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15.23G: Genital Ulcer Diseases - Biology

15.23G: Genital Ulcer Diseases - Biology


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Genital ulcers are skin ulcers on the genital area caused by sexually transmitted diseases or noninfectious conditions.

Learning Objectives

  • List the causes and symptoms of genital ulcers

Key Points

  • The most common STDs that present with genital ulcers are genital herpes, syphilis, chlamydia and chancroid.
  • Other than ulceration, enlarged lymph nodes in the groin area may be present, along with blisters and sores.
  • To improve the outcome, treatment often starts before identification is complete, with medications chosen based on symptoms and epidemiological circumstances.

Key Terms

  • Behcet’s syndrome: Behcet’s syndrome, or Behcet’s disease, is an immune disorder that leads to inflammation of the blood vessels. Common symptoms include mouth and genital ulcers, as well as ocular issues.

Genital ulcers are skin ulcers located on the genital area and can be caused by a number of sexually transmitted diseases or other noninfectious conditions such as yeasts, trauma, lupus, rheumatoid arthritis or Behcet’s syndrome.

Sexually Transmitted Genital Ulcers

When the reason for a genital ulcer is an infection, it can be caused by a number of sexually transmitted diseases. Among the most common are Herpes simplex virus (HSV), the genital herpes agent; Treponema pallidum, that causes syphilis; Chlamydia trachomatis, the cause of chlamydia; and Haemophilus ducreyi, the chancroid agent. In the United States, the most common reasons for genital ulcers in young and sexually active patients are genital herpes and syphilis.

Symptoms and Diagnosis

Genital ulcers can be painful or painless depending on the type of infection. Their appearance can be slightly different from one disease to another. Other than ulceration, enlarged lymph nodes in the groin area can be present, along with blisters and sores. Proper diagnosis cannot be obtained solely through examination and medical history. Testing for a specific infectious agent depends on the likelihood of its presence. In the U.S., testing is recommended for syphilis (by serology and darkfield microscopy) and HSV (culture, serology or PCR), and in cases of chancroid outbreaks or based on the medical history, for the presence of Haemophilus ducreyi. In about 25% of the cases, the reason for the ulcer will not be identified by laboratory testing. Syphilis, genital herpes and chancroid have all been associated with increasing the risk for HIV transmission. The CDC recommends routine HIV screening for all patients who present with genital ulcers.

Treatment

Since the ulcers are symptoms of a number of infectious agents, the treatment is chosen according to the disease agent if it can be identified. Quite often, therapy has to start before identification is complete in order to decrease the chances for transmission and to increase the probability of successful treatment. The choice of medication is made, after careful examination of the symptoms and all epidemiological circumstances, based on the most likely causative agent.


15.23G: Genital Ulcer Diseases - Biology

While sexually transmitted diseases (STDs) affect individuals of all ages, STDs take a particularly heavy toll on young people. CDC estimates that youth ages 15-24 make up just over one quarter of the sexually active population, but account for half of the 20 million new sexually transmitted infections that occur in the United States each year. Many infections are asymptomatic. When a person is infected with a sexually transmitted pathogen and does not show signs or symptoms that person is said to have a sexually transmitted infection (STI). Although STIs and STDs are caused by the same pathogen, they differ as whether symptoms are present.

STDs/STIs can be transmitted by the following activities (depending upon the type of pathogen)

Common Types of std/i

Bacterial vaginosis (BV), a common cause of vaginal discharge in women of childbearing age, is a polymicrobial clinical syndrome resulting from a change in the vaginal community of bacteria. Although BV is often not considered an STD, it has been linked to sexual activity. Women may have no symptoms or may complain of a foul-smelling, fishy, vaginal discharge.

