|Year : 2018 | Volume
| Issue : 1 | Page : 1-7
Sexually transmitted infections: Need for extragenital screening
Jyoti Rawre, Sonu Agrawal, Benu Dhawan
Department of Microbiology, All India Institute of Medical Sciences, New Delhi, India
|Date of Web Publication||2-May-2018|
Dr. Benu Dhawan
Department of Microbiology, All India Institute of Medical Sciences, New Delhi
Source of Support: None, Conflict of Interest: None
Extragenital infections can occur concurrently with simultaneous urogenital infections. Extragenital sites are believed to serve as hidden reservoirs and play a critical role in their transmission. The etiological relationship of the most widespread Sexually transmitted diseases (STD) pathogen to reproductive tract has long been established, but the distribution to extragenital sites appears to be infrequent and its correlation with the sexual practice still requires to be investigated. Optimal-screening strategies for extragenital infections are largely unknown. However, there is a lack of data on clinical outcomes and optimal treatment regimens for rectal and pharyngeal extragenital infections. Further studies are needed in settings other than reproductive health and STD clinics, especially in primary care clinics and resource-limited settings.
Keywords: Extragenital sites, men having sex with men, screening, sexual contact, sexually transmitted disease pathogen
|How to cite this article:|
Rawre J, Agrawal S, Dhawan B. Sexually transmitted infections: Need for extragenital screening. Indian J Med Microbiol 2018;36:1-7
|How to cite this URL:|
Rawre J, Agrawal S, Dhawan B. Sexually transmitted infections: Need for extragenital screening. Indian J Med Microbiol [serial online] 2018 [cited 2018 Sep 21];36:1-7. Available from: http://www.ijmm.org/text.asp?2018/36/1/1/231682
| ~ Introduction|| |
Sexually transmitted diseases (STD) are a group of communicable diseases that are transmitted predominantly by sexual contact. The bacterial agents known to cause STDs include Neisseria gonorrhoeae (NG), Chlamydia trachomatis (CT), Treponema pallidum, Haemophilus ducreyi, genital mycoplasmas (Mycoplasma genitalium, Ureaplasma spp. and Mycoplasma hominis). The asymptomatic nature of these infections makes screening essential if control of these infections is to be achieved.
Given that sexually transmitted infections (STIs) are asymptomatic, regular testing and timely treatment remains the cornerstone for optimal prevention of spread of these infections and the development of sequelae within individuals.
Majority of these infections occur at extragenital sites that are rectum and/or oropharynx and may play an important role in sustaining the high rates of bacterial STI observed in this population. Anorectal and oropharyngeal chlamydia and gonorrhoea are important bacterial STIs common in men who have sex with men (MSMs) (1%–24%) and in high-risk women (1%–15%). Extragenital screening for agents of STI has been advocated in a number of clinical and public health scenarios.
Centers for Disease Control and Prevention (CDC) recommends that in addition to the usual genital route of transmission of CT, all MSM and women who indulge in oral and receptive anal sex, should be screened annually (or every 3–6 months, if at 'increased risk') for HIV, syphilis, urethral, rectal and pharyngeal gonorrhoea and urethral and rectal chlamydia. Extragenital sites are believed to serve as hidden reservoirs for ongoing transmission of infection. In addition, treatment for extragenital STI is different from that of genital infection.
Screening of extragenital sites including the oropharynx and rectum is an emerging practice based on the recent studies from Western countries, highlighting the prevalence of infection at these sites.
At present, recommendations, for detection at pharyngeal sites, are there only for gonorrhoea. Many studies have reported the prevalence of pharyngeal chlamydia though asymptomatic and with unclear implications. However, no guidelines exist for screening of Ureaplasma spp. or any genital mycoplasma at these sites. Along with the expansion of comprehensive screening of STI, procurement of samples from various anatomical sites, i.e. rectal, pharyngeal and urine specimens increases the overall identification of male and female STI carriers. Surveillance data suggest that MSM is disproportionately affected by STDs. This could possibly be because of the hidden reservoir of extragenital infections in them. Nevertheless, these infections continue to serve as reservoirs at non-genital sites and may also lead to increased risk of HIV acquisition.
