Chlamydia trachomatis Infection in Women

Abstract

Chlamydia trachomatis infections are the most commonly encountered sexually transmitted disease worldwide. Multiple partners and failure to use condoms are the well-defined risk factors. A significant proportion of females are asymptomatic. Treatment modalities such as a single 1-g dose of azithromycin orally, or doxycycline 100 mg twice per day for 7 days have been widely used for noncomplicated genital infections. However, untreated C. trachomatis infections can cause late complications, including salpingitis, ectopic pregnancy, and female factor infertility. Screening is a possible strategy to control asymptomatic cases and women at increased risk of infection in a proportional group of women.

1. Introduction

Chlamydia trachomatis is the most commonly seen bacterial sexually transmitted infection worldwide. Studies have shown that women between 16 and 19 years have the highest prevalence of the infection [1]. On the other hand, it has also been reported that the true incidence and prevalence of the infection among women population is not well described [2] According to the WHO (World Health Organization) data, while annually about 100 million new cases have been registered, the majority of women with genital tract infections remains asymptomatic and undiagnosed [2]. Therefore, in a large group of women with chlamydia infection, treatment is neglected or delayed, which can lead to pelvic inflammatory disease (PID), ectopic pregnancy, preterm labor, infertility, and chronic pelvic pain. Additionally, untreated chlamydial infection during labor can be vertically transmitted, which may cause conjunctivitis and pneumonitis in infants [1, 3]. Obviously, it is very important to diagnose and identify chlamydial infection in women accurately and rapidly. Prompt and effective antibiotic treatment can prevent patients from the mentioned serious complications [3]. Moreover, it has been reported that the treatment of chlamydial infections and related complications has a tremendous impact on health services in several countries [2, 3].

All together this information clearly shows that it is essential to diagnose and properly treat infected women and their partners. Nowadays, screening programs performed by both gynecologists and urologist are strongly suggested. However, more importantly, physicians dealing with sexually transmitted diseases should have sufficient experience and knowledge to effectively treat chlamydial infection and associated complications.

2. General information: C. trachomatis

Chlamydial species have been described as gram-negative, aerobic, and obligate intracellular pathogens. Molecular studies have shown that they are unable to synthesize their ATP, and therefore they need to use their host cell’s energy resources [1]. Due to this scientific fact, previously chlamydial species have been considered as viruses. C. trachomatis and Chlamydia pneumonia are pathogens causing infections in human. C. trachomatis has been divided into 19 serovars, according to the specificity of major outer protein membrane protein (MOPM) epitopes [4, 5]. It has been reported that while serovars A, B, Ba, and C are pathogens causing trachoma, serovars D, Da, E, F, G, Ga, H, I, Ia, J, and K are the most commonly encountered sexually transmitted agents. Furthermore, serovars L1, L2, L2a, and L3 are described as the bacteria, which are the pathogens of transmission of lymphogranuloma venereum (LGV) [4, 6].

Microbiological investigations provided that the chlamydial life cycle includes two different phases. The first phase is called the infectious phase, which occurs outside the target cells. During this phase, chlamydia trachomatis forms elementary forms, which cause the transmission of infection. After its transmission to the target cells, chlamydia forms the so-called reticulate forms, which are capable of replication. Basically, once the chlamydial elementary bodies infect non-ciliated columnar cells and macrophages, chlamydia induces its own endocytosis. Inside the host cell, the elementary bodies convert to reticulate bodies, which begin to replicate every 3 hours after an incubation of 7 to 21 days. Finally, after a certain production, the reticulate bodies change again into elementary bodies and shed off the cell membrane through exocytosis. It has been reported that because of its unique cell-wall structure chlamydial pathogens are able to survive against phagocytosis and destruction by lysosomal enzymes [4, 5, 6].

