Trichomoniasis: Pathophysiology, Clinical Evaluation and Diagnostic Testing

Trichomoniasis

Trichomoniasis is a sexually transmitted infection frequently encountered in the emergency department setting that is caused by Trichomonas vaginalis.  According to Patel, Gaydos, Packman, Quinn, and Tobian (2015), it has become the most common non-viral sexually transmitted infection seen in the United States as well as internationally.  T. vaginalis infections often can go undetected for long periods of time before an individual begins to experience symptoms.  Although it is considered a minor and treatable sexually transmitted infection, the incidence and prevalence of Trichomoniasis continues to rise (Menezes, Frasson, & Tasca, 2016).  Trichomoniasis can impact the quality of health of an individual and lead to other genitourinary complications.  In the past decade, it has been recognized as an important source of reproductive disease and can increase the likelihood of an individual contracting human immunodeficiency virus (HIV) (Kissinger, 2015). Swift recognition and treatment of Trichomoniasis can reduce reproductive problems associated with the infection and can diminish an individual’s susceptibility to other sexually transmitted diseases.  The purpose of this paper is to describe the significance, pathophysiology, clinical evaluation and diagnostic testing, and evidence-based treatment modalities of Trichomoniasis.

Significance

Trichomoniasis is a parasitic infection that is transmitted via sexual contact.  It is one of the most prevalent sexually transmitted infections in the United States, leading to approximately 3.7 million infections; including 2.3 million reported among women and 1.4 million among men (Meites, Gaydos, Hobbs, Kissinger, Nyirjesy, Schwebke, & Workowski, 2015).  The occurrence rates of Trichomoniasis is significantly higher when compared to other sexually transmitted diseases.  Mielczarek and Blaszkowska (2016) reported that in 2008 there were 187.1 million occurrences of Trichomoniasis which is greater than Chlamydia (100.4 million), Gonorrhea (36.4 million) and Syphilis (36.4 million) collectively. The annual incidence rates of Trichomoniasis among women supersedes reported infections among men.  Out of 1.1 million T. vaginalis infections reported annually, 680,000 are among women while 415,000 were among men (Meites et. al., 2015).  Trichomoniasis has been reported in various age groups in the United States.  The occurrence of Trichomoniasis among adolescents has become a growing concern in recent years.  In a sample of 12,440 teenagers in grades 7-12 in the United States, the prevalence was reported to be 2.8% in females and 1.7% among males (Meites et. al., 2015).  The incidence among adults demonstrates an increase rate among adult women.  According to Workowski and Bolan (2015), amongst women 40 years of age and older, infection rates were greater than 11%.  Trichomoniasis has shown to be higher in the African American and Hispanic populations compared to non-Hispanic white women.  The incidence of Trichomoniasis among African American women is 13.3% which is considerably greater than 1.8% of Hispanic women or 1.3% of non-Hispanic white women (Meites et. al., 2015).  There are many factors that can increase an individual’s susceptibility of contracting Trichomoniasis.  Some of the risk factors that can increase the incidence include sexual activity, number of sexual partners, presence of other sexually transmitted infections, and illicit drug use (Mielczarek & Blaszkowska, 2016).  Incidence rates of Trichomoniasis is significantly higher in patients that have human immunodeficiency virus (HIV).  Among HIV-infected women, 52.6% have been found to be coinfected with Trichomoniasis (Meites et. al., 2015).

The rise in the incidence rates of Trichomoniasis in the United States has significantly contributed to the financial burden of the health care system.  According to Menezes, Frasson, and Tasca (2016), the lack of a surveillance system to detect drug resistance and few public health programs that focus on sexually transmitted infections has resulted in an approximate $24 million each year for the treatment of Trichomoniasis alone.  This estimated cost does not take into account the amount spent to treat complications associated with Trichomoniasis.  The medical complications associated with Trichomoniasis exacerbate the financial encumbrance, as hidden expenses for pregnancy adverse outcomes, infertility, cervical and prostate cancer has not been factored in the annual expenditure (Menezes et. al., 2016).  Furthermore, the costs associated with treatment of individuals that are co-infected with HIV has also attributed to the increase financial strain on the health care system.  An estimated $167 million each year is spent for the treatment of individuals with T. vaginals-attributable HIV infections (Menezes, 2016). The financial implications for the treatment of Trichomoniasis and associated medical complications

Pathophysiology

Lewis, D. (2014)

-Trichomoniasis is caused by the protozoan, Trichomonas vaginalis.It is a common sexually transmitted infection, particularly among women, in whom it causes a vaginal discharge and vulvitis.

