Herpes Simplex In-Depth

Introduction

Herpes simplex virus (HSV) is a common cause of infections of the skin and mucous membranes and an uncommon cause of more serious infections in other parts of the body. HSV is one of the most difficult viruses to control and has plagued mankind for thousands of years.

Herpes simplex is part of a group of other herpes viruses that include human herpesvirus 8 (the cause of Kaposi's sarcoma) and herpes zoster (the virus responsible for shingles and chicken pox). They differ in many ways, but they share certain characteristics, notably the word "herpes," which is derived from a Greek word meaning "to creep." This refers to the unique characteristic pattern of all herpes viruses to "creep along" local nerve pathways to the nerve clusters at the end, where they remain in an inactive state for some indeterminate time.

There are two forms of the herpes simplex virus:

• Herpes simplex virus 1 (HSV-1)
• Herpes simplex virus 2 (HSV-2)

These viruses are distinguished by different proteins on their surfaces. They can occur separately, or they can both infect the same individual. Until recently, the general rule has been to assume that HSV-1 infections occur in the oral cavity (mouth) and are not sexually transmitted, while HSV-2 attacks the genital area and is sexually transmitted. It is now widely accepted, however, that either type can be found in either area and at other sites. In fact, in new cases of genital herpes the number of HSV-1 cases now matches and even exceeds that of HSV-2.

The Disease Process

To achieve an initial infection, the following conditions must apply:

• The herpes simplex virus requires transportation in bodily fluids (saliva, semen, fluid in the female genital tract) or in fluid from herpes sores.
• The virus must have direct access to the noninfected person through injuries in their skin or mucus surfaces (such as in the mouth or genital area).

When HSV enters the body, the infection process typically takes place as follows:

• The virus penetrates vulnerable cells in the lower layers of skin tissue and attempts to replicate itself in the cell nuclei. Scientists are close to decoding the genetic structure of HSV and to discovering how the virus works its way into specific cells. They think that specially shaped proteins called cell adhesion molecules may facilitate the entry of HSV into healthy cells. For example, protein receptors on cells called nectin 1 and 2 may bind to some subtypes of HSV and promote the transmission of the infection from cell to cell.
• Even after it has penetrated the cells, the virus never causes symptoms in most cases.
• However, if the HSV's replication process destroys the host cells, symptoms erupt in the form of inflammation and fluid-filled blisters or ulcers. Once the fluid is absorbed, scabs form and the blisters disappear without scarring.
• After the initial replication, the viral particles are carried from the skin through branches of nerve cells to clusters at the nerve-cell ends (the dorsal root ganglia).
• Here, the virus persists in an inactive (latent) form. The virus does not replicate, but both the host cells and the virus survive.
• At unpredictable times, the virus begins multiplying again. It then goes through a period called shedding. During those times, the virus can be passed into bodily fluids and infect other people. Unfortunately, a third to half of the times shedding occurs without any symptoms at all.
• Eventually, the symptoms do recur in nearly all cases, causing a new outbreak of blisters and sores.

This close-up view of early herpes outbreak shows small, grouped blisters (vesicles) and lots of inflammation (erythema).

Symptoms

Symptoms vary depending on the stage of the virus, the initial or primary outbreak, and recurrence. Both herpes simplex viruses 1 and 2 produce similar symptoms, but they can differ in severity depending on the site of infection. More than 60% of new HSV-2 infections and about a third of new HSV-1 infections do not produce symptoms.

General Symptoms of a First (Primary) Herpes Simplex Infection

Skin Eruptions and Pain. The first time a person experiences a herpes simplex outbreak, skin eruptions appear 2 - 12 days after the initial exposure to the virus.

• The first sign of infection is fluid accumulation (edema) at the infection site, which is quickly followed by small, grouped blisters -- the characteristic HSV lesions.
• These form on an inflamed skin base, which is more visible in dry skin areas.
• The blisters then dry out and heal rapidly without scarring within 7 - 10 days. Blisters in moist areas heal more slowly than others. The lesions may sometimes itch, but itching decreases as lesions heal.
• When the crust falls off, the lesions are no longer contagious. (The virus may still be active in nearby tissue, but such persistence is rare.)
• Once HSV gains entry to a site in the body, the virus can also spread to nearby mucosal areas through nerve cells. This characteristic spreading can cause fairly large infected areas to erupt at some distance from the initial crop of sores.

The primary skin infection with either HSV-1 or HSV-2 lasts up to 2 - 3 weeks, but skin pain can last 1 - 6 weeks in a primary (the initial) HSV attack.

Other Symptoms. Some patients experience other symptoms as well, which may occur before the actual outbreak (called a prodrome).

• Fever rising to about 102°F, muscle aches, headache, and flu-like malaise. These general symptoms usually resolve within a week.
• Lymph glands near the site may be swollen as well.

It may be especially important to identify a primary infection (if possible) and to treat it as soon as possible, since some preliminary research suggests that early treatment may limit the number of viruses that remain latent in the body and reduce the frequency of recurrent outbreaks.

Asymptomatic Stages: Latency and Shedding

Latency. After an outbreak, the herpes simplex virus goes into a stage known as latency. During that phase, HSV produces no symptoms at all, and the virus is not transmissible.

Asymptomatic Shedding. At certain times, the virus undergoes shedding. During this phase the virus replicates and is capable of being transmitted through fluids and infecting other people. This occurs during an outbreak, but, unfortunately, in a third to half of cases shedding occurs without any symptoms at all. One study reported that about 40% of all HSV-infected people experienced asymptomatic shedding of the virus more than 5% of the time. (Other evidence suggests shedding occurs much more often -- between 9 - 28% of the time.) About half of asymptomatic shedding episodes occur within a few days before or after an outbreak and last about 1.5 days. Asymptomatic shedding is much more common with HSV-2 than with HSV-1.

