Mycoplasma, Ureaplasma infections

Clinical manifestations in men

Nongonococcal urethritis

Nongonococcal urethritis (NGU) is the most frequently occurring sexually transmitted disease in men.
Data from international medical literature is not conclusive in determining whether or not various Mycoplasma strains cause NGU, or whether their presence in NGU patients can be considered an etiological factor.
Results published by Taylor-Robinson et al show that M. hominis does not itself cause NGU and its presence can be demonstrated more frequently in men who do not suffer from NGU, than in those who present with NGU symptoms (Holmes). The pathogenic role of M. penetrans is not known and has not been demonstrated in a single acute NGU patient (Degushi).
U urealyticum can be demonstrated in 0-56% of healthy males (McCormack, Hudson, Gambini), as compared to 5.6-42% of urethritis patients (Gal, Mazuecos). Although earlier studies assumed a role for U. urealyticum in NGU, the role the microbe truly plays in the disorder in the case when the bacteria has demonstrated in NGU patients is still not clear.
The most conclusive evidence supporting the existence of a correlation between U. urealyticum and NGU stems from human experimental studies. Symptoms appeared following experimental inoculation, pus cells (polymorphonuclear leukocytes) were present in the first stream of urine, as well as large numbers of the microorganism; following a six-day regimen of minocycline, symptoms gradually disappeared as did the Ureaplasma from the first stream of urine. This study involving volunteers shows that that U. urealyticum can cause illness when introduced into the urethra, but this is followed by asymptomatic colonizations (Taylor-Robinson), which may explain why ureaplasma can be so often demonstrated in the urethra of healthy men.

Another theory suggests that U. urealyticum actually consists of two different strains, only one of which is associated with NGU, while the other is present as asymptomatic colonization.
Although there is increasing evidence supporting a role for M. genitalium in causing NGU, this is not nearly as unequivocal as for Chlamydia trachomatis. This is partly due to the fact that M. genitalium was recognized far later than C. trachomatis and the pathogenic role of M. genitalium in non-chlamydial NGU was difficult to analyze in the absence of culturing and serological procedures. The development of PCR-based techniques now make it possible to study the occurrence of M. genitalium in various populations (Jensen, Palmer).
M. genitalium occurs significantly more frequently in NGU patients than in healthy populations (Horner, Janier, Gambini, Jensen, Totten), its prevalence in urethritis patients ranging from 8% (urology patients) to 29% (STD patients). Its prevalence in asymptomatic patients ranged from 0% (urology patients) to 9% (STD patients). The examination of asymptomatic and NGU patients support an etiological role for M. genitalium in NGU, independently of the occurrence of Chlamydia trachomatis (Keane, Horner, Jensen, Björnelius). Furthermore, patients suffering from non-gonorrheal urethritis are found to be typically infected with either M. genitalium or C. trachomatis, but not both simultaneously (Keane, Totten). M. genitalium has been demonstrated more frequently in C. trachomatis-negative NGU patients, than in those suffering from Chlamydial urethritis (Jensen, Maeda). M. genitalium is likely to have a pathogenic role in NGU, and may be responsible for 13-45% of non-Chlamydial NGU infections.

A few studies have been done in which the microscopic signs of urethritis and the presence of the microorganism in the urethra have been compared. These studies show that there is a strong correlation between the presence of M. genitalium and the number of polymorphonuclear leukoytes, which is as significant statistically as that found for gonorrheal urethritis (Janier).
The relationship between persisting and recurring urethritis and M. genitalium infection is supported by several authors. M. genitalium has been demonstrated in 19-27% of patients with persistent urethritis, which points to an etiological role for M.genitalium (Hooton, Taylor-Robinson).
The medical history of patients infected with M. genitalium includes urethritis more often than that of patients with non-CT-NGU (p=0.02). This indicates, that urethritis associated with M. genitalium tends to be recurring. According to the most recent research findings, persistent urethritis caused by M. genitalium is due to chronic or recurring infections, not an inflammation based on an immunological mechanism. M. genitalium is also thought to have a role in chronic “abacterial” prostatitis.


Prostatitis, epidydimitis, infertility

Based on the 1999 recommendation of the National Institute of Diabetes and Kidney Diseases, the symptom group known as prostatitis syndrome can be divided into four groups: acute bacterial prostatitis, chronic bacterial prostatitis, chronic abacterial prostatitis (or chronic pelvic pain syndrome), and asymptomatic prostatitis. Among these, the naming of the third – chronic abacterial prostatitis – is misleading, since this clinical picture is caused, in some cases, by bacteria without cell walls, namely Chlamydia or Mycoplasm. The “abacterial” label indicates that the results of the conventionally used microbiological culture techniques are negative.

