Chlamydia trachomatis: A Tiny Being beyond the Nature

Abstract

Chlamydia trachomatis is the most common cause of sexually transmitted genital infections. Females are at high risk of cervix infections, and a significant proportion may also have urethral infections. Pelvic inflammatory disease (PID) can develop as a result of C. trachomatis ascending to the upper reproductive tract. C. trachomatis is an obligate intracellular bacterium that infects the genital tract and may cause chronic inflammation, damage to epithelial tissues, and pelvic inflammation. It has also been clinically associated with cervical atypia and metaplasia. C. trachomatis is the most prevalent sexually transmitted pathogen, and it can cause infertility if left undetected and untreated. Infertile women may be more susceptible to chlamydial infections due to their longer periods of active sexual life. Several diagnostic techniques are available to diagnose chlamydia, including DNA amplification testing (NAAT), culture, antigen detection, and genetic probes; microscopy is not useful for this purpose Chlamydia is treated with empiric therapy, which includes tetracyclines, macrolides, and some fluoroquinolones.

1. Introduction

1.1 A brief introduction

The most common cause of sexually transmitted genital infections is Chlamydia trachomatis [1]. Almost all the affected individuals are asymptomatic, thus providing an ongoing reservoir of infection. Conjunctivitis and pneumonia can occur in infants born through an infected birth canal. The rectum and conjunctivae are common epithelial sites where males and females can develop clinical syndromes due to infection. There is an incubation period of 5–15 days following infection before symptomatic disease develops. The infection may remain active in asymptomatic individuals for an indefinite period before they become symptomatic.

Among 10 studies of untreated, uncomplicated genital chlamydial infections, 56–89% detected the presence of chlamydia over the short term (weeks to months after diagnosis), and 46–57% detected the presence of chlamydia over the long term [2]. There is, however, a lack of documentation of the date of infection or evaluation of whether the infection was persistent or recurrent. This limits our understanding of the duration of untreated chlamydial infections. According to subsequent modeling studies, chlamydial infections are less likely to establish. In contrast, once established, the disease progresses slowly and more slowly in males than in females (mean undetected durations of 2.84 and 1.35 years, respectively, in males and females [3, 4]. The treatment of all patients with Chlamydia is recommended, despite the possibility of spontaneous resolution.

1.2 A clinical analysis of female syndromes

The majority of females who are infected with C. trachomatis are asymptomatic, but the pathogen is a significant contributor to several clinical syndromes that are common among women.

1.2.1 Genitourinary tract infection

Females are at high risk of cervix infections [5], and a significant proportion may also have urethral infections. When left untreated, cervical cavity infections may progress into the upper genital tract, resulting in pelvic inflammatory disease, infertility, and chronic pain. Pregnant women with genital chlamydial infections are also at risk for complications.

An increased risk of chlamydial infection has been associated with cervical ectropion (columnar epithelium on the outer surface of the cervix in addition to the endocervical canal). Furthermore, some studies have linked cervical neoplasia to the infection [6, 7], but the extent of this effect remains unknown.

1.2.2 Cervicitis

In most cases (at least 85%) of females with cervicitis, no symptoms are observed, which is why young, sexually active females should undergo routine annual screenings. There was only 6–14% of females who developed a new infection within a year of testing who had symptoms of genital chlamydial infection in four out of five sites in a multinational study that looked at women at high risk for genital chlamydial infection using polymerase chain reaction testing of vaginal swabs [8]. Some of the symptoms that can be confused with vaginitis or genital tract pathology are a change in vaginal discharge, intermenstrual vaginal bleeding, and post-coital bleeding. These symptoms can present in many ways, such as an increase in release, a change in color or odor, an increase in itching or burning, or an increase in pain or discomfort during intercourse. The discharge may also have an abnormally high pH, indicative of an infection. Abnormal exam findings are found in approximately 10–20% of females with genital chlamydial infection. When signs of cervicitis are present, they include mucopurulent discharge from the endocervical cavity, easily induced bleeding from the endocervical cavity, and edematous ectopy.