-Urethral symptoms in men are usually mild and transient.

-It has been associated with adverse pregnancy outcome and enhances HIV transmission.

-T. vaginalis is usually isolated from the vagina; the urethra and Skene’s glands are also commonly infected.

-Asymptomatic infections are well documented, occurring in 10-15% of women attending STI clinics.

-Symptomatic women present with vaginitis and vulvitis.  The classical vaginal discharge of trichomoniasis is green, frothy, itchy and malodorous, though in clinical practice the discharge is often grey and non-itchy.

-The vaginal walls and cervix may be erythematous, and a ‘strawberry cervix’ is seen on speculum examination in about 2% of cases.

-Women may also complain of dyspareunia, dysuria, and urinary frequency.

-T vaginalis may infect the urethra, the epididymides and the prostate gland. Most men remain asymptomatic. Those with symptoms usually present with non-specific urethritis. Rarely, T. vaginalis causes clinically apparent balantitis, epididymitis, or prostatitis.

Kissinger, 2015

-T. Vaginalis is a flagellated parasitic protozoan, typically pyriform but occasionally amoeboid in shape, extracellular to genitourinary track epithelium with a primarily anaerobic lifestyle.

-Four flagella project from the anterior portion of the cell and one flagellum extends backwards to the middle of the organism, forming an undulating membrane.

-T. vaginalis is a highly predatory obligate parasite that phagocytoses bacteria, vaginal epithelial cells, and erythrocytes and is itself ingested macrophages.

-T. vaginalis uses carbohydrates as its main energy source via fermentative metabolism under aerobic and anaerobic conditions

-T. vaginalis primarily infects the squamous epithelium of the genital tract.

-The incubation time is generally between 4 and 28 days.

-T. vaginalis resides in the female lower genital tract and the male urethra and prostate, where it replicates by binary fission.

-T. vaginalis is transmitted among humans primarily by sexual intercourse

-Infection may persist for long periods, possibly months or even years in women but generally persists less than 10 days in males.

-The parasite does not appear to have a cyst form and does not survive well in the external environment, but can survive outside the human body in a wet environment for more than 3 hours.

-T vaginalis can be infected with double-stranded RNA (dsRNA) viruses that may have important implications for trichomonal virulence and disease pathogenesis

-The majority of women (85%) and men (77%) with T. vaginalis are asymptomatic.

-One third of asymptomatic women become symptomatic within 6 months

-Among women, common sites of infection include the vagina, urethra, and endocervix. Symptoms among women include vaginal discharge (often diffuse, malodorous, and yellow-green), dysuria, itching, vulvar irritation, and abdominal pain.

-The normal vaginal pH is 4.5, but with T. vaginalis infection, this increases markedly, often to >5.

-Colpitis macularis or strawberry cervix is seen in about 5% of women, though with colposcopy, this rises to nearly 50%

-Other complications include infection of the adnexa, endometrium, and Skene’s and Bartholin’s glands.

Mielczarek, E., & Blaszkowska, J. (2016)

-Trichomonas vaginalis, which is colonizes the genitourinary tract of men and women, is a sexually transmitted parasite causing symptomatic or asymptomatic trichomoniasis.

-The host-parasite relationship is very complex, and clinical symptoms cannot likely be attributed to a single pathogenic effect.

-The flagellated protozoan parasite Trichomonas vaginalis occurring in the human urogenital tract, is the etiological agent of trichomoniasis, the most common worldwide non-viral sexually transmitted infection.

-The incidence of trichomoniasis rate depends on many factors including age, sexual activity, number of sexual partners, the presence of other STDs, sexual customs, phase of the menstrual cycle, techniques of examination, specimen collection and laboratory technique.

-Trichomonas vaginalis is an amitochondrial, microaerotolerant flagellate which has various shapes and sizes, but on average measures about 9x7um.  It has five flagella; four are present anteriorly and the other flagellum is incorporated within the undulating membrane

-It has unique energy-producing double membrane organelles known as hydrogenosomes.

-It produces every 8-12 hours by longitudinal binary fission.

-T. vaginalis is an obligate parasite that phagocytoses bacteria, vaginal epithelial cells, spermatozoids, and erythrocytes.

-Outside the host, the parasite can survive for 6-24 hours in urine, semen, and swimming poos water, but only up to 30 minutes when exposed to air.

