IN SPITE OF THE IMPORTANCE of male urethritis in the world, there are few epidemiologic studies of this problem and of the characteristics of the different etiologies of urethritis. 1Neisseria gonorrhoeae was previously the most common pathogen in cases of urethritis, but its prevalence has declined in developed countries, and it accounts for only 20% of the cases described in recent studies. 2,3 Nongonococcal urethritis (NGU) is the most prevalent form because of the high frequency of Ureaplasma urealyticum and Chlamydia trachomatis infections, which account for 25% to 40% of cases. 1,2 In recent years, Mycoplasma genitalium has been implicated in 17% to 30% of cases. 4,5
The objective of the current study was to show the clinical experience in our country and to evaluate the trends in the prevalence of the pathogens in male urethritis, as well as the epidemiologic patterns in a large series of 2101 patients who attended two sexually transmitted disease (STD) clinics during the period of 12 years from 1989 to 2000.
Patients and Methods
Our two STD units were attended by 12,893 males with dermatological disease and/or STD between 1989 and 2000. The patients included in the study were the 2101 males (16.3%) with urethral problems (discharge, meatitis) noted at examination, symptoms of urethritis (discharge, burning sensation on micturition, dysuria, urgency), and symptoms not directly related to urethritis but described by the patients (urethral itching, erythema). The two units, in the cities of Oviedo and Gijón in Asturias (Spain), 28 km apart, were attended by 959 and 1142 patients, respectively.
We followed the same protocol for all patients. A gram-stained smear of the urethral exudate or an endourethral sample taken with an alginate swab inserted 3 to 4 cm into the urethra (if no exudate was present) was examined. The presence of more than 5 polymorphonuclear lymphocytes per high-power field (×100) in the gram-stained urethral smear was considered evidence of urethritis.
Two alginate swabs were used to inoculate each of the following media: chocolate agar with 1% Isovitalex and VCAT (vancomycin, colimycin, amphotericin B, and trimethoprim) for N gonorrhoeae; HBT (human blood bilayer Tween) agar for Gardnerella vaginalis; Sabouraud agar for yeast; chocolate agar with 1% Isovitalex; and blood agar for other pathogens (all from bioMeriéux, Marcy-l'Etoile, France). Diamond medium (Oxoid, Basingstoke, UK) cultured directly in the STD units was used for Trichomonas vaginalis. Streptococcus agalactiae, Haemophilus species, G vaginalis, and other bacteria were identified according to previously published methods. 6 β-Lactamase production in N gonorrhoeae was detected with Nitrocefin (SR112) sticks (Oxoid).
Samples for Mycoplasma hominis and U urealyticum culture (the fourth swab) were obtained on a routine basis and inoculated in A9 agar and with a Mycoplasma Test Kit (bioMeriéux). The culture was considered to be positive when ≥104 color changing units (ccu)/ml were observed. During the period of study, M genitalium was not sought on a routine basis.
Samples for C trachomatis detection were taken with a plastic swab (the fifth swab) to detect chlamydial lipopolysaccharide antigen by EIA (Chlamydiazime; Abbott Laboratories, Abbott Park, IL); after 1997, PCR (Amplicor; PCR Diagnostic, Roche Diagnostic Systems, NJ) and LCR (LCx Chlamydia; Abbott Laboratories) were used for detection. We included testing for syphilis (RPR, TPHA, and FTA), HIV (EIA and Western blotting), and genital herpes (a swab from a lesion was tested with direct IF [Syva Microtrack; Behring Diagnostics, Cupertino, CA] or tested with a viral pack [Biomedics, Barcelona, Spain] and shell-vial with immunofluorescence and conventional culture). The presence of H ducreyi was considered on a clinical basis when a genital ulcer was present and negative serological tests excluded syphilis and genital herpes.
Statistical analysis was performed with use of the chi-square test with Yates correction when appropriate. Values of P < 0.05 were taken to denote statistical significance.
