Herpes Research Today is a free monthly online journal that collates and summarizes the latest research about Herpes, including details on herpes simplex virus (hsv), genital, oral, symptoms, treatment.

Herpes simplex is a viral disease caused by Herpes simplex viruses (HSV). Infection with the herpes virus is categorized into one of several distinct disorders based on the site of infection. Oral herpes, the visible symptoms of which are colloquially called cold sores, infects the face and mouth. Infection of the genitals, commonly known as herpes, is the second most common form of herpes. Disorders such as herpetic whitlow, herpes gladiatorum, ocular herpes, herpes encephalitis, Mollaret's meningitis, neonatal herpes, and possibly Bell's palsy are also caused by herpes simplex viruses. Herpes simplex is not typically life-threatening for immunocompetent people.

Herpes viruses cycle between periods of active disease—presenting as blisters containing infectious virus particles—that last 2–21 days, followed by a remission period, during which the sores disappear. Genital herpes, however, is often asymptomatic, though viral shedding may still occur. After initial infection, the viruses move to sensory nerves, where they reside as life-long, latent viruses. Causes of recurrence are uncertain, though some potential triggers have been identified. Over time episodes of active disease reduce in frequency.

HSV is most easily transmitted by direct contact with a sore or the body fluid of an infected individual. Transmission may also occur through skin-to-skin contact when no symptoms are present if the infected person is experiencing asymptomatic shedding. Despite this risk, barrier protection methods are the most reliable method of preventing transmission of herpes. Oral herpes is easily diagnosed if the patient presents with the common visible sores or ulcers. Early stages of orofacial herpes and gential herpes are harder to diagnose; laboratory testing is usually required. Prevalence of HSV infections varies throughout the world. Socioeconomic status appears to be an important factor associated with infection levels. Additionally, studies have identified several increased risk factors for both strains of herpes.

There is currently no cure for herpes; no vaccine is currently available to prevent or eliminate herpes. Treatments are available to reduce viral reproduction and shedding, prevent the virus from entering the skin, and reduce the severity of herpetic symptoms.

Disorders

Several distinct disorders are caused by HSV infection of the skin or mucosa including those that affect the face and mouth (orofacial herpes), genitalia (genital herpes), or hands (herpes whitlow). More serious problems arise when the virus infects and damages the eye (herpes keratitis) or invades the central nervous system to damage the brain (herpes encephalitis). Newborn infants, with their immature immune systems, are also prone to serious complications due to HSV infection (neonatal herpes), as are transplant recipients who are immuno-suppressed, and AIDs patients who are immuno-incompetent.

Orofacial infection

Infection by the type 1 strain of herpes simplex virus (HSV-1) is the most common cause of herpes that affects the face and mouth (orofacial herpes) although recent years are seeing an increase in oral type 2 strain (HSV-2) infections.^[1] In third world countries, a majority of primary HSV-1 infections occur during childhood and early adolescence and are usually limited to oral infection if the virus came into contact with the mucosa or abraded skin, causing acute herpetic gingivostomatitis (inflammation of the mucosa of the cheek and gums) within 5–10 days. Some other symptoms may also develop, including fever, sore throat, and painful ulcers.^[1] In Industrialized (developed) nations, the adolescent HSV-1 seroprevalence (rate of infection), has been steadily dropping for 5 decades, due to a decrease in overcrowding, smaller family size, and better hygiene. But due to huge human reservoir of the virus, the seroprevalence increases in the fourth and fifth decade of life and almost matches that of undeveloped nations. Primary HSV infection in adolescents frequently manifests as severe pharyngitis with lesions developing on the cheek and gums. Some individuals develop difficulty in swallowing (dysphagia) and swollen lymph nodes (lymphadenopathy).^[1] Primary HSV infections in adults often results in pharyngitis similar to that observed in glandular fever (infectious mononucleosis), but gingivostomatitis is less likely. Primary HSV-1 infection in adolescents and adults can also manifest itself as a herpetic whitlow, herpes gladitorium, or genital infection. Herpes infections are largely asymptomatic, but when symptoms (lesions) appear, they will typically resolve within two weeks.^[1]

