Genitourinary Tract Infections

GENITOURINARY TRACT INFECTIONS

Please supplement and learn theory on the basis of the lecture, Mim’s book and supplementary materials before class!!!

INTRODUCTION

GENITOURINARY TRACT INFECTIONS

NORMAL FLORA

URETHRA

Anterior of urethra Urethra

Sparse: ………………………………………………………. ………………………………………………………. …………………………………………………..…. ………………………………………………………. …………………………………………………..…. ……………………………………………………………………………… ………………………………………………………. ………………………………………………………………………………..

Internal organs such as testis, ovary etc. Male urethra is relatively are sterile in healthy individuals sterile than female urethra

NORMAL FLORA of VAGINA

Normal flora of vagina depends upon …………………………………………………………………………………..…..

VAGINA

After puberty and before menopause Before puberty and after menopause

……………………………………………………………………………………………………….. ……………………………………………………………………………………………………………

………………………………………………………………………………………………………… ……………………………………………………………………………………………………………

………………………………………………………………………………………………………… …………………………………………………………………………………………………………….

…………………………………………………………………………………………………………. …………………………………………………………………………………………………………….

GENITOURINARY TRACT INFECTIONS

ACUTE MANIFESTATION OF STD

……………………………………………………………. …………………………………………………………….

………………………………………………………… ………………………………………………………. ………………………………………………………… ………………………………………………………….. ………………………………………………………… ………………………………………………………… ………………………………………………………… ……………………………………………………….. ………………………………………………………….

………………………………………………………………………… …………………………………………………………………………… ………………………………………………………………………… …………………………………………………………………………… ………………………………………………………………………… …………………………………………………………………………… ………………………………………………………………………… …………………………………………………………………………… ………………………………………………………………………… …………………………………………………………………………… ………………………………………………………………………… …………………………………………………………………………… ………………………………………………………………………… …………………………………………………………………………… ……………………………………………………………………… ………………………………………………………………………..

STUDENT NOTES ------

GENITOURINARY TRACT INFECTIONS

Vaginosis vs vaginitis

VAGINOSIS may lead to VAGINITIS ……………………………………………………………. ……………………………………………………………

Etiology But similar symptoms: Etiology ………………………………………………………… …………………………………………………………… …………………………………………………………… ………………………………………………………… …………………………………………………………… …………………………………………………………… ………………………………………………………… ………………………………………………………….. …………………………………………………………… …………………………………………………………

…………………………………………………………

………………………………………………………..

STUDENT NOTES ------

GENITOURINARY TRACT INFECTIONS

Figure. Cytology indicating inflammation (multiple PMN cells visible)

GENITOURINARY TRACT INFECTIONS DISEASE ETIOLOGY Bacteria Syphilis Gonorrhea Lymphogranuloma venereum (LGV) Granuloma inguinale (donovanosis) Chancroid Viruses Genital herpes Anogenital warts, anogenital cancer Fungi Candidiasis Parasites Trichomoniasis Other diseases caused by many different microorganisms Vaginosis

Cervicitis

Nongonococcal urethritis NGU

Balantitis

Epididymitis

Proctitis, proctolitis

GENITOURINARY TRACT INFECTIONS

DIAGNOSIS

SYPHILIS

Microscopy a) Dark-field microscopy – observation of alive treponames in inflammatory exudate taken from primary lesion or skin and mucous lesions (primary and secondary syphilis), but in reference laboratories only. Dark-field microscopy is the most specific technique for diagnosing syphilis when an active chancre or condyloma latum is present. However, its accuracy is limited by the experience of the operator performing the test, the number of live treponemes in the lesion, and the presence of non-pathologic treponemes in oral or anal lesions. In preparation for dark-field microscopy, the lesion is cleansed and then abraded gently with a gauze pad. Once a serous exudate appears, it is collected on a glass slide and examined under a microscope equipped with a dark-field condenser. T. pallidum is identified by its characteristic corkscrew appearance. Given the inherent difficulties of dark-field microscopy, negative examinations on three different days are necessary before a lesion may be considered negative for T. pallidum. Spiral bacteria can also be observed in phase contrast microscopes. Figure: Treponema pallidum in dark-field microscope.

Treponemes can also be stained in patients tissues with silver staining technique (See picture below).

However, because of low content of proteins in the cell wall of treponemes and because they are really thin, other techniques are useless to stain these bacteria.

Serology Description of these reactions is presented in the Diagnostic Tool Part – please read carefully to understand. A. NON-TREPONEMAL TESTS 1) Antilipoidal antibodies (reaginic antibodies) Assays: VDRL and PRP. The antigen used is cardiolipin, a lipid extract from the heart muscle of cattle. This serological test is performed according to the standards of the Venereal Disease Research Laboratory (USA) and is known as the VDRL flocculation reaction.

It must be remembered that tests for the presence of these nonspecific anti-lipid antibodies are meant as a presumptive screening test for syphilis. Similar regain-like antibodies may also be present as a result of other diseases such as malaria, leprosy, infectious mononucleosis, systemic lupus erythematosis, viral pneumonia, measles, and collagen diseases and may give false-positive results.

B. TREPONEMAL TESTS Specific, antitreponemal antibodies – these antibodies are specific to treponemal antigens. The antigens (ultrasonically-treated suspension of Treponema pallidum, Nichols strain, cultured in rabbit testicles) are coupled to particles (carrier e.g., latex beads or erythrocytes.