In the period of study, we attended to 2101 males. There were 97 patients (4.6%) with gonococcal urethritis and 2004 (95.4%) with nongonococcal urethritis (Table 1). The most frequent microorganisms in nongonococcal urethritis were U urealyticum, in 525 cases (26.2% of the 2004 patients with nongonococcal urethritis; 25% of the total of 2101 patients);C trachomatis, in 122 cases (6.1% and 5.8%, respectively);T vaginalis, in 24 cases (1.2% and 1.1%, respectively); other pathogens, in 516 cases (25.7% and 24.6%, respectively); and no identified microorganisms, in 735 patients (36.7% and 35%, respectively). Mixed urethritis was found in 82 patients (3.9%).
We analyzed the differences in the prevalence of the pathogens in the first 6 years versus the last 6 years (Table 1). A statistical increase in U urealyticum, Candida species, and Haemophilus species and a decrease in N gonorrhoeae, C trachomatis, M hominis, and S agalactiae were found in the period of study. Similar figures were found in both clinics.
Of the 735 patients in whom no microorganism was identified, 44 (6%) had used condoms, as had 53 (10.3%) of the 516 patients infected with other pathogens.
We analyzed the 850 patients with gonococcal, ureaplasmal, chlamydial, trichomonal, and mixed urethritis. Only 40 patients (4.7%) had used condoms, and 653 (76.8%) had had contact with female prostitutes. The previous STDs or genital pathogens in this population were mainly gonococcal urethritis (22.6%), Phthirus pubis (18.5%), and syphilis (7.2%). At the time of the occurrence of urethritis, 51 patients (6%) were positive for HIV antibody, 24 (2.8%) had syphilis, 10 (1.2%) were hepatitis B surface antigen–positive, 2 (0.2%) had genital warts, and 1 (0.1%) had P pubis infection.
In Table 2 are shown the epidemiologic factors associated with the different types of urethritis, such as sexual orientation, age, and previous STDs. Sixty-six (7.8%) of the patients were men who had sex with other men (MSM), 256 (30.1%) of the men were older than age 30 years, and 603 (70.9%) had had an STD previously. With regard to sexual orientation of the patients, there was a significant association between heterosexuality and both gonococcal and ureaplasma urethritis and between MSM and chlamydial urethritis. Age younger than 30 years showed a significant association with both U urealyticum and mixed urethritis, whereas age older than 30 years showed an association with trichomoniasis. Finally, our analysis showed that there was a significant association between history of a previous STD and the presence of gonococcal, chlamydial, and ureaplasma urethritis considered separately. In Table 2, we also show the relationship between HIV antibody positivity and the different types of urethritis. We found the association between the presence of HIV antibodies and trichomonal urethritis to be statistically significant.
Examination findings, symptoms of urethritis, and other symptoms of the 850 patients are shown in Table 3. Purulent discharge was present in the highest percentage (92.8%) of the cases of gonococcal urethritis and in a lower percentage of the other types of urethritis.
The most frequent treatments for urethritis were administration of quinolones, tetracyclines, and macrolides, with or without nitroimidazoles, and these together accounted for 86% of the treatments. Recurrence occurred in 92 cases of U urealyticum urethritis (17.5%): 42 patients had received treatment with a macrolide, 22 with ofloxacin, and 16 with tetracyclines. Recurrence also occurred in 2 cases of gonococcal urethritis (2.1%) treated with ofloxacin (1 case with high resistance) and in 16 cases of chlamydial urethritis (13.1%; 3 treated with a macrolide, 3 with tetracycline, and 1 with ofloxacin).
N gonorrhoeae has dramatically decreased in prevalence at our clinics in recent years, but we found an increase in the number of cases due to gonococci involving MSM (data not shown), as has occurred in the rest of Western countries in Europe since 1999. 7,8 Epidemiologic studies have shown an association with increased acquisition of HIV infection, 9 whereas others have found no significant association, in line with our findings. 10
U urealyticum is identified relatively frequently in studies of men with symptomatic urethritis, but it is also found commonly in asymptomatic men, 11 and M genitalium is present in as many as 25% of men with NGU 2,4 and as the sole infecting organism in 14% of men with NGU. 12 In a recent study, 5 it was shown that this pathogen could be the etiological agent in acute NGU. We did not search for this pathogen on a regular basis, but M genitalium infection could have been present in our patients without detection of the microorganisms.