Once a primary oral HSV-1 infection has resolved, the HSV enters the nerves surrounding the primary lesion, migrates to the cell body of the neuron, and becomes latent in the trigeminal ganglion. At the same time, seroconversion (development of antibodies) will prevent an additional HSV-1 infection elsewhere from the site of the original infection. (HSV-2 can still be contracted) In some people, the virus reactivates to cause recurrent infection - this is more common with HSV-1 than HSV-2 oral infection. Prodromal symptoms often precede a recurrence, which typically begins with reddening of the skin around the infected site, with eventual ulceration to form fluid-filled blisters that affect the lip (labial) tissue and the area between the lip and skin (vermilion border). The recurrent infection is thus often called herpes simplex labialis. Rare reinfections occur inside the mouth (intraoral HSV stomatitis) affecting the gums, alveolar ridge, hard palate, and the back of the tongue - this may be accompanied with herpes labialis.^[1][2] Oral herpes is spread by direct contact with an infected person's active sores, for instance during kissing. However virus can be transmitted through the skin in the absence of a lesion. Oral herpes and cold sores can sometimes be confused with canker sores.

Genital infection

Clusters of inflammed papules and vesicles on the outer surface of the genitals represent the typical symptoms of a primary HSV-1 or HSV-2 genital infection. These usually appear 4–7 days after sexual exposure to HSV for the first time,^[3] and may resemble cold sores.^[4] In males, the lesions occur on the 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.^[4] 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.^[3] Women often experience additional symptoms that include painful urination (dysuria) and cervicitis, while herpetic proctitis (inflammation of the anus and rectum) is common for individuals participating in anal intercourse.^[3] After 2–3 weeks, existing lesions progress into ulcers and then crust and heal, although lesions on mucosal surfaces may never form crusts.^[3] The virus is not removed from the body by the immune system, but enters nerve ganglia that serve the infected dermatome where it becomes dormant.^[3]

Many HSV infected people experience a recurrence within the first year of infection, when the virus reactivates from its latent state.^[3] Development of lesions follows prodrome - which warns of a recurrence and includes tingling (paresthesia), itching, and pain where lumbosacral nerves innervate the skin - by hours to days. In some individuals, starting to take antiviral treatment when prodrome is experienced can reduce the appearance and duration of lesions. Fewer lesions are likely to develop that cause less pain and heal faster (5–10 days without antiviral treatment) than during the primary infection.^[3] Subsequent outbreaks tend to be periodic or episodic, occur on average four to five times a year when not using antiviral therapy, and may be triggered by stress, illness, fatigue, or menstruation. HSV-2 is widespread, affecting an estimated 1 in 4 females and 1 in 5 males in the United States. Although certain therapies can prevent outbreaks or reduce the risk of transmission to partners, no cure is yet available.^[4][3]

Herpes whitlow

Herpes whitlow (herpetic whitlow) is a painful infection that typically manifest itself on fingers or thumbs and occasionally on the toes, or on the nail cuticle, and is caused by HSV-1 or HSV-2.^[5] It is typically contracted by healthcare workers that come in contact with the virus; it is most commonly contracted by dental workers and medical workers exposed to oral secretions.^[6][7] Again, the HSV seronegative person is at highest risk of acquiring this condition. Herpes whitlow is also caused by autoinoculation of HSV into broken skin prior to an infected person developing antibodies against the virus (e.g. during primary infection before seroconversion).^[5] It is often observed in thumb-sucking children with primary HSV-1 infection, and in adults aged 20 to 30 following contact with HSV-2-infected genitals.^[8]

Symptoms of herpetic whitlow include swelling, reddening and tenderness of the skin of infected finger. This may be accompanied by fever and swollen lymph nodes. Small, clear vesicles initially form that merge and becomes cloudy. Associated pain often seems large relative to the physical symptoms. The herpes whitlow lesion usually heals in two to three weeks.^[9]

