Significance of Chlamydia Infections

• Introduction
• Microbiology 
• Immune Response to Chlamydia Infections 
• Disease in the Female
• Disease in the Male
• Pitfalls in treating Chlamydia infections of the prostate
• Treatment of Chlamydia Prostatitis 
• Sonogram images

Introduction

Chlamydia trachomatis has emerged recently as one of the most significant pathogens causing symptomatic or asymptomatic genital tract infections and infertility. In our laboratory currently over two thirds of prostatitis patients presenting with previously negative cultures, so called “abacterial”, are turning up with Chlamydia elementary bodies assessed by immune-fluorescent stain. We are convinced therefore that this organism is the most significant cause of chronic prostatitis.

A thorough knowledge of the unique life cycle of Chlamydia, its effect on living tissues and its interaction with the immune system is necessary to make the right diagnosis and design the proper therapy for the condition. The high frequency of the isolation rate of this organism from both infertile populations and from patients with symptomatic prostatitis makes it necessary to give a skeletal summery of the basic features of Chlamydia microbiology and Chlamydia caused pathology.

Microbiology

Members of the genus Chlamydia are unique bacteria exhibiting, not unlike viruses, an intracellular development phase, the reticulate body (RB) and a highly infectious extra cellular form, the elementary body (EB). The reproduction of the organism is obligate intracellular, relying on the host’s cell components for nourishment. They show Gram negative staining in histological specimens. These bacteria can cause numerous eye, genital and respiratory infections in humans and animals.

Small differences within the genetic content of the organisms allow classification into four major species. C. trachomatis, C. pneumoniae, C. psittaci and C. pecorum.

Within each of these groups individual serovars are separated by differences in certain surface proteins, antigens. Serovars allow organisms to be classified at the sub-species level.

Ocular infection is caused by the distinct serovar of Chlamydia trachomatis that causes Trachoma (the most common preventable blinding tropical disease).

In males Chlamydia trachomatis is the number one cause of non-specific urethritis (NSU), prostatitis and epidydimitis.

Chlamydia pneumoniae was long known to cause mild respiratory infections but has recently emerged as an important pathogen associated with atherosclerosis, adult-onset asthma and certain other chronic diseases.

Chlamydia psittaci a zoonotic bacterium (causes diseases in animals that can be transmitted from animals to humans) constitutes an occupational hazard for workers in the poultry and farming industry, and persons exposed to infected avian species. Chlamydia pecorum has not been associated with any human disease.

Chlamydia infection and Immune Response

The elementary body is the highly infectious form of Chlamydia.

Both specific blood borne and T lymphocytes (thymus derived lymphocytes) cell-mediated immune responses are elicited following Chlamydia infection. Nasopharyngeal, genital, and anal mucosal surfaces are the most important entry sites for the elementary bodies. Specialized immune cells will transport on their surfaces certain characteristic protein groups of the Chlamydia surface membrane (antigens) from the mucosal epithelium to the lymph nodes. Here, T lymphocytes are responding and migrate to the entry site of the infection. Anti-Chlamydia immunity is established primarily by a T lymphocyte response (CD4+ and CD8+ Th1) and their established long-term presence in local mucosa at the site of infection. The infection also activates a host of co-stimulators (IL-1, IL-12, ICAM-1, LFA-3, CD40 and B7 molecules)

Specific humoral immune responses, in addition to the T lymphocyte response, including secretory and systemic antibodies, play a role in protective immunity.

Humoral and cell mediated immunity cooperate to clear Chlamydia infection.

After the Chlamydia is eliminated, the T cells remain in the mucosa with memory of the infection preserved. In case of a new infection these cells will promptly respond, shortening the duration of subsequent infections. In healthy individuals a fast and vigorous T response after a new infection will rapidly arrest Chlamydia replication, clear the infection, eliminate residual antigens and prevent the establishment of latent infection.

In humans, there are wide ranging genetic differences in the degree of immune response. Several generations can live with the bacterium and to a certain extent inherit protecting antibodies. Even reproduction is possible. Whether stigmata of the infection surfaces in one or the other individual in subsequent generations or any pregnancies complicated are multifaceted issues. Chlamydia can develop immune evasive mechanisms. Surface antigens can change and thus evade recognition by T lymphocytes. Such cases can lead to Chlamydia latency or persistence, inadequate chronic host reaction and tissue damage. It is also suspected that Chlamydia can develop immune-pathogenic Chlamydia antigens. The outer membrane protein (OMP2) of several Chlamydia trachomatis serovars, Chlamydia pneumoniae and Chlamydia psittaci capable of inducing autoimmune inflammation and are suspected to be responsible for the pathogenesis of Chlamydia-associated inflammatory and autoimmune-like diseases.

