Introduction The spectrum of genital infections caused by serotypes of C trachomatis has only recently become appreciated.

Chlamydia (from Greek, meaning "cloak") infections are the most commonly reported notifiable disease in in industrialized countries. In 2004, 929,462 chlamydia infections were reported to the CDC, which is 2.5 times greater than the number of cases of gonorrhea. As many as 10 percent of women of childbearing age are infected in inner cities in the UK. Women under 25 years of age have the highest prevalence. Genital infection with this organism is the most common sexually transmitted bacterial disease in women. Certain factors may be predictive of women with a greater likelihood of acquiring C trachomatis. Sexually active women younger than 20 years have chlamydial infection rates 2 3 times higher than the rates of older women. The number of sexual partners and, in some studies, lower socioeconomic status are associated with higher chlamydial infection rates. Persons who use barrier contraception are less frequently infected by C trachomatis than are those who use no contraception, and women who use oral contraceptives may have a higher incidence of cervical infection than women not using oral contraceptives. Cervical infection in pregnant women varies from 2 24% and is most prevalent in young, unmarried women of lower socioeconomic status in inner-city environments. The CDC recommends screening sexually active adolescent girls at their routine yearly gynecologic examination, as well as women 20 24 years old, especially those who have new or multiple partners, and those who inconsistently use barrier contraceptives.

Pathogenesis Chlamydiae are small (250-1000 nm) obligate intracellular microorganisms that have a cell wall similar to that of gram-negative bacteria. They belong to family Chlamydiaceae and class Chlamydia They are classified as bacteria and contain both DNA and RNA. There are 4 different types of Chlamydia: C. trachomatis (agent of urogenital chlamydia, trachoma, Lymphogranuloma venereum), C. psittaci (causes SARS arthritis, pyelonephritis), C. pneumoniae (pathogen ARD, pneumonia), C. resogit (role in the pathogenesis of humans is not known). They divide by binary fission, but like viruses they grow intracellularly. They can be grown only by tissue culture. It has a unique developmental cycle, includes two forms of existence: the elementary bodies (infectious form adapted for extracellular survival) and reticular cells (vegetative form, which provides intracellular multiplication). Elementary bodies of phagocytes of the host organism, but it is not digested (incomplete phagocytosis), and transformed into reticular cells and actively proliferate. Developmental cycle of chlamydia is 48-72 h and ends with the rupture of the host cell and yield of elementary bodies in intercellular space.

Chlamydia is unstable in the environment, it is easy to die when exposed to antiseptics, ultraviolet light, boiling, drying. Infection occurs mainly through sexual contact with an infected partner, transplacentally and intrapartum, rarely through household way via toiletries, laundry, and bed. With the exception of the L serotypes, chlamydiae attach only to columnar epithelial cells without deep tissue invasion. As a result of this characteristic, clinical infection may not be apparent. For example, infections of the eye, respiratory tract, or genital tract are accompanied by discharge, swelling, erythema, and pain localized to these areas only. C. trachomatis infections are associated with many adverse sequelae due to chronic inflammatory changes as well as fibrosis (eg, tubal infertility and ectopic pregnancy). Serovars A-C cause trachoma, infecting the conjunctiva. Serovars D-K cause genital infections. Specific LGV serovars (Ll-L3) cause LGV. They gain entry to the cells by binding to specific surface receptors. Once inside the cell, inclusion bodies form, which contain the metabolically active reticulate bodies. These divide by binary fission. After a 48-hour life cycle, reticulate bodies condense into elementary bodies which are released from the cell surface. Heavily infected cells die but it is the inflammatory response to infection that contributes most to damaging the epithelial surface. The proposed mechanism for the pathogenesis of chlamydial disease is an immune-mediated response. This mechanism has been supported C. trachomatis vaccine studies in humans and monkeys as well as other animal model studies. Evidence indicates that a 57-kDa chlamydial protein, which is a member of 60-kDa heat shock proteins, plays a role in the immunopathogenesis of chlamydial disease. Humoral immunity may protect from reinfection, but antibodies are serovar specific and the protection is short lived. Cell-mediated immunity, with activation of cytotoxic T cells and production of interferon-gamma, is more important for controlling established infection.