Recurrence Symptoms, Triggers, and Timing

Symptoms of Recurrence. Herpes simplex nearly always recurs. The anatomic site and the type of virus influence the frequency of recurrences. It usually takes the following course:

• Prodrome. The outbreak of infection is often preceded by a prodrome, an early group of symptoms that may include itching skin, pain, or an abnormal tingling sensation at the site of infection. The patient may also experience headache, enlarged lymph glands, and flu-like symptoms. The prodrome, which may be as brief as 2 hours or as long as 2 days, terminates when the blisters develop. About 25% of the time, recurrence does not develop beyond the prodrome stage.
• Outbreak. Recurrent outbreaks of HSV feature most of the same symptoms at the same sites as the primary attack, but they tend to be milder and briefer. After blisters erupt, they typically heal in 6 - 10 days. Occasionally, the symptoms may not resemble those of the primary episode but appear as fissures and scrapes in the skin or as general inflammation around the affected area.

Triggers of Recurrence. It is not completely known what triggers renewed infection, but several different factors may be involved. These include sunlight, wind, fever, local physical injury, menstruation, suppression of the immune system, and emotional stress. One study linked recurrence in genital herpes to persistent stress (lasting longer than a week) and high levels of anxiety. Temporary mood changes, short-term stress, and life-changing events were not linked to recurrence. Reactivation of oral herpes can be provoked within about 3 days of intense dental work, particularly root canal or tooth extraction, as well as after laser skin resurfacing, a popular form of cosmetic surgery.

Timing of Recurrences. Recurrent outbreaks may occur at intervals of days, weeks, or years. For most people, outbreaks recur with more frequency during the first year after an initial attack. During that period, the body mounts an immune response to HSV, and in most healthy people recurring infections tend to become progressively less severe and less frequent. The immune system, however, cannot eradicate the virus completely.

Specific Symptoms of Oral Herpes

Oral herpes (herpes labialis) is most often caused by HSV-1 but can also be caused by HSV-2. It usually affects the lips and, in some primary attacks, the mucous membranes in the mouth. A facial herpes infection on the cheeks or in the nose may occur, but this condition is very uncommon.

Primary Oral Herpes Infection. If the primary (or initial) oral infection causes symptoms, they can be very painful, particularly in small children.

• Blisters form on the lips but may also erupt on the tongue.
• The blisters eventually rupture as painful open sores, develop a yellowish membrane before healing, and disappear within 3 - 14 days.
• Increased salivation and foul breath may be present.
• Rarely, the infection may be accompanied by difficulty in swallowing, chills, muscle pain, or hearing loss.

In children, the infection usually occurs in the mouth. In adolescents, the primary infection is more apt to occur in the upper part of the throat and cause soreness.

Recurrent Oral Herpes Infection. Most patients experience only a couple of outbreaks a year, although up to 10% of patients experience more frequent recurrences. (HSV-2 oral infections recur less frequently than HSV-1.) Recurrences are usually much milder than primary infections and are known commonly as cold sores or fever blisters (because they may arise during a bout of cold or flu). They usually show up on the outer edge of the lips and rarely affect the gums or throat. (Cold sores are commonly mistaken for the crater-like mouth lesions known as canker sores, which are not associated with HSV.)

Specific Symptoms of Genital Herpes

Genital herpes, which typically affects the penis, vulva, or rectum, is usually caused by HSV-2, although the rate of HSV-1 genital infection is increasing. Studies now report, in fact, that the cases of new symptomatic genital infections are equally split between HSV-1 and HSV-2. Some studies even report a higher incidence of genital HSV-1 cases. (The distinction may not matter, however, since there is no difference in treatments.) Initial genital infections due to HSV-1 may be more severe than those caused by HSV-2. Recurrences tend to be milder and less frequent than with HSV-2, however.

Primary Genital Herpes Infection. The first outbreak usually occurs in or around the genital area between 3 days and 2 weeks after exposure to the virus. If there is a long duration between the initial infection and the first outbreak of symptoms, the episode may be quite mild because the immune system has produced antibodies to the virus by that time. Also, such primary infections are less transmissible, heal faster, and produce fewer symptoms.

In about 80% of initial outbreaks of genital herpes, patients develop diffuse symptoms (flu-like discomfort and fever). The virus sheds for about 3 weeks. Symptoms in men and women are very different from each other.

In women, the pattern of a first infection is often more complicated and severe than in men with some or all of the following events:

• In addition to general flu-like discomfort, women may experience nerve pain, itching, lower abdominal pain, urinary difficulties, and yeast infections before or during the eruption of the skin blisters.
• When the outbreak occurs, blisters form raw sores (ulcers) almost immediately. Later they become crusted and fill with a grayish-white fluid. A new crop often occurs during the second week and is accompanied by swollen lymph glands in the groin. The symptoms may last as long as 6 weeks.
• Lesions commonly appear around the vaginal opening, on the buttocks, in the vagina, or on the cervix. If lesions occur inside the vagina, they are not visible and pain may be minimal. Such women, then, may be unaware that they have genital herpes. In such cases, the blisters produce a discharge that is still highly infectious.
• Lesions develop in places other than the genital region in 10 - 18% of primary HSV-2 infections. In most of these cases, outbreaks occur in the urethra (the channel that carries urine) where they can cause painful burning during urination. Inflammation of the internal reproductive organs, including the uterus lining (endometrium) and the fallopian tubes, is rare.