-T. vaginalis can grow over a wide range of pH values with an optimum level between 6 and 6.3

Edwards, T., Burke, P., Smalley, H., & Hobbs, G. (2016).

-During infection, while in contact with host epithelial cells, the morphology of the cell assumes an amoeboid conformation, and adheres to the epithelial surface

-The cytoplasm contains a single defined nucleus, and several hydrogenosomes; primitive redox organelles, evolved from mitochondria, which produce molecular hydrogen and ATP

-Transmission occurs almost exclusively via sexual contact, although transmission via fomites has bene documented but is rarely encountered and controversial

-During sexual intercourse, T. vaginalis cells in the genital tract of the infected partner and transferred to the uninfected partner, and come in to contact with the genital epithelia

-When in contact with epithelial cells, the typically ovoid T. vaginalis cell morphologically adjusts, assuming an amoeboid conformation

-The cells attach to the epithelial surface, with the amoeboid morphology enabling the parasite to increase the surface area contact, and interaction, with the epithelial cell.

-T. vaginalis adhesion is largely mediated by a range of iron-dependent surface adhesins.

-With the exception of AP51 (adhesins), the genes encoding these proteins are all transcriptionally upregulated by the presence of iron, which is an essential mediator of T. vaginalis growth and a key factor in virulence.

-After adherence, the T. vaginalis cells recruit further parasites to the location, forming sizeable aggregates of amoeboid cells on the epithelial surface

-The primary mediator of cytoadherence to the host epithelia is surge lipophosphoglycan, the most highly expressed protein on the T. vaginalis surface membrane which binds to the surface of human epithelial cells

-The adherence of T. vaginalis to the epithelial cell surface is a crucial factor in pathogenesis; adherence of the parasite is cytotoxic, and typically results in the lysis of the host cell, and erosion of the epithelial monolayer.

-This process also instigates the inflammatory response, involve the release of chemokines such as IL-8 and the recruitment of neutrophils to infected tissues

-Damage to the vaginal epithelial monolayer during infection is known to occur via a variety of mechanisms, and this contact dependent killing does not involve phagocytosis

-Adherence of T. vaginalis to epithelial cells cause a weakening of the junctional complex between individual cells in the epithelial monolayer

-This weakening results in a decrease in trans-epithelial electrical resistance, an increase in the gap between neighboring cells, an also modification of the distribution of junction complex proteins, all resulting from the interaction with the parasite

-T. vaginalis infection in females is symptomatic in around 50% of cases, and around 30% of asymptomatic cases develop some symptoms in the 6-month period post-infection

-Common symptoms include itching and pain during intercourse, a frothy discharge, and vaginitis, which can range from mild to severe

-Infection of the male genitourinary tract is generally asymptomatic, although mild urethritis, epididymitis, and prostatitis can occur

-T. vaginalis colonization of the prostate can lead to chronic infection and is thought to be the cause of more persistent infections in males.

-Trichomonads have been detected in the prostatic urethra, and in the surrounding tissues of the prostate, including the glandula lumina, submucosa and stroma.

-The presence of T. vaginalis in female patients can cause extensive changes in the vaginal microbiome, and trichomoniasis often occurs in tandem with bacterial vaginosis, a condition involving the imbalance in the bacterial flora of the vagina causing vaginal inflammation

-T. vaginalis infection instigates a robust mucosal immune response, involving localized inflammation and the recruitment of lymphocytes and macrophages. This increases the number of potential cells for the virus to invade and proliferate in, and would make transmission more likely in a HIV-negative individual.

-In addition, in a HIV-positive individual, the increase in cells infected with the virus localized in the genital tract would aid HIV shedding during sexual contact, exposing any partners to a higher level of viral particles, facilitating transmission

-HIV-positive men with symptomatic urethritis caused by T. vaginalis have been shown to have a higher seminal viral load than those with either T. vaginalis negative, or with an asymptomatic

-Diagnosis of trichomoniasis in female patients is frequently carried out microscopically, by the examination of a “wet mount” of vaginal or cervical exudates for motile parasites. This method is very simple to carry out, fast, and cost effective, when compared with alternative diagnostic options.

Clinical Evaluation and Diagnostic Testing

Lewis, 2014

-Microscopic examination of saline wet mounts taken from the posterior vaginal fornix or urethra is the conventional method used to demonstrate the presence of motile T. vaginalis. However, the sensitivity of this technique is at best about 70-80% compared with broth culture methods

Kissinger, 2015

-Traditional wet mount is cheap, fast, and widely available; however, it is insensitive (58%).