Classification A widely accepted clinical classification does not exist. Clinically, it maybe divided into acute (disease duration up to 2 months), chronic (disease is more than 2 months); and carrier state of schlamydial infection. In addition, the disease is divided based on location into uncomplicated chlamydia of the lower urogenital system, upper urogenital syatem and pelvic organs, and chlamydia at other sites.

Clinical Findings Symptoms and Signs Women with chlamydial infection not uncommonly are asymptomatic: approximately 50 per cent in men and 80 per cent in women. In men it is the most important cause of NGD. In women it causes

cervicitis and PID. Women with cervical infection generally have a mucopurulent discharge with hypertrophic cervical inflammation. Genital strains can colonize the throat and also cause conjunctivitis. It can infect the rectum, although only lymphogranuloma venereum (LGV) strains of Chlamydia cause a severe proctitis. Salpingitis may be unassociated with symptoms. Suspected chlamydial infection may cause Figure 2 Chlamydial cervicitis in a female patient characterized by mucopurulent junction adhesions between cervical discharge, erythema, and the liver and the parietal inflammation. peritoneum (perihepatitis), also known as syndrome of Fitz-HughCurtis. It is usually detected during laparoscopy or laparotomy. Due Figure 1 Conjunctivitis due to chlamydia. to scarce and/or non-specific symptoms, disease is impossible to identify based on clinical signs and symptoms. Diagnosis of Chlamydia trachomatis is based only on the results of laboratory studies. Essentials of Diagnosis y y y y y y Mucopurulent cervicitis. Salpingitis. Urethral syndrome. Nongonococcal urethritis in males. Neonatal infections. Lymphogranuloma venereum.

Laboratory Findings The diagnosis of chlamydial infection is based solely on laboratory tests. Diagnosis of C trachomatis using cell culture isolation has a sensitivity of 70 90%; however, this specialized modality is not widely available. Cell culture is the detection method of greatest specificity (almost 100%), but the cost can be prohibitive, and a 3to 7-day delay in diagnosis is required. Despite its disadvantages, cell culture is presently the standard for quality assurance of nonculture chlamydia tests and it is the "Gold standard" for detection
Figure 3 Pap smear showing C. trachomatis (H&E stain)

of intracellular parasites. The CDC recommends cell culture for specimens from the urethra, rectum, and vagina of prepubertal

