pain, to women globally. While limited data are available from low- and middle-income countries, national databases from the United States and Europe suggest that PID incidence may be decreasing but the rate of decrease may differ by the etiologic cause. Recent studies of women with PID have reported that fewer than half of women receiving a diagnosis of PID have gonococcal or chlamydial infection, while Mycoplasma genitalium, respiratory pathogens, and the constellation of bacteria associated with bacterial vaginosis may account for a substantial fraction of PID cases. The clinical diagnosis of PID is nonspecific, creating an urgent need to develop noninvasive tests to diagnose PID. Advances in serologic testing for Chlamydia trachomatis and Neisseria gonorrhoeae could advance epidemiologic studies, while the development of vaccines against these sexually transmitted pathogens could affect incident PID and associated morbidity.

Immune Responses to Neisseria gonorrhoeae: Challenges and Opportunities With Respect to Pelvic Inflammatory Disease.

Pelvic inflammatory disease and infertility frequently develop after female genital tract infection with Neisseria gonorrhoeae, but determining their etiology from among various possibilities presents difficulties. Exploitation of serology to identify the causative agent is complicated by numerous factors, and no immunological test currently exists to determine unequivocally whether an individual currently is, or has been, infected with N. gonorrhoeae. The extensive antigenic variability of N. gonorrhoeae and its expression of antigens shared with other Neisseria species commonly carried in humans render problematic an assay that is specific for all gonococcal strains. However, novel conserved gonococcal antigens identified for potential vaccines may find additional application in diagnostic assays. N. gonorrhoeae also interferes with the adaptive immune response, and antibody responses to uncomplicated infection are usually weak. Elucidating the mechanisms whereby N. gonorrhoeae manipulates the human immune system may lead to improved understanding of the pathogenesis of pelvic inflammatory disease and infertility.

What Can Serology Tell Us About the Burden of Infertility in Women Caused by Chlamydia?

Chlamydia trachomatis (CT) causes pelvic inflammatory disease, which may result in tubal factor infertility (TFI) in women. Serologic assays may be used to determine the proportion of women with and without TFI who have had previous CT infection and to generate estimates of infertility attributable to chlamydia. Unfortunately, most existing CT serologic assays are challenged by low sensitivity and, sometimes, specificity for prior CT infection; however, they are currently the only available tests available to detect prior CT infection. Modeling methods such as finite mixture modeling may be a useful adjunct to quantitative serologic data to obtain better estimates of CT-related infertility. In this article, we review CT serological assays, including the use of antigens preferentially expressed during upper genital tract infection, and suggest future research directions. These methodologic improvements, coupled with creation of new biomarkers for previous CT infection, should improve our understanding of chlamydia's contribution to female infertility.

Bacterial Vaginosis and Behavioral Factors Associated With Incident Pelvic Inflammatory Disease in the Longitudinal Study of Vaginal Flora.

BACKGROUND: Pelvic inflammatory disease (PID) leads to long-term reproductive consequences for cisgender women. Bacterial vaginosis (BV) and behavioral factors may play a role in PID pathogenesis. We assessed associations between BV, behavioral factors, and incident PID. METHODS: We analyzed participants (N = 2956) enrolled in the National Institutes of Health Longitudinal Study of Vaginal Flora, a cohort of nonpregnant cisgender women followed quarterly for 12 months. PID was defined by at least 1 of the following: cervical motion tenderness, uterine tenderness, or adnexal tenderness (160 cases). We tested associations between BV (measured using Nugent and Amsel criteria) and PID at the subsequent visit. Sociodemographic factors, sexual behaviors, and Chlamydia trachomatis (CT), untreated at baseline and concurrent with BV, were covariates in Cox proportional hazards models. Adjusting for the few Neisseria gonorrhoeae and Trichomonas vaginalis cases did not alter results. RESULTS: In multivariable modeling, Nugent-BV (adjusted hazard ratio [aHR], 1.53 [95% confidence interval {CI}, 1.05-2.21]), symptomatic Amsel-BV (aHR, 2.15 [95% CI, 1.23-3.75]), and vaginal douching (aHR, 1.47 [95% CI, 1.03-2.09]) were associated with incident PID. CONCLUSIONS: BV was associated with incident PID in a large prospective cohort, controlling for behavioral factors and sexually transmitted infections (STIs). Larger studies on how BV, STIs, behaviors, and host responses interactively affect PID risk are needed.

Preclinical Testing of Vaccines and Therapeutics for Gonorrhea in Female Mouse Models of Lower and Upper Reproductive Tract Infection.

Murine models of Neisseria gonorrhoeae lower reproductive tract infection are valuable systems for studying N. gonorrhoeae adaptation to the female host and immune responses to infection. These models have also accelerated preclinical testing of candidate therapeutic and prophylactic products against gonorrhea. However, because N. gonorrhoeae infection is restricted to the murine cervicovaginal region, there is a need for an in vivo system for translational work on N. gonorrhoeae pelvic inflammatory disease (PID). Here we discuss the need for well-characterized preclinical upper reproductive tract infection models for developing candidate products against N. gonorrhoeae PID, and report a refinement of the gonorrhea mouse model that supports sustained upper reproductive tract infection. To establish this new model for vaccine testing, we also tested the licensed meningococcal 4CMenB vaccine, which cross-protects against murine N. gonorrhoeae lower reproductive tract infection, for efficacy against N. gonorrhoeae in the endometrium and oviducts following transcervical or vaginal challenge.