GENITOURINARY TRACT INFECTIONS

The following tests use treponemal antigens: a) FTA – ABS (indirect immunofluorescence assay) b) MHA – TP (passive hemagglutination); Treponema pallidum particle agglutination (TP-PA), d) ELISA GONORRHEA - DIAGNOSIS Specific microbiologic diagnosis of infection with N. gonorrhoeae should be performed in all persons at risk for or suspected to have gonorrhea; a specific diagnosis can potentially reduce complications, reinfections, and transmission.

Microscopy Because of its high specificity (>99%) and sensitivity (>95%), a Gram stain of urethral secretions that demonstrates polymorphonuclear leukocytes with intracellular Gram-negative diplococci can be considered diagnostic for infection with N. gonorrhoeae in symptomatic men. However, because of lower sensitivity, a negative Gram stain should not be considered sufficient for ruling out infection in asymptomatic men. Detection of infection using Gram stain of endocervical, pharyngeal, and rectal specimens also is insufficient and is not recommended. Methylene blue (MB) stain of urethral secretions is an alternative diagnostic test with performance characteristics similar to Gram stain. Presumed gonococcal infection is established by documenting the presence of WBC containing intracellular purple diplococci in MB/GV smears.

Figure: Gonococci within polymorphonuclear leukocytes (blue arrows)

Culture Patient’s sample: endocervical (women) or urethral (men), rectal, oropharyngeal, and conjunctival swabs specimens.

In cases of suspected or documented treatment failure, clinicians should perform both culture and antimicrobial susceptibility testing because non-culture tests cannot provide antimicrobial susceptibility results. Because N. gonorrhoeae has demanding nutritional and environmental growth requirements, optimal recovery rates are achieved when specimens are inoculated directly and when the growth medium is promptly incubated in an increased CO2 environment. Several non-nutritive swab transport systems are available that might maintain gonococcal viability for up to 48 hours in ambient temperatures.

Nucleic acid amplification tests (NAATs) allow to detect gonorrhea for the widest variety of specimen types, including endocervical swabs, vaginal swabs, urethral swabs (men), and urine (from both men and women). The sensitivity of NAAT for the detection of N. gonorrhoeae in urogenital and nongenital anatomic sites is superior to culture, but varies by NAAT type.

CHLAMYDIA

URETHRITIS Urethritis can be documented on the basis of any of the following signs or laboratory tests:  Mucoid, mucopurulent, or purulent discharge on examination.  Gram stain of urethral secretions demonstrating ≥2 WBC per oil immersion field. The Gram stain is a diagnostic test for evaluating urethritis that is highly sensitive and specific for documenting both urethritis and the presence or absence of gonococcal infection. 6

GENITOURINARY TRACT INFECTIONS

 Positive leukocyte esterase test on first-void urine or microscopic examination of sediment from a spun first-void urine demonstrating ≥10 WBC per high power field.  If symptoms are present but no evidence of urethral inflammation is present, NAAT testing for C. trachomatis and N. gonorrhoeae might identify infections. Nongonococcal Urethritis (NGU) NGU is a nonspecific diagnosis that can have many infectious etiologies. NGU is confirmed in symptomatic men when staining of urethral secretions indicates inflammation without Gram negative or purple diplococci. All men who have confirmed NGU should be tested for chlamydia. Testing for T. vaginalis should be considered in areas or populations of high prevalence.

CERVICITIS Two major diagnostic signs characterize cervicitis: 1) a purulent or mucopurulent endocervical exudate visible in the endocervical canal or on an endocervical swab specimen (commonly referred to as mucopurulent cervicitis) and 2) sustained endocervical bleeding easily induced by gentle passage of a cotton swab through the cervical os.

Either or both signs might be present. Cervicitis frequently is asymptomatic, but some women complain of an abnormal vaginal discharge and intermenstrual vaginal bleeding (e.g., after sexual intercourse). A finding of leukorrhea (a whitish or yellowish discharge of mucus from the vagina) (>10 WBC per high-power field on microscopic examination of vaginal fluid) has been associated with chlamydial and gonococcal infection of the cervix. In the absence of the major diagnostic signs of inflammatory vaginitis, leukorrhea might be a sensitive indicator of cervical inflammation with a high negative predictive value (i.e., cervicitis is unlikely in the absence of leucorrhea). When an etiologic organism is isolated in the presence of cervicitis, it is typically C. trachomatis or N. gonorrhoeae. Cervicitis also can accompany trichomoniasis and genital herpes (especially primary HSV-2 infection). However, in most cases of cervicitis, no organism is isolated. Infection with M. genitalium or BV might cause cervicitis.