Chlamydia is a common sexually transmitted disease (STD) caused by infection with Chlamydia trachomatis. It can cause cervicitis in women and urethritis and proctitis in both men and women. Chlamydial infections in women can lead to serious consequences including pelvic inflammatory disease (PID), tubal factor infertility, ectopic pregnancy, and chronic pelvic pain. Lymphogranuloma venereum (LGV), another type of STD caused by different serovars of the same bacterium, occurs commonly in the developing world, and has more recently emerged as a cause of outbreaks of proctitis among men who have sex with men (MSM) worldwide. 1,2

Gonorrhea is a sexually transmitted disease (STD) that can infect both men and women. It can cause infections in the genitals, rectum, and throat. It is a very common infection, especially among young people ages 15-24 years.

Genital herpes is an STD caused by two types of viruses. The viruses are called herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2).Oral herpes is usually caused by HSV-1 and can result in cold sores or fever blisters on or around the mouth. However, most people do not have any symptoms. Most people with oral herpes were infected during childhood or young adulthood from non-sexual contact with saliva. Oral herpes caused by HSV-1 can be spread from the mouth to the genitals through oral sex. This is why some cases of genital herpes are caused by HSV-1.Genital herpes is common in the United States. More than one out of every six people aged 14 to 49 years have genital herpes.

Human Papillomavirus (HPV) is the most common sexually transmitted infection (STI). HPV is a different virus than HIV and HSV (herpes). 79 million Americans, most in their late teens and early 20s, are infected with HPV. There are many different types of HPV. Some types can cause health problems including genital warts and cancers. But there are vaccines that can stop these health problems from happening.

Syphilis is a sexually transmitted infection that can cause serious health problems if it is not treated. Syphilis is divided into stages (primary, secondary, latent, and tertiary), with different signs and symptoms associated with each stage. A person with primary syphilis generally has a sore or sores at the original site of infection. These sores usually occur on or around the genitals, around the anus or in the rectum, or in or around the mouth. These sores are usually (but not always) firm, round, and painless. Symptoms of secondary syphilis include skin rash, swollen lymph nodes, and fever. The signs and symptoms of primary and secondary syphilis can be mild, and they might not be noticed. During the latent stage, there are no signs or symptoms. Tertiary syphilis is associated with severe medical problems. A doctor can usually diagnose tertiary syphilis with the help of multiple tests. It can affect the heart, brain, and other organs of the body.

Trichomoniasis (or “trich”) is a very common sexually transmitted disease (STD). It is caused by infection with a protozoan parasite called Trichomonas vaginalis. Although symptoms of the disease vary, most people who have the parasite cannot tell they are infected.T richomoniasis is the most common curable STD. In the United States, an estimated 3.7 million people have the infection. However, only about 30% develop any symptoms of trichomoniasis. Infection is more common in women than in men. Older women are more likely than younger women to have been infected with trichomoniasis.


Laboratory Diagnosis of Sexually Transmitted Diseases (STDs)

In this article we will discuss about the laboratory diagnosis of various sexually transmitted diseases (STDs). The various sexually transmitted diseases whose diagnosis has been discussed are: 1. Urethritis 2. Genital Ulcers 3. Vaginal Discharge.

Sexually Transmitted Disease # 1. Urethritis:

Causative agents of urethritis are listed in Table 16.1:

Laboratory diagnosis:

Urethral, vaginal, cervical, and anal exudates are examined and cultured.

Gram-stained smear of discharge reveal abun­dant pus cells (polymorphonuclear leucocytes). About one in twenty of the pus cells, contains plenty of bean-shaped Gram-negative intracytoplasmic diplococci.

A positive smear is virtually diagnostic of gonococci.

It is sometimes difficult to interpret the smear finding in mixed normal flora in females. Veillonella parvula is also a Gram-negative diplo-coccus normally present in vaginal flora.

Moreover, asymptomatic carriage is high in females, especially with endocervical lesion. Hence positive identi­fication of the organism by culture or immuno-fluorescent study using genetic probes (e.g. DNA probe) is necessary to confirm the diagnosis.

2. Trichomoniasis:

A direct wet film of freshly collected specimen shows motile trichomonad with polymorphonuclear leucocytes.

Microscopical examination of vaginal secretions in 10% potassium hydroxide show yeast cells.