Gonococcal Pelvic Inflammatory Disease: Placing Mechanistic Insights Into the Context of Clinical and Epidemiological Observations.

While infection by Neisseria gonorrhoeae is often asymptomatic in women, undetected infections can ascend into the upper genital tract to elicit an inflammatory response that manifests as pelvic inflammatory disease, with the outcomes depending on the intensity and duration of inflammation and whether it is localized to the endometrial, fallopian tube, ovarian, and/or other tissues. This review examines the contribution of N. gonorrhoeae versus other potential causes of pelvic inflammatory disease by considering new insights gained through molecular, immunological, and microbiome-based analyses, and the current epidemiological burden of infection, with an aim to highlighting key areas for future study.

Pelvic Inflammatory Disease Due to Neisseria gonorrhoeae and Chlamydia trachomatis: Immune Evasion Mechanisms and Pathogenic Disease Pathways.

Pelvic inflammatory disease (PID) results from ascension of sexually transmitted pathogens from the lower genital tract to the uterus and/or fallopian tubes in women, with potential spread to neighboring pelvic organs. Patients may present acutely with lower abdominal or pelvic pain and pelvic organ tenderness. Many have subtle symptoms or are asymptomatic and present later with tubal factor infertility, ectopic pregnancy, or chronic pelvic pain. Neisseria gonorrhoeae and Chlamydia trachomatis are the 2 most commonly recognized PID pathogens. Their ability to survive within host epithelial cells and neutrophils highlights a need for T-cell-mediated production of interferon γ in protection. Data indicate that for both pathogens, antibody can accelerate clearance by enhancing opsonophagocytosis and bacterial killing when interferon γ is present. A study of women with N. gonorrhoeae- and/or C. trachomatis-induced PID with histologic endometritis revealed activation of myeloid cell, cell death, and innate inflammatory pathways in conjunction with dampening of T-cell activation pathways. These findings are supported by multiple studies in mouse models of monoinfection with N. gonorrhoeae or Chlamydia spp. Both pathogens exert multiple mechanisms of immune evasion that benefit themselves and each other at the expense of the host. However, similarities in host immune mechanisms that defend against these 2 bacterial pathogens instill optimism for the prospects of a combined vaccine for prevention of PID and infections in both women and men.

Chlamydia trachomatis, Pelvic Inflammatory Disease, and Epithelial Ovarian Cancer.

Epidemiologic, clinical, molecular and translational research findings support an interrelationship between Chlamydia trachomatis, pelvic inflammatory disease (PID), and epithelial ovarian cancer (EOC). Overall, the link between C. trachomatis, PID, and EOC seems to be relatively weak, although nondifferential misclassification bias may have attenuated the results. The predominant tubal origin of EOC and the role of chronic inflammation in tumorigenesis suggest that the association is biologically plausible. Thus, C. trachomatis and PID may represent potential risk factors or risk markers for EOC. However, many steps in this chain of events are still poorly understood and need to be addressed in future studies. Research gaps include time of exposure in relation to the long-term consequences and lag time to EOC. Data of differential risk for EOC between chlamydial and nonchlamydial PID is also needed. Another major research gap has been the absence of high-performance biomarkers for C. trachomatis, PID, and EOC, as well as EOC precursors. Biomarkers for C. trachomatis and PID leading to increased risk of EOC should be developed. If the association is confirmed, C. trachomatis and PID prevention efforts may play a role in reducing the burden of EOC.

Multipeptide Assays for Sensitive and Differential Detection of Anti-Chlamydia Trachomatis Antibodies.

Detection of anti-Chlamydia trachomatis (Ctr) antibodies is compromised by cross-reactivity and poor sensitivity of classic Ctr-antigens. We discovered 48 strongly reactive peptide antigens of Ctr-specific B-cell epitopes from 21 immunodominant proteins. In this study, we review the utility of peptide assays for diagnosis of Ctr infections. By combining many of these Ctr-specific B-cell epitopes from several proteins in separate or mixed multipeptide assays, they achieved vastly superior assay sensitivity and specificity over standard enzyme-linked immunosorbent assays. Such multipeptide assays eliminate cross-reactivities (false positives) and correct for stochastic gaps in antibody responses (false negatives). More importantly, we developed and validated a novel microarray platform in which hundreds of peptides from many proteins are spotted in a single reaction well. This offers the possibility of high-throughput screening of many candidate peptides for routine serological fingerprinting of Ctr infections. Discovery of optimal sets of antibody responses that associate with clinical pelvic inflammatory disease (PID) may identify diagnostically useful PID biomarker antigens.