In men, about 6 - 10 blisters typically develop on the head or shaft of the penis. They rarely occur at the base. In some cases, they can occur on the buttocks, around the anus, or on the thighs.

Recurrent Genital Herpes Infection. In general, recurrences are much milder than the initial outbreak. The virus sheds for a much shorter period of time (about 3 days) compared to in an initial outbreak of 3 weeks. Women may have only minor itching, and the symptoms may be even milder in men.

On average, individuals experience four recurrences a year, although this varies widely depending on the severity of the initial outbreak. Men, for example, have 20% more recurrences of genital herpes than women even though their symptoms are milder. There are also some differences in frequency of recurrence depending on whether genital herpes is caused by HSV-2 or HSV-1:

• HSV-2 Genital Herpes Recurrences. HSV-2 genital infections recur more often than HSV-1, and they tend to be more severe. Up to 90% of HSV-2 genital infections recur within the first year after primary infection. Many patients report 5 - 8 recurrences in the first year, but some experience them as often as every 2 weeks. Some, though, have only one initial outbreak without any subsequent recurrences, a rate more typical of those with HSV-1.
• HSV-1 Genital Herpes Recurrences. In one study, 38% of patients with HSV-1 genital infections had no recurrences in the first year after primary infection, 35% had one recurrence, and 27% had 2 or more recurrences. The average time to recurrence was about 7.5 months. Only 7% of those with genital HSV-1 had two or more recurrences annually for at least 2 years.

According to one study, patients with genital herpes usually notice a significant reduction in recurrence by the seventh year after infection. Some patients, however, particularly those with genital HSV-2, may actually face an increase in recurrence during the first 5 years.

A herpetic whitlow is an infection of the herpes virus around the fingernail. In children, this is often caused by thumbsucking or finger sucking while they have a cold sore. It is seen in adult health care workers, such as dentists, because of increased exposure to the herpes virus. The use of rubber gloves prevents herpes whitlow in health care workers.

Click the icon to see an image of herpetic esophagitis.

Transmission

To infect people, the herpes simplex viruses (both HSV-1 and HSV-2) must access the body through broken skin or a mucous membrane such as inside the mouth or on the genital area. Each virus can be carried in bodily fluids (such saliva, semen, fluid in the female genital tract) or in fluid from herpes sores. The risk for infection is highest with direct contact of blisters or sores during an outbreak.

Once the virus has contact with the mucosal surfaces or skin wounds, it begins to replicate. The virus is then transported within nerve cells to their roots where it remains inactive (latent) for some period of time. During latent periods, the virus is not transmissible. However, at some point, it often begins to replicate again without causing symptoms (called shedding). During shedding, the virus is again transmissible through bodily fluids and can infect other people. Shedding is an especially insidious stage because there are no sores or symptoms and it possibly accounts for about a third of all HSV-2 infections.

In some cases, infected people can transmit the virus and infect other parts of their own bodies (most often the hands, thighs, or buttocks). This process, known as autoinoculation, is uncommon, since people generally develop antibodies that protect against this occurrence.

Transmission of Oral Herpes

Oral herpes (usually HSV-1) has been detected in both the saliva and blood of patients with active oral infections. It is the most prevalent form of HSV, and infection is most likely to occur during preschool years. Oral herpes is easily spread by direct exposure to saliva or even from droplets in breath. Skin contact with infected areas is sufficient to spread it. Transmission most often occurs through close personal contact, such as kissing. In addition, because HSV-1 can be passed in saliva, people should also avoid sharing toothbrushes or eating utensils with an infected person.

Transmission of Genital Herpes

Genital herpes is most often transmitted through sexual activity, and people with multiple sexual partners are at high risk. HSV, however, can also enter through the anus, skin, and other areas.

People with active symptoms of genital herpes are at very high risk for transmitting the infection. Unfortunately, evidence suggests about one-third of all HSV-2 infections occur during times when the virus is shedding but producing no symptoms. In addition, only about 10 - 25% of people who carry HSV-2 actually know that they have the infection. In other words, most people either have no symptoms or don't recognize them when they appear.

Until recently, genital herpes was mostly caused by HSV-2, but HSV-1 genital infection is increasing, most likely to due to oral sex. Shedding of genital HSV-1 is less common than with HSV-2, so HSV-1 is less likely to be transmitted, although transmission obviously still occurs, as evidenced by the rising prevalence of genital HSV-1. In fact, a person who carries both HSV-1 and HSV-2 poses a greater risk for sexually transmitting HSV-2 than a person who only carries HSV-2. A person who is infected only with HSV-1 has some protection against being infected by HSV-2.

Risk Factors

Everyone is at risk for herpes simplex virus. According to the latest U.S. data from 1999 - 2004, 57.7% of Americans ages 14 – 49 years are infected with the HSV-1 virus, the main cause of oral herpes and some cases of genital herpes. About 17% of Americans in the same age range test positive for the HSV-2 virus, the main cause of genital herpes. Infection rates for both viruses have declined since the late 1980s. However, infection is lifelong, so once a person is infected, he or she remains infected.

Individuals at Risk for Oral Herpes

Oral herpes is usually caused by HSV-1, which is easily transmitted and is the most common form of the herpes simplex virus. Most people with HSV-1 infection were first infected during childhood, with the highest incidence of first infection occurring between 6 months and 3 years of age. The incidence in children varies among regions and countries, with the highest rates occurring in crowded and unsanitary regions. Studies suggest that by age 5 more than a third of children in low-income areas are infected compared to 20% of children in middle-income areas. However, by the time this more privileged group reaches their thirties, about 60% have become infected with HSV-1. After age 40, socioeconomic differences in infection rates become even less pronounced.