4. Non-gonococcal urethritis:

Smear stained by Giemsa stain shows intracytoplasmic inclusion bodies, suggestive of C. trachomatis. When diagnosis of C. trachomatis cannot be made by light microscopy, a definitive diagnosis is to be made by either culture or by anti­gen detection.

Specimen is inoculated into McCoy or HeLa cell tissue cultures. Tissue culture is not routinely available.

(iii) Detection of antigen:

Smear made from exu­date is examined by immunofluorescence test with a monoclonal antibody or by ELISA to detect LPS antigens (either soluble or in the elementary body cell wall) of C. trachomatis.

Sexually Transmitted Disease # 2. Genital Ulcers:

1. Hard chancre (Syphilis) — by T. pallidum

2. Soft chancre (Chancroid) – by H. ducreyi

3. Herpes progenitalis – by Herpes simplex virus types 1 and 2, primarily type 2.

4. Donovanosis (granuloma inguinale) – by Calymmatobacterium granulomatis.

5. Lymphogranuloma venereum – by C. tracho­matis types L1, L2, L3.

Laboratory diagnosis — See Table 16.2.

(i) Dark-field microscopy of specimen collected from a syphilitic primary chancre as well as secon­dary rash may reveal motile Treponema pallidum.

(ii) Gram stain of exudate from cases of chancroid may show Gram-negative ovoid bacilli. The bacte­ria en mass have configuration of “shoals of fish”.

(iii) Giemsa/Wright staining of exudate of geni­tal herpes often show multinucleated giant cells or intra-nuclear inclusions.

Chlamydiae though Gram-negative, but they stain well by Castaneda’s method and Giemsa stain. The inclusions in cell culture are stained by both the stains well.

In donovanosis, Donovan bodies (round cocco- bacilli, 1 x 2 μm) may be found in smear from ulcer stained by Giemsa stain. The Donovan bodies lie within the cystic spaces in the cytoplasm of large mononuclear cells. Capsule appears as a dense aci­dophilic zone around the bacterium, resembling a closed safety pin or “telephone handle”.

Syphilis is diagnosed in most pa­tients on the basis of serological tests. Positive re­sult is obtained from about two weeks after the appearance of primary sore.

Two types of tests: non­specific (non-treponemal) and specific (trepo­nemal) tests are used (Table 16.3):

Non-treponemal tests mea­sure IgG and IgM antibodies (known as reagin antibodies) produced against lipids released from damaged cells during the early stage of the disease which are also present on cell surface of treponemes.

(b) Specific or treponemal tests:

These are used to confirm positive VDRL or RPR tests. The most commonly used treponemal tests are FTA-ABS test and MHA-TP test. These tests can become positive before the non-treponemal tests in early syphilis, or remain positive when the non-treponemal tests revert to negative in some patients with late syphi­lis.

Western blot test using whole cell T. pallidum as antigen has recently been used successfully to con­firm non-treponemal tests. VDRL and TPHA are more useful tests for diag­nosis of syphilis in most laboratories. When these tests are done together, they provide an effective screen for early and late syphilis.

Serological tests (e.g. CFT) with patient’s HSV infection. The antibody titre is usually within 32, especially in genital herpes.

1. Syphilis is best treated with large doses of penicillin. Long-acting benzathine penicillin is recommended in early syphilis, and penicillin G for congenital and late syphilis. Tetracycline and doxycycline’s are alternative drugs.

2. Herpes simplex can be treated with acyclovir.

3. Chancroid is treated with sulfonamides or aminoglycosides.

Sexually Transmitted Disease # 3. Vaginal Discharge:

Causes include gonorrhoea, infection due to C. tracho­matis, bacterial vaginosis, trichomonas vaginalis and Vulvovaginal candidiasis.

The vaginal discharge may be due to more than one of the above mentioned microorganisms.

Laboratory diagnosis:

1. pH — greater than 4.5.

When vaginal fluid is mixed with a 10% solution of KOH, fishy odor is immediately liberated. The odor is due to volatile amines present in vaginal fluid.