Testing for chlamydia is indicated in patients with urogenital, anorectal, and ocular symptoms, patients with STI other than chlamydia, sexual contacts of persons with STI, and persons destined for chlamydia screening

Localized infections are examined by assays for direct pathogen detection, like: a) culture b) tests detecting antigens of C. trachomatis (EIA, direct fluorescent antibody (DFA) c) NAAT tests. I Chronic and invasive infections are examined by indirect methods like serology that depends on detection of antibodies against C. trachomatis and may be applied for diagnostic evaluation of chronic/invasive infection (PID, LGV) and post infectious complications, like sexually acquired reactive arthritis (SARA). In these conditions, pathogens have crossed the epithelial and may no longer be detectable in swabs. As persistent C. trachomatis infections and complications of ascending infections are usually associated with a positive antibody response, negative serology most likely rules out the involvement of chlamydia. On the other hand, positive serology represents no definite proof of associated chlamydia infection. The microimmunofluorescence (MIF) test was long considered the reference method of chlamydia antibody testing. The MIF test has been used to diagnose neonatal C. trachomatis pneumonia. Serum IgM titer of 1:32 or greater is considered diagnostic of infection. In contrast, testing for IgG is not useful because they may represent passively transferred maternal antibody. Current guidelines from the Centers for Disease Control and Prevention (USA), the 7

GENITOURINARY TRACT INFECTIONS

British Association of Sexual Health and HIV (BASHH) and the International Union against STI (IUSTI), however, do not recommend serologic testing to diagnose infant pneumonia. In addition, the MIF test is time-consuming and labor-intensive, and the reading of fluorescence signals is prone to subjective evaluation. Therefore, enzyme immunoassays (EIA) and immunoblots assays are currently used more frequently to detect chlamydia antibodies. Chlamydial LPS is generally considered a genus-specific antigen, but cross-reactivity with antibodies against LPS of other Gram-negative bacteria has been observed

CULTURE Patients specimens suitable for culture (must be collected using special devices and transport media) include: swabs from different anatomical sites (endocervix, urethra, anal canal, conjunctiva). Cell lines cultured in vitro are infected with patient specimen and analyzed for the development of characteristic intracytoplasmatic inclusions after 48–72 h by staining with Giemsa, iodine, or fluorescence labelled antibodies to chlamydial antigens (LPS or MOMP). When using MOMP-specific antibodies for staining cell culture, detection is highly specific.

Figure. Direct immunofluorescence. Green luminescent cells are infected with chlamydia

Disadvantages: Culture depends on vital organisms thus the detection rate is at best 60%–80%. Sensitivity of culture may be impaired by inadequate specimen collection, storage and transport, toxic substances in clinical specimens and overgrowth of cell cultures by commensal microbes. Additional disadvantages are represented by the extended turn-around time, labor intensity and difficulties in standardization. Thus, cell culture is rarely used nowadays in diagnostic laboratories, but the methodology is still needed, at least in some reference laboratories, to monitor antibiotic susceptibility and changes of virulence, or when a test with the highest specificity is required as in case of suspected sexual assault.

Nucleic acid amplification tests (NAATs) NAATs are the most sensitive assays with a specificity similar to cell culture and are considered the method of choice for C. trachomatis detection. In addition, NAATs can be performed on various clinical specimens that do not depend on specific transport and storage conditions, since NAATs do not require infectious bacteria. In the case of lower genital tract infections, first void urine and vaginal swabs are the recommended specimens for testing males and females, respectively. Infections of anorectal, oropharyngeal and ocular epithelia should also be tested by NAAT analysis of corresponding mucosal swabs. In particular, anorectal infections of men who have sex with men (MSM) should include evaluation of lymphogranuloma venereum (LGV) by identification of genotypes L1, L2 or L3. Detection of CT antigens by enzyme immunoassay (EIAs) or rapid diagnostic tests (RDTs) are unsuitable due to insufficient sensitivity and specificity.

HERPES VIRUS INFECTIONS Testing for HSV-1 and -2 is accomplished through the use of a) light microscopy b) viral culture c) serology 8

GENITOURINARY TRACT INFECTIONS

d) molecular methods (NAATs)

The gold standard for herpes diagnosis is a viral culture test or nucleic acid amplification test (NAAT) of a sample of skin, crust, or fluid from the lesion, which is usually obtained with a gentle swab of the area. In general, the results of the test are reliable (not a high chance of false positives or false negatives) when active lesions are present. a) light microscopy Preparations of mucocutaneous scrapings (Tzanck smears) are collected by unroofing vesicles and gently swabbing the vesicle base. These specimens are stained with Giemsa, methylene blue, or Wright stain and are examined for the presence of HSV cytopathic effects (CPE).

Tzank test for rapid detection of HSV infections.

Light microscopy has the advantage of being inexpensive, rapid, and simple to perform. It also enables simultaneous screening for other pathologies, such as bullous impetigo, candidiasis, or pemphigus. This method can be utilized for diagnosis of HSV infection in a wide variety of other clinical specimens, ranging from cervical brushings to surgical specimens. The sensitivity of light microscopy is heavily reliant on proper sampling. For optimal results, scrapings must be obtained from the base of the lesion and enough tissue must be obtained for adequate lesion sampling. This may be difficult if lesions are rare or the patient is in pain. Sensitivity is also affected by the stage of the lesion, with the highest positivity rate being observed in early vesicular lesions. b) culture Culture is dependent on the collection of a high-quality specimen, such as a swab or needle aspiration, as well as on proper transport and handling to maintain infectivity. Since the virus is enveloped and extremely labile, specimens collected using a swab must be transferred to suitable viral transport media. These media are buffered saline solutions containing albumin to aid in the stabilization of virions and are supplemented with antimicrobials, including amphotericin B, vancomycin, and colistin to reduce overgrowth of bacterial and fungal organisms that may be present in the specimen. Preservation of virus infectivity and reduction of overgrowth of other microbes is important when specimens will be used for cell culture. These issues are of less concern when a molecular method of detection is employed. Cultures are observed microscopically for CPE, including cell rounding, cytoplasmic granulation, syncytium formation, and eventually lysis. Virus typing is subsequently conducted using HSV-1 and -2 monoclonal antibodies (often using DIF assay). Recovery of HSV from a lesion is evidence of acute infection. Virus-induced CPE using standard culture are typically detectable within 5 days, although they may require up to 14 days to become apparent.