Herpes gladiatorum

Individuals that participate in contact sports such as wrestling, rugby, and soccer sometimes acquire a condition caused by HSV-1 known as herpes gladiatorum, scrumpox, wrestler’s herpes or mat herpes. Abraded skin caused by contacts sports provides an area of entry for HSV-1. Symptoms present within 2 weeks of direct skin-to-skin contact with an infected person, and include skin ulceration on the face, ears, and neck. This disorder may cause fever, headache, sore throat and swollen glands, and occasionally affects the eyes. Physical symptoms sometimes recur in the skin.^[10]

Ocular herpes

Ocular herpes is generally caused by HSV-1 and is a special case of facial herpes infection known as herpes keratitis. It begins with infection of epithelial cells on the surface of the eye and retrograde infection of nerves serving the cornea.^[11] Primary infection typically presents as swelling of the conjunctiva and eye-lids (blepharoconjunctivitis), accompanied by small white itchy lesions on the surface of the cornea, which vary from minor damage to the epithelium (superficial punctate keratitis) to formation of dendritic ulcers.^[12] Infection is unilateral, affecting one eye at a time. Additional symptoms include dull pain deep inside the eye, mild to acute dryness and sinusitis. Most primary infections resolve spontaneously in a few weeks or with the use of oral and topical antivirals. However, the virus continues to inhabit the neurons of the eye and to multiply.

Subsequent recurrences may be more severe, with infected epithelial cells showing larger dendritic ulceration and lesions forming white plaques.^[12] The epithelial layer is sloughed off as the dendritic ulcer grows and mild inflammation (iritis) may occur in the underlying stroma of iris. Sensation loss occurs in lesional areas producing generalised corneal anaesthesia with repeated recurrences.^[12] This may be accompanied by chronic dry eye, low grade intermittent conjunctivitis or chronic unexplained sinusitis. When the concentration of viral DNA reaches a critical limit, the presence of the virus can trigger a massive autoimmune response in the eye, resulting in an individual's immune system destroying the corneal stroma.^[12] This usually results in loss of vision due to opacification of the cornea and is a result of an antibody responses against the viral antigen expression in the stroma following persistent infection.^[12] This is known as immune-mediated stromal keratitis.

Treatment with corneal transplants was once ineffective (with only 14%-61% rate of survival without antiviral therapy), as reinfection of the transplant is common when the virus reactivates. However, with concurrent use of antivirals the chance of graft acceptance has improved.^[13]

Herpes simplex encephalitis

Herpes simplex encephalitis (HSE) is a very serious disorder and one of the most severe viral infections of the human central nervous system. It is estimated to affect at least 1 in 500,000 individuals per year.^[14] HSE is thought to be caused by the retrograde transmission of virus from a peripheral site on the face to the brain along a nerve axon following HSV-1 reactivation.^[14] Approximately 50% of individuals that develop HSE are over 50 years of age.^[15] About 1 in 3 cases of HSE result from primary HSV-1 infection predominantly occurring in individuals under the age of 18. Although 2 in 3 cases occur in seropositive persons, few of these individuals have history of recurrent orofacial herpes. The virus lies dormant in the ganglion of the trigeminal or fifth cranial nerve but the reason for reactivation, and its pathway to gain access to the brain, remains unclear. The olfactory nerve may also be involved in HSE.^[16]

Without treatment, HSE results in rapid death in around 70% of cases.^[14] Even with the best modern treatment, it is fatal in around 20% of cases treated, and causes serious long-term neurological damage in over half the survivors. For unknown reasons the virus seems to target the temporal lobes of the brain. Only a small population of survivors (2.5%) regain completely normal brain function.^[15] Most individuals with HSE show a decrease in their level of consciousness and an altered mental state presenting as confusion and changes in personality. Increased numbers of white blood cells can be found in their cerebrospinal fluid without the presence of pathogenic bacteria and fungi, and they typically have a fever.^[14] Some patients with HSE will have seizures. The electrical activity of the brain (detected using EEG, CT, or MRI scans) changes as the disease progresses, first showing abnormalities in one temporal lobe of the brain, which spread to the other temporal lobe 7–10 days later.^[14]

