Differential diagnosis

This patient presented with untreated male urethritis syndrome (MUS) based on his symptoms and the observation of penile discharge upon examination. It is not uncommon for men not to notice discharge or to report discharge in the morning only or as mucoid threads in the urine. MUS can be a gonococcal (Neisseria gonorrhoeae) or non-gonococcal urethritis. In the latter case, Chlamydia trachomatis, Mycoplasma genitalium and Trichomonas vaginalis are common aetiology [2].

Management

The patient was treated syndromically for MUS with stat dose of azithromycin (1 gram single oral dose) and ceftriaxone (250mg intramuscular injection) as per South African STI Management Guidelines [3]. Metronidazole was not given since the patient did not know if his wife had any symptoms. He was given an appointment to discuss his laboratory results and to provide further management if required. A partner notification slip was issued.

Laboratory investigations

v First-void urine was collected for laboratory testing for STIs using established molecular assays for detection of the four most common STIs: Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis and Mycoplasma genitalium. The molecular test for Trichomonas vaginalis was positive with a cycle threshold value of 27.4 in real-time PCR; the other three STIs were not detected.

Midstream urine was collected for MCS. Urine microscopy did not reveal any abnormalities; leukocytes, erythrocytes and bacteria were not observed. No growth was observed in bacterial culture after seven days of incubation.

Case presentation continued

The patient was diagnosed with Trichomonas vaginalis urethritis. He returned with his wife a week later and was given targeted treatment with a 2gram stat dose of metronidazole. Another week later he reported that his symptoms had resolved.

The 65-years old wife came with her husband bringing the notification slip. She reported having vaginal discharge since five months with some genital itch; there was no abdominal pain, dysuria or abnormal vaginal blood loss. She had not sought care before as she said she had been unaware that these symptoms warranted treatment. She denied sexual partners other than her husband.

On examination, she was afebrile (37.4 °C). There was no inguinal lymphadenopathy or abdominal pain on palpation, but a milky white-greenish vaginal discharge was observed. The cervix had a normal aspect for age; there was no cervical tenderness or pain. The rapid HIV test was negative.

A smear of vaginal fluid was collected for microscopy and vaginal swab obtained for molecular STI testing. Based on the vaginal discharge syndrome (VDS) presentation and her husband’s laboratory results, she was given 2g of metronidazole stat dose for suspected genital Trichomonas vaginalis infection. A week later she returned complaining of persistent genital discharge. She did not report sexual intercourse with her husband or another partner since the previous visit. Laboratory results of the vaginal swab confirmed the initial presence of Trichomonas vaginalisinfection; the tests for Chlamydia trachomatis, Neisseria gonorrhoeae and Mycoplasma genitalium were negative. Microscopy did not reveal signs of bacterial vaginosis (based on Nugent score) or Candida species.

Differential diagnosis

VDS has a diverse aetiology with bacterial vaginosis as the commonest cause in South Africa followed by Candida species, Neisseria gonorrhoeae, Chlamydia trachomatis, Trichomonas vaginalis and Mycoplasma genitalium as causative microorganisms [4]. However, although another newly-acquired infection or antimicrobial resistance could not be ruled out, persistent Trichomonas vaginalis infection due to treatment failure of metronidazole was considered the most likely aetiology.

Management

We confirmed persistent presence of Trichomonas vaginalis by point-of-care wet mount microscopy of vaginal fluid, whereby alive protozoa were observed. The diagnosis of persistent Trichomonas vaginalis infection was explained and she was issued with a seven days’ course of 400mg twice daily metronidazole. At telephonic follow-up a week later she reported that the symptoms had resolved.

Final diagnosis

An elderly patient couple with MUS respectively VDS caused by Trichomonas vaginalis infection that, in case of the wife, presented with treatment failure to single dose metronidazole.

Case discussion

South Africa has one of the highest STI rates in the world with MUS and VDS as common presentation; an estimated 310 000 cases of MUS are treated annually in the public sector [5]. Despite this high burden, there is a large unmet need for STI care with only an estimated 60% of symptomatic cases treated [5]. A recent study showed that various factors play a role for individuals not to attend healthcare services for their STI-associated complaints [1]. Lack of awareness of symptoms, ‘the genitally unaware’, is common among women. Disappointment with previous services in general and with the lack of response to treatment for STI symptoms given during previous consultation(s) are major reasons for individuals to stop accessing healthcare services as well [1]. In our case, the husband and wife presented with similar reasons for not accessing care earlier than in the context of our research project. There are clear gaps in the quality of STI service provision in the South African public sector, including incorrect implementation of the current guidelines [6]. As such, basic service delivery of STI services has to strengthened to address this unmet need.

Our case emphasizes the importance of genital examination including milking of the urethra of men reporting dysuria, however, this practice is often neglected [6]. Our patient also reported that he was not examined during previous visits. The consequence is that the patient enters the therapeutic track for urinary tract infection receiving course(s) of broad-spectrum antibiotics that are not effective to most of the causes of MUS.

