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Mycoplasmal PID: a review of natural and experimental infections.

The present report is a review of data assuming an etiological relationship between pelvic inflammatory disease (PID) and Mycoplasma hominis. Thus the organism can be isolated from the vagina/cervix more frequently in PID patients than in any other clinical group, i.e., in half to three-fourths of all such cases. One-fourth of PID patients develop a significant antibody response to M. hominis during the course of the disease. The antibody response can be detected by indirect hemagglutination tests. Grivet monkeys infected experimentally with M. hominis develop PID, predominantly parametritis; the infection seems to spread via lymphatics to the parametria. These animals develop a significant antibody response. The animals, like naturally infected women, develop a marked increase in the serum level of IgM. In tissue cell cultures of human fallopian tubes experimentally infected with M. hominis, a decrease of the mucociliary wave activity occurs. So far, few clinical data support an etiological role for Ureaplasma urealyticum in PID. In grivet monkeys, the organism does not produce PID.


INTRODUCTION
Pelvic inflammatory disease (PID) is increasingly common. This increase seems to be the result of the pandemic situation with regard to sexually transmitted diseases (STD) that has prevailed in recent years in several developing countries. Sterility as a sequelae to PID [1] has reached such proportions that it has even begun to influence the population structure.
The etiology of PID is multifactorial. Approximately 15 percent of PID cases in western industrial countries are associated with iatrogenic measures, such as insertion of an intrauterine contraceptive device (IUD) [2]. Most of the remaining cases seem to be "venereal" in origin, that is, occurring as an STD [3]. Also among "iatrogenic" PID cases, however, such agents can be the cause of PID, as they often occur in asymptomatic carriers, including women consulting for birth control.
Chlamydia trachomatis and Neisseria gonorrhoeae are among the most common causative agents of PID. Anaerobic bacteria seem to be more often associated with PID in some geographic areas than in others (cf. [4]). Mycoplasma hominis, or pleuropneumonia-like organisms (PPLO), have also been considered an etiological agent of PID [4,5,6,7,8,9,10,11,12,13,14,15,16,17], though the proportion of such cases is, however, still not clear. with M. hominis and Ureaplasma urealyticum. The occurrence of these organisms in the lower female genital tract is also briefly considered.
OCCURRENCE OF MYCOPLASMA HOMINIS AND UREAPLASMA  UREAL YTICUM IN THE LOWER FEMALE GENITAL TRACT  Mycoplasma hominis The first human isolate of mycoplasma was made as early as 1937 by Dienes and Edsall [18] in pus from a Bartholin's gland abscess. The strain seems to have been a strain of M. hominis. This species was named in 1956 by Edward and Freundt [19].
M. hominis represents the vast majority of isolates of "classic" or large colonyforming mycoplasmas from the genital tract (cf. [20]).
M. hominis has been found in 40-70 percent of all women with lower genital tract infection (LGTI). In women lacking signs of LGTI, significantly lower percentages of carriers of M. hominis have been reported. The occurrence of M. hominis in healthy controls varies considerably between different studies. In general it would seem that 5-20 percent of all sexually active women of child-bearing age seem to harbor M. hominis. After the menopause, the incidence decreases. The proportion of M. hominis culture-positive women is correlated to sexual experience, i.e., the carrier rate increases with the number of sexual partners a person has experienced [21].
In the vast majority of women colonized by M. hominis, the vaginal smear has a characteristic "dirty" appearance. Correlation has also been found between slight to moderately severe dysplasia of cervical epithelial cell and colonization with M. hominis. Antibiotic treatment resulting in the eradication of M. hominis was followed by disappearance of the "dirty" appearance of vaginal smears [22].
The association of M. hominis with cervicitis and vaginitis is still ill-defined. M. hominis can occur also in the upper respiratory tract, i.e., in 3-4 percent. In persons practicing fellatio, the corresponding figure was up to almost 15 percent. In experimental studies, M. hominis produced exudative pharyngitis [23]; however, whether this is also the case in naturally acquired infection is not known. Ureaplasma urealyticum Ureaplasmas occur in the lower genital tract of the majority of women of childbearing age [24]. As with M. hominis, the incidence of U. urealyticum is influenced by age, sexual activity, and hormonal status; the highest frequency is demonstrated in pregnant women [21,24]. No significant difference in the occurrence of U. urealyticum between women with and without signs of genital infection has been demonstrated [24]. ASCENDANT Hirsch [7], Gotthardson and Melen [6], and Stokes [17]) reported the recovery of PPLO in women with PID (in some instances later identified as M. hominis) from the fallopian tubes or tubovarian abscesses. The strain isolated by Freundt [25] represented M. fermentans (which is a rare finding in the genital tract).
In a series of 50 women with laparoscopic signs of acute salpingitis, Mardh and Westrom [11] found four (8 percent) to harbor M. hominis in pure culture in the tubes. The organism was isolated from the cervix in 31 (9 percent) of the women. None of 34 women without laparoscopic signs of salpingitis was found to have M. hominis. Laparoscopy, in addition to permitting sampling from the oviduct, provides an objective diagnosis of PID [3]. In another series, Sweet and co-workers [26] found one of 26 PID patients to be culture-positive for M. hominis from cul-de-sac. Eschenbach and co-workers [27] isolated M. hominis from the cervix of 145 of 204 women with PID. From 54 of these 204 women samples were aspirated from cul-de-sac. M. hominis was recovered from two of the 54 samples [15] of 166 Danish PID patients, 91 (55 percent) harbored M. hominis in the cervix. In another Danish study [10], 30 of 95 PID cases had positive culture for M. hominis from the cervix. This latter study also showed that double infections with M. hominis and other STD agents are common. The results of some culture studies in PID patients are summarized in Table 1.

