Viral Diseases of the Reproductive System

Genital Herpes

Herpes genitalis (or genital herpes) refers to a genital infection by Herpes simplex virus.

Learning Objectives

Recognize the causes and symptoms of herpes simplex virus (HSV) 1 and 2

Key Takeaways

Key Points

  • Although genital herpes is largely believed to be caused by HSV-2, genital HSV-1 infections are increasing and now exceed 50% in certain populations.
  • In males, symptoms of genital herpes include lesions that occur on the glans penis, shaft of the penis or other parts of the genital region, on the inner thigh, buttocks, or anus. In females, lesions appear on or near the pubis, labia, clitoris, vulva, buttocks or anus.
  • Presently, genital herpes cannot be cured. Moreover, genital herpes can be transmitted by viral shedding prior to and following the visual signs of symptoms. There are however some drugs that can shorten outbreaks and make them less severe or even stop them from happening.

Key Terms

  • acyclovir: An antiviral drug used in the treatment of genital herpes.
  • viral shedding: the successful reproduction, expulsion, and host-cell infection caused by virus progeny.

Herpes genitalis (or genital herpes) refers to a genital infection by Herpes simplex virus. Following the classification HSV into two distinct categories of HSV-1 and HSV-2 in the 1960s, it was established that “HSV-2 was below the waist, HSV-1 was above the waist”.

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Transmission electron micrograph of herpes simplex virus.: TEM micrograph of a herpes simplex virus.

Although genital herpes is largely believed to be caused by HSV-2, genital HSV-1 infections are increasing and now exceed 50% in certain populations, and that rule of thumb no longer applies. HSV is believed to be asymptomatic in the majority of cases, thus aiding contagion and hindering containment. When symptomatic, the typical manifestation of a primary HSV-1 or HSV-2 genital infection is clusters of genital sores consisting of inflamed papules and vesicles on the outer surface of the genitals, resembling cold sores. These usually appear 4–7 days after sexual exposure to HSV for the first time. Genital HSV-1 infection recurs at rate of about one sixth of that of genital HSV-2.

In males, the lesions occur on the glans penis, shaft of the penis or other parts of the genital region, on the inner thigh, buttocks, or anus. In females, lesions appear on or near the pubis, labia, clitoris, vulva, buttocks or anus. Other common symptoms include pain, itching, and burning. Less frequent, yet still common, symptoms include discharge from the penis or vagina, fever, headache, muscle pain (myalgia), swollen and enlarged lymph nodes and malaise. Women often experience additional symptoms that include painful urination (dysuria) and cervicitis. Herpetic proctitis (inflammation of the anus and rectum) is common for individuals participating in anal intercourse.After 2–3 weeks, existing lesions progress into ulcers and then crust and heal, although lesions on mucosal surfaces may never form crusts. In rare cases, involvement of the sacral region of the spinal cord can cause acute urinary retention and one-sided symptoms and signs of myeloradiculitis (a combination of myelitis and radiculitis): pain, sensory loss, abnormal sensations (paresthesia) and rash. Historically this has been termed Elsberg syndrome, although this entity is not clearly defined.

Treatment

Medical research has not been able to find a way to halt the spread of herpes and the number of infected people keeps growing. In the United States alone, 45 million people are infected, with an additional one million new infections occurring every year. Presently, genital herpes cannot be cured. Moreover, genital herpes can be transmitted by viral shedding prior to and following the visual signs of symptoms. There are however some drugs that can shorten outbreaks and make them less severe or even stop them from happening.

Among these drugs are: acyclovir, valacyclovir and famciclovir.Acyclovir is an antiviral drug used against herpes viruses, varicella-zoster, and Epstein-Barr Viruses. This drug reduces the pain and the number of lesions in the initial case of genital herpes. Furthermore, it decreases the frequency and severity of recurrent infections. It comes in capsules, tablets, suspension, injection, powder for injection, and ointment. The ointment is used topically and it decreases pain, reduces healing time, and limits the spread of the infection.Valacyclovir is also used to treat herpes virus infections. Once in the body, it becomes the anti-herpes medicine, acyclovir. It helps relieve the pain and discomfort and the sores heal faster. It only comes in caplets and its advantage is that it has a longer duration of action than acyclovir. Famciclovir is another antiviral drug that belongs to the same class of acyclovir and valacyclovir. Famciclovir is a prodrug that is converted to penciclovir in the body. The latter is the one active against the viruses. This drug has a longer duration of action than acyclovir and it only comes in tablets.