3. Epidemiology of C. trachomatis infection

C. trachomatis is the most common sexually transmitted infection causing cervicitis in female [2]. Chlamydial infections affect mainly young females between 16 and 24 years of age. According to the recent literature, a high number of sexual partners, unprotected sex, being unmarried, young age, low educational level, high-risk human papillomavirus (HPV) positivity, and black ethnicity increase the risk of chlamydial infections [4, 7]. Several studies have shown that the estimated prevalence of chlamydial infection vary between 1 and 12% [3, 4, 5]. Specifically, while the prevalence rate in the UK was reported as 10.3%, in Switzerland and France the prevalence rates were 2.8% and 3%, respectively. In a study group with a large number of individuals, the overall prevalence of chlamydial infection was 9.2%, with a peak of 12.2% among the 17-year-old women [8]. Ghazal-Aswad et al. investigated the prevalence of chlamydia infection in a middle eastern community and they reported that the estimated prevalence rate was about 2.6% and extremely higher in women screened in secondary care [9]. In a study from Brasil, the overall prevalence of C. trachomatis infection was reported as 11%, whit the highest prevalence seen in women between 16 and 20 years of age [10]. More recently, in a study from China, it has been shown that the overall prevalence of C. trachomatis, HPV, and C. trachomatis/HPV coinfection was 4.7%, 15.5%, and 1.2%, respectively, while the prevalence of asymptomatic infection of that was 3.8%, 10.8%, and 0.6%, respectively [11].

More importantly, studies have shown that prevalence rates range from 2 to 17% in asymptomatic women, which provides the importance of screening tests. In a screening study from France, it has been shown that there was a large difference between tested populations, ranging from 6 to 11% in women attending family planning centers, 1–3% in women attending preventive medical centers [4]. More recently in a study from India, prevalence of chlamydia infection was assessed among women visiting a gynecology outpatient clinic. In this study, the evaluation was performed by an in-house PCR assay. The authors reported 23% positive cases and chlamydial infection was predominantly seen between the ages of 18 and 33 years [12].

4. Clinical manifestation and diagnosis of C. trachomatis infection

Chlamydial infection of the lower genital tract, which causes endocervicitis in women, can be asymptomatic or may the patients complain of mucopurulent, odorless vaginal discharge, or postcoital bleeding. Additionally, edema and congestion of the cervix can also be observed. Urethritis can be concomitant with cervicitis. In such cases, a culture-negative leukocyturia is commonly suggestive for C. trachomatis. Furthermore, chlamydial infection in the lower genital tract does not cause vaginitis. Therefore, in the presence of vaginal findings, a different diagnosis should be considered. An ascending infection can lead to pelvic inflammatory disease (PID) [4, 13]. Endometritis is commonly related to an ascending infection and may cause irregular uterine bleeding. On the other hand, salpingitis and PID are usually asymptomatic. It has been shown that C. trachomatis is the cause of at least 60% of cases of acute PID [4, 14]. Some of the very well-known symptoms of PID include absent to severe abdominal pain with high fever, dyspareunia, prolonged menses, and intramenstrual bleeding. It has been shown that about 20% of women who developed PID become infertile, while 18% develop chronic pain and 9% eventually experience a tubal pregnancy (Ref. 13). Studies suggested that infertile women should be routinely tested for chlamydial infection. Moreover, specific anti-chlamydial antibodies are considered as valuable, noninvasive diagnostic methods [15, 16].

More recently, it has been reported that the estimated risk of post-chlamydial PID varies between 0.5 and 72%, depending on the study population and the definition criteria used in these investigations [16]. Subfertility and ectopic pregnancy occurred in 0.1–6% and 0–1% of women, respectively, after chlamydial infection [16]. Furthermore, studies have revealed that repeated diagnoses of C. trachomatis infections increased the risk of PID by 22% [16]. In another study from the UK, it has been reported that 20% of PIDs, 5% of ectopic pregnancies, and 30% of tubal factor subfertility pathologies are associated with post-chlamydial infections in women between the age of 16 to 44 years of age [16, 17].

In summary, studies suggest that several factors, including clinical symptoms, coinfections, reinfections, and sexual risk habits, probably affect the development of post-chlamydial complications in the female population. However, to definitely determine the risk and predisposing risk factors of the mentioned late complications, prospective studies are needed to provide robust data for prevention strategies related to C. trachomatis infections and complications [18, 19].

Nowadays, specific anti-chlamydial antibodies have been accepted as a valuable, noninvasive diagnostic tool. On the other hand, because C. trachomatis is an obligate intracellular bacteria, cell culture is considered as a reference method. However, various commercial non-culture-based diagnostic techniques are available [4]. Specimens for diagnosis can be obtained either by invasive or noninvasive approaches. While invasive approaches include endocervical and urethral swabs; self-collected specimens, such as first-void urine (FVU) and vulvovaginal swabs (VVS), are considered as noninvasive techniques [4].