The aetiological surveillance of STI syndromes at sentinel sites conducted by the National Institute for Communicable Diseases shows that Neisseria gonorrhoeae (82%) is the commonest cause followed by Chlamydia trachomatis (22%), Mycoplasma genitalium (4%) and Trichomonas vaginalis (4%) infection [7]. In contrast, the aetiological profile of VDS consists of bacterial vaginosis (57%) followed by Candida species (22%), Neisseria gonorrhoeae (18%), Chlamydia trachomatis (18%), Trichomonas vaginalis (14%) and Mycoplasma genitalium (9%) [7]. The vast majority of Trichomonas vaginalis infections is asymptomatic; genital prevalence rates of more than 20% have been reported among women in South Africa [8,9]. The prevalence of this infection is lower among men, however,Trichomonas vaginalis is not an uncommon infection as approximately 5% of MUS cases is caused by this pathogen [2,10]. Rectal Trichomonas vaginalis infection has been reported in men who have sex with men; there is a lack of evidence that oral infection occurs [11]. The 5-nitroimidazole drugs (metronidazole and tinidazole) are the mainstay of treatment.

Trichomonas vaginalis is an anaerobic flagellate protozoan. Infection is sexually acquired, however, non-sexual transmission through fomites such as shared soap, bath towels and water sources has also been reported [12,13]. Trichomonas vaginalis usually presents as vaginal discharge or urethritis but can also manifest as epididymitis, prostatitis or pelvic inflammatory disease. The infection has been associated with reproductive tract complications (e.g. tubal pathology), adverse birth outcomes and pre-term labour [14]. A recent meta-analysis showed that individuals infected with Trichomonas vaginalis infection are 1.5 times (95% CI 1.3-1.7 times; p< 0.001) more likely to acquire HIV compared to individuals not infected with Trichomonas vaginalis [15].

In our case, both patients were symptomatic and, had the husband reported his wife’s symptoms, he would have received metronidazole as indicated in the syndromic management regimen. In reality, however, many men are not aware of their sexual partner’s symptoms or their partner is asymptomatic. The impact is that a man with MUS is unlikely to receive treatment with metronidazole based on the current treatment algorithms, that only indicate metronidazole in case the sexual partner has VDS, resulting in persistent symptoms. This highlights the need for a second-line guideline to manage individuals with STI-associated symptoms that do not respond to initial syndromic management.

Microbiological detection of Trichomonas vaginalis can be done with various methods. Protozoal culture constitutes the gold standard, however, this process is logistically complex due to the fastidious nature of the organism and the requirement for specific media and incubation temperature. Wet mount microscopy of a smear of vaginal fluid is a convenient bedside test with immediate result. As in our case, this method can be useful to identify the presence of Trichomonas vaginalis infection, however, the sensitivity (50-65% compared to molecular amplification tests) of this method is not high enough to use it for routine diagnostics. The positive predictive value nevertheless is high so the observation of alive protozoa confirms the diagnosis; in our case this method was useful to confirm the persistent presence of infection.

An alternative bedside test, with processing time of approximately 10 minutes, is the OSOM TV antigen detection assay [16]. This test has not been used widely, but has a higher accuracy than wet mount microscopy with a sensitivity of 82-95% and specificity of 97-100% [17]. The Xpert® TV Assay provides another alternative to detect Trichomonas vaginalis infection at the point-of-care. This test was successfully implemented to screen HIV-infected pregnant women for Trichomonas vaginalis infection at primary healthcare level [18]. However, it is unfeasible to have the Xpert® test available at all healthcare facilities for Trichomonas vaginalis diagnosis and leveraging of existing laboratory infrastructure would be more appropriate. In that context, various other commercial and non-commercial real-time PCR assays could be used as well. An important therapeutic caution of using molecular tests is that Trichomonas vaginalis DNA may persist in the genital tract for several weeks in the absence of viable microorganisms [13].

The standard treatment recommendation by the Centers for Disease Control (CDC) forTrichomonas vaginalis infection is a stat dose of 2gram metronidazole; this is also included in the South African STI management guidelines [19]. In vitro resistance of Trichomonas vaginalis to metronidazole is uncommon [20]. Treatment failure of single dose of metronidazole, however, has been reported to occur in 5-30% of cases [21,22]. This may be cause by reinfection or repeat infection with Trichomonas vaginalis but also due to relatively low therapeutic levels in the genital tract. A course of 500mg twice daily of metronidazole for seven days provides superior treatment with higher cure rate as recently confirmed in a randomised clinical trial as well as in a systematic review [21,22]. The advantage of single dose metronidazole, however, is that directly-observed treatment is provided and adherence to the course regimen is not required. Our patient also showed treatment failure based on the single dose, but achieved resolution of symptoms following a course of treatment. Of note is that the dose of metronidazole (400mg) used in South Africa is lower than recommended by CDC (500mg) but in line with the 400-500mg recommended by the World Health Organization [3,19,22]. Tinidazole 2gram stat dose provides an alternative in case metronidazole does not result in cure. Metronidazole gel does not reach therapeutic levels in the urethra and perivaginal glands and is therefore not recommended [19].

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