Proper laboratory diagnostics methods are essential for controlling STIs. With the introduction of highly sensitive and specific laboratory assays, i.e. nucleic acid amplification assays tests (NAAT), anorectal and pharyngeal testing for CT and NG has become more common place in STI clinics., NAATs are now standard of care for STI testing, but they do not test for Ureaplasma spp, M. hominis and M. genitalium and therefore may be missing important infections.
| ~ Epidemiology|| |
It is important to know the incidence and prevalence of various STIs to evaluate the algorithms used in the management strategies. Due to lack of epidemiological data and absence of national registry, the estimates on the prevalence of various STIs in India can at best be approximate. Although high prevalence of extragenital infections in men as well as in women was noted from several countries, no data are available from India.
A study from a tertiary care hospital of North India represents the first analysis of CT testing from both genital and extragenital sites. Of total of 439 genital and extragenital samples collected from 417 patients (245 women and 172 men), samples from women had a higher positivity rate than men (13.6% and 11%). CT detected in men was rectal, 30.4%; genital 8% and pharyngeal, 0%. There were seven rectal-only cases, all of whom were symptomatic. The detection of CT in women was rectal, 100%; genital, 11%; and pharyngeal, 0%. The proportion of infected patients with isolated extragenital infections was 13.2%. Further studies are needed to help formulate guidelines and recommendations for extragenital screening in a population. Screening of patients should be also guided by their sexual behaviour irrespective of their gender identity. Dhawan et al. reported the first case of CT proctitis in a bisexual male. This case highlights the importance of high incidence of clinical suspicion and appropriate microbiological testing to achieve its proper diagnosis.
Extragenital infections in men having sex with men
Extragenital infections among MSM have been studied more extensively compared to women. MSM experience high rates of both extragenital gonorrhoea and chlamydia. The majority of extragenital infections among MSM are asymptomatic, with estimates ranging from 25% to 100% from reported studies. The prevalence of extragenital infection among MSM ranged from 0.2%–24% for rectal gonorrhoea 0.5%–16.5% for pharyngeal gonorrhoea, 2.1%–23% for rectal chlamydia and 0%–3.6% for pharyngeal chlamydia; the differences are due to different clinical settings and methods of diagnosis.,,,,,,,,,,, In a large cohort of 3,034 MSM who attended an STD clinic in Seattle, Washington in 2011, extragenital infections were common and included pharyngeal gonorrhoea (6.5%) and chlamydia (2.3%) and rectal gonorrhea (9.7%) and chlamydia (11.9%). About 57% of cases were found in only extragenital sites (non-urogenital). Similarly, among 21,994 MSM screened as part of the CDC STD Surveillance Network, composed of 42 STD clinics across the US, the prevalence of infection was 7.9% for pharyngeal gonorrhoea, 2.9% for pharyngeal chlamydia, 10.2% for rectal gonorrhoea and 14.1% for rectal chlamydia. Over 70% of extragenital infections in this sample would have been missed with urogenital screening alone. In summary, urogenital testing alone misses a significant percentage of gonorrhoea and chlamydia infections among MSM; if MSM were screened for urogenital infections alone.,,,,,,
Extragenital infections in women
The reported prevalence of extragenital infections in symptomatic women range from 0.6%–35.8% for rectal gonorrhoea, 0%–29.6% for pharyngeal gonorrhoea, 2.0%–77.3% for rectal chlamydia and 0.2%–3.2% for pharyngeal chlamydia. The study population sites included STD clinics, high-risk settings; few primary care settings, clinics focusing on women's care and centres focusing on transgender patient care. Most extragenital infections in women are asymptomatic, with estimates including 93% of pharyngeal gonorrhoea, 53%–100% of rectal gonorrhoea, 100% of pharyngeal chlamydia  and 36%–100% of rectal chlamydia cases.,, Extragenital screening at pharyngeal or rectal sites increases the yield of detection of either gonorrhoea or chlamydia by approximately 6%–50% when compared to screening urogenital specimens alone.,,,,,,,,,, Based on prevalence data, universal screening for extragenital infection due to NG or CT in settings which care for women who are at risk of these infections (e.g., those who are sexually active with concurrent or non-mutually monogamous partners, regardless of reported exposure sites) should be considered.