It has been observed that some of these females report symptoms of urinary tract infections, such as frequency and dysuria, but they do not report symptoms specific to the urethra. If not subjected to specific tests for C trachomatis, these females may be mistaken for cystitis [9, 10]. Despite pyuria in the urine analysis, no organisms are detected in the Gram stain or bacterial culture. Therefore, it is reasonable to suspect that sexually active females with pyuria and no bacteriuria may have a chlamydial infection of the urethra based on the combination of symptoms described above.

As a result of these conditions, several possible diagnoses are available, including low-colony urinary tract infections (such as Staphylococcus saprophyticus), which cannot be confirmed by culture or detected by urinalysis, or urethritis caused by another STI, such as Neisseria gonorrhoeae, Trichomonas vaginalis, or herpes simplex.

1.2.3 Pelvic inflammatory disease

As a result of C trachomatis ascending to the upper reproductive tract (uterus, fallopian tubes, and ovaries), pelvic inflammatory disease (PID) can develop [16–20]. The prevalence of clinical PID in females presenting to STI clinics ranged from 2 to 4.5% between the diagnosis of chlamydia infection and the follow-up visit [2]. Following the administration of ineffective antibiotics against Chlamydia, a small study of 20 females with N. gonorrhoea and C. trachomatis coinfection reported a 30% incidence of PID [11]. As a result, no cases of clinical PID have been reported in studies of females at low risk of exposure to chlamydia after a year without treatment. As many cases of PID do not cause symptoms and are only detected later in cases of tubal infertility, these studies may underestimate the incidence of PID in chlamydial infection.

Most commonly, abdominal and pelvic pain is present with symptoms of PID. Infection with chlamydia in conjunction with cervicitis should raise a significant suspicion that the upper genital tract is involved. PID is characterized by cervical motion and tenderness in the uterus or adnexa. PID caused by C trachomatis is associated with a higher rate of subsequent tubal infertility, ectopic pregnancy, and chronic pelvic pain as compared with PID caused by gonorrhea, which typically presents in an acute manner [12].

1.2.4 Invasive cervical carcinoma (ICC)

Invasive cervical carcinoma (ICC) is most likely caused by the human papillomavirus (HPV). Research investigating the etiology of cervical neoplasia and invasive cervical carcinoma has recently examined factors that may affect susceptibility to or progression of HPV infection [13]. C. trachomatis may be a significant HPV cofactor for cervical cancer among sexually transmitted diseases other than HPV. As well as HPV, C. trachomatis may play an important role in cervical cancer development. C. trachomatis is an obligate intracellular bacterium that infects the genital tract [14]. Genital C. trachomatous infection may cause chronic inflammation, damage to epithelial tissues, and pelvic inflammation in some cases. In addition, it has been clinically associated with cervical atypia and metaplasia, increasing women’s risk of cervical neoplasia [15].

A case-control study from England and a pooled analysis of cohort studies from Finland, Norway and Sweden have found positive associations between C. trachomatis microimmunofluorescence (MIF) seropositivity and ICC [16, 17]. According to a Swedish cohort study, C. trachomatis DNA is highly predictive of the development of ICC [18].

Squamous cell ICC may also be increased by infections with C. trachomatis by increasing a host’s susceptibility to HPV and enhancing its effects. Infection with C trachomatis may lead to inflammation, which can produce reactive oxygen species, which can damage DNA and increase the risk of HPV-associated cancer [19]. According to in vitro experiments, Chlamydia-infected cells are also less likely to undergo the normal process of programmed cell death [19, 20]. The cadherin-catenin junction structure in cervical epithelial cells is altered by C trachomatis, increasing the risk of infection with HPV. As opposed to cellular mechanisms, humoral mechanisms (Th2) may mediate the immune response to a particular antigen [21]. The symptoms of cervical neoplasia may be difficult to control in women with C trachomatis infection. An increase in HPV persistence after 12 months was associated with a previous history of C trachomatis, according to a study conducted among Swedish women aged 32–38 years old [22].