Meites, E., Gaydos, C. A., Hobbs, M. M., Kissinger, P., Nyirjesy, P., Schwebke, J. R., . . . Workowski, K. A. (2015).

-Highly sensitive NAATs are now available for detection of T. vaginalis. Clinical diagnosis may be less sensitive than molecular tests, with a sensitivity of 84.6% and a specificity of 99.6% compared with molecular testing.

-The APTIMA Trichomonas vaginalis assay was FDA-cleared in 2011 for detection of T. vaginalis from endocervical or vaginal swabs or urine from symptomatic or asymptomatic women. This assay detects T. vaginalis RNA by transcription-mediated amplification with clinical sensitivity of 95.2%-100% and specificity of 95.3-100%

-The Cobas Amplicor CT/NG PCR assay is a commercially available, FDA-cleared assay for detection of chlamydia and gonorrhea infections that can be modified for T. vaginalis detection in vaginal or endocervical swabs or urine. The assay may perform with sensitivities from 88-97% and specificities from 98-99%

-The most common method for diagnosing trichomoniasis may be microscopic evaluation of genital secretions (“wet mount”), due to the convenience and relatively low cost. Unfortunately, the sensitivity of wet mount for T. vaginalis diagnosis is poor (51-65% sensitivity) in vaginal specimens.  Furthermore, sensitivity declines as evaluation is delayed, decreasing by up to 20% within 1 hour after collection, although storage in saline may prolong specimen viability

-In male urine, wet mount is even less sensitive.

Evidence-Based Treatment Modalities

Lewis, 2014

-The single-dose regimen achieves better patient compliance and has fewer adverse effects, but may be slightly less effective.

-Cure rates with metronidazole are high when the patient complies with treatment and is not re-infected by untreated partner

Kissinger, 2015

-Class B drug and found to be safe in pregnant women in all stages of pregnancy

-The Centers for Disease Control and Prevention (CDC) guidelines for treatment of T. vaginalis include MTZ or TNZ 2g single dose as the recommended regimens. Abstinence from alcohol use should continue for 24 hours after completion of MTZ or 72 hours after completion of TNZ.

Meites, E., Gaydos, C. A., Hobbs, M. M., Kissinger, P., Nyirjesy, P., Schwebke, J. R., . . . Workowski, K. A. (2015).

-Medications approved by the US Food and Drug Administration for treatment of trichomoniasis include metronidazole and tinidazole

-Standard therapy consists of either metronidazole or tinidazole in a single 2-g dose taken orally, or, if necessary, intravenously.

-The CDC also recommends an alternative regimen of metronidazole 500 mg orally twice a day for 7 days.

-Persistent or recurrent infection due to antimicrobial-resistant T. vaginalis or other causes should be distinguished from the possibility of reinfection from an untreated or insufficiently treated partner.

-Following treatment failure, persistent or recurrent trichomoniasis has been treated successfully with longer courses or additional doses of the same medications used in standard therapy.

-Infection is readily passed between sex partners during penile-vaginal sex, although partners may be unaware of their infection; a prospective multicenter study found that 72% of male sex partners of women with trichomoniasis were also infected with T. vaginalis, and 77% of these men were asymptomatic.  Treatment of all sexual partners can prevent recurrences in the index cases, reduce transmission, and prevent new cases in the community

-Screening and prompt treatment for trichomoniasis are recommended at least annually for all HIV-infected women, based on the high prevalence of T. vaginalis infection, the increased risk of PID associated with this infection, and the ability of treatment to reduce genital tract viral load and vaginal HIV shedding

-Among sexually active individuals, the most effective way to prevent trichomoniasis is by using condoms consistently and correctly during vaginal-penile sexual encounters

-Periodic presumptive treatment for high-risk individuals such as sex workers can effectively reduce trichomoniasis.

-Male circumcision might reduce the risk of infection in both circumcised men and their female sex partners

Edwards, T., Burke, P., Smalley, H., & Hobbs, G. (2016).

-Diagnosis of trichomoniasis in female patients is frequently carried out microscopically, by the examination of a “wet mount” of vaginal or cervical exudates for motile parasites. This method is very simple to carry out, fast, and cost effective, when compared with alternative diagnostic options.