Extragenital infections in men having sex with women
Overall, there are limited prevalence data of extragenital infections among MSW. The prevalence of extragenital infections among MSW in the studies reviewed ranged from 0% to 5.7% for rectal gonorrhea, 0.4%–15.5% for pharyngeal gonorrhea, 0%–11.8% for rectal chlamydia and 0%–22.0% for pharyngeal chlamydia. These data represent studies that evaluated heterosexually identified men, some of whom may have engaged in sex with other men  a distinction which emphasises the need to consistently focus on sexual behaviour rather than identity.
Extragenital infections due to genital mycoplasmas
There are limited studies on the prevalence of extragenital infections due to genital mycoplasmas. The colonisation rates of M. hominis and U. urealyticum in the oral cavities of healthy adults are usually low. Isolation from the pharynges of both men- and women-seeking treatment at several clinics in the United States yielded respective prevalence rates of M. hominis and U. urealyticum, including U. parvum (biovar 1) and U. urealyticum (biovar 2), which were not distinguishable from each other at the time of isolation, of 14.3% and 14.8%. A history of having performed fellatio was significantly associated with M. hominis and U. urealyticum pharyngeal infections. M. genitalium which is detected in both urethral and cervical specimens was isolated from throat specimens from military recruits. The presence of these ureaplasma and mycoplasmas suggested that they could be transmitted from the genital tract to the pharynx.
Suri et al. reported the first case of oropharyngeal U. urealyticum infection in a retrovirus positive bisexual male. The patient tested positive for U. urealyticum. This report highlights the importance of screening for these infections at extragenital sites in immunocompromised patients as these sites can serve as a reservoir of infection in a population and play a critical role in their transmission.
A study of 1778 men screened by urine and anorectal swabs revealed 91 (5.1%) were positive for M. genitalium. Of note, 71.4% of patients were positive for M. genitalium in anorectal swabs. Another study using anal swabs reported 4.2% of patients were positive for M. genitalium among HIV-positive MSMs. In addition, 24.3% of M. genitalium infected women were noted to have positive anorectal swabs.M. genitalium has been found in the anorectal region, but its pathogenicity in causing clinical proctitis has not been elucidated and more research is required.
| ~ Clinical Features|| |
NG, CT, Mycoplasma and Ureaplasma can also be detected in the pharynx and rectum. Clinical syndromes caused by extragenital infections are shown in [Table 1]. Infections with these infectious agents are typically asymptomatic. When present, symptoms tend to be consistent with localised mucosal inflammation. Extragenital infections in the rectum can result in symptoms of proctitis such as pain in the rectum, anorectal bleeding, mucoid/haemopurulent rectal discharge, tenesmus and constipation. Colonoscopic examination commonly reveals rectal ulcers with erythema and friability, with mucosal biopsies demonstrating lymphohistiocytic infiltrates, crypt abscesses or granulomatous changes. The differential diagnosis for proctitis, the list includes inflammatory bowel disease, lymphoma, anorectal carcinoma and other STIs (e.g., herpes, syphilis). If untreated, extragenital infections can lead to irreversible tissue destruction and scarring. In cases of rectal involvement, perirectal abscesses, anal fistulas and strictures are possible. Extragenital infections in the pharynx can results in symptoms of pharyngitis.,
| ~ Current Management|| |
Detection of extragenital infections is best done by NAAT. Such tests are highly sensitive and specific and are valid and robust for extragenital detection.,,, The focus in current health care is not on extragenital testing; it has largely remained on genital testing. Extragenital testing, when it is done, is done in the STI clinic setting, and CT and NG are usually tested simultaneously because most commercially available NAATs detect both. However, such extragenital testing tends to focus on MSM, not women, and test practices vary widely between STI clinics, even within a country. However, no guidelines exist for testing of extragenital mycoplasmas infections.,,
Current international guidelines for extragenital testing include a pharyngeal or anorectal test after symptoms and after behavioural exposure, i.e. receptive oral sex or receptive anal sex, respectively.,,,, Most guidelines focus on MSM and some also include specific groups of women, such as sex workers. Unfortunately, the recommendation to restrict testing to certain exposure risks has not been based on evidence.