Individuals at Risk for Genital Herpes

The number of Americans with genital herpes increased by 30% from the late 1970s through the early 1990s. However, recent surveys indicate that prevalence is decreasing. A 2006 study in the Journal of the American Medical Association found that among Americans ages 14 - 49 years, the prevalence of HSV-2 (the main cause of genital herpes) decreased by 19% from 1988 - 2004. The decrease was greatest among adolescents between the ages of 14 - 19.

The prevalence of HSV-1 (the main cause of oral herpes) also declined, but the percentage of genital herpes infections caused by HSV-1 more than tripled. Among people infected with HSV-1, but not HSV-2, 1.8% were diagnosed with genital herpes in 1999 -- 2004 compared with 0.4% in 1988 -- 1994. (HSV-2 still causes the majority of genital herpes infections.)

Although the prevalence of genital herpes is declining in the United States, it still remains in epidemic proportions. According to the U.S. Centers for Disease Control and Prevention (CDC), at least 45 million Americans ages 12 and over have had genital herpes. About 1 in 5 adolescents and adults are infected with genital herpes.

Genital herpes is most commonly spread by genital-to-genital or oral-to-genital contact during the days preceding an outbreak (the prodrome period).

Gender. Anyone who is sexually active is at risk for genital herpes, and it is on the rise. Studies indicate that around 22% of Americans are infected with HSV-2, with the risk higher in women (26%) than in men (18%). Men, however, have twice as many recurrent infections as women.

Women have an 80 - 90% chance of contracting HSV-2 after unprotected sexual activity with an infected partner and are 4 times more likely to be infected than men. In one study of sexually active American adolescents, 15% of the females had evidence of being infected with HSV-2, compared to none of the males. Having a drinking problem greatly increased the likelihood of infection in these young women.

Ethnicity. Although African Americans are more likely to test positively for HSV-2, Caucasians have a higher risk for active genital symptoms, and over the past few years the greatest increase in HSV-2 has been observed in white adolescents.

Compromised Immune Systems. People with compromised immune systems, notably patients with HIV, the virus that causes AIDS, are at very high risk for HSV-2. Between 68 - 81% of patients with HIV are infected with HSV-2. Such patients are also at risk for more severe complications from herpes. Other immunocompromised patients include those taking drugs that suppress the immune system and transplant patients.

Individuals at Risk for Specific Forms of Herpes

The following are examples of groups that are at particularly risk for specific forms of herpes.

• Health care providers, including doctors, nurses, and dentists. This group is at higher than average risk for herpetic whitlow, which is herpes that occurs in the fingers.
• Wrestlers, rugby players, and other athletes who participate in direct contact sports without protective clothing. These individuals are at risk for herpes gladiatorum, an unusual form of HSV-1 that is spread by skin contact with exposed herpes sores and usually affects the head or eyes.

Complications

The severity of symptoms depends on where and how the virus enters the body. Except in very rare instances and in special circumstances, the disease is not life threatening, although it can be very debilitating and cause great emotional distress.

Effects of Herpes Virus on Pregnancy

Depending on specific factors, HSV can have serious effects on both a pregnant woman and her child. It should be noted, however, that about 1 million pregnancies occur each year in women who have been infected with HSV-2, but complications occur in less than 4 in 1,000 infected pregnant women.

Infants may acquire congenital herpes from a mother with an active, possibly inapparent herpes infection at the time of birth. Aggressive treatment with antiviral medication is required, but may not be effective in the case of systemic herpes.

Effects on the Brain and Central Nervous System

Herpes Encephalitis. Each year in the U.S., herpes accounts for 2,100 cases of encephalitis, a rare but extremely serious brain disease. HSV-1 is almost always the culprit, except in newborns. In about 70% of infant herpes encephalitis, the disease occurs when a latent HSV-2 virus is activated. Untreated, herpes encephalitis is fatal in over 70% of cases. Respiratory arrest can occur within the first 24 - 72 hours. Fortunately, rapid diagnostic tests and treatment with acyclovir have significantly improved both survival rates (up to about 80%) and reduced complication rates (to nearly 40%). For those who recover, nearly all suffer some impairment, ranging from very mild neurological changes to paralysis. Recovery from HSV encephalitis is dependent on the patient's age, the level of consciousness, duration of the disease, and the promptness of treatment. The best chances for a favorable outcome occur in patients who are treated with acyclovir within 2 days of becoming ill.

Herpes Meningitis. Herpes meningitis, an inflammation of the membranes that line the brain and spinal cord, occurs in up to 10% of cases of primary genital HSV-2. Women are at higher risk for herpes meningitis than men are. Symptoms include headache, fever, stiff neck, vomiting, and sensitivity to light. Fortunately, herpes meningitis usually resolves without complications, lasting for only 2 - 7 days, although recurrences have been reported.

Click the icon to see an image of the meninges of the brain.

Alzheimer's Disease. Some studies indicate a higher risk for Alzheimer's in people who have both HSV-1 and a gene called ApoE4, a known risk factor for Alzheimer's. Furthermore, a protein found in HSV-1 has been shown to mimic beta amyloid, a protein now strongly believed to be a critical player in the Alzheimer's disease process.

Other Neurologic Diseases. Other neurologic syndromes that have been linked to HSV infection include epilepsy, multiple sclerosis, atypical pain syndromes, ascending or transverse myelitis (inflammation of the spinal column), and neuralgia (severe stabbing pain along a nerve or group of nerves).