In 1977, Hofstetter et al found that mycoplasms, especially Ureaplasm were isolated significantly more frequently from urethro-prostatitis patients than from normal control individuals. Since it is not easy to determine whether the source of pathogens appearing in the prostatic secretions is truly the prostate, Hoftstetter isolated the microbe from perineal biopsies. At the same time, others (Meares, Vinje) were unable to demonstrate the presence of ureaplasma in chronic abacterial prostatitis patients. In later studies, numerous authors (Mard) found the pathogen in the prostatic secretions of patients suffering from prostatitis of “unknown origin”.

Brunner and Weidner isolated U. urealyticum in large numbers from semen and prostatic secretions, while finding leukocytes in the semen; the condition responded well to tetracycline treatment.

Numerous studies (Harnisch, Berger, Hawkins) indicate that epididymitis in heterosexual men under the age of 35 is most frequently due to N. gonorrhoeae or C. trachomatis, while the condition can usually be attributed to gram negative rods in older and homosexual men. Genital mycoplasms were also searched for in these examinations. Although ureaplasms were found in many patients with epididymitis, these were usually present in low numbers and were not demonstrable in percutaneous aspiration samples. These authors are of the opinion that the Ureaplasmas do not play a role in the development of epididymitis.

The role of the mycoplasmas in male infertility may be related to the inflammatory conditions, as well as the direct, harmful effect on the gametes.
Corradi et al found mycoplasm in the semen of 22% of examined clinically asymptomatic andrology patients. The pathogen could be cultured from the urethra of only 12.5% of the same patients. These results are of similar order of magnitude as those found in various other countries (8-40%) (Busolo, Naessens, Taylor).
According to Braun and Foy, the acquisition of the infection can occur as early as birth. This may be supported by the fact that the number of asymptomatic mycoplasma carriers is higher among women (20-60%).
The rate of infection among boys gradually decreases until puberty, after which time it increases depending on the degree of sexual activity. According to the results of Weidner et al, symptoms of clinical illness are rarely apparent at concentrations below 10 CFU/ml.
In examining the relationship between fertility and infection, Corradi et al found that the motility of sperm was significantly weaker in the infected group, accompanied by weakening of the integrity of the membrane. In addition to the competition for nutrients, the weakening of the sperm functions may also be due to the production of toxic materials, as U. urealyticum produces ammonia and M. hominis produces arginine derivatives (Bredt, Fowler).
The mediators of the harmful effects may also be the immunologic changes associated with the infection, in the event that changes in the surface of the sperm become antigens that induce autoimmune processes. Corradi et al showed that anti-sperm antibodies are present significantly more frequently in infected semen.
This can be the result of a type of cross-immunization (Soffer), where the glycoproteids in the cell membrane of the mycoplasma resemble the antigens of the host cell membrane, leading to the production of antibodies against the host cell.


Clinical manifestations in women

Vaginitis

Genital mycoplasma are the most important pathogenic factors in the synergistic, diversified flora causing bacterial vaginosis (BV), but it is not understood which microbe is absolutely necessary for the development of this clinical condition.
Numerous studies show that Mycoplasma hominis is present in pregnant and non-pregnant women with BV.
M. hominis has been demonstrated in 58-76% of women with BV, while this percentage is much lower in women with normal vaginal flora (Hill, Keane, Keane).
The relationship between BV and Ureaplasma urealyticum is less obvious: U. urealyticum was isolated in 62-92% of patients with BV, which is a higher percentage than that found for the control group (Hill, Keane, Keane).
Very little has been published about the possible relationship between Mycoplasma genitalium and BV. In testing patients with BV for M. hominis, M. genitalium and U. urealyticum, M. hominis was found to be the only genital mycoplasma which was consistently isolated more frequently in patients with BV than in healthy individuals. Although U. urealyticum was isolated more frequently in patients with BV as compared to healthy controls, the difference was not statistically significant, which is probably due to the fact that the microbe can be isolated in sexually active women without BV. No correlation has been found between M. genitalium and BV, because M. genitalium was not isolated from patients with BV (Keane). Others isolated M. genitalium from only 2 out of 38 women, while Chlamydia trachomatis was isolated from 5 out of 38 women in the same patient group; in other words, the correlation between M. genitalium and BV is much more reminiscent of the C. trachomatis-BV relationship than the M. hominis-BV link (Keane).


Pelvic inflammatory disease (PID)

It appears that M. hominis and U. urealyticum do not have a pathogenic role in mucopurulent cervicitis (Paavonen).
The presence of M. genitalium in women with non-chlamydial cervicitis who were suffering from adnexitis was 2 / 49 or 4.1%, which suggests that cervical infection by M. genitalium can ascend through the endometrium (Uno) to the organs of the upper genital tract.