girls and from the nasopharynx of infants so that columnar epithelial cells are harvested. In infants with inclusion conjunctivitis, Giemsa stain of purulent discharge from the eye is used to identify chlamydial inclusions, but similarly stained slides of exudates in adults with genital infections are only approximately 40% accurate in the diagnosis of these infections. Serologic methods, either the complement fixation or microimmunofluorescence test, are not totally accurate, as 20 40% of sexually active women have positive antibody titers. In fact, most women with microimmunofluorescent antibody do not have a current infection. In order to clarify the diagnosis and determine the phase of the disease we can identify chlamydial antibodies classes A, M, G in the serum. In the acute phase of chlamydial infection, the titer of IgM increases, the transition to a chronic phase causes the increase of IgA titers, and then IgG. Reduced titers of chlamydial antibody classes A, G in the treatment process is an indication of treatment positive effects. Diagnosis of urogenital Chlamydia trachomatis by detection Figure 4 Chlamydia trachomatis inclusion bodies (brown) in a McCoy of antibodies IgA, IgM, IgG is not recommended by global and national cell culture. guidelines. Moss and colleagues examined antibody responses to chlamydia species in patients who attended a genitourinary clinic and found that up to 50% of all chlamydia IgG-positive cases were due to nongenital chlamydiae (C pneumoniae and C psittaci). The low specificity of the chlamydia serology tests is attributed to these antibodies as well as to the presence of group-specific antibodies. Therefore, it is of utmost importance to use serologic tests capable of distinguishing antibodies to C trachomatis from antibodies to C pneumoniae and C psittaci (nongenital chlamydial pathogens). Direct smear fluorescent antibody testing or direct fluorescent antibody (DFA) test requires a fluorescence microscope, and processing time is only 30 40 minutes. Sensitivity is 90% or higher, with a specificity of 98% or higher if an experienced microscopist and a satisfactory specimen are available. This test appears to be the most promising, and when tissue samples (endometrial or uterine tube) are being evaluated, it has been reported to be more accurate. ELISA tests cannot be used reliably on rectal or conjunctival swabs, for which DFA is more appropriate. PCR, ligase chain reaction, and current DNA probes used for detection of C trachomatis may be more rapid and less expensive. They can be applied to urine samples or vaginal swabs and have detection rates superior to ELISA tests on cervical swabs. This means that non-invasive screening for Chlamydia is now possible. Unfortunately, higher cost has limited the availability of such tests in the UK. Nucleic acid hybridization methods (DNA probe) require only 2 3 hours of processing time. The DNA probe assay is specific for C trachomatis; cross-reactivity with C pneumoniae and C psittaci has not been reported. To ensure high specificity, a competitive probe assay has been produced and is currently being evaluated in clinical trials. Recent reports indicate PCR positivity with negative culture. PCR may be the most sensitive and specific test method for chlamydia.

Table 1 Interpreting the results of serological examination for Chlamydia Stage of disease Acute chlamydia (2 weeks from onset) Acute chlamydia (2,5 - 3 weeks from onset) Acute chlamydia (3-4 weeks from onset) Exacerbation of long course of chlamydia (2 weeks from onset) Duration of the current chlamydia Past (after) infection Recovery In negative result IgM + + + + IgA + + + +/reduce titer by 2-4 times after successful treatment IgG + + +/+ reduce titer by 4-8 times over 1-1.5 months after successful treatment -

The only situation where a serological blood test for chlamydia has no practical application is in tubal infertility in women. In the presence of the triad:
y y y

The presence of antibodies class G to C. trachomatis Established by instrumental methods fact tubal infertility Elevated levels of C-reactive protein (CRP) in blood plasma,

anti-chlamydial treatment is initiated, but the diagnosis of urogenital Chlamydia trachomatis is not confimed.
Table 2 Laboratory investigations and their pros and cons Method Sensitivity Specificity Benefits Shortcomings Microscopy * 74% -90% 98% -99% Fast and cheap subjective Antigen - ELISA 71% -97% 97% -99% fast expensive, require special equipment PCR 90% 99% -100% sensitive expensive

* Using a fluorescence microscope for direct immunofluorescence reaction or DFA (direct immunofluorescence assay)

In Scandinavian countries, nationwide screening programmes have reduced the incidence of chlamydial infection, with concomitant reductions in the incidence of PID and ectopic pregnancy. A national screening programme is starting in the UK. Serological tests are not performed routinely in the diagnosis of chlamydial infections. Micro-immunofluorescence can be used to detect serum antibodies, which are not present in all infected individuals. The highest antibody titres are found in women with PID or disseminated infection. These highest titres are present in 60 per cent of women with tubal factor infertility.

Differential Diagnosis Mucopurulent cervicitis is frequently caused by N. gonorrhoeae, and selective cultures for this organism should be performed. As discussed above, C. trachomatis alone may be associated with as many as 20 35% of cases of acute salpingitis in the United States. In both cervicitis and salpingitis, cultures frequently may be positive for both organisms.