Neonatal herpes simplex

Neonatal HSV disease is a rare but serious condition, usually the consequence of vertical transmission of the virus from mother to newborn child, although an estimated 10% of cases may be acquired postnatally from a parent, caretaker, or sibling. From 1/3,000 to 1/20,000 of live births are infected with neonatal herpes in the U.S.. Approximately 22% of pregnant women in the U.S. have had a previous exposure to HSV-2, and a further 2% or more women acquire the virus during pregnancy.^[17] Among young adults, genital herpes infections are increasingly caused by HSV-1.^[18] The risk of transmission is 30-57% in cases of primary infection acquisition by the mother in the third trimester of pregnancy. Risk of transmission by a mother with existing antibodies for both HSV-1 and HSV-2 has a much lower (1-3%) transmission rate. This in part is due to the presence of significant titer of protective maternal antibodies in the fetus from about the seventh month of pregnancy.^[19] However, shedding of HSV-1 from both primary genital infection and reactivation is associated with high transmission from mother to infant.^[19]

HSV-1 neonatal herpes is extremely rare in developing countries because primary exposure to HSV-1 (and therefore development of HSV-1 specific antibodies) usually occurs in childhood or adolescence, precluding a genital HSV-1 infection; HSV-2 infections are much more common in these countries. In industrialized nations, the adolescent HSV-1 seroprevalance has been dropping steadily for the last 5 decades as a result of better hygiene, less over-crowding, and smaller family size. The resulting increase in the number of young women entering the sexually active/child bearing years as HSV-1 seronegative, has been a harbinger of increased HSV-1 genital herpes, and as a result, increased HSV-1 neonatal herpes in developed nations. A recent three year study in Canada (2000-2003) revealed a neonatal HSV incidence of 5.9 per 100,000 live births. HSV-1 was the cause of 62.5% of cases of neonatal herpes, and 98.3% of transmission was asymptomatic.^[20] Asymptomatic genital HSV-1 has been shown to be more infectious to the neonate and is more likely to produce neonatal herpes than HSV-2. ^[21][22] However with prompt application of antiviral therapy, the prognosis of neonatal HSV-1 infection is better than that for HSV-2.

Neonatal herpes manifests itself in three forms: skin, eyes and mouth (SEM) herpes, disseminated (DIS) herpes, and central nervous system (CNS) herpes.^[23] SEM herpes is characterized by external lesions but no internal organ involvement, and has the best prognosis. Lesions are likely to appear on trauma sites such as the attachment site of fetal scalp electrodes, forceps or vacuum extractors that are used during delivery, in the margin of the eyes, the nasopharynx, and in areas associated with trauma or surgery (including circumcision).^[19] DIS herpes affects internal organs, especially the liver. CNS herpes is an infection of the nervous system and the brain that can lead to encephalitis. Infants with CNS herpes present with seizures, tremors, lethargy, and irritability, they feed poorly, have unstable temperatures, and their fontanelle (soft spot of the skull) may bulge.^[19] CNS herpes is associated with highest morbidity, and DIS herpes has a higher mortality rate. These categories are not mutually exclusive and frequently overlap. Untreated, SEM herpes may spread to the internal organs and result in DIS or CNS herpes with its attendant increases in mortality and morbidity. Death from neonatal HSV disease in the US is currently decreasing; The current death rate is about 25%, down from as high as 85% a few decades ago. Reductions in morbidity and mortality are due to the use of antiviral treatments such as vidarabine and acyclovir.^{[23][24][25][26]} However, morbidity and mortality still remain high due to diagnosis of DIS and CNS herpes coming too late for effective antiviral administration; early diagnosis is difficult in 20-40% of infected neonates that have no visible lesions.^[27] Herpes simplex virus infection in the newborn "carries high mortality and morbidity rates from central nervous system involvement," according to Harrison's Principles of Internal Medicine, which recommends that pregnant women with active genital herpes lesions at the time of labor be delivered by cesarean section. Women whose herpes is not active can be managed with acyclovir.^[28]