Additional infections with different serovars, the role of stress, age of the individual at the time of infection and many other factors are postulated but the details are unclear. Unfortunately, recently it became clear that Chlamydia could develop immune evasive mechanisms and produce immune-pathogenic Chlamydia antigens. Such immunosuppressive mechanisms have the potential to modify T response leading to Chlamydia latency or persistence, chronic host reaction and tissue damage. Special concern is the multi drug resistant Chlamydia strains and the rapidly developing resistance to single drug regimens.

Disease in the Female

In the female, infections with several serovars of Chlamydia trachomatis lead to cervicitis and urethritis as the primary sexually transmitted diseases (STDs). Pelvic Inflammatory Disease (PID) and Tubal Factor Infertility (TFI) are major complications of genital Chlamydia infection. Reports suggesting that genital Chlamydia infection may predispose to HIV-related AIDS and human Papilloma virus-associated cervical dysplasia have heightened these concerns. Presence of Chlamydia trachomatis is independently associated with increased cervical cancer risk. The female genital tract presents special situation. In vertically or horizontally infected individuals Chlamydia trachomatis may reside in the vaginal canal without symptoms until puberty or until sexual activity begins. Chlamydia can reach the upper compartment either by rapid surface growth following the first menstruation or by direct transfer using motile sperms. While the lower compartment can harbor asymptomatic Chlamydia infection for years, the upper compartment will respond to Chlamydia infection with a wide-ranging alteration in reproductive performance, hormonal changes and immunological reactions.

The lack of understanding of this dual behavior of the female genital organs is the most common reason behind mismanaging the majority of the secondary infertility cases and the incomplete understanding of how pelvic pathology caused by Chlamydia develops. Pregnancy, an immune suppressed state of the uterus often unmasks an undetected Chlamydia infection.

Disease in the Male

The male genital tract is invaded by Chlamydia through the urethra. Mild to moderate urethral pain is followed by clear, mucous or bloody discharge within hours or up to several days. The infection progresses along the mucous wall of the urethra and once it has reached the prostatic urethra it will jump into the prostate and urinary bladder with the development of typical symptoms (urgency, frequency, disuria and nocturia). Often the progression is so rapid that the patient will recall the cystitis as the very first symptom. By now, the semen, EPS and urine sediment will reveal numerous white and red blood cells and bacterial forms.

The progressing infection forms bead like scarring in the urethra that can advance to different degree of stricture and visible on histological specimens or through trans rectal ultrasound (Figure 1). Invasion of the prostate shows up as early scar tissue, snow flakes (Figure 2) and as the infectious scarring progresses can forms grape like clusters (Figure 3). With time, nodular and lobular enlargement of the prostate will follow. In the scarred areas, due to acidic conditions, calcium salts will precipitate around clusters of bacteria (Figure 4). The cyclically recurring infection will progress to the ductus deferens and to the seminal vesicles. On sonogram examination, unilateral involvement will show a single Gothic arch, where the tip of the arch is the ejaculatory duct and the median duct is the ductus deferens and the lateral one represents the outflow duct of the seminal vesicle. Double Gothic arches represent bilateral involvement (Figure 5). It seems, vertically acquired Chlamydia infection causes more diffuse scarring with less calcification (Figure 6). The grape like clusters of beads are relatively rare.

Involvement of the seminal vesicles will gradually destroy the secretory lining and the volume of the ejaculate will gradually diminish. Figure 4 shows a normal seminal vesicle and an end-stage, chronically inflamed gland where the scar tissue almost completely replaced the functioning gland. A long term therapy course with repeated antibiotic injections was needed to cure the patient.

The Major Pitfalls in Treating the First Episode of Prostatitis

1. Underestimating the frequency of Chlamydia infections in prostatitis
2. Incomplete knowledge of the life cycle of Chlamydia.
3. A complete lack of appreciation of the fact that this organism not only develops resistance to antibiotics but it has infinite resources to evade detection. Chlamydia is polymorphic both in its antigenic and its pathogenic potentials.
4. Finally, Chlamydia will bewilder patients and doctors alike due to the simple fact that acute or chronic prostatitis can develop for no apparent reason from vertically inherited strains of this bacterium.