GENITOURINARY TRACT INFECTIONS c) serologic tests It takes about one to two weeks when detectable antibodies against herpes virus will occur during primary infection. The presence of antibodies evidences acute or past infection. Enzyme-linked immunosorbent assays (ELISAs) utilize whole-antigen preparations from HSV-1- or HSV-2-infected cell lines. These assays are sensitive (92 to 100%) and not expensive, and are easy to perform.

Direct immunofluorescence – specific antibody detecting cultured cells infected with HSV-2 virus (bright green color).

There are two kinds of commercially available serologic tests for herpes: Type-specific herpes serologic tests (EIA, immunoblott, IIF) detect antibodies against a herpes virus type HSV-1 or HSV-2. General herpes serologic tests (EIA, immunoblott, IIF) antibodies against any type of herpes, and they do not specify whether it is type HSV-1 or HSV-2.

HSV infections of CNS Diagnosis of neonatal herpes is challenging. Generally, babies are not screened for herpes infection. Symptoms such as lesions around the mouth or eye may alert caregivers. This should prompt diagnostic testing, which can be done using a swab sample. However, more complicated neonatal herpes infections, such as encephalitis, require more specific tests such as a lumbar puncture. While HSV can rarely be cultured from the CSF, molecular assays can yield results in a matter of hours, which can be important when dealing with possible HSV encephalitis or meningitis. Initial CSF viral load has been shown to be an independent predictor of treatment outcome.

PAPILLOMAVIRUS A human papillomavirus (HPV), a member of the papillomavirus, is a double-stranded DNA virus and produces cytopathic effect in epithelium. Genital mucosal infection is persistent and multifocal and can be subclinical. More than 30 to 40 types of HPV are typically transmitted through sexual contact and infect the anogenital region. Some sexually transmitted HPV types may cause genital warts. Persistent infection with “high-risk” HPV types different from the ones that cause skin warts, may progress to precancerous lesions and invasive cancer. HPV infection is a cause of nearly all cases of cervical cancer; however, most infections with these types do not cause disease. The traditional methods of viral diagnosis such as electron microscopy, cell culture, and certain immunological methods are not suitable for HPV detection. HPV cannot be cultured in cell cultures. The methods to diagnose HPV infection are:  Colposcopy and acetic acid test  Biopsy  NAATs  Pap smear

Colposcopy and acetic acid test Colposcopy is the examination of the cervix, vagina, and in some instances the vulva after the application of acetic acid solution; coupled with obtaining colposcopically directed biopsies of all lesions suspected of representing neoplasia. Colposcopic findings are graded according to degree of acetowhite lesion, surface contour, mosaic pattern, and punctuation. Greater abnormalities of these parameters are related to severity of the lesions.

The use of colposcopy screening is only to be recommended for:  Immunosuppressed transplant recipients.  Human immunodeficiency virus (HIV) positive women.

GENITOURINARY TRACT INFECTIONS

 Women with three consecutive inadequate samples, after three tests in a series reported as borderline nuclear change in squamous cells, and be referred for colposcopy after one test reported as borderline nuclear change in endocervical cells.  Positive cervical cytology for malignant cells or suspicious cells but clinically normal looking cervix. Biopsy

HPV-Infected Squamous Cell (Koilocyte) of the Cervix; Pap stain, ThinPrep cervicovaginal cytology specimen.

Colposcopy allows tissue sampling (biopsy) that is targeted to the abnormal areas. The biopsy of abnormal areas is a critical part of colposcopy because treatment will depend on how severe the abnormality is on the biopsy sample. If the biopsy results show pre-cancer (dysplasia) or cancer, then treatment is recommended. The dysplasia may be mild, moderate, or severe. In genital warts, the most characteristic feature is the presence of koilocytes, which are mature squamous cells with clear perinuclear zone. The nuclei of koilocytes may be enlarged and hyper chromatic, double nuclei are seen often as well.

PAP smear or PAP test It is a screening test first describe by Papanicolaou and Traut. Apart from premalignant and malignant changes, viral infections like HPV infection and Herpes can also be detected. Positive test requires further confirmatory tests like coloscopy, cervical biopsy, and DNA tests like PCR. The established routine method for viral detection is the hybridization of viral nucleic acids. DONOVANOSIS Granuloma inguinale is a genital ulcerative disease caused by the intracellular gram-negative bacterium Klebsiella granulomatis (formerly known as Calymmatobacterium granulomatis). The disease is endemic in some tropical and developing areas, including India; Papua, New Guinea; the Caribbean; central Australia; and southern Africa. Clinically, the disease is commonly characterized as painless, slowly progressive ulcerative lesions on the genitals or perineum without regional lymphadenopathy; subcutaneous granulomas (pseudobuboes) also might occur. The lesions are highly vascular (i.e., beefy red appearance) and bleed. Extragenital infection can occur with extension of infection to the pelvis, or it can disseminate to intra- abdominal organs, bones, or the mouth. The lesions also can develop secondary bacterial infection and can coexist with other sexually transmitted pathogens. Diagnosis The causative organism of granuloma inguinale is difficult to culture, and diagnosis requires visualization of dark-staining Donovan bodies on tissue crush preparation or biopsy. NAATs are available.