1.2.5 Infertility

Worldwide, infertility is becoming an increasingly prevalent health issue [12]. C. trachomatis is becoming a more prominent sexually transmitted disease as a result of the increase in cases [23]. Currently, C. trachomatis is the most prevalent sexually transmitted pathogen. The symptoms of chlamydial infection are less severe than those of other sexually transmitted diseases. A patient may be unaware of the infection until secondary or tertiary symptoms develop due to these deceptively mild symptoms. Infections such as acute salpingitis and pelvic inflammatory disease that go undetected and untreated can result in not only significant morbidity but also infertility [24].

Infertility associated with C. trachomatis can be prevented if detected early [25]. Infertile women are estimated to be infected with chlamydial infections by 18–20%, according to a WHO study [23].

It is reported that infertility is reported to last between 2 and 4 years in chlamydia-positive women [26]. Women with secondary infertility were more likely to contract C. trachomatis infection. Due to their long period of active sexual life, they may be more susceptible to chlamydial infections. There was a surprisingly high percentage of infertile women (38%) who were positive for C. trachomatis. There was no history of previous upper genital tract infection in the majority of these women [23].

1.2.6 Complications of pregnancy

Furthermore, the chlamydial genital infection may increase the risk of premature rupture of the membranes during labor, preterm delivery, and low birth weight infants in addition to the risk of future ectopic pregnancy [27]. According to a study of 3913 pregnant Dutch women screened for C. trachomatis, those with chlamydial infection had a higher risk of preterm delivery (adjusted odds ratio 4.35, 95% CI 1.3–15.2). However, the chlamydial infection did not predict miscarriage or perinatal death [24].

1.2.7 Perihepatitis (Fitz-Hugh-Curtis syndrome)

Perihepatitis is an inflammation of the liver capsule and adjacent peritoneal surfaces that may occur in patients with chlamydia infection. An acute PID is more likely to result in perihepatitis, which occurs in 5–15% of cases. In most cases, there is no abnormality in liver enzymes, but there can be a pain in the right upper part of the rig or pleuritic pain. We do not fully understand the pathogenesis of this condition. An immunological mechanism may be involved, or the infected material could be directly transmitted from the cul-de-sac to the lymphatics and peritoneum [28, 29].

1.2.8 Reactive arthritis/reactive arthritis triad (RAT)

STIs can trigger reactive arthritis. There is a small percentage of patients with sexually acquired reactive arthritis who develop the complete reactive arthritis triad, consisting of arthritis, conjunctivitis, uveitis, and urethritis. It has been shown that C. trachomatis causes sexually acquired reactive arthritis most frequently.

Detection of chlamydial nucleic acids in synovial tissue further supports the association between chlamydia and reactive arthritis. Seven out of nine patients with RAT had a positive in situ hybridization for chlamydial RNA in synovial tissue samples compared to three out of thirteen patients without RAT (the cause of arthritis was not otherwise determined). In addition, five of eight sexually acquired reactive arthritis patients and one control patient with another form of arthritis had stored synovial tissues that contained chlamydial DNA found by polymerase chain reaction.

1.2.9 Conjunctivitis

Serovars D through K of C. trachomatis can cause genital disease in the conjunctival epithelium. The most common method for achieving this goal is directly inoculating infected genital secretions. Inclusion conjunctivitis, which may appear cobbled, is a typical presentation of sexually acquired chlamydial conjunctivitis. Serovars A through C cause endemic trachoma, but this type of infection differs.

1.2.10 Pharyngitis

There is no evidence that C. trachomatis is a significant cause of pharyngitis. However, nucleic acid amplification testing has detected C trachomatis in the pharynx, and some investigators believe this site serves as a reservoir for the infection.

1.2.11 L serovars

In European and North American MSM, particularly those living with HIV, lymphogranuloma venereum (LGV) has been reported to be caused by C. trachomatis L1, L2, and L3 serovars [30]. Symptoms occur in most cases. It has been reported in case studies that anorectal pain, discharge, tenesmus, rectal bleeding, and constipation are among the symptoms reported. It is also possible to experience systemic symptoms such as fever and malaise as well as local symptoms. Several anatomic findings can be observed under anesthesia, including mucopurulent exudate, internal lesions, masses, or polyps. As a result of this presentation, it is sometimes mistaken for an inflammatory bowel disease [31]. Rectal infections caused by the L1, L2, and L3 serovars can result in fistulas and strictures if left untreated [32].