Regarding inflammatory conditions of the female upper genital tract (endometritis, salpingitis, tubo-ovarian abscess, pelveoperitonitis), the methodological guide issued by the CDC (Centers for Disease Control and Prevention) on the treatment of sexually transmitted infections assigns significance not only to the primarily recognized N. gonorrhoeae and C. trachomatis, but also to the microorganisms of the vaginal flora (anaerobes, G. vaginalis, H. influenzae, enteral Gram negative rods, Streptococcus agalactiae), and refers to M. hominis and U. urealyticum as etiological factors. In contrast to the cautious opinions published in the international professional literature, in which the genital pathogenic role of these agents is questionable or disputable, this very practical therapeutic guide seriously considers this possibility (CDC).


Miscarriage associated with fever, puerperal fever

Numerous authors hypothesize or acknowledge that mycoplasma has a pathogenic role in obstetric complications, such as miscarriage associated with fever and puerperal fever (Lamont, Phillips, Patai).
Andrews et al (Andrews 1995) showed that U. urealyticum, as a sole pathogen, frequently causes endometritis following cesarean section and proved that colonization by U. urealyticum of the chorioamnion, even when the amniotic sac is intact, is an important risk factor in the development of inflammation of the uterine mucous membrane associated with cesarean section.
Roberts et al (Roberts) proved that the microbe has a significant role in wound infection following cesarean section.
Patai et al (Patai) suggest that the antibiotic combination administered prophylactically in cesarean section should be supplemented with a medication which is effective against mycoplasma.


Impairment of reproductive capacity, perinatal complications

In the event that Ureaplasma urealyticum or M. hominis colonizes the female lower genital tract, it can be isolated from the amniotic fluid in the 16th week of pregnancy and can infect the fetus in utero or during childbirth. Cassell et al isolated these two microbes in severe chorioamnionitis which was followed by premature birth (Cassell).
Mycoplasma have been identified in the organs of spontaneously aborted, stillborn and premature fetuses (Taylor-Robinson).

According to Gannon’s summary and case report (Gannon), infection of the newborn by U. urealyticum is a consequence of maternal infection, and the results of the most recent studies show that pneumonia caused by U. urealyticum in immature newborns is associated with significantly increased frequency of chronic lung disease later in life. Clinically, U. urealyticum-caused pneumonia frequently occurs together with hyaline membrane disease, leukopenia and thrombocytopenia, which can result in respiratory distress if the pathogen remains unknown and adequate treatment is not applied. The diagnosis can be established by culturing the secretions of the trachea; the appropriate treatment is erythromycin and thorough pulmonary hygiene.


Urinary disorders (kidney stones, pyelonephritis and urinary infections)

The role of mycoplasma in the development of urinary diseases was studied as early as 1970 (Friedlander) in animal experimental models. Inoculation of the urinary bladder and renal pelvis of male rats resulted in the formation of ammonium phosphate stones. Since treatment with urease inhibitors prevented formation of the stones, it was assumed that the stones were due to the urease activity of U. urealyticum, which breaks urea down into ammonia, bicarbonate and carbonate. The ammonia damages the glycosamine glycan layer of the ureothelium, the alkaline pH induces the supersaturation of the ions in the urine.
Kaya et al found a significant correlation between the occurrence of U. urealyticum infection and the subsequent development of stones in human studies conducted in 1993 (Kaya).
The international professional literature abounds with numerous, conflicting publications regarding the possible role of M. hominis and U. urealyticum in cystitis and acute pyelonephritis in both human (Thomsen, Thomsen, Birch) and animal studies (Krieger, Pickering). The authors recommend further studies to achieve conclusive results.


Reiter’s syndrome, arthritis, sexually acquired reactive arthritis (SARA)

The role of U. urealyticum and M. hominis in SARA or Reiter’s syndrome is not clear. The microbes can be isolated fro the genital tracts of patients suffering from these two conditions just as frequently as from patients with non-gonorrheal urethritis (Taylor-Robinson).
Keat et al (Keat) found that HLA-B27-positive men, who suffered from Chlamydia-negative, non-gonorrheal urethral inflammation, acquired arthritis just as frequently as Chlamydia-positive subjects.
An automimmune mechanism induced by common antigens is probably the basis of the chronic joint inflammation in reactive arthritis. In 1994, Horowitz et al (Horowitz) found U. urealyticum in patients with Reiter’s syndrome, and Taylor-Robinson et al (Taylor-Robinson) found M. genitalium in arthritis patients, albeit in a very small number of subjects.

In 1995, Erlacher et al (Erlacher) studied a significantly larger population suffering from reactive arthritis and found 14% positivity for Mycoplasma and 28% for Ureaplasma.(In their study, they were able to isolate pathogen from the urethral secretions of 44% of seronegative oligoarthritis patients; this is considered to be the largest, useful sample to substantiate the infectious origin of the illness.)
Numerous authors have studied the possible pathogenic role of mycoplasma in septic arthritis. These microbial pathogens are thought to have a role in acute arthritis (Cassel), hypogamma-globulinemic acute polyarthritis (Lehmer, Furr) and protracted, chronic joint inflammation following acute, febrile infection with mycoplasma (Sequeira).

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