This photomicrograph of a tissue sample extracted from a lesion in the inguinal region of the female granuloma inguinale, or Donovanosis patient, shows a white blood cell (WBC) containing the pathognomonic finding of Donovan bodies, which are encapsulated, Gram-negative rods, representing the responsible bacterium Klebsiella granulomatis, formerly known as Calymmatobacterium granulomatis.

GENITOURINARY TRACT INFECTIONS

TREATMENT What are treatment options for diseases listed in the table? Supplement!

DISEASE TREATMENT Bacteria Syphilis Gonorrhea Lymphogranuloma venereum Granuloma inguinale (donovanosis) Chancroid Viruses Genital herpes Anogenital warts, anogenital cancer Fungi Candidiasis Parasites Trichomoniasis Other diseases caused by many different microorganisms Vaginosis Cervicitis Nongonococcal urethritis NGU Balantitis Epididymitis Proctitis, proctolitis

GENITOURINARY TRACT INFECTIONS

CLINICAL CASES

Case 1. Elizabeth, 28 years old. Attends the genitourinary medicine clinic for a check-up. She has recently started work in a ‘massage parlour’, and it is the policy of the owner to ensure all ‘grills’ attend for regular assessment. She has no relevant past medical history and is not on any regular medication apart from the oral contraceptive pill. Her last menstruation was 2 weeks ago. She has noticed a whitish vaginal discharge, not very profuse, over the past couple of days, but no other symptoms related to the genitourinary tract, in particular, no dysuria or vaginal irritation. On examination, the vaginal walls do not look inflamed, although there is a small amount of a mucopurulent discharge coming from the cervix.

What is your provisional diagnosis? ------What organism may cause this condition? ------What investigation should you perform? What kind of sample should be taken from patient? ------How will the laboratory attempt to confirm etiology? ------What treatment should you offer Elizabeth at this stage? ------What are the other principles of management of a patient with a sexually transmitted disease?

a) ------b) ------c) ------

Elizabeth’s cervical smear examined in the clinic shows polymorphs but no organisms are seen. You should prescribe a 1-week course of doxycycline and counsel Elizabeth about the

GENITOURINARY TRACT INFECTIONS risks of spreading her infection, advising her to abstain from sexual intercourse for 7 days. She should return to the clinic in 2 weeks time to make a post-treatment assessment.

What are clinical syndrome associated with genital C. trachomatis infection? ------

Case 2. Sharon, a 24-year old personnel manager, attends the genitourinary medicine clinic in great stress. She has developed several painful blisters in and around her vagina over the past 72 hours. She complaints that passing urine is painful, and she also finding it difficult to walk. On examination, Sharon is febrile (38°C) and looks generally unwell. Painful inguinal lymphadenopathy is noted bilaterally and there are ulcers visible on the cervix.

What is diagnosis? ------How to confirm diagnosis? ------What complications may arise from an attack of primary genital herpes? ------How should you manage this patient? ------However, her husband of five years, Jason, wants to know how his wife acquired her infection. He has never had genital herpes, and therefore believes that she must be having an extramarital affair. Sharon steadfastly denies this.

How then might Sharon have acquired the infection? ------14

GENITOURINARY TRACT INFECTIONS

------What are risks of recurrent disease? ------The common causes of ulceration confined to the genital area include: ------Etiology and treatment of NSU include: ------Etiology and treatment of PID include: ------

GENITOURINARY TRACT INFECTIONS

CLASS TASK Laboratory evaluation of vaginal discharge (vaginal biocenosis) on the basis of Gram stain smear

Supplement tables using the following evaluation criteria:

Leucocytes: absent; single (≤ 3 per field); few (4- 10 per field); increased (>10) Lactobacillus spp: absent, single (≤ 10 per field); few (11- 50 per field); numerous (>50 per field) Other bacteria: absent, single (≤ 10 per field); few (11- 50 per field); numerous (>50 per field) Yeats: absent; single (≤ 3 per field); few (4- 10 per field); increased (>10) epithelial cells: normal, clue cells

Case 1.

Student's evaluation of vaginal discharge Leukocytes Lactobacillus Other bacteria Epithelial cells Yeats pH 5.5

Case 2.

Student's evaluation of vaginal discharge Leukocytes Lactobacillus Other bacteria Epithelial cells Yeats pH 5.5

GENITOURINARY TRACT INFECTIONS

Case 3.

Student's evaluation of vaginal discharge Leukocytes Lactobacillus Other bacteria Epithelial cells Yeats pH 5.0

Case 4.

Student's evaluation of vaginal discharge Leukocytes Lactobacillus Other bacteria Epithelial cells Yeats pH 6.5

GENITOURINARY TRACT INFECTIONS

Case 5

Student's evaluation of vaginal discharge Leukocytes Lactobacillus Other bacteria Epithelial cells Yeats pH 6.0

Case 6.