Eczema Herpeticum

A form of herpes infection called eczema herpeticum, also known as Kaposi's varicellum eruption, can afflict patients with preexisting skin disorders and immunocompromised patients. The disease tends to develop into widespread skin infection and resemble impetigo. Symptoms appear abruptly and can include fever, chills, and malaise. Clusters of dimpled blisters emerge over 7 - 10 days and spread widely. They can become secondarily infected with staphylococcal or streptococcal organisms. When treated, lesions heal in 2 - 6 weeks. Untreated, this condition can be extremely serious and possibly fatal.

Ocular Herpes and Vision Loss

Herpetic infections of the eye (ocular herpes) occur in about 50,000 Americans each year. In most cases it causes inflammation and sores on the lids or outside of the cornea that resolves in a few days.

Click the icon to see an image of the eye.

Stromal Keratitis. Stromal keratitis occurs in up to 25% of ocular herpes. In this condition, deeper layers of the cornea are involved, possibly as an abnormal immune response to the original infection. In these rare cases, scarring and corneal thinning develop, which may cause the eye's globe to rupture and result in blindness. Although rare, it is the major cause of corneal blindness in the US.

Iridocyclitis. Iridocyclitis is another serious complication of ocular herpes, in which the iris and the area around it become inflamed.

Gingivostomatitis

HSV can cause multiple painful ulcers on the gums and mucous membranes of the mouth, a condition called gingivostomatitis. This condition usually affects children 1 - 5 years of age. It nearly always subsides within 2 weeks. In rare cases, it can progress to a systemic viral infection. Children with gingivostomatitis commonly develop herpetic whitlow (herpes of the fingers).

Other Disorders Linked to Herpes Simplex

Several conditions have been linked to HSV infections, although the association has not been substantiated in most cases.

• Arthritis, usually in a single joint, has been sporadically reported as a result of HSV infection.
• People with HSV-2 may have an increased susceptibility for sexually transmitted hepatitis C.
• Some evidence suggests that HSV-1 may slightly increase the risk for certain cancers of the mouth or throat in people who are already at higher risk because of cigarette smoking or infection with another microorganism called human papillomavirus.
• Some studies have reported associations between herpes simplex and other infections with heart disease, including lower survival rates. Such infections may produce persistent inflammation in the arteries leading to heart trouble. Research is ongoing.
• Other rare complications of herpes simplex include erosion or ulcers in the lining of the esophagus and stomach. Certain kidney and blood diseases have also been reported in conjunction with HSV infection. These are very uncommon, however, particularly in people with healthy immune systems.

Emotional and Social Effects of Genital Herpes

Not least among the damaging effects of genital herpes is its impact on the social and emotional life of patients. In one survey of patients with herpes, 82% felt depressed, and 75% were worried about rejection. Over 25% had suicidal thoughts. In nearly 80% of the respondents, the disease had a profound effect on their sexual lives. The patient must notify sexual partners, past and present, about their condition, a deeply humiliating experience. Guilt and anger are common emotions, and relationships may be shattered. It is important to note that the condition is often dormant for many years and may not have been transmitted by a current sexual partner. Support groups or couple therapy can be very helpful.

Herpes in Patients with Compromised Immune Systems

Herpes simplex is particularly devastating when it occurs in immunocompromised patients, and, unfortunately, coinfection is common. People infected with HSV have a fourfold increased risk for contracting HIV, the virus that causes AIDS. Furthermore, studies have reported that between 68 - 81% of patients with HIV are also infected with HSV-2. Other immunocompromised patients include those with cancer or burns, and people who are using immunosuppressant drugs (drugs used after organ transplantation, long-term or high-dose steroids).

Patients with HIV are particularly vulnerable to complications. When both viruses are present, there appears to be a synergy between them, with each increasing the severity of the other. However, herpes simplex in any patient with a seriously compromised immune system can cause serious and even life-threatening complications, including:

• Pneumonia
• Inflammation of the esophagus
• Encephalitis (inflammation of the brain)
• Destruction of the adrenal glands
• Disseminated herpes (spread of infection throughout the body)
• Liver damage, including hepatitis

Hepatitis caused by primary or recurrent HSV can sometimes develop into a life-threatening condition called fulminant liver failure. This condition is treatable with medications or even a liver transplant when diagnosed promptly. Early symptoms may include nausea, vomiting, and abdominal pain. (This is an uncommon complication in HSV-infected people with healthy immune systems, but cases have been reported, such as after surgical procedures.)

Less serious conditions include stomach and anal ulcers, inflammation in the colon, and eczema herpeticum.

Diagnosis

The herpes simplex virus is usually identifiable by its characteristic lesion: A thin-walled blister on an inflamed base of skin. If the diagnosis is uncertain, more tests will be needed. Patients diagnosed with genital herpes should be tested for Chlamydiatrachomatis and other sexually transmitted diseases.

Microscopic Examination of Tissue Scrapings (Tzanck Test)

The Tzanck test uses scrapings from herpes lesions and is useful for identifying the presence of herpes simplex. The scrapings are stained and microscopically examined. Findings of specific giant cells with many nuclei or distinctive particles that carry the virus (called inclusion bodies) indicate HSV infection. The test is quick but accurate in only 50 - 70% of cases. It cannot distinguish between the HSV types or between herpes simplex and herpes zoster.

Viral Cultures

An accurate diagnosis of HSV is best made by taking a fluid sample, or culture, from the lesions as early as possible, ideally within the first 3 days of appearance. The viruses, if present, will reproduce in this fluid sample and can usually be detected after a few days, although if infection is severe, technology exists that can shorten this period to 24 hours. Viral cultures are almost 100% accurate if lesions are still in the clear blister stage. Such tests are not as effective for older ulcerated sores, recurrent lesions, or latency. At these stages the virus may not be active enough to reproduce sufficiently to produce a visible culture.