Although cell culture has almost 100% specificity, it is not recommended for routine use, due to its pretty low sensitivity and its technical difficulty. Transport and storage difficulties of the specimens are additional drawbacks associated with the cell culture method. This technique should only be considered for medico-legal issues and for antibiotic susceptibility testing purposes [4].

While direct fluorescent staining with monoclonal antibodies (DFA) is a rapidly performed and specific test; it is subjective and not suitable for a large number of specimens [4]. Enzyme immunoassay (EIA) is an automated test and more usable than DFA, and the sensitivity is comparable to that of cell culture.

Nucleic acid hybridization tests, including DNA probing, have been described as the first molecular DNA test for C. trachomatis, which was widely used for a certain period. Studies showed that the performance of these tests is comparable to that of the DFA/EIA and cell culture [4].

Recently, nucleic acid amplification tests (NAATs) are suggested as the “Gold Standart” technique because of their high specificity and sensitivity, and their availability for a large range of sample types such as VVS and FVU in cases with chlamydial infections. There are various NAATs that use different technologies, including PCR and real-PCR, strand displacement amplification, transcription-mediated amplification, and nucleic acid sequence-based amplification. These measurement techniques are automated and can be used for screening programs and for the detection of C. trachomatis as well as Neisseria gonorrhoeae in the same sample [4].

5. Screening for C. trachomatis infections

Screening programs should be considered for mainly two approaches, including proactive, screening the entire target population, and opportunistic, targeting individuals attending a family planning or healthcare center. Studies have shown that opportunistic screening should target sexually active women under 25 years of age. Additionally, selective C. trachomatis screening of pregnant women according to risk factors can improve the benefit obtained from screening programs [18, 19].

6. Treatment of urogenital C. trachomatis infection

The treatment of C. trachomatis infection is exactly related to the localization of the infection, the age of the patient, and if the infection is complicated or noncomplicated. Additionally, the treatment of pregnant women differs from than of nonpregnant individuals.

For noncomplicated C. trachomatis infection cases; orally single doses of 1 g azithromycin or 100 mg doxycycline orally twice per day for 7 days are recommended. It has been reported that these treatment modalities have similar efficacy rates and adverse events profiles [13]. According to recent guidelines patients with urethritis need to be followed up if symptoms persist or in the presence of recurrence. In the case of a recurrence or persistent urethritis, treatment with 2 g metronidazole in a single dose combined with 500 mg erythromycin four times per day for 7 days, or 800 mg erythromycin orally four times per day for 7 days is recommended [13]. Importantly patients should be informed that they need to abstain from sexual intercourse for 7 days after starting the treatment. Of note, both patients and their sexual partners must be treated simultaneously.

While routine repeat testing for chlamydia after any treatment is not recommended, in pregnant cases or in patients with persisting symptoms, repeated test need to be performed. Because of the high rate of reinfection routine screening test need to be done 3 to 4 months after antibiotic treatment. The use of Postal testing kits PTK (partners post urine for testing) or patient-delivered partner therapy (PDPT) has been considered as novel intervention to reduce reinfection in women with chlamydia infection. In a controlled study, it has been described that these techniques do not reduce reinfection rates in women with chlamydia infection when compared with patient referral [20].

In PID cases treatment can be performed in a outpatient setting. However, in pregnant cases, in patients with severe illness, nausea or vomiting, in the presence of high fever concomitant with tuba-ovarian abscess hospitalization is mandatory. Additionally, hospitalization is indicated if there is a possibility of surgical emergencies. In patients who are unable to tolerate oral treatment regimens need also followed up on an inpatient basis.

Pregnant cases should not be treated with doxycycline and ofloxacin because their use is contradicted during pregnancy. Instead of these agents, erythromycin or amoxicillin should be the choice of treatment for chlamydia infection in pregnant women [13].

7. Prevention strategies

Recent guidelines suggest several main points for the prevention of the women population from genitourinary C. trachomatis infection. Primary prevention is mainly based on the change in sexual habits, which increase the risk of sexually transmitted diseases (STDs). In that issue, physicians should properly inform young women related to STDs and the importance of sexual behaviors.

Secondary prevention includes standard screening and treatment of STDs. Annual screening for chlamydial infection should be performed in all sexually active women 25 years and younger. Furthermore, women older than 25 years of age who have a new sex partner or have a history of multiple sex partners should be considered as high-risk cases, and need to be yearly screened for chlamydial infection [4, 13].