Student's evaluation of vaginal discharge Leukocytes Lactobacillus Other bacteria Epithelial cells Yeats pH 7.0

GENITOURINARY TRACT INFECTIONS

Case 7.

Student's evaluation of vaginal discharge Leukocytes Lactobacillus Other bacteria Epithelial cells Yeats pH 7.0

GENITOURINARY TRACT INFECTIONS

Issues to be discusses 1. Why vaginitis may lead to vaginosis and vice versa? What is the association of vaginosis with normal flora? ------2. What is a clue cell and what is its diagnostic value? ------

3. What is whiff test and what it indicates? ------4. Why we cannot rely on serology in Chlamydia trachomatis infections? ------

5. How is it possible for a mother who has no symptoms of infection to give birth to a child with HSV infection? ------

6. Why it is so important to check if pregnant women are carriers of Streptococcus agalactiae (GBS)? ------

GENITOURINARY TRACT INFECTIONS

SEFL-ASSESMENT

1. Name etiologic agents of genitourinary tract infections – divide them according to groups of microbes e.g. bacteria, viruses, etc. Can you do it? Let try! It would be best if you write down the names of microorganisms while learning so to be able to correctly name them – it would be a shame if you, as a doctor, couldn't write the correct name for the etiological factor of the disease – name them according to the disease.

2. Name microorganisms causing ulcerative genitourinary tract infections.

3. Name microorganisms causing genitourinary tract infections that present with inflammatory discharge – name them according to the disease.

4. Try to name diseases caused by Chlamydia trachomatis – take into consideration serotypes involved.

5. What do you know about gonorrhea? What is etiology? How people can acquire the disease? How it should be treated? How it can be diagnosed? If you would have a patient with suspected gonorrhea what would you do to confirm the diagnosis?

6. Name etiologic agents of STD.

7. Name stages of syphilis .

8. Which antimicrobial is used to treat gonorrhea, syphilis, NGU/cervicitis, vulvovaginal candidiasis, bacterial vaginosis, trichomoniasis and herpes. Name groups of antibiotics, representatives of groups, mechanism of action, mechanisms of bacterial resistance to that antimicrobials ( if exist).

9. What complications may occur as a consequence of gonorrhea, syphilis, NGU/cervicitis, vulvovaginal candidiasis, bacterial vaginosis, trichomoniasis and herpes.

10. Specimen collection and handling depending on the disease.

11. Name laboratory tests used for best diagnosis of gonorrhea, syphilis, NGU/cervicitis, vulvovaginal candidiasis, bacterial vaginosis, trichomoniasis and herpes.

12. Name natural flora of genitourinary tract of men and women.

13. How bacterial vaginosis is diagnosed.

14. Name serological tests used for diagnosis of syphilis? What importance they have as screening tests, confirmation tests and treatment controls?

Remember! To get credit of class all materials must be supplemented!

Credit of class ------(teacher’s signature)

Date ------21

GENITOURINARY TRACT INFECTIONS

SUPPLEMENTARY MATERIALS

SYPHILIS

GONORRHEA Disseminated Gonococcal Infection Disseminated gonococcal infection (DGI) frequently results in petechial or pustular acral skin lesions, asymmetric polyarthralgia, tenosynovitis, or oligoarticular septic arthritis. The infection is complicated occasionally by perihepatitis and rarely by endocarditis or meningitis. Some strains of N. gonorrhoeae that cause DGI can cause minimal genital inflammation. If DGI is suspected, NAAT or culture specimens from urogenital and extragenital sites, as applicable, should be collected and processed in addition to specimens from disseminated sites of infection (e.g., skin, synovial fluid, blood, and the CNS). All N. gonorrhoeae isolates should be tested for antimicrobial susceptibility. Gonococcal Infections Among Neonates Prenatal screening and treatment of pregnant women is the best method for preventing gonococcal infection among neonates. Gonococcal infection among neonates results from perinatal exposure to the mother’s infected cervix. It is usually an acute illness that manifests 2–5 days after birth. The prevalence of infection among infants depends on the prevalence of infection among pregnant women, whether pregnant women are screened and treated for gonorrhea, and whether newborns receive ophthalmia prophylaxis. The most severe manifestations of N. gonorrhoeae infection in newborns are ophthalmia neonatorum and sepsis, which can include arthritis and meningitis. Less severe manifestations include rhinitis, vaginitis, urethritis, and infection at sites of fetal monitoring. Ophthalmia neonatorum prophylaxis

Ophthalmia neonatorum can result in blindness !!! To prevent gonococcal ophthalmia neonatorum, a prophylactic agent should be instilled into both eyes of all newborn infants; this procedure is required by law in most countries. Ocular prophylaxis can prevent sight-threatening gonococcal ophthalmia, has an excellent safety record, is easy to administer, and is inexpensive.

The recommended prophylactic regimen is erythromycin (0.5%) ophthalmic ointment in each eye in a single application at birth. This preparation should be instilled into both eyes of all neonates as soon as possible after delivery, regardless of whether they are delivered vaginally or by cesarean section.