C trachomatis is isolated from 25% to 60% (usually 30–40%) of men who have NGU and 4% to 35% (usually 15–25%) of men with gonococcal urethritis. 13 Our data for these conditions—7.3% (140 of 2004) and 5.7% (7 of 123), respectively—and the statistically significant decrease during the study period are in line with recent study reports suggesting that C trachomatis is a less frequent cause of NGU today. 14,15 The sensitivity of PCR or LCR is higher than EIA, but modification of the techniques in the two periods did not interfere with our results because we used the most sensitive techniques (PCR and LCR) in the later period. Because EIA methods are 15% to 40% less sensitive than PCR and LCR, 16,17 the real figures in the first period are very likely to be higher than those reported by us, and the decrease during the period of study likely was more pronounced, from an estimated theoretical frequency of 10% (supposing the mean difference in sensitivity between EIA and PCR or LCR to be 25% and the real frequency to be proportionally higher) to 3.9% in the second period. A statistically significant relationship was found between C trachomatis infections and a previous STD, as in other reports. 18,19 In recent years it has been found to be an increasingly important cause of urethritis in MSM, 20 and this is supported by the significant association seen in our study.
The incidence of trichomoniasis in men is most likely grossly underestimated because of the insensitivity of wet-mount preparations and a low level of reporting of cases. 21 It may account for 15% to 20% of cases of urethritis in certain populations, 22,23 but these figures are lower in developed countries such as France and Spain. 2,24–26 Furthermore, we did not see any increase during the period of study, a finding which is in agreement with the reported data of other studies in which trichomoniasis represented less than 5% of the total cases of urethritis. 27
A significant majority of cases of trichomonal urethritis occurred in patients older than 30 years of age, and therefore it is possible that the right approach in this group would be to routinely culture for T vaginalis.
There was also a significant relationship between trichomonal urethritis and HIV, although other reports have not found differences in the rate of HIV seropositivity in comparison with other types of urethritis. 22T vaginalis is associated with an increased hazard ratio for the acquisition of HIV, although the findings often do not reach statistical significance. 28 Studies in Africa suggest a twofold to threefold increase in HIV transmission. 29 There is no clear explanation for our findings and for the association between HIV and trichomoniasis, because there was not a change in the recruitment of patients in the period of study and the majority of patients were heterosexual men. One possible explanation is the relatively mild nature of the disease in comparison with that due to other pathogens;T vaginalis urethritis is often asymptomatic (33.3% of our patients), and affected persons are likely to continue to engage in sexual activity. 30
The use of condoms by women prostitutes (71% in a previous study 31) or changes in the sexual behavior pattern that were unknown to us could be factors leading to the decrease in pathogens such as N gonorrhoeae and C trachomatis, as well as others such as Candida species or S agalactiae but not Haemophilus species; perhaps some cases due to the latter pathogen are due to orogenital activity.
The findings in this report are subject to at least two limitations. First, although during the period of study the laboratory testing methods were not changed, except for the methods used to detect C trachomatis, the sensitivity of some methods employed in the study, such as using urethral swabs alone for detection of T vaginalis, is lower than that of other available methods such as spun urine and urethral swab testing together. A second limitation could be the change in the composition of the population during the period of study. The significance and effects of this change are difficult to determine, for although the male population remains mainly Spanish, more than 90% of female prostitutes are now from other countries.
In conclusion, our data show a change in the epidemiology and etiology of urethritis. Furthermore, there are statistical differences depending on the type of urethritis, and thus urethritis cannot be seen as a homogenous entity. Studies over a long period of time, such as ours, can help to show changes and trends in urethritis patterns as well as changes in patterns of behavior, such as the increase in chlamydial urethritis in MSM.
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