Genital Warts

Genital warts is a highly contagious sexually transmitted disease caused by some sub-types of human papillomavirus (HPV).

Learning Objectives

List the causes and various management procedures for genital warts

Key Takeaways

Key Points

  • Warts are the most easily recognized symptom of genital HPV infection, where types 6 and 11 are responsible for 90% of genital warts cases.
  • Genital warts spread through direct skin-to-skin contact during oral, genital, or anal sex with an infected partner.
  • Genital warts, histopathologically, characteristically rise above the skin surface due to enlargement of the dermal papillae, have parakeratosis and the characteristic nuclear changes typical of HPV infections (nuclear enlargement with perinuclear clearing).
  • There is no cure for HPV, but there are methods to treat visible warts, which could reduce infectivity, although there are no trials studying the effectiveness of removing visible warts in reducing transmission.

Key Terms

  • human papillomavirus: A virus that affects humans, sometimes causing cervical or other cancer; it is sometimes classified as a sexually transmitted disease.

Genital warts (or Condylomata acuminata, venereal warts, anal warts and anogenital warts) is a highly contagious sexually transmitted disease caused by some sub-types of human papillomavirus (HPV ). It is spread through direct skin-to-skin contact during oral, genital, or anal sex with an infected partner. Throat, mouth, and eye genital warts can also be transmitted through oral, genital, or anal sex. Warts are the most easily recognized symptom of genital HPV infection, where types 6 and 11 are responsible for 90% of genital warts cases.

Although it is estimated that only a “small percentage” (between 1% and 5%) of those infected with genital HPV develop genital warts, those infected can still transmit the virus. Other types of HPV also cause cervical cancer and probably most anal cancers, however it is important to underline that the types of HPV that cause the overwhelming majority of genital warts are not the same as those that can potentially increase the risk of genital or anal cancer. HPV prevalence at any one time has been observed in some studies at 27% over all sexually active people, rising to 45% between the ages of 14 and 19.

Diagnosis

Genital warts, histopathologically, characteristically rise above the skin surface due to enlargement of the dermal papillae, have parakeratosis and the characteristic nuclear changes typical of HPV infections (nuclear enlargement with perinuclear clearing).

Prevention

Gardasil (sold by Merck & Co.) is a vaccine that protects against human papillomavirus types 16, 18, 6, and 11. Types 6 and 11 cause genital warts, while 16 and 18 cause cervical cancer. The vaccine is preventive, not therapeutic, and must be given before exposure to the virus type to be effective, ideally before the beginning of sexual activity. The vaccine is widely approved for use by young women, it is being tested for young men, and has been approved for males in some areas, such as the UK, the US and Canada.

Management

There is no cure for HPV, but there are methods to treat visible warts, which could reduce infectivity, although there are no trials studying the effectiveness of removing visible warts in reducing transmission. Every year, Americans spend $200 million on the treatment of genital warts. Genital warts may disappear without treatment, but sometimes eventually develop a fleshy, small raised growth. There is no way to predict whether they will grow or disappear.

Warts can sometimes be identified because they show up as white when acetic acid is applied, but this method is not recommended on the vulva because microtrauma and inflammation can also show up as acetowhite. Magnifying glasses or colposcope may also be used to aid in identifying small warts. Depending on the sizes and locations of warts (as well as other factors), a doctor will offer one of several ways to treat them. Podofilox is the first-line treatment due to its low cost.Almost all treatments can potentially cause depigmentation or scarring. A 0.15% – 0.5% podophyllotoxin (also called podofilox) solution in a gel or cream. Marketed as Condylox (0.5%), Wartec (0.15%) and Warticon (0.15%), it can be applied by the patient to the affected area and is not washed off. It is the purified and standardized active ingredient of the podophyllin (see below). Podofilox is safer and more effective than podophyllin. Skin erosion and pain are more commonly reported than with imiquimod and sinecatechins. Its use is cycled (2 times per day for 3 days then 4–7 days off); one review states that it should only be used for four cycles.

Imiquimod (Aldara) is a topical immune response cream, applied to the affected area. It causes less local irritation than podofilox but may cause fungal infections (11% in package insert) and flu-like symptoms (less than 5% disclosed in package insert). Sinecatechins (marketed as Veregen and Polyphenon E) is an ointment of catechins (55% epigallocatechin gallate) extracted from green tea and other components. Mode of action is undetermined. It appears to have higher clearance rates than podophyllotoxin and imiquimod and causes less local irritation, but clearance takes longer than with imiquimod. Liquid nitrogen cryosurgery is safe for pregnancy. It kills warts 71–79% of the time, but recurrence is 38% to 73% 6 months after treatment. Local infections have been reported. Trichloroacetic acid (TCA) is less effective than cryosurgery, and is not recommended for use in the vagina, cervix, or urinary meatus. Surgical excision is best for large warts, and has a greater risk of scarring. Laser ablation does not seem to be any more effective than other physician-applied methods, but is often used as a last resort and is extremely expensive. A 20% podophyllin anti-mitotic solution, applied to the affected area and later washed off. However, this crude herbal extract is not recommended for use on vagina, urethra, perianal area, or cervix, and must be applied by a physician.

Reported reactions include nausea, vomiting, fever, confusion, coma, renal failure, ileus, and leukopenia; death has been reported with extensive topical application, or application on mucous membranes. Interferon can be used; it is effective, but it is also expensive and its effect is inconsistent. Electrocauterization can be used; it is an older procedure but recovery time is generally longer. In severe cases of genital warts, treatment may require general or spinal anesthesia. This is a surgical procedure. More effective than cryosurgery and recurrence is at a much lower rate. Oral Isotretinoin is a therapy that has proven effective in experimental use, but is rarely used due to potentially severe side effects. In a small-scale study, low dose oral isotretinoin showed considerable efficacy and may represent an alternative systemic form of therapy for Genital Warts. Yet, albeit this indicative evidence not many studies have been conducted to further confirm the findings. In most countries this therapy is currently unapproved and only used as an alternative therapy if other therapies failed.

HIV and AIDS

Human immunodeficiency virus infection/acquired immunodeficiency syndrome is a disease of the human immune system caused by HIV.

Learning Objectives

Describe the mode of transmission, mechanisms of infection, treatment options, and WHO and CDC classifications for the human immunodeficiency virus (HIV)

Key Takeaways

Key Points

  • During the initial HIV infection a person may experience a brief period of influenza-like illness. This is typically followed by a prolonged period without symptoms.
  • HIV is transmitted primarily via unprotected sexual intercourse (including anal and even oral sex), contaminated blood transfusions and hypodermic needles, and from mother to child during pregnancy, delivery, or breastfeeding.
  • Abacavir, a nucleoside analog reverse transcriptase inhibitor (NARTI or NRTI) is used to treat HIV. Current HAART options are combinations (or “cocktails”) consisting of at least three medications belonging to at least two types, or “classes,” of antiretroviralagents.

Key Terms

  • immunodeficiency: A depletion in the body’s natural immune system, or in some component of it.
  • AIDS: an infectious disease, caused by HIV, that causes the gradual degeneration of the body’s immune system

Human immunodeficiency virus infection / acquired immunodeficiency syndrome (HIV/ AIDS ) is a disease of the human immune system caused by the human immunodeficiency virus (HIV ). During the initial infection a person may experience a brief period of influenza-like illness. This is typically followed by a prolonged period without symptoms. As the illness progresses it interferes more and more with the immune system, making people much more likely to get infections, including opportunistic infections, and tumors that do not usually affect people with working immune systems.

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HIV-1: Scanning electron micrograph of HIV-1, colored green, budding from a cultured lymphocyte.

HIV is transmitted primarily via unprotected sexual intercourse (including anal and even oral sex), contaminated blood transfusions and hypodermic needles, and from mother to child during pregnancy, delivery, or breastfeeding. Some bodily fluids, such as saliva and tears, do not transmit HIV. Prevention of HIV infection, primarily through safe sex and needle-exchange programs, is a key strategy to control the spread of the disease. There is no cure or vaccine; however, antiretroviral treatment can slow the course of the disease and may lead to a near-normal life expectancy. While antiretroviral treatment reduces the risk of death and complications from the disease, these medications are expensive and may be associated with side effects.

Virology

HIV is the cause of the spectrum of disease known as HIV/AIDS. HIV is a retrovirus that primarily infects components of the human immune system such as CD4+ T cells, macrophages and dendritic cells. It directly and indirectly destroys CD4+ T cells.HIV is a member of the genus Lentivirus, part of the family of Retroviridae. Lentiviruses share many morphological and biological characteristics. Many species of mammals are infected by lentiviruses, which are characteristically responsible for long-duration illnesses with a long incubation period. Lentiviruses are transmitted as single-stranded, positive-sense, enveloped RNA viruses. Upon entry into the target cell, the viral RNA genome is converted (reverse transcribed) into double-stranded DNA by a virally encoded reverse transcriptase that is transported along with the viral genome in the virus particle. The resulting viral DNA is then imported into the cell nucleus and integrated into the cellular DNA by a virally encoded integrase and host co-factors. Once integrated, the virus may become latent, allowing the virus and its host cell to avoid detection by the immune system. Alternatively, the virus may betranscribed, producing new RNA genomes and viral proteins that are packaged and released from the cell as new virus particles that begin the replication cycle anew. Two types of HIV have been characterized: HIV-1 and HIV-2. HIV-1 is the virus that was originally discovered (and initially referred to also as LAV or HTLV-III). It is more virulent, more infective, and is the cause of the majority of HIV infections globally. The lower infectivity of HIV-2 as compared with HIV-1 implies that fewer people exposed to HIV-2 will be infected per exposure. Because of its relatively poor capacity for transmission, HIV-2 is largely confined to West Africa.

Classifications of HIV infection

Two main clinical staging systems are used to classify HIV and HIV-related disease for surveillance purposes: the WHO disease staging system for HIV infection and disease, and the CDC classification system for HIV infection. The CDC’s classification system is more frequently adopted in developed countries. Since the WHO’s staging system does not require laboratory tests, it is suited to the resource-restricted conditions encountered in developing countries, where it can also be used to help guide clinical management. Despite their differences, the two systems allow comparison for statistical purposes.

The World Health Organization first proposed a definition for AIDS in 1986. Since then, the WHO classification has been updated and expanded several times, with the most recent version being published in 2007. The WHO system uses the following categories:

Primary HIV infection: May be either asymptomatic or associated with acute retroviral syndrome.

Stage I: HIV infection is asymptomatic with a CD4+ T cell count (also known as CD4 count) greater than 500/uL. May include generalized lymph node enlargement.

Stage II: Mild symptoms which may include minor mucocutaneous manifestations and recurrent upper respiratory tract infections. A CD4 count of less than 500/uL.

Stage III: Advanced symptoms which may include unexplained chronic diarrhea for longer than a month, severe bacterial infections including tuberculosis of the lung as well as a CD4 count of less than 350/uL.

Stage IV or AIDS: severe symptoms which includes toxoplasmosis of the brain, candidiasis of the esophagus, trachea, bronchi or lungs and Kaposi’s sarcoma. A CD4 count of less than 200/uL.

The United States Center for Disease Control and Prevention also created a classification system for HIV, and updated it in 2008. In this system HIV infections are classified based on CD4 count and clinical symptoms, and describes the infection in three stages:

Stage 1: CD4 count ≥ 500 cells/uL and no AIDS defining conditions

Stage 2: CD4 count 200 to 500 cells/uL and no AIDS defining conditions

Stage 3: CD4 count ≤ 200 cells/uL or AIDS defining conditions

Unknown: if insufficient information is available to make any of the above classificationsFor surveillance purposes, the AIDS diagnosis still stands even if, after treatment, the CD4+ T cell count rises to above 200 per µL of blood or other AIDS-defining illnesses are cured.

Antiviral therapy

Abacavir, a nucleoside analog reverse transcriptase inhibitor (NARTI or NRTI) is used to treat HIV. Current HAART options are combinations (or “cocktails”) consisting of at least three medications belonging to at least two types, or “classes,” of antiretroviralagents. Initially treatment is typically a non-nucleoside reverse transcriptase inhibitor (NNRTI) plus two nucleoside analogue reverse transcriptase inhibitors(NRTIs). Typical NRTIs include: zidovudine (AZT) or tenofovir (TDF) and lamivudine (3TC) or emtricitabine (FTC). Combinations of agents which include a protease inhibitors (PI) are used if the above regime loses effectiveness.

Human Papillomavirus (HPV)

Human papillomavirus (HPV) is a virus from the papillomavirus family that is capable of infecting humans.

Learning Objectives

Discuss the relationship between the human papillomavirus (HPV) and the development of cancer

Key Takeaways

Key Points

  • HPVs establish productive infections only in keratinocytes of the skin or mucous membranes.
  • While the majority of the known types of HPV cause no symptoms in most people, some types can cause warts (verrucae), while others can – in a minority of cases – lead to cancers of the cervix, vulva, vagina, penis, oropharynx and anus.
  • In more developed countries, cervical screening using a Papanicolaou (Pap) test or liquid-based cytology is used to detect abnormal cells that may develop into cancer. If abnormal cells are found, women are invited to have a colposcopy.
  • HPV vaccines (Cervarix and Gardasil), which prevent infection with the HPV types (16 and 18) that cause 70% of cervical cancer, may lead to further decreases in cervical cancer.

Key Terms

  • verrucae: warts
  • Papanicolaou (Pap) test: screening of the cervical cells used to detect abnormal cells that may develop into cancer.

Human papillomavirus (HPV) is a virus from the papillomavirus family that is capable of infecting humans. Like all papillomaviruses, HPVs establish productive infections only in keratinocytes of the skin or mucous membranes. While the majority of the known types of HPV cause no symptoms in most people, some types can cause warts (verrucae), while others can – in a minority of cases – lead to cancers of the cervix, vulva, vagina, penis, oropharynx and anus. Recently, HPV has been linked with an increased risk of cardiovascular disease. In addition, HPV 16 and 18 infections are strongly associated with an increased odds ratio of developing oropharyngeal (throat) cancer.

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EM of HPV: TEM of papillomavirus.

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.

Most HPV infections in young females are temporary and have little long-term significance. Seventy percent of infections are gone in 1 year and ninety percent in 2 years. However, when the infection persists — in 5% to 10% of infected women — there is high risk of developing precancerous lesions of the cervix, which can progress to invasive cervical cancer. This process usually takes 10–15 years, providing many opportunities for detection and treatment of the pre-cancerous lesion. Progression to invasive cancer can be almost always prevented when standard prevention strategies are applied, but the lesions still cause considerable burden necessitating preventive surgeries, which do in many cases involve loss of fertility.

In more developed countries, cervical screening using a Papanicolaou (Pap) test or liquid-based cytology is used to detect abnormal cells that may develop into cancer. If abnormal cells are found, women are invited to have a colposcopy. During a colposcopic inspection, biopsies can be taken and abnormal areas can be removed with a simple procedure, typically with a cauterizing loop or, more commonly in the developing world — by freezing (cryotherapy). Treating abnormal cells in this way can prevent them from developing into cervical cancer.

Pap smears have reduced the incidence and fatalities of cervical cancer in the developed world, but even so there were 11,000 cases and 3,900 deaths in the U.S. in 2008. Cervical cancer has substantial mortality in resource-poor areas; worldwide, there are an estimated 490,000 cases and 270,000 deaths each year.

HPV vaccines (Cervarix and Gardasil), which prevent infection with the HPV types (16 and 18) that cause 70% of cervical cancer, may lead to further decreases.