Vaginal discharge contains clue cells (squamous epithelial cells coated with coccobacillary organisms). Leucocytes are virtually absent.

The normal vaginal flora of lacto- bacilli in vagina is largely replaced by G. vaginalis and other anaerobes.


Structure of the herpes simplex virus type 2 C-capsid with capsid-vertex-specific component

Herpes simplex viruses (HSVs) cause human oral and genital ulcer diseases. Patients with HSV-2 have a higher risk of acquiring a human immunodeficiency virus infection. HSV-2 is a member of the α-herpesvirinae subfamily that together with the β- and γ-herpesvirinae subfamilies forms the Herpesviridae family. Here, we report the cryo-electron microscopy structure of the HSV-2 C-capsid with capsid-vertex-specific component (CVSC) that was determined at 3.75 Å using a block-based reconstruction strategy. We present atomic models of multiple conformers for the capsid proteins (VP5, VP23, VP19C, and VP26) and CVSC. Comparison of the HSV-2 homologs yields information about structural similarities and differences between the three herpesviruses sub-families and we identify α-herpesvirus-specific structural features. The hetero-pentameric CVSC, consisting of a UL17 monomer, a UL25 dimer and a UL36 dimer, is bound tightly by a five-helix bundle that forms extensive networks of subunit contacts with surrounding capsid proteins, which reinforce capsid stability.

Conflict of interest statement

The authors declare no competing interests.

Figures

Architecture of the HSV-2 C-capsid.…

Architecture of the HSV-2 C-capsid. a Surface representation of HSV-2 C-capsid. The table…

Structural comparison of the pentonal…

Structural comparison of the pentonal vertex of α-, β-, and γ-herpesviruses. Surface representations…

The CVSC structure. a Cryo-EM…

The CVSC structure. a Cryo-EM densities of the CVSC surrounding a pentonal vertex.…

Interactions between CVSC and surrounding…

Interactions between CVSC and surrounding capsid proteins. The CVSC is shown as cartoon…


A third of new sexually transmitted HIV infections directly due to infection with herpes simplex

Approximately 30% of new sexually transmitted HIV infections can be attributed to herpes simplex virus-2 (HSV-2), according to research published in The Lancet Infectious Diseases. Africa was the world region with the highest proportion of incident HIV attributable to HSV-2, followed by the Americas. The investigators, led by Dr Katherine Looker of Bristol University Medical School, suggest that interventions to treat and prevent HSV-2 would not only improve the quality of millions of people's lives, but also have a tangible impact on the spread of HIV.

“These estimates are useful for understanding the potential magnitude of the contribution of HSV-2 infection to HIV, which can help stimulate the development of new interventions and guide where future prevention efforts would be best targeted for optimal effect,” comment the authors. “New interventions against HSV-2, such as vaccines, new antivirals, or microbicides, have the potential to substantially reduce genital ulcer disease, which affects millions of people worldwide."

An estimated 42 million people globally have HSV-2, a lifelong STI that can cause recurrent, painful genital ulcers. Prevalence of the infection is highest in Africa where an estimated 31% of adults carry the infection. There is also a high burden of HIV infection in this region.

Glossary

A viral infection which may cause sores around the mouth or genitals.

A drug that acts against a virus or viruses.

Any of several diseases that are characterised by genital sores, blisters or lesions. Genital ulcer diseases (including genital herpes, syphilis and chancroid) are usually sexually transmitted.

The study of the causes of a disease, its distribution within a population, and measures for control and prevention. Epidemiology focuses on groups rather than individuals.

A product (such as a gel or cream) that is being tested in HIV prevention research. It could be applied topically to genital surfaces to prevent or reduce the transmission of HIV during sexual intercourse. Microbicides might also take other forms, including films, suppositories, and slow-releasing sponges or vaginal rings.

In 2017, Dr Looker and colleagues conducted a meta-analysis of 55 prospective studies which showed that the risk of infection with HIV was tripled for people with HSV-2 infection, and quadrupled for individuals with recently acquired HSV-2.