Serological Studies
Several methods have been devised to detect antibodies to M. hominis. They include complement fixation [9,14], metabolic inhibition [28], growth inhibition [29], and indirect hemagglutination (IHA) tests [30,31]. IHA tests-performed as described by Krogsgaard-Jensen [30]-have been found to be superior to the other tests mentioned for detection of antibodies to M. hominis in women. A similar experience has been reported in grivet monkeys, experimentally infected with M. hominis, which developed PID [32].
Antibodies to M. hominis as demonstrated by CF tests occurred in nine (33 percent) of 27 women with PID [21], and in 20 (39 percent) of 51 women with PID [9]. IHA antibodies to the organism occurred in 28 (54 percent) of 52 women in whom the diagnosis of PID was verified by laparoscopy, as compared to 11 percent in 56 women in whom laparoscopy showed no infectious conditions, e.g., cysts and endometriosis [12]. Eschenbach et al. [27] found that 17 (22 percent) of 84 PID patients had antibodies to M. hominis. Of 60 consecutive cases with acute salpingitis, IHA antibodies to M. hominis occurred in 24, ten of whom developed a significant titer change [13]. Antibodies to C. trachomatis and N. gonorrhoeae occurred in 80 percent and 11 percent, respectively, of these 60 PID patients. A significant antibody response to these two latter organisms occurred in 20 and three women, respectively [13]. In a series of 166 Danish women with PID, 23 percent showed a significant antibody response to M. hominis. Interestingly, 14.6 percent of the 75 M. hominis culture-negative cases also developed such an antibody response [15] (Table 2).
Increased serum levels of IgM (> 155 mg per 100 ml) was demonstrated in 18 of 53 women with salpingitis and serological evidence of a significant antibody  [33]. There was a significant (p < 0.001) correlation between the IgM increase and the presence of serum IHA antibodies to M. hominis.
The IgM level of 200-299 itg per 100 ml was found in 11 percent and of > 300 in seven of 53 PID cases. The maximum level was 380 mg per 100 ml. In a few cases there was also a slight increase in the serum IgG and IgA [33].
As in M. pneumoniae infections [34] the increased IgM levels found in PID patients presumably could not be explained by the formation of antibodies specifically directed against M. hominis. Most probably they denote an unspecific stimulation of the immune system [331. So far, there is, however, no evidence that M. hominis acts as a polyclonal B-cell stimulator. Antibodies to M. pneumoniae did not occur more commonly in the PID patients than in the general population of the study area [33]. A corresponding rise in the IgM antibody level was found in grivet monkeys experimentally infected with M. hominis, which developed parametritis rather than endosalpingitis [32]. Lack of IgM to IgG Conversion Some patients with M. hominis-associated salpingitis did not show conversion from essentially an IgM to an IgG antibody response to M. hominis. Persistence of mainly IgM antibody formation was found for several months [33]. This is in conformity with findings in patients with M. pneumoniae [34].

Mode of Infection Spread with Mycoplasma hominis to the Upper Genital Tract
How M. hominis ascends in the female genital tract is not known. Experiments in grivet monkeys (see the section following), however, suggested spread via lymphatics and blood vessels rather than canalicularily from the uterus to the tubes [35].