Complications Adverse sequelae of salpingitis, specifically infertility due to tubal obstruction and ectopic pregnancy, are the most direct complications of these infections. Pregnant women with cervical chlamydial infection can transmit infections to their newborns; evidence indicates that up to 50% of infants born to such mothers will have inclusion conjunctivitis. In perhaps 10% of infants, an indolent chlamydial pneumonitis develops at 2 3 months of age. This pathogen may cause otitis media in the neonate. Whether maternal cervical infection with Chlamydia causes significantly increased fetal and perinatal wastage by abortion, premature delivery, or stillbirth is uncertain. Increasing evidence indicates that chlamydial infection in pregnancy is a risk marker for premature delivery and postpartum infections. Women at greatest risk are those with recent chlamydial infection detected by anti-chlamydial IgM. Those with chronic or recurrent infection do not have increased risk for preterm delivery. It is hypothesized that asymptomatic cervicitis predisposes to mild amnionitis. This event activates phospholipase A2 to release prostaglandins, which cause uterine contractions that may lead to premature labor. Chlamydial infection is associated with higher rates of early postpartum endometritis as well as delayed infection from Chlamydia that often presents several weeks postpartum.

Treatment In most cases, Chlamydia can be eradicated from the cervix by doxycycline 100 mg orally twice daily for 7 days (for non-pregnant patients), or azithromycin 1 g orally as a single dose. Compliance with treatment may play a major role in controlling chlamydial infections. One group of researchers evaluated the compliance with anti-chlamydial and antigonorrheal therapy and found that 63% of patients treated with the standard 7-day regimen of tetracycline or erythromycin were compliant. An alternate regimen is erythromycin base 500 mg or erythromycin ethylsuccinate 800 mg orally 4 times daily given for a minimum of 7 days. Patients who cannot tolerate erythromycin should consider ofloxacin 300 mg twice daily or levofloxacin 500 mg orally once daily for 7 days. Administration of high doses of ampicillin has resulted in elimination of C. trachomatis from the cervices of women with acute

salpingitis. Addition of the irreversible -lactamase enzyme inhibitor sulbactam increases in vitro antichlamydial activity. Pregnant women are advised to take erythromycin base 500 mg 4 times daily for 7 days, or amoxicillin 500 mg 3 times daily for 7 days. Alternate regimens include erythromycin base 250 mg orally 4 times daily for 14 days, erythromycin ethylsuccinate 800 mg orally 4 times daily for 7 days, erythromycin ethylsuccinate 400 mg orally 4 times daily for 14 days, or azithromycin 1 g orally as a single dose. In addition, we can prescribe anti-oxidants, vitamins, physical therapy, and eubiotics to adjust the vaginal microflora. Current studies indicate that 3 5% of pregnant women and as many as 15% of sexually active nonpregnant women have an asymptomatic chlamydial cervical colonization. Whether attempts to eradicate asymptomatic colonization will prevent chlamydial cervicitis, salpingitis, or neonatal infections is not known. Post-treatment cultures are not usually advised if doxycycline, azithromycin, or ofloxacin is taken as described above and symptoms are not present; cure rates should be higher than 95%. Retesting may be considered 3 weeks after completing treatment with erythromycin. A positive post-treatment culture is more likely to represent noncompliance by the patient or sexual partner or reinfection rather than antibiotic resistance. It is important to ensure that the sexual partner is treated, as most post-treatment reinfections occur because the sexual partner was not treated. Clinicians should advise all women with chlamydial infection to be re-screened 3 4 months after treatment before sexual intercourse is resumed.



Currently, vaccines against urogenital chlamydia are not presence, but studies in this area has been conducted for over 10 years by ANTEX INC biologics, which has already created vaccines prototypes TRACVAX (Chlamydia trachomatis vaccine) and TWARVAX (Chlamydia pneumoniae vaccine). They are currently undergoing preclinical test. Experiments show that the vaccine protected the animals from TRACVAX infertility caused by Chlamydia trachomatis infection.

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