Risk is increased because the ulcers caused by HSV-2 infection provide a direct physical route of entry for HIV in an uninfected person. Another factor is the immune system's response to HSV-2 infection – activated T-cells and dendritic cells, which are prone to HIV infection, are present in significant numbers at the site of the herpes infection.

Dr Looker wanted to build on their previous research by calculating the proportion of new sexually transmitted HIV cases (incident infections) attributable to infection with HSV-2: the population attributable fraction (PAF). They did this by looking at global epidemiological data from 2016. The calculations also took account of established risk factors for HIV acquisition. Analysis was restricted to individuals aged between 15 and 49 years.

In 2016, there were an estimated 1.4 million incident sexually transmitted new HIV infections among 15 to 49 year olds. The investigators calculated that 420,000 of these infections (30%) were due to HSV-2.

The proportion of HSV-2 attributable infections was highest for the African region (37%), followed by the Americas (21%). In all other regions, the proportion of new HIV infections due to HSV-2 was estimated to be between 11 and 13%.

The percentage of new HIV infections due to HSV-2 was higher among women than men (36% vs 26%) and among individuals aged between 25 and 49 years compared to those in the 15 to 24 years age group (32% v 23%). This was due to underlying trends in the epidemiology of HSV-2, with prevalence being higher among women and older adults.

"Innovative treatments and technologies are needed for the prevention, treatment and control of HSV-2."

Just over a quarter (27%) of new HIV infections among female sex workers were due to HSV-2. A fifth of incident HIV cases in men who have sex with men (MSM) were attributed to HSV-2.

An editorial comment on the paper suggests that the proportion of HIV infections due to HSV-2 could be even higher when onward transmission among key risk groups such as gay and other MSM is taken into account.

Only 4% of incident HIV infections were due to recently acquired HSV-2. “This finding can be explained by many more people having established than recently-acquired HSV-2, especially at older ages,” write the authors.

Find out more: Herpes

The investigators believe their findings show the importance of public health interventions to control HSV-2. But they note that research looking at existing antiviral treatment for HSV-2 found that it had no effect on HIV infections. This is possibly because the drugs used in the study had insufficient impact on levels of cells susceptible to HIV in skin tissue around HSV-2 lesions. Innovative treatments and technologies are therefore needed for the prevention, treatment and control of HSV-2.

“New, more effective interventions could hold more promise for translating an effect on HSV-2 infection or shedding and disease into gains for reduction of HIV incidence,” conclude Dr Looker and her colleagues. “A potential indirect effect of interventions against HSV-2 on HIV incidence will need to be evaluated in the context of existing HIV prevention interventions and for new interventions against HSV-2, particularly HSV-2 vaccines. Our estimates suggest that HSV-2 prevention measures could be an important additional tool in the fight against HIV.”

Mishra S et al. Rethinking the population attributable factor for infectious diseases. The Lancet Infectious Diseases, online ahead of print, 2019 (open access).


Etiology of Genital Ulcer Disease in Dakar, Senegal, and Comparison of PCR and Serologic Assays for Detection of Haemophilus ducreyi

Fig. 1 . Characterization of insert in pHDH1A4S, the target sequence for the H. ducreyi recD PCR showing homology to H. influenzae. (A) Map of the insert of pHDH1A4S, showing the locations of HaeIII sites and the target sequence for primers SJ1A and SJ2A. The location in the insert of the pHD probe used to detect the H. ducreyi specific PCR product is also shown. (B) Nucleotide comparison of sequences in theH. ducreyi amplicon and H. influenzae genomic sequences (GenBank accession number HIU32811). Numbers to the left reflect nucleotides numbered from the start of SJ1A (H. ducreyi) and as published for the H. influenzae genome (15). Vertical lines indicate homology in nucleotides fromH. ducreyi and H. influenzae. The sequence of theH. ducreyi amplicon has been deposited in GenBank under the accession number AF090193.



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