Erythromycin is the only antibiotic ointment recommended for use in neonates. Silver nitrate and tetracycline ophthalmic ointment is no longer recommended. If erythromycin ointment is not available,

GENITOURINARY TRACT INFECTIONS infants at risk for exposure to N. gonorrhoeae (especially those born to a mother at risk for gonococcal infection or with no prenatal care) can be administered ceftriaxone in a single dose. Nongonococcal causes of neonatal ophthalmia include Moraxella catarrhalis and other Neisseria species, organisms that are indistinguishable from N. gonorrhoeae on Gram-stained smear but can be differentiated in the microbiology laboratory. These infections can be treated with ceftriaxone (one dose).

Disseminated gonococcal infection in neonates DGI might present as sepsis, arthritis, or meningitis and is a rare complication of neonatal gonococcal infection. Detection of gonococcal infection in neonates who have sepsis, arthritis, meningitis, or scalp abscesses requires cultures of blood, CSF, and joint aspirate. Specimens obtained from the conjunctiva, vagina, oropharynx, and rectum are useful for identifying the primary site(s) of infection. Antimicrobial susceptibility testing of all isolates should be performed. Positive Gram-stained smears of exudate, CSF, or joint aspirate provide a presumptive basis for initiating treatment for N. gonorrhoeae. Gonococcal infections among infants and children Sexual abuse is the most frequent cause of gonococcal infection in infants and children. For preadolescent girls, vaginitis is the most common manifestation of this infection; gonococcal-associated PID after vaginal infection can be less common in preadolescents than adults. Among sexually abused children, anorectal and pharyngeal infections with N. gonorrhoeae are frequently asymptomatic.

CHLAMYDIA Chlamydial infections among neonates Prenatal screening and treatment of pregnant women is the best method for preventing chlamydial infection among neonates. C. trachomatis infection of neonates results from perinatal exposure to the mother’s infected cervix. Initial C. trachomatis neonatal infection involves the mucous membranes of the eye, oropharynx, urogenital tract, and rectum, although infection might be asymptomatic in these locations. Instead, C. trachomatis infection in neonates is most frequently recognized by conjunctivitis that develops 5–12 days after birth. C. trachomatis also can cause a subacute, afebrile pneumonia with onset at ages 1–3 months. Ophthalmia neonatorum caused by C. trachomatis This infection is transmitted vaginally from an infected mother, and can present within the first 15 days of life. One-third of neonates exposed to the pathogen during delivery may be affected. Symptoms include conjunctival injection, various degrees of ocular discharge, and swollen eyelids. The diagnostic standard is to culture a conjunctival swab from an everted eyelid, using a Dacron swab or another swab specified for this culture. The culture must contain epithelial cells; exudates are not sufficient. The recommended treatment is oral erythromycin. Prophylaxis with silver nitrate solution or antibiotic ointments does not prevent vertical perinatal transmission of C. trachomatis, but it will prevent ocular gonococcal infection and should therefore be administered. Treatment of ophthalmia neonatorum Recommended Regimen: Erythromycin Alternative Regimen: Azithromycin

Infant pneumonia caused by C. trachomatis Chlamydia pneumonia in infants typically occurs at 1–3 months and is a subacute pneumonia. Characteristic signs of chlamydial pneumonia in infants include: 1) a repetitive staccato cough with tachypnea and 2) hyperinflation and bilateral diffuse infiltrates on a chest radiograph. In addition, peripheral eosinophilia (≥400 cells/mm3) occurs frequently. Because clinical presentations differ, all infants aged 1–3 months suspected of having pneumonia (especially those whose mothers have a history of chlamydial infection) should be tested for C. trachomatis and treated if infected.

GENITOURINARY TRACT INFECTIONS

Specimens for chlamydial testing should be collected from the nasopharynx. Tissue culture is the definitive standard diagnostic test for chlamydial pneumonia. Nonculture tests (e.g., DFA and NAAT) can be used. Tracheal aspirates and lung biopsy specimens, if collected, should be tested for C. trachomatis. Ocular C. trachomatis infection occurs in three distinct disease patterns: ophthalmia neonatorum/neonatal conjunctivitis (described above), adult inclusion conjunctivitis, and trachoma.

ADULT INCLUSION CONJUNCTIVITIS This acute mucopurulent conjunctival infection is associated with concomitant genitourinary tract chlamydia infection. If the diagnosis is suspected, a specimen from an everted lid collected using a Dacron swab should be sent for culture. Special culture media are required. Treatment consists of doxycycline or erythromycin. TRACHOMA Trachoma is a chronic or recurrent ocular infection that leads to scarring of the eyelids. This scarring often inverts the eyelids, causing abnormal positioning of the eyelashes that can scratch and damage the bulbar conjunctiva. Trachoma is the primary source of infectious blindness in the world, affecting primarily the rural poor in Asia and Africa. The initial infection is usually contracted outside of the neonatal period. It is easily spread via direct contact, poor hygiene, and flies. Although it has been eradicated in the United States, physicians may encounter cases in immigrants from endemic areas or during global health work. Treatment has focused primarily on antibiotics. Topical treatment is not effective. Mass community treatment, in which all members of a community receive antibiotics, has been found to be effective for up to two years following treatment, but recurrence and scarring remain problematic.