EXPERIMENTAL INFECTION WITH MYCOPLASMA HOMINIS IN MONKEYS
In grivet monekys, parametritis and salpingitis developed within three days when M. hominis was inoculated directly into the fallopian tubes. Thus there was swelling and hyperemia of the tubes and the parametria became edematous. The tubal subserosa was heavily infiltrated with lymphoid cells and an increased number of polymorphonuclear leukocytes. In the parametria many lymphocytes and some granulocytes were found, as well as fat necrosis and granulation tissue. After four to five weeks the upper genital tract of the monkeys was virtually normal again [36].
PATHOGENETIC MECHANISMS OF MYCOPLASMA HOMINIS IN PID In experimentally infected explants of human fallopian tubes, the mucociliary wave activity can be registered by the light-beam reflex method [37]. Qualitative and quantitative studies of the ciliary beating can be made. The tubal specimens are placed in a chamber with regulated gas temperature and humidity, where they are lighted through a glass fiber optic. The changes in the light reflexes caused by the beating cilia are registered by a photomultiplicator. Inhibitory effects on the ciliary activity by infection can be registered by such measurements. Infection with M. hominis caused a reduced ciliary activity [37].
In experimentally infected explants of human tubes, M. hominis caused swelling of the cilia, either of the tips or the entire cilia. The mechanism underlying the swelling is not known. An arginine deficit in the tissue culture medium, caused by the metabolism of M. hominis, might mediate the ciliostatic effect.

ASCENDANT INFECTIONS WITH UREAPLASMA UREAL YTICUM IN NATURALLY ACQUIRED INFECTIONS IN WOMEN AND IN EXPERIMENTAL INFECTIONS IN MONKEYS
U. urealyticum has been recovered from the fallopian tubes [27], from cul-de-sac of a woman with a tubovarian abscess [38], and in a woman with signs of acute salpingitis [11]. A significant antibody response, i.e., of metabolic-inhibition antibodies, to U. urealyticum (to a strain isolated from the fallopian tube of a PID patient) has been demonstrated in one woman with acute salpingitis [24]. Eschenbach et al. [27] found 15 of 204 PID patients to develop ureaplasmacidal antibodies. Sweet et al. [26] found U. urealyticum in cul-de-sac fluid in four of 26 women with PID (also in the fallopian tubes of one of them).
In animal experiments, viz., in grivet monkeys, no pathogenic effect of U. urealyticum was demonstrable [39]. Mycoplasmas have also been recovered from the bovine oviduct [40]. In experimentally infected heifers, ureaplasmas and mycoplasmas could induce damage to the oviduct mucosa [41,42].
TREATMENT OF MYCOPLASMAL PID M. hominis is resistant to betalactam antibiotics and nitroimidazoles, which are drugs often used in the treatment of PID.
A tetracycline-resistant strain of M. hominis was isolated from a pregnant woman who had arrived in Sweden from Jordan the day before sampling and delivery [45]. The MIC of tetracycline for this strain was 32 mg/l. A tetracycline-resistant strain of M. hominis could also be isolated from the cerebrospinal fluid of her offspring, who had signs of meningoencephalitis [45]. Strains of U. urealyticum with a decreased susceptibility to tetracycline have also been reported to be relatively common.
M. hominis generally can be eradicated from the female genital tract by a standard course of tetracycline for one or two weeks [44]. This is in contrast to U. urealyticum, which often persists after standard courses with tetracycline. Thus the organism has been found in up to one-third of the patients given such therapy [44].
In the case of deep, complicated genital infections and in systemic infections by M. hominis, at least two weeks of tetracycline treatment should be given.
The risk that M. hominis can spread to the newborn infant, resulting in infections of the skin [46,47], the eyes [48], and the central nervous system [45], must not be disregarded.

SEQUELAE OF MYCOPLASMAL PID
No studies have so far been presented concerning sequelae of PID stratified with regard to the major common etiological agents of PID, including M. hominis. The risk of sterility after PID is known to be high-roughly 10-15 percent after one episode of the disease, 35 percent after two, and 75 percent after three or more such episodes [1]. Chronic abdominal pain and increased risk for etopic pregnancy [49] are other common sequelae after PID. Whether such sequelae also occur after M. hominis-associated PID is not known.

CHALLENGES FOR FUTURE RESEARCH
Further studies on antigenic differences [50] among organisms now classified as M. hominis ought to be performed.
More epidemiological data concerning M. hominis infections of the upper genital tract are required. So far, most epidemiological reports have derived from the Scandinavian countries or from the U.S.
Whether there is a discrepancy between findings in grivet monkeys experimentally infected with M. hominis and naturally infected human beings with PID remains to be determined. In the monkeys, the parametria rather than the fallopian tubes seem to be affected.
Clinical observations indicate also that the parametria might be involved in PID in women who are culture-positive for M. hominis and in whom a significant antibody response to the organism can be demonstrated. Furthermore, a biopsy of the parametria of such a woman revealed similar inflammatory changes as those seen in monkeys experimentally infected by M. hominis [M0ller BR: personal communication]. Further clinical studies on parametritis are required.
More studies are also needed to establish pathogenetic mechanisms in M. hominis infections, including PID.
Finally, possible sequelae of mycoplasmal PID must be further studied.