Viral meningitis

HSV-2 is the most common cause of Mollaret's meningitis, which is a type of recurrent viral meningitis.^[29][30] This condition was first described in 1944 by French neurologist Pierre Mollaret. Recurrences usually last a few days or a few weeks, and resolve without treatment. They may recur weekly or monthly for approximately 5 years following primary infection.^[31]

Bell's palsy

A type of facial paralysis called Bell's palsy has been linked to the presence and reactivation of latent HSV-1 inside the sensory nerves of the face, known as geniculate ganglia, particularly in a mouse model.^[32][33] This is supported by findings that show the presence of HSV-1 DNA in saliva at a higher frequency in patients with Bell's palsy relative to those without the condition.^[34] However, since HSV can also be detected in these ganglia in large numbers of individuals that have never experienced facial paralysis, and high titers of antibodies for HSV are not found in HSV-infected individuals with Bell's palsy relative to those without, this theory has been contested.^[35] Other studies, which fail to detect HSV-1 DNA in the cerebrospinal fluid of Bell's palsy sufferers, also question whether HSV-1 is the causative agent in this type of facial paralysis.^[36][37] The potential effect of HSV-1 in the etiology of Bell's palsy has prompted the use of antiviral medication to treat the condition. The benefits of acyclovir and valacyclovir have been studied.^[38]

Alzheimer's disease

Scientists discovered a link between Herpes Simplex Type I and Alzheimer’s disease in 1979.^[39] In the presence of a certain gene variation (APOE-epsilon4 allele carriers), HSV type 1 appears to be particularly damaging to the nervous system and increases one’s risk of developing Alzheimer’s disease. The virus interacts with lipoproteins, their components, and their receptors in the brain which may lead to the development of the disease.^[40] This now makes the virus the pathogen most clearly linked to the establishment of Alzheimer’s.^[41] It is important to note, however, that without the presence of the gene allele, HSV type 1 does not appear to cause any neurological damage and thus increase the risk of Alzheimer’s.^[42]

Recurrences and triggers

Following active infection, herpes viruses become quiescent to establish a latent infection in sensory and autonomic ganglia of the nervous system. The double-stranded DNA of the virus is incorporated into the cell physiology by infection of the cell nucleus of a nerve's cell body. HSV latency is static - no virus is produced - and is controlled by a number of viral genes including Latency Associated Transcript (LAT).^[43]

The causes of reactivation from latency are uncertain but several potential triggers have been documented. Physical or psychological stress can trigger an outbreak of herpes.^[44] Local injury to the face, lips, eyes or mouth, trauma, surgery, wind, radiotherapy, ultraviolet light or sunlight are well established triggers.^{[45][46][47][48][49]} Some studies suggest changes in the immune system during menstruation may play a role in HSV-1 reactivation.^[50][51] In addition, concurrent infections, such as viral upper respiratory tract infection or other febrile diseases, can cause outbreaks, hence the historic terms "cold sore" and "fever blister".

The frequency and severity of recurrent outbreaks may vary greatly depending upon the individual. Outbreaks may occur at the original site of the infection or in close proximity to nerve endings that reach out from the infected ganglia. In the case of a genital infection, sores can appear near the base of the spine, the buttocks, back of the thighs, or they may appear at the original site of infection. Immunocompromised individuals may experience episodes that are longer, more frequent and more severe. The human body is able to build up an immunity to the virus over time and antiviral medication has been proven to shorten the duration and/or frequency of the outbreaks.^[52]

Transmission and prevention

Herpes can be contracted through direct contact with an active lesion or body fluid of an infected person.^[53] Infected people that show no visible symptoms may still shed and transmit virus through their skin, and this asymptomatic shedding may represent the most common form of HSV-2 transmission.^[54] There are no documented cases of infection via an inanimate object (e.g. a towel, toilet seat, drinking vessels). To infect a new individual, HSV travels through tiny breaks in the skin or mucous membranes in the mouth or genital areas. Even microscopic abrasions on mucous membranes are sufficient to allow viral entry. Herpes transmission occurs between discordant partners; a person with a history of infection (HSV seropositive) can pass the virus to an HSV seronegative person.^[3] Antibodies that develop following an initial infection with that type of HSV prevents reinfection with the same herpes type - a person with a history of a cold sore caused by HSV-1 cannot contract a herpes whitlow or genital infection caused by HSV-1. In a monogamous couple, a seronegative female runs a >30% per year risk of contracting an HSV-1 infection from a seropositive male partner. If an oral HSV-1 infection is contracted first, seroconversion will have occurred after 6 weeks to provide protective antibodies against a future genital HSV-1 infection.