Treatment of Chlamydia Prostatitis

The fact that Chlamydia has both extra and intracellular development forms as well as stationery cryptic forms (spores) poses special challenge for the therapy. Commonly recommended single drug regimens for a given 2 to 3 weeks duration are the current standard of therapy. Chlamydia shows in vitro sensitivity to a number of antibiotics including tetracycline, erythromycin, clindamycin, clarithromycin, and fluoroquinolones such as ofloxacin and sparfloxacin.

Despite in vitro susceptibility, Chlamydia infections will relapse in a significant number of patients following antibiotic therapy with these agents. In vitro studies on the persistence of Chlamydia despite specific and appropriate antibiotic therapy have suggested that the presence of antibiotics promotes the formation of an intracellular, non-replicating state, referred to as the latent or cryptic phase. The cryptic phase becomes rapidly resistant to single drug therapy and as soon as the antibiotic course is finished clinical recurrence takes place. It is not unusual. due to the rapid development of drug resistance, for symptoms to return even before the course is finished. Therefore there is an acute need for reliable, accurate methods for diagnosing Chlamydia infection, as well as a need for new therapeutic approaches that prevent the development of resistant strains and is directed against both intra and extra cellular developmental phases of Chlamydia. Only an early onset, all out, multilateral assault with combination antibiotics will prevent the long-term sequels of a chronic infection.

The antibiotic mixtures should contain at least two agents, each effective against a different phase of the Chlamydia life cycle. One agent should be effective against the elementary body phase and the other against the replicating phase and cryptic phase of the Chlamydia life cycle. A number of effective agents are available against the initial phase of Chlamydia infection (i.e., transition of the Chlamydia EB to an RB). This growth phase involves electrons and electron transfer proteins, as well as nitroreductases. Therefore this phase of Chlamydia infection is susceptible to the antimicrobial effects of nitroimidazoles, nitrofurans and similar agents. The degradation of these drugs within the microbial cell forms highly toxic electrophilic radicals. Best known are Metronidazol (Flagyl) and Nitrofurantoin (Macrobid).

Zithromax, Erythromycin, Clarythromycin, Doxicycline are all suitable candidates against the extra cellular elementary body.

Following my intense, ten day (IV and uterine lavages/direct prostate injections) antibiotic courses, I order Zithromax (500 mg daily) or Biaxin (500 mg twice daily), for a 30 to 60 day course. These antibiotics are given together with macrodantin (Macrobid) 100mg twice daily for the same length of time


The drugs are well tolerated. Other drugs, commonly prescribed include, Ciprofloxacin and Levaquin; both have limited usefulness in the treatment on chronic prostatitis. One or two a day dosages assure patient compliance.

Since Chlamydia can also infect monocytes and macrophages reducing effective clearing function by the host, a further mechanism for the development of chronic infection, INH (Isonicotinic acid), an old anti tuberculosis drug offers new therapeutic hopes. In laboratory experiments INH can eradicate Chlamydia from macrophages and monocytes and restores these cells to full functionality to fight infection.

If INH is approved it will have to be used with agents that target other phases of the life cycle of Chlamydia.

Sonogram Images of Prostate in Chlamydia Infection

1 In early phase of Chlamydia infection "Beads" like scarred areas form inside the wall of the prostatic urethra.


2 After extension of the infection from the urethra into the prostate itself, the scarring areas show up like delicate "Snowflakes".


3. Denser scar tissue forms after longer lasting infection and will show up as "Clusters of Grape" – like structures.


4. With time, the clusters of beads coalesce and calcium salts deposit.
5. A chronic infection can cause scarring of the entire intraprostatic segment  of both ductus deferentes and the terminal ducts of the seminal vesicles. An extreme case is the formation of the "Double Gothic Arches". The two median segments of the arches represent the two ductus deferentes, while the lateral segments are the two excretory ducts of the seminal vesicles. Bilaterally, the tip of the arches represents the fusion of the two structures into the ejaculatory ducts. 


6. Sonographic image of a prostate with chronic prostatitis. There was no known association of the onset of the prostatitis with any sexual activity.  Strong parental history of infectious reproductive complications was noted, however. His father suffered from BPH. The Chlamydia test was negative.  Note the lack of typical locally scarring phenomena associated with Chlamydia prostatitis. The scarring appears more diffuse and involves most of the prostate.