-Despite these advantages microscopic evaluation is not considered the optimal detection method, due to low sensitivity afforded by this technique with a sensitivity of around 60%

-Microscopy is unlikely to detect low level infections.  The sensitivity of this method decreases rapidly if delays are present between sample acquisition and examination, with a reduction in sensitivity to 20%. This loss of sensitivity occurs due to the reduction in parasite motility, making the trichomonads difficult to identify

-The diagnostic testing for T. vaginalis infection in male patients is rarely undertaken, for a number of reasons

-Microscopy of urethral discharge, if present, has a poorer sensitivity with male samples.  Cultures can be undertaken from male samples, and the optimal sample type is considered to be a combination of urethral swabbing and collection of urine sediment, however, as with microscopy, sensitivity is poor.

Conclusion

Workowski, K. A., & Bolan, G. A. (2015).

The prevention and control of STDs are based on the following five major strategies (5): • accurate risk assessment and education and counseling of persons at risk on ways to avoid STDs through changes in sexual behaviors and use of recommended prevention services; • pre-exposure vaccination of persons at risk for vaccinepreventable STDs; • identification of asymptomatically infected persons and persons with symptoms associated with STDs; • effective diagnosis, treatment, counseling, and follow up of infected persons; and • evaluation, treatment, and counseling of sex partners of persons who are infected with an STD.

References

• Edwards, T., Burke, P., Smalley, H., & Hobbs, G. (2016). Trichomoniasis vaginalis: Clinical relevance, pathogenicity and diagnosis. Critical Reviews in Microbiology, 42(3), 406-417. doi: 10.3019/1040841X.2014.958050
• Keizur, E. M., & Klausner, J. D. (2018). The need for new treatment recommendations for trichomoniasis among women. The Lancet Infectious Disease, 18(11),1168-1169. doi: 10.1016/S1473-3099(18)30544-9
• Kissinger, P. (2015). Epidemiology and treatment of trichomoniasis. Current Infectious Disease Reports, 17(6), 1-9. doi:http://dx.doi.org.go.libproxy.wakehealth.edu/10.1007/s11908-015-0484-7
• Lewis, D. (2014). Trichomoniasis. Medicine, 42(7), 369-371. Doi: 10.1016/j/mpmed.2014.01.001
• Liu, E. W., Workowski, K. A., Taouk, L. H., Schulkin, J., Secor, W. E., & Jones, J. L. (2019). Survey of obstetrician-gynecologists in the united states about trichomoniasis, 2016. Sexually Transmitted Diseases, 46(1), 9-17. doi: 10.1097/OLQ.0000000000893
• Meites, E., Gaydos, C. A., Hobbs, M. M., Kissinger, P., Nyirjesy, P., Schwebke, J. R., & Workowski, K. A. (2015). A review of evidence-based care of symptomatic trichomoniasis and asymptomatic trichomonas vaginalis infections. Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America, 61 Suppl 8(12), S837.
• Menezes, C. B., Frasson, A.P., & Tasca, T. (2016). Trichomoniasis – are we giving the attention to the most common non-viral sexually transmitted disease. Microbial Cell, 3(9), 404-481. doi: 10.1598/mic2016.09.526
• Mielczarek, E., & Blaszkowska, J. (2016). Trichomonas vaginalis: Pathogenicity and potential role in human reproductive failure. Infection, 44(4). doi: 10.1007/s15010-015-0860-0
• Muzny, C. A., Richter, S., & Kissinger, P. (2019). Is it time to stop using single-dose oral metronidazole for the treatment of trichomoniasis in women? Sexually Transmitted Disease, 45(5), e57-e59. doi: 10.1097/OLQ.0000000000959
• Patel, E. U., Gaydos, C. A., Packman, Z. R., Quinn, T. C., & Tobian, A. R. (2015). Prevalence and correlates of trichomonas vaginalis infection among men and women in the united states. Infection Disease Society of America. doi:https://watermark.silverchair.com/ciy079.pdf?token=AQECAHi208BE49Ooan9kkhW_Ercy7Dm3ZL_9Cf3qfKAc485ysgAAAjcwggIzBgkqhkiG9w0BBwagggIkMIICIAIBADCCAhkGCSqGSIb3DQEHATAeBglghkgBZQMEAS4wEQQMGWqsNlcA9-9PbLWjA
• Workowski, K. A., & Bolan, G. A. (2015). Sexually transmitted diseases treatment guidelines, 2015. In Centers for Disease Control and Prevention. Retrieved from https://www.cdc.gov/mmwr/pdf/rr/rr6403.pdf