For genital herpes, condoms are a highly effective in limiting transmission of herpes simplex infection.^[55][56] However, condoms are by no means completely effective. The virus cannot get through latex, but their effectiveness is somewhat limited on a public health scale by the limited use of condoms in the community,^[57] and on an individual scale because the condom may not completely cover blisters on the penis of an infected male, or base of the penis or testicles not covered by the condom may come into contact with free virus in vaginal fluid of an infected female. In such cases, abstinence from sexual activity, or washing of the genitals after sex, is recommended. The use of condoms or dental dams also limits the transmission of herpes from the genitals of one partner to the mouth of the other (or vice versa) during oral sex. When one partner has herpes simplex infection and the other does not, the use of antiviral medication, such as valaciclovir, in conjunction with a condom, further decreases the chances of transmission to the uninfected partner.^[3] Topical microbicides contain chemicals that directly inactivate the virus and block viral entry are currently being investigated.^[3] Vaccines for HSV are currently undergoing trials. Once developed, they may be used to help with prevention or minimize initial infections as well as treatment for existing infections. ^[58]

As with almost all sexually transmitted infections, women are more susceptible to acquiring genital HSV-2 than men.^[59] On an annual basis, without the use of antivirals or condoms, the transmission risk of HSV-2 from infected male to female is approximately 8-10%.^{[citation needed]} This is believed to be due to the increased exposure of mucosal tissue to potential infection sites. Transmission risk from infected female to male is approximately 4-5% annually.^{[citation needed]} Suppressive antiviral therapy reduces these risks by 50%.^{[citation needed]} Antivirals also help prevent the development of symptomatic HSV in infection scenarios by about 50%, meaning the infected partner will be seropositive but symptom free. Condom use also reduces the transmission risk by 50%.^{[citation needed]} Condom use is much more effective at preventing male to female transmission than vice-versa. ^[55] The effects of combining antiviral and condom use is roughly additive, thus resulting in approximately a 75% combined reduction in annual transmission risk.^{[citation needed]} These figures reflect experiences with subjects having frequently-recurring genital herpes (>6 recurrences per year). Subjects with low recurrence rates and those with no clinical manifestations were excluded from these studies.^{[citation needed]}

To prevent neonatal infections, seronegative women are recommended to avoid unprotected oral-genital contact with an HSV-1 seropositive partner and conventional sex with a partner having a genital infection during the last trimester of pregnancy. Mothers infected with HSV, are advised to avoid procedures that would cause trauma to the infant during birth (e.g. fetal scalp electrodes, forceps and vacuum extractors) and, should lesions be present, to elect caesarean section to reduce exposure of the child to infected secretions in the birth canal.^[3] The use of antiviral treatments, such as aciclovir, given from the 36th week of pregnancy limits HSV recurrence and shedding during childbirth, thereby reducing the need for caesarean section.^[3]

HSV seropositive individuals practising unprotected sex with HIV positive persons pose a high risk of HIV transmission, and are even more susceptible to HIV during an outbreak with active sores.^[60]

Asymptomatic shedding

HSV asymptomatic shedding occurs at some time in most individuals infected with herpes. It is believed to occur on 2.9% of days while on antiviral therapy, versus 10.8% of days without and is estimated to account for one third of the total days of viral shedding.^[54] Asymptomatic shedding is more frequent within the first 12 months of acquiring HSV, and concurrent infection with HIV also increases the frequency and duration of asymptomatic shedding.^[61] It can occur more than a week before or after a symptomatic recurrence in 50% of cases.^[54] There are some indications that some individuals may have much lower patterns of shedding, but evidence supporting this is not fully verified - no significant differences are seen in the frequency of asymptomatic shedding when comparing persons with 1 to 12 annual recurrences to those that have no recurrences.^[54]