1.2.12 D through K serovars

In addition to causing genital infection in MSM, these non-LGV serovars are also capable of causing rectum infection. This infection, however, is usually asymptomatic, unlike LGV. For example, according to a study of MSM screened for rectal chlamydial infection, only 16% (49 of 301 cases) of non-LGV infections were symptomatic compared to 95% (58 of 62 cases) of rectal LGV infections [32, 33].

Infected females with rectal C trachomatis usually have D through K serovars and are generally asymptomatic. It is also possible for females to develop symptomatic proctitis [33], but this occurs less frequently than in MSM.

2. Diagnosis of chlamydial infections

Several diagnostic techniques are available to diagnose chlamydia, including DNA amplification testing (NAAT), culture, antigen detection, and genetic probes; microscopy is not useful for this purpose. Nevertheless, NAAT is the preferred diagnostic technique due to its superior sensitivity, specificity, and wide availability [34, 35].

2.1 Nucleic acid amplification testing (test of choice)

DNA or RNA sequences from C. trachomatis are amplified using polymerase chain reaction (PCR), transcription-mediated amplification (TMA), or strand displacement amplification (SDA). The “gold standard” of diagnostics is to use these sensitive, specific tests if they are available [34, 36].

2.2 The preferred testing specimen for diagnosis varies by syndrome

2.2.1 Genitourinary infection or screening in females

A vaginal swab is the most appropriate specimen that the patient can collect. NAAT can be performed on either endocervical specimens (for example, cervical specimens collected into liquid cytology medium for Pap testing) or vaginal swabs for females undergoing speculum exams (for example, to evaluate symptoms of cervicitis). Compared to vaginal and endocervical swab samples, first-catch urine samples detect up to 10% fewer infections in females [36, 37].

2.2.2 Test performance

The NAATs can collect specimens without a pelvic examination in females [38]. The most sensitive specimen for diagnosing chlamydial infection in females is a swab of vaginal fluid [38, 39]. Compared with urine and, in some cases, endocervical swabs, NAAT on vaginal swab fluid on females had higher sensitivity than urine and, in some cases, endocervical swabs. Several studies have shown that NAAT on rectal specimens can detect rectal chlamydia more accurately than culture and still have high specificity [40]. Men who have sex with men (MSM) can also self-collect these samples to facilitate screening [41].

2.3 Other diagnostic techniques

2.3.1 Rapid tests for chlamydia

Even though NAAT has replaced culture as the new “gold standard,” same-day results have not been available traditionally. NAAT-based rapid tests have been developed. Their use will likely be influenced by practical issues, such as waivers for non-laboratory use and cost, as they become more available [41].

2.3.2 The XPert C trachomatis/N gonorrhea (CT/NG) assay

A NAAT, the XPert C trachomatis/N gonorrhea (CT/NG) test provides results for chlamydia (and gonorrhea) within 90 minutes [42]. It is FDA-approved for use on vaginal and endocervical swabs. Using electrochemical detection technology, the Binx io CT/NG NAAT assay produces results within 30 min [43]. It is FDA-approved for use on vaginal swabs. 96, 99, 91, and 100% were the sensitivity, specificity, positive, and negative predictive values for CT. Culture methods for detecting chlamydiosis are now limited to research and reference laboratories due [44]. Serology for C trachomatis (complement fixation titers >1:64) is usually performed infrequently, is non-standardized, and requires a high level of expertise for interpretation. Furthermore, it may not perform as well as a test to diagnose rectal infections in males as in females with upper genital tract infections [45, 46, 47]. Testing for antigens requires invasive methods such as cervix swabs or urethral swabs. Compared to culture, this method has an 80–95% sensitivity. Currently available genetic probe methods require invasive testing with a direct cervix or urethral swab since they do not amplify genetic targets. This assay is 80% more sensitive than culture. Although these tests are relatively inexpensive, their sensitivity is significantly lower than NAAT, and NAAT has become more cost-competitive, so they are no longer as commonly used.