Immunologic Tests

To confirm results of a Tzanck smear and viral cultures, blood tests are available that can identify antibodies that are specific to the herpes virus and its type. (Antibodies are selective in their attack on viruses, so detecting high levels of an antibody to a specific virus is evidence of infection.)

Immunologic tests are most accurate when administered 12 - 16 weeks after exposure to the virus. The three standard tests are:

• Western Blot Test. This is the gold standard for researchers with accuracy rates of 99%. It is costly and time consuming, however.
• HerpeSelect. This includes two tests: ELISA (enzyme-linked immunosorbent assay) and Immunoblot. They are both highly accurate in detecting HSV-1, -2, or both. Results take 1 - 2 weeks.
• POCkit. This test detects HSV-2 only. Its major advantages are that it requires only a finger prick and results are provided in less than 10 minutes. It is very accurate, although slightly less so than the other tests. It is also less expensive. It is not usually used for pregnant women.

Because HSV-1 recurring infections tend to have a milder course than those due to HSV-2, some doctors now regularly test all infected patients for HSV type. These tests may be specifically beneficial for women who are pregnant or wish to conceive and for the partners of such women. They have limitations, however. For example, it is not clear if these tests are highly accurate in children. They also give no information on the location or duration of the infection.

Immunologic tests using urine or saliva, which would be particularly useful for testing children, are under investigation.

Tests for HSV Encephalitis

Diagnosis of HSV encephalitis may require a number of tests.

Imaging Tests. Electroencephalography traces brain waves and can identify about 80% of cases. Computed tomography (CT) or magnetic resonance imaging (MRI) scans may be used to differentiate encephalitis from other conditions.

Brain Biopsy. Brain biopsy is the most reliable method of diagnosing HSV encephalitis, but it is also the most invasive and is generally performed only if the diagnosis is uncertain.

Polymerase Chain Reaction (PCR). The polymerase chain reaction (PCR) assay looks for tiny pieces of the DNA of the virus, and then replicates them millions of times until the virus is detectable. This test can identify specific strains of the virus and asymptomatic viral shedding. PCR identifies HSV in cerebrospinal fluid and gives a rapid diagnosis of HSV encephalitis in most cases, eliminating the need for biopsies. Sensitivity is almost equal to viral culture and results are also much quicker. (An automatic PCR assay -- the LightCycler -- provides results in 2 hours.)

Similar Conditions

Canker Sores (Aphthous Ulcers). Common canker sores (known medically as aphthous ulcers) are often confused with the cold sores of HSV-1. Canker sores frequently crop up singly or in groups on the inside of the mouth or on or under the tongue. They are usually white or grayish crater-like ulcers with a sharp edge and a red rim. They usually heal in 2 weeks without treatment.

Canker sores (Aphthous ulcers) are very common. Typically, they are a shallow ulcer with a white or whitish/yellow base surrounded by a reddish border. This ulcer is seen in an individual with AIDS and is located in front and just below the bottom teeth.

Thrush (Candidiasis). Candidiasis is a yeast infection that causes a whitish overgrowth in the mouth. It is most common in infants but can appear in people of all ages, particularly those with impaired immune systems.

Click the icon to see an image of thrush.

Other conditions that may be confused with oral herpes include herpangina (a form of the Coxsackie A virus), sore throat caused by strep or other bacteria, and infectious mononucleosis.

Genital Disorders

Conditions that may be confused with HSV-2 include bacterial and yeast infections, genital warts, herpes zoster (shingles), molluscum (a virus disease which produces small rounded swellings), scabies, syphilis, and certain cancers.

Urinary Tract Infections

In a few cases, HSV-2 may occur without lesions and resemble cystitis and urinary tract infections.

Eye Injuries

Simple corneal scratches can cause the same pain as herpetic infection, but these usually resolve within 24 hours and don't exhibit the corneal lesions characteristic of herpes simplex.

Skin Disorders

Skin disorders that may mimic herpes simplex include shingles and chicken pox (both caused by varicella-zoster, another herpes virus), impetigo, and Stevens-Johnson syndrome, a serious inflammatory disease usually caused by a drug allergy.

Click the icon to see an image of the shingles.

Click the icon to see an image of chickenpox.

Home Remedies and Prevention

Most herpes simplex infections that develop on the skin can be managed at home with over-the-counter painkillers and symptomatic relief.

Symptomatic Relief

Several simple steps can produce some relief:

• Hygiene is important. Avoid touching the sores. Wash hands frequently during the day. Fingernails should be scrubbed daily. Keep the body clean.
• Drink plenty of water.
• Blisters or sores should be kept clean and dry with cornstarch or similar product. (Women should not use talcum powder because it may increase their risk for ovarian cancer.)
• Some people report that drying the genital area with a blow dryer on the cool setting offers relief.
• Avoid tight-fitting clothing, which restricts air circulation and slows healing of the sores.
• Choose cotton underwear, rather than synthetic materials.
• Local application of ice packs may alleviate the pain and help reduce recurrences by suppressing the virus.
• Lukewarm baths may be helpful. (For people who have pain on urination, some experts recommend urinating in the bath water at the end of the bathing time. This dilutes the urine and prevents burning the sores. Urinating in a cool shower is also helpful and is less offensive to many people. )
• Wearing sun block helps prevent sun-triggered recurrence of HSV-1.
• Sex should be avoided both during the outbreaks and the prodromes (the early symptoms of herpes), which include tingling, itching, or tenderness in the infected areas.
• Over-the-counter medications such as aspirin, acetaminophen (Datril, Panadol, Tylenol), or ibuprofen (Advil, Medipren, Motrin, Nuprin), can be used to reduce fever and local tenderness. Children should take acetaminophen. Never give children aspirin.