Selected Differential Diagnosis of Genital Lesions CHARACTERISTICS OF GENITAL DISORDER OR DISEASE LESION ETIOLOGY

Primary syphilis: chancre Solitary, painless ulcer with Treponema indurated border pallidum

Secondary syphilis: Slightly raised or flat, round or T. pallidum condyloma latum oval papules covered by gray exudate

Genital herpes Cluster of shallow, small, Herpes simplex painful ulcers on a red base virus

Chancroid Painful ulcer with sharp, Haemophilus undermined borders ducreyi

Venereal warts Soft, usually painless skin- Human colored or red papules papillomavirus

GENITOURINARY TRACT INFECTIONS

CHARACTERISTICS OF GENITAL DISORDER OR DISEASE LESION ETIOLOGY

Lymphogranuloma Painless papule, shallow Chlamydia venereum: primary stage erosion, or ulcer; may be trachomatis multiple or single

Diseases Characterized by Urethritis and Cervicitis Urethritis Urethritis, as characterized by urethral inflammation, can result from infectious and noninfectious conditions. Symptoms, if present, include dysuria; urethral pruritis; and mucoid, mucopurulent, or purulent discharge. Signs of urethral discharge on examination can also be present in persons without symptoms. Although N. gonorrhoeae and C. trachomatis are well established as clinically important infectious causes of urethritis, Mycoplasma genitalium has also been associated with urethritis and, less commonly, prostatitis. Etiology Several organisms can cause infectious urethritis. The presence of Gram-negative intracellular GN intracellular diplococci on urethral smear is indicative of presumed gonorrhea infection, which is frequently accompanied by chlamydial infection. NGU, which is diagnosed when microscopy of urethral secretions indicates inflammation without intracellular diplococci, is caused by C. trachomatis in 15%–40% of cases; however, prevalence varies by age group, with a lower burden of disease occurring among older men. Complications of C. trachomatis-associated NGU among males include epididymitis, prostatitis, and reactive arthritis. M. genitalium, can be sexually transmitted, is associated with symptoms of urethritis as well as urethral inflammation However, FDA-approved diagnostic tests for M. genitalium are not available. T. vaginalis can cause NGU in heterosexual men, but the prevalence varies substantially by region and within specific subpopulations. In some instances, NGU can be acquired by fellatio (i.e., oral penile contact), sometimes because of specific pathogens such as HSV, Epstein Barr Virus (EBV), and adenovirus. Enteric bacteria have been identified as an uncommon cause of NGU and might be associated with insertive anal intercourse.

LYMPHOGRANULOMA VENEREUM (LGV) Lymphogranuloma venereum (LGV) is caused by C. trachomatis serovars L1, L2, or L3. The most common clinical manifestation of LGV among heterosexuals is tender inguinal and/or femoral lymphadenopathy that is typically unilateral. A self-limited genital ulcer or papule sometimes occurs at the site of inoculation. However, by the time patients seek care, the lesions have often disappeared. Rectal exposure in women or MSM can result in proctocolitis mimicking inflammatory bowel disease, and clinical findings may include mucoid and/or hemorrhagic rectal discharge, anal pain, constipation, fever, and/or tenesmus. Outbreaks of LGV protocolitis have been reported among MSM (men having sex with men). LGV can be an invasive, systemic infection, and if it is not treated early, LGV proctocolitis can lead to chronic colorectal fistulas and strictures; reactive arthropathy has also been reported. However, reports indicate that rectal LGV can be asymptomatic. Persons with genital and colorectal LGV lesions can also develop secondary bacterial infection or can be coinfected with other sexually and nonsexually transmitted pathogens.

Diagnostic Considerations Diagnosis is based on clinical suspicion, epidemiologic information, and the exclusion of other etiologies for proctocolitis, inguinal lymphadenopathy, or genital or rectal ulcers. Genital lesions, rectal specimens,

GENITOURINARY TRACT INFECTIONS and lymph node specimens (i.e., lesion swab or bubo aspirate) can be tested for C. trachomatis by culture, direct immunofluorescence, or nucleic acid detection. MSM presenting with protocolitis should be tested for chlamydia; NAAT performed on rectal specimens is the preferred approach to testing. Additional molecular procedures (e.g., PCR-based genotyping) can be used to differentiate LGV from non-LGV C. trachomatis in rectal specimens. Chlamydia serology (complement fixation titers >1:64 or microimmunofluorescence titers >1:256) might support the diagnosis of LGV in the appropriate clinical context. Comparative data between types of serologic tests are lacking, and the diagnostic utility of these older serologic methods has not been established. Serologic test interpretation for LGV is not standardized, tests have not been validated for clinical proctitis presentations, and C. trachomatis serovar-specific serologic tests are not widely available. Treatment At the time of the initial visit (before diagnostic tests for chlamydia are available), persons with a clinical syndrome consistent with LGV, including proctocolitis or genital ulcer disease with lymphadenopathy, should be presumptively treated for LGV. Treatment cures infection and prevents ongoing tissue damage, although tissue reaction to the infection can result in scarring. Buboes might require aspiration through intact skin or incision and drainage to prevent the formation of inguinal/femoral ulcerations. Recommended treatment: Doxycycline Alternative treatment: Erythromycin

Although clinical data are lacking, azithromycin is probably effective based on its chlamydial antimicrobial activity. Fluoroquinolone-based treatments also might be effective, but the optimal duration of treatment has not been evaluated.