Adolescent girls and young women may no longer be required to visit their doctors annually since there is no longer a need for annual cervical cancer screening. A young woman’s annual visit is an important opportunity to obtain advice and information regarding her reproductive health, access contraception, receive counseling regarding sexually transmitted diseases (STDs), and to be screened for these diseases.

2.4 Who are the candidates to test for chlamydial infections

2.4.1 Symptomatic and at-risk asymptomatic patients

The diagnosis of C. trachomatis should be based on the clinical signs and symptoms associated with chlamydia in sexually active individuals. There is a high risk of infection and complications associated with chlamydia in sexually active patients. Most of these infections are asymptomatic because most chlamydial infections do not present any symptoms. Furthermore, chlamydia should also be tested on patients who have a history of documented gonococcal infection. Moreover, patients treated for chlamydia should be rescreened around 3 months after treatment, regardless of whether they think their sexual partners have been treated as well [44]. In the months following an initial infection with chlamydia, a high rate of reinfection has been documented as well [43, 48].

2.4.2 Patients with persistent symptoms

Symptoms that persist after appropriate treatment and good adherence to confirmed chlamydial infection are usually not the results of primary treatment failure. NAAT testing and ompA genotyping were used to characterize the reinfection or persisting infection rates in a longitudinal cohort of adolescent females assessed every 3 months [49]. There were 478 infections observed among 210 participants. Of these females, 121 experienced repeated infections. Only 2.2% were infections that persisted without documented treatment. Most of these infections (84%) were likely reinfections, 14% were probable or possible treatment failures, and 14% persisted without documented treatment.

2.4.3 Recurrence of symptoms

When chlamydia, gonorrhea, bacterial vaginosis, and other sexually transmitted diseases that cause urethritis or cervicitis have resolved after a first evaluation, a repeat evaluation is recommended for the prior treatment; NAAT remains the test of choice to diagnose reinfection in symptom recurrence [37]. Repeat diagnosis of chlamydia in previously treated patients usually indicates reinfection, as noted above [37].

Diagnosing C. trachomatis should also prompt testing for N. gonorrhoeae since both pathogens cause similar clinical syndromes and coexist in a significant proportion of patients with chlamydial infection [36].

3. Treatment of Chlamydia trachomatis infection

Males and females alike are most at risk for bacterial sexually transmitted infections (STIs) caused by C. trachomatis, a small gram-negative bacterium.

Preventing complicated infections caused by chlamydia and its sequelae are the primary goals of management (e.g., pelvic inflammatory disease, infertility, chronic pelvic pain, ectopic pregnancy, and epididymitis). The screening and treatment of young females for C. trachomatis infection, for example, has been shown to reduce the risk of subsequent PID [50]; however, early treatment of PID, particularly when C. trachomatis is detected, reduces the risk of ectopic pregnancy and infertility compared to delayed treatment [51]. Treatment with doxycycline or azithromycin results in clinical improvement in 83 and 86 per cent of symptomatic patients with cervicitis and urethritis, respectively [51, 52]. The risk of reinfection is high for persons who have previously contracted chlamydia. Persons with symptoms such as cervicitis, PID, urethritis, epididymitis, and acute proctitis may benefit from empiric therapy for chlamydial infection.

Empiric therapy should also be offered to patients recently exposed to chlamydia. A patient with documented gonococcal infection should also receive empiric chlamydia treatment unless the nucleic acid amplification test (NAAT) is negative [51].

3.1 Antimicrobial susceptibility of C trachomatis

Tetracyclines, macrolides, and some, but not all, fluoroquinolones are uniformly effective against C. trachomatis [53]. The in vitro persistence of C. trachomatis is associated with penicillins [53, 54], but amoxicillin has also been effective. The aminoglycosides and sulfonamides have limited activity against C. trachomatis, but antibiotic resistance is sporadic for those agents [55].