Diagnosis

Primary orofacial herpes is readily identified by clinical examination in persons without a previous history of lesions, and with reported contact with an individual with known HSV-1 infection. The appearance and distribution of sores, in these individuals, typically presents as multiple, round, and superficial oral ulcers, accompanied by acute gingivitis.^[10] Adults with non-typical presentation are more difficult to diagnose. However, prodromal symptoms that occur before the appearance of herpetic lesions helps to differentiate HSV symptoms from the similar symptoms of, for example, allergic stomatitis. Occasionally, when lesions do not appear inside the mouth, primary orofacial herpes is mistaken for a bacterial infection known as impetigo. Common mouth ulcers (aphthous ulcer), also resemble intraoral herpes, but do not present a vesicular stage.^[10]

Genital herpes can be more difficult to diagnose than oral herpes since most HSV-2-infected persons have no classical signs and symptoms.^[10] To confuse diagnosis, several other conditions resemble genital herpes, including lichen planus, atopic dermatitis, or urethritis.^[10] Laboratory testing is, therefore, often used to confirm genital herpes. Laboratory tests include culture of the virus, direct fluorescent antibody (DFA) studies to detect virus, skin biopsy, polymerase chain reaction (PCR) to test for presence of viral DNA. A Tzanck test (or smear), can also be performed although this cannot differentiate between herpes simplex or varicella (chicken pox) (the primary infection of varicella zoster virus (VZV or shingles). Although these procedures produce highly sensitive and specific diagnoses, their high costs and time constraints discourage their regular use in clinical practice.^[10] Serological tests for antibodies to HSV are rarely useful to diagnosis but are important in epidemiological studies. Serologic assays cannot differentiate between antibodies generated in response to a genital versus an oral HSV infection and as such cannot confirm the site of infection. Absence of antibody to HSV-2 does not exclude gential infection because of the increasing incidence of genital infections caused by HSV-1. For these reasons and the diagnostic delay; serology is not routinely used in clinical practice.^[10]

Epidemiology

Although many people infected with HSV develop labial or genital lesions, many more are either undiagnosed or display no physical symptoms - individuals with no symptoms are described as asymptomatic or with subclinical herpes.^[62] Since asymptomatic individuals are often are unaware of their infection, they are considered at high risk for spreading HSV. Many studies have been performed around the world to estimate the numbers of individuals infected with HSV-1 and HSV-2 by determining if they have developed antibodies against either viral species.^[63] This information provides population prevalence of HSV viral infections in individuals with or without active disease.

Europe

Large differences in HSV-1 seroprevalence are seen in different European countries. HSV-1 seroprevalence is high in Bulgaria (83.9%) and The Czech Republic (80.6%) and lower in Belgium (67.4%), The Netherlands (56.7%) and Finland (52.4%).^[66] The typical age at which HSV-1 infection is acquired ranges from 5–9 years in Eastern European countries like Bulgaria and the Czech Republic to over 25 years of age in Northern European countries such as Finland, The Netherlands, Germany, and England and Wales. Young adults in Northern European countries are less likely to be infected with HSV-1. However, European women are more likely to be HSV-1 seropositive than men.^[66] HSV-2 seropositivity is widely distributed in Europeans older than 12, although there are large differences in the percentage of the population that had been exposed to HSV-2. Bulgaria has a high (23.9%) HSV-2 seroprevalence relative to other European countries: Germany (13.9%), Finland (13.4%), Belgium (11.1%), The Netherlands (8.8%), the Czech Republic (6.0%) and England and Wales (4.2%).^[66] Women are more likely to be seropositive than men, and likely acquire the virus at an earlier age. In each country of Europe, HSV-2 seropositivity becomes more common from adolescence onwards and increases in the population with age, with a decline in the older age groups in some countries.^[66]

North America

United States

In healthy adults, HSV-2 infection occurs more frequently in the USA than in Europe, and appears to be increasing; in individuals over 12 years old, HSV-2 seroprevalence has increased from 16.4% in 1976 to 21.8% in 1994 and is still rising.^[67] Thus, the current incidence of genital herpes caused by HSV-2 in the U.S. is roughly one in four or five adults, with approximately 50 million people infected with genital herpes and an estimated 0.5 million new genital herpes infections occurring each year.^[10] African Americans appear more susceptible to HSV-2, although the presence of active genital symptoms is more likely in Caucasian Americans. The largest increase in HSV-2 acquisition during the past few years is in white adolescents. People with many lifetime sexual partners and those who are sexually active from a young age are also at higher-risk for the transmission of HSV-2 in the U.S.^{[68][69][70][71]} Women are at higher risk than men for acquiring HSV-2 infection, and the chance of being infected increases with age.^[10]

African Americans and immigrants from developing countries typically have an HSV-1 seroprevalance in their adolescent population that is two or three times higher than that of Caucasian Americans, possibly reflecting differences in their socioeconomic backgrounds.^[10] Many white Americans enter sexual activity, marriage and child bearing years seronegative for HSV-1. The absence of antibodies from a prior oral HSV-1 infection leaves these individuals susceptible to primary HSV-1 genital infections. This brings with it a risk of vertical transmission to the neonate if the mother contracts a primary infection during the third trimester of pregnancy. A seronegative mother has up to a 57% chance of conveying an HSV infection to her baby during childbirth whereas a woman seropositive for both HSV-1 and HSV-2 has around a 1-3% chance of transmitting infection to her infant.^[72] Women that are seropositive for only one type of HSV fall somewhere in between but are still only half as likely to transmit HSV as the seronegative mother. Genital infection caused by HSV-1, in the U.S. is now thought to be about 50%^{[73] [74]}and contributes to a rate of 6 to 20 cases of neonatal herpes per 100,000 live births in the U.S. depending on region and demographics. ^[75][76]

Canada

Following a study in Ontario, up to 55% of Canadians age of 15 to 16, and 89% of individuals in their early forties are estimated have antibodies to HSV-1. Teenagers are less likely to be seropositive for HSV-2 - antibodies against this virus is only found in 0-3.8% of 15-16 year olds. However, 21% of individuals in their early forties have antibodies against HSV-2 reflecting the sexually transmitted nature of this virus. When standardising for age, HSV-2 seroprevalence in Ontario, for individuals between the ages of 15 to 44, was 9.1%. This is much lower than estimated levels of HSV-2 seroprevalence in people of a similar age range in the United States.^[77] HSV-2 seroprevalence in pregnant women, between the ages of 15-44, in British Columbia is similar, with 57% having antibodies for HSV-1 and 13% having antibodies for HSV-2.^[63]

Africa

Sub-Saharan Africa

HSV-2 is more common in some countries, such as those of Sub-Saharan Africa, than in Europe or the North America. Up to 82% of women, and 53% of men in Sub-Saharan Africa are seropositive for HSV-2 (see table), representing the highest levels of HSV-2 infection in the world, although exact levels vary from country to country in this continent.^[78] In most African countries, HSV-2 prevalence increases with age. However, age-associated decreases in HSV-2 seroprevalence has been observed for women in Uganda and Zambia, an in men in Ethiopia, Benin and Uganda.^[63]

Northern Africa

Genital herpes appears less common in Northern Africa compared to Sub-Saharan Africa, with only 26% of middle-aged women having antibodies for HSV-2 in Morocco.^[64] Woman are more likely to be infected with HSV-2 once they are over the age of 40.^[64] Children in Egypt are often infected with HSV from a young age - HSV-1 or HSV-2 antibodies are estimated in 54% in children under the age of 5 years and 77% in children over 10 years of age.^[79] Algerian children are also likely to acquire HSV-1 infection at a young age (under 6) and 81.25% of the population has antibodies to HSV-1 by the age of 15.^[80]

Central and South America

HSV-2 seroprevalency is high in Central and South America, relative to