Stress Management

In one study, stress management techniques developed using cognitive-behavioral methods not only were effective in reducing depression in those with HSV-2 but blood test results also revealed lower levels of HSV-2 antibodies, a possible sign of decreased viral activity. In any case, reducing stress using relaxation techniques does no harm.

Herbal and Other Alternative Remedies

Many herbal and dietary supplement products claim to help fight herpes infection by boosting the immune system. There has been little research on these products, and little evidence to show that they really work. Some are capsules taken by mouth. Others come in the form of ointment that is applied to the skin. Popular herbal and supplement remedies for herpes simplex include:

• Echinacea (Echinacea purpurea )
• Siberian ginseng (Eleutherococcus senticosus )
• Aloe (Aloe vera )
• Bee products that contain propolis, a tree resin collected by bees
• Lysine
• Zinc

Preventing Transmission

Infected people should take several steps to avoid transmitting the virus to others. It is almost impossible to defend against the transmission of oral HSV-1 since it can be transmitted by very casual contact.

Preventing Transmission During an Outbreak. When an outbreak of herpes occurs the following precautions are useful:

• Persons carrying any herpes virus should carefully wash their hands and nails after contact with the infected area so as not to transmit the virus to other sites on the body.
• Although transmission from objects such as toilet seats and towels is unlikely, keeping personal items separate during an active infection may help to reduce transmission to other household members. The virus can live for up to 2 hours on cloth and for 4 hours on plastic.
• If genital lesions are present, infected persons should abstain from sexual intercourse.

Preventing Sexually Transmitted Disease. Any infected man or a partner of an infected woman should wear a condom during any sexual activity, even when symptoms are not present. Condoms are also important during oral sex, as an increasing number of new genital herpes cases are due to HSV-1, particularly among younger people.

The use of condoms for preventing the transmission of HSV-2 is not foolproof. Even a small tear can permit passage of the virus. However, studies show that regular condom use can significantly reduce the risk of HSV-2 infection.

Condoms made of latex are less likely to slip or break than those made of polyurethane. “Natural” condoms made from animal skin do not protect against HSV infection because herpes viruses can pass through them.

Women appear to be better protected than men are by male condoms. The reason may be that men shed HSV-2 from the skin of the penis, which is covered by the condom. However, in women the virus is often shed from skin areas around the genital area, which can have contact to skin areas in the male outside the condom.

The female condom is another option for infected women or partners of infected men. The female condom covers a large area and is an effective barrier to sexually transmitted viruses.

Note on Lubricants and Spermicides. Only water-based lubricants (K-Y Jelly, Astroglide, AquaLube, glycerin) should be used. Oil-based lubricants (petroleum jelly, body lotions, cooking oil) can weaken latex.

Some condoms come prelubricated with sperm-killing substances called spermicides, which are no longer recommended. The standard active ingredient in spermicides is nonoxynol-9, which attacks the surface of the sperm cell. Nonoxynol-9 does not provide any additional protection against sexually transmitted diseases (STDs). It can cause yeast and urinary tract infections in women. In addition, it can cause irritation around the genital areas, which makes it easier for herpes and other STDs to be transmitted. In fact, research now suggests that it actually increases the risk for HIV in women.

Treatment for Genital Herpes

No drug can cure herpes simplex virus. The infection may recur after treatment has been stopped, and, even during therapy, a patient can still transmit the virus to another person. Drugs can, however, reduce symptoms and improve healing times.

Acyclovir and Related Drugs

Antiviral drugs called nucleosides or nucleotide analogues are the main drugs used to treat genital herpes. They are taken by mouth. (Acyclovir is also available as an ointment, but the oral form is much more effective.) These drugs limit herpes viral replication and its spread to other cells. They are not cures, however.

Three drugs are approved to treat genital herpes:

• Acyclovir (Zovirax or generic)
• Valacyclovir (Valtrex)
• Famiciclovir (Famvir)

These drugs are used either episodically or suppressively:

• Episodic treatment is used when a patient has an outbreak or suspects one is going to occur. Outbreaks are usually preceded by prodrome -- a group of symptoms that include itching, pain, or tingling. If the drug is taken when these symptoms first appear, it can help prevent the outbreak from occurring. If the outbreak has already occurred, the drug can lessen the severity of symptoms and speed healing time. For episodic treatment, acyclovir is taken 5 times a day for 5 days, valacyclovir twice a day for 5 days, or famiciclovir twice a day for 1 day. (In 2006, famiclovir was approved as the first one-day treatment for recurrent genital herpes.)
• Suppressive treatment requires taking pills daily on a long-term basis. (Acyclovir and famiciclovir are taken twice a day, valacyclovir once a day.) Suppressive treatment may help prevent outbreaks from occurring. It is generally recommended for patients who have frequent recurrences (6 or more outbreaks per year).

Acyclovir and valacyclovir are also approved to treat an initial attack of herpes. When a patient has herpes for the first time, the drug is taken several times a day for 10 days

Side Effects. Nausea and headache are the most common side effects, but in general these drugs are safe. Although there is some evidence these drugs may reduce shedding, they probably do not prevent it entirely. The use of condoms during asymptomatic periods is still essential, even when patients are taking these medications.