Moreover, the extracellular elementary body of C. trachomatis, an infectious organism, is metabolically inert and resistant to killing, so the breadth of active agents is limited [56]. Therefore, antibiotics need to target the sequestered intracellular and intravacuolar phases of this pathogen’s life cycle, which is why antibiotics with good intracellular penetration are vital [57].

Maintaining antibiotic concentrations throughout the organism’s life cycle, ranging from 36 to 48 hours, is also necessary. To ensure adequate levels of antibiotics, either a prolonged course of therapy or the selection of an antibiotic with a long half-life is required [57, 58].

Moreover, the elementary body is relatively inert, limiting replication opportunities and resulting in antibiotic-resistant mutations [59].

3.2 Defining antibiotic efficacy

As part of its four primary outcomes of recommending antimicrobial regimens for treating sexually transmitted infections (along with symptom resolution, prevention of sequelae, and prevention of transmission), the Center for Disease Control and Prevention explicitly incorporated microbial eradication (along with symptom resolution, prevention of sequelae, and prevention of transmission) to one of four outcomes. The effectiveness of a drug can be more reliably predicted by its ability to cure bacteria than by its ability to cure the patient for two reasons: many patients have other coinfections that are not responsive to treatment [59], and most patients are not manifesting clinical symptoms at the beginning of the treatment.

3.3 Comprehensive treatment approach

The complete care of C trachomatis-infected patients includes antibiotic treatment, evaluation, and treatment of other sexually transmitted diseases (STIs, such as gonorrhea and HIV), counseling on adherence and sexual activity, follow-up testing, and managing sex partners. Females and males are more likely to have asymptomatic infections that can only be detected on screening; however, these should also be treated promptly [56].

3.4 Antibiotic treatment of chlamydia

3.4.1 Doxycycline as the preferred agent

For optimal outcomes, patients should be counseled to adhere to the prescribed dosage of 100 mg twice daily for 7 days [60]. It is safe and effective to administer delayed-release doxycycline (200 mg daily for 7 days) compared with twice-daily doxycycline. However, it is more costly and may not be accessible to all patients [60]. Previously, azithromycin was considered an alternative option, but mounting evidence indicates that doxycycline is a more effective microbial agent, especially for rectal infections and possibly pharyngeal infections [61]. Azithromycin is now considered an alternative. For this reason, azithromycin is reserved for individuals who are unlikely to be able to complete the seven-day doxycycline course (e.g., patients with adherence issues) and is administered as a single, directly observed dose of 1 g. It is also the preferred antibiotic for pregnant women [62].

3.4.2 Levofloxacin (500 mg orally once daily for 7 days)

Levofloxacin and ofloxacin (300 mg twice daily for 7 days) are highly effective against C. trachomatis. There may be limited availability of this alternative fluoroquinolone. They are more expensive than doxycycline, and neither offers a significant advantage. Fluoroquinolones should not be used for uncomplicated infections since they are associated with severe adverse effects. Therefore, fluoroquinolones as a treatment for C. trachomatis is rare. Then, levofloxacin (or ofloxacin) can be used as an antichlamydial agent. Before, these fluoroquinolones were utilized primarily for treating coexisting gonococcal and chlamydial infections. Despite this, due to drug resistance, fluoroquinolones no longer provide adequate protection against N. gonorrhoeae [63, 64].

Fluoroquinolones are less well-studied for targeted therapy for C. trachomatis than doxycycline or azithromycin. Studies comparing fluoroquinolones (e.g., ofloxacin) to doxycycline have failed to demonstrate any difference in microbiologic cure rates. Fluoroquinolones are inappropriate; ciprofloxacin has poor microbiologic outcomes. Alternatively, moxifloxacin has not been studied as a targeted therapy for C. trachomatis, it has shown promising efficacy in treating PID and is recommended as an alternative treatment regimen for select females with PID [65, 66].

Penicillins and erythromycin are significantly less effective than penicillin, resulting in a microbial cure, with cure rates ranging from 85 to 89%. Therefore, penicillins (such as amoxicillin) are primarily prescribed to pregnant women who cannot tolerate other antibiotics [67, 68].