Barriers to implementation of extragenital testing
To assess potential solutions for increasing frequency of screening for extragenital infections in asymptomatic patients, it is important to evaluate current barriers that may be preventing implementation of evidence-based recommendations that extragenital infections screening should be performed in MSM and that more frequent than annual screening should be performed in high-risk MSM populations.,,,, Based on a review of the literature, barriers can be broken down into three categories: lack of uniformity in diagnostic and laboratory resources, provider competency and constraints and patient comfort and awareness.
| ~ Diagnosis of Extragenital Infections|| |
The CDC recommends annual screening of all sexually active women aged 25 years and at-risk MSM. Culture detection of CT and NG has long been available for the detection of rectal or oropharyngeal gonococcal infection. Culture is still the only approved method for diagnosis at these sites; however, the implementation of NAAT for this pathogen has been reported to double their detection from rectal samples and increase their detection from pharyngeal samples 5 fold.
Nucleic acid amplification tests
The gold standard for the diagnosis of urogenital infection due to NG and CT are NAATs. However, NAAT assays are not approved by the US Food and Drug Administration (FDA) for detecting NG and CT from pharyngeal or rectal specimens. However, NAAT is the most sensitive test for detecting CT and NG and is recommended for this purpose by the CDC. NAAT has demonstrated higher sensitivity and specificity compared to culture for detecting extragenital infections.
The main disadvantage of performing NAAT testing over culture is the inability to determine antimicrobial susceptibilities and bacterial viability. Potentially lower sensitivity of NAAT for NG in the pharynx and rectum may be linked to substantial colonisation of these extragenital sites by a wide range of other organisms, including other Neisseria species, possibly leading to interference with NG isolation. For suspected or documented treatment failure, NG cultures should be obtained and antimicrobial susceptibilities performed. Extragenital specimens are collected through a swab of the rectum or pharynx, by either a clinician or a self-collected swab. Self-collected swab as a means of collecting pharyngeal and rectal specimens is supported by the CDC guidelines and has been found to be an acceptable means of obtaining specimens among women and MSM, which may lead to an increase in extragenital diagnoses due to the non-invasive nature of the procedure.
The use of highly sensitive and specific laboratory assays, i.e. (NAAT) has revealed the frequent presence of CT, NG and genital mycoplasmas at extragenital sites. Infections at extragenital sites are common in both MSM and women. In MSM, this led to specific control guidelines including expanded testing. In women, such guidelines are beginning to emerge. However, the occurrence of extragenital infections also has led to international debate on the (need for) control of such infections by testing and treatment.
Several studies using various platforms have shown that NAAT for detection of CT, NG and genital mycoplasmas in rectal and pharyngeal samples is more sensitive than culture. NAAT is less labour intensive than culture and provides quick turnaround of results leading to quicker treatment.
| ~ Treatment|| |
The treatment of extragenital infections is similar to those for the treatment of urogenital infections. Pharyngeal and rectal extragenital infections may clear spontaneously even in the absence of treatment., If extragenital sites are a reservoir for ongoing transmission, suboptimal treatment of extragenital infections could lead to the spread of any existing resistant organisms. If persistent infection or treatment failure is suspected, care should be taken during treatment and retesting of extragenital infections. The recommended regimens for common causes of extragenital infections are shown in [Table 2].
|Table 2: The recommended regimens for common causes of extra-genital infections|
Click here to view
Treatment of extragenital Chlamydia trachomatis infections
The treatment for CT infection includes azithromycin (1 g orally single dose) or doxycycline (100 mg orally twice daily for 7 days). However, CDC recommends doxycycline (100 mg orally twice daily for 21 days) or erythromycin base (500 mg orally 4 times a day for 21 days) for the treatment of lymphogranuloma venereum. Efficacy of chlamydia treatments may differ for extragenital infections at rectal and pharyngeal sites. Doxycycline has shown slightly greater efficacy as compared to azithromycin for extragenital chlamydia infection.,,, In a small study for treatment of pharyngeal chlamydia showed treatment failure rate was more common with azithromycin (10% of patients) as compared to doxycycline (2%). In a meta-analysis for the treatment of rectal chlamydia reports, doxycycline was >99% effective compared to 83% efficacy of azithromycin. On reviewing literature, we found that no studies have evaluated treatment regimens for extragenital chlamydia infection and further studies are required to evaluate optimal regimens for these infections.
Treatment of extragenital Neisseria gonorrhoeae infections
The current treatment recommendations for NG infections involve a dual therapy regimen of azithromycin 1 g orally in a single dose in addition to ceftriaxone 250 mg intramuscularly as a single dose. This dual therapy has the advantage of treating CT infection, which frequently accompanies NG infection. The treatment efficacy for rectal infections with this regimen is >98%., Pharyngeal gonorrhoea is more difficult to treat and have showed ceftriaxone resistance and treatment failure in a number of countries outside the US.,,,,, In both pharyngeal and rectal NG infection, persistence of the organism after treatment may be due to reinfection but can also reflect an elevated MIC to antibiotic regimens. Till date, guidelines still recommend treating pharyngeal infection by NG with dual regimen (ceftriaxone and azithromycin).
Treatment of extragenital mycoplasmas infections
The regimen for treatment of ureaplasma is azithromycin 1 g single dose or doxycycline 100 mg orally twice a day for 7 days. Further, in case of persistent ureaplasma infection, prolonged course of antibiotics may be required., The referred regimens for treatment of M. genitalium is azithromycin single dose 1 g orally or a 5-day-course – 500mg stat dose followed by 250mg daily for next four days or one gram stat dose followed by 250mg daily for next four days. Azithromycin single-dose treatment is more likely to induce macrolide resistance to a higher extent than the 5 days therapy in M. genitalium infection and should be avoided if M. genitalium is not ruled out. However, there are no studies comparing the different regimens so the recommendation to use a 5 days regimen is based on expert opinion alone. Azithromycin is widely used as first-line treatment but seems to have contributed to the increasing M. genitalium resistance. The treatment failure in M. genitalium is extremely common. In some M. genitalium strains, azithromycin, especially the single-dose regimen, will induce macrolide resistance and will cure only the macrolide susceptible strains. Similar to NG, dual therapy for M. genitalium infection too, should likely be introduced in the near future.
The importance of identifying these infections is that definitive therapy [Table 2] with good cure rates can be instituted early, before the onset of complications.
Sex partners should be evaluated, tested and treated. Further, there is no evidence that natural immunity provides complete protection against this damaging immune pathology. Therefore, developing an effective vaccine is a highly desired, ambitious goal. Emerging challenges to antimicrobial resistance, prevention of STIs create a new urgency for these vaccines. Although challenges remain, the STI vaccine roadmap provides a guide for capitalising on the momentum to develop STI vaccines. With continued support and collaboration, these much-needed vaccines can be made a reality.
| ~ Follow Up|| |
Test of cure for extragenital infections <3 weeks after treatment is not recommended except in cases where there are persistent symptoms, therapy was not completed or reinfection is suspected. Retesting can result in false-positive results due to the highly sensitive nature of NAAT, the possibility of detection of non-viable organisms and NAATs not being FDA-cleared at this time. Culture is the only retesting method that can be used to properly assess the efficacy of antibiotic treatments. The patients who are positive for NG and CT should generally be tested for reinfection three to 6 months after treatment.
| ~ Conclusion|| |
Several issues exist regarding screening and management of extragenital infections. Urogenital screening is generally performed to reduce complications and its sequale. Optimal screening strategies for extragenital infections are largely unknown. However, there is a lack of data on clinical outcomes and optimal treatment regimens for rectal and pharyngeal extragenital infections. Further studies are needed in reproductive health and STD clinics, especially in resource-limited settings on extragenital infections.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2]