Risk for Resistant Viruses. As with antibiotics, doctors are concerned about signs of increasing viral resistance to acyclovir and similar drugs, particularly in immunocompromised patients (such as those with AIDS). Some experts believe, however, that the prevalence of drug-resistant viruses will be low for many years. They argue that widespread use of antiviral drugs will prevent many cases of herpes from developing and will slow the spread of the disease. Even patients on long-term suppressive drug therapy show few signs of drug resistance. In addition, research indicates that many people infected with strains that appear to be drug-resistant in laboratory tests still respond to these drugs.

Foscarnet

Foscarnet (Foscavir) is a powerful anti-viral drug known as a pyrophosphate analogue, and is the first choice for treatment for HSV strains that have become resistant to acyclovir and similar drugs. Administered intravenously, the drug can have toxic effects, including impaired kidney function (which is reversible) and seizures. Fever, nausea, and vomiting are common side effects. It can also cause ulcers on genital organs. As with other drugs, it does not cure herpes.

Cidofovir

Cidofovir (Vistide) is active against many viruses and may be useful in some cases of HSV. Intravenous cidofovir, for example, may be a good choice for patients with HIV/AIDS or bone marrow transplant recipients whose condition is resistant to acyclovir and foscarnet. Cidofovir shows promise as a topical treatment of recurrent genital herpes infections, although it can have severe side effects, including kidney damage.

Investigational Drugs for Herpes

Helicase-Primase Inhibitors. A new class of drugs, called helicase-primase inhibitors, suppress an enzyme vital for HSV replication and growth. They have shown early promise in animal studies, but it will be some years before they are tested for safety and effectiveness in people.

Vaccines. Some experts believe that developing an effective HSV vaccine is the only practical way to control the disease and the spread of infection. Furthermore, if such a vaccine becomes available, then universal immunization may be the best approach. Vaccines also hold the potential for eliminating latent, lifelong infections.

In 2002, the National Institute of Allergy and Infectious Diseases (NIAID) launched the Herpevac Trial for Women. The NIAID seeks to enroll 7,500 women between the ages of 18 and 30 who test negative for both HSV-1 and HSV-2 infection. The trial is being conducted at more than 40 sites in the United States and Canada. Participants are randomly assigned to receive either three doses of the experimental herpes vaccine or an investigational hepatitis A vaccine. The women will be observed for 20 months following the initial vaccination to determine if they contract genital herpes (or, for the control group, hepatitis A) during this time. The vaccine used in the trial does not contain live virus and will not itself cause infection.

The premise for the Herpevac trial is based on results from two studies published in the New England Journal of Medicine in 2002. In these studies, a glycoprotein D vaccine was effective in preventing genital herpes in women who were not infected with HSV-1 or HSV-2. For uninfected women, the risk of contracting genital herpes was reduced by nearly 75 percent. The vaccine was not useful, however, for women already infected with HSV-1 and was ineffective in men regardless of HSV status.

Treatment for Oral Herpes

Oral Treatments

Acyclovir (Zovirax), valacyclovir (Valtrex), and famciclovir (Famvir) -- the anti-viral pills used to treat genital herpes -- can also treat the cold sores associated with oral herpes. In addition, acyclovir is available in topical form (see below), as is penciclovir (a related drug).

Topical Treatments

These ointments or creams help shorten healing time and duration of symptoms. However, none are truly effective in eliminating outbreaks.

• Penciclovir (Denavir) heals HSV-1 sores on average about half a day faster than without treatment, stops viral shedding, and reduces the duration of pain. Ideally, the patient should apply the cream within the first hour of symptoms, although benefits have also been noted with later application. It is continued for 4 consecutive days, and should be reapplied every 2 hours while awake.
• Acyclovir cream (Zovirax) works best when applied early on (at the first sign of pain or tingling).
• Docosanol cream (Abreva) is the only FDA-approved non-prescription ointment for oral herpes. It is applied five times a day, beginning at the first sign of tingling or pain. Studies have been mixed on it benefits.
• Over-the-counter topical anesthetics may provide modest relief. They include Anbesol gel, Blistex lip ointment, Campho-phenique, Herpecin-L, Viractin, and Zilactin.

Lots More Information

Resources

• www.ashastd.org -- American Social Health Association
• www.niaid.nih.gov -- National Institute of Allergy and Infectious Diseases
• www.cdc.gov/std/herpes -- Centers for Disease Control and Prevention
• www.herpes-foundation.org -- American Herpes Foundation
• www.herpesalliance.org -- International Herpes Alliance
• www.gotherpes.com -- Herpes support site
• www.niaid.nih.gov/dmid/stds/herpevac -- Herpevac (herpes vaccine) clinical trial information

References

Andrews WW, Kimberlin DF, Whitley R, Cliver S, Ramsey PS, Deeter R. Valacyclovir therapy to reduce recurrent genital herpes in pregnant women. Am J Obstet Gynecol. 2006 Mar;194(3):774-81.

Sheffield JS, Hill JB, Hollier LM, Laibl VR, Roberts SW, Sanchez PJ, et al. Valacyclovir prophylaxis to prevent recurrent herpes at delivery: a randomized clinical trial. Obstet Gynecol. 2006 Jul;108(1):141-7.

Wald A, Langenberg AG, Krantz E, Douglas JM Jr, Handsfield HH, DiCarlo RP, et al. The relationship between condom use and herpes simplex virus acquisition. Ann Intern Med. 2005 Nov 15;143(10):707-13.

Xu F, Sternberg MR, Kottiri BJ, McQuillan GM, Lee FK, Nahmias AJ, et al. Trends in herpes simplex virus type 1 and type 2 seroprevalence in the United States. JAMA. 2006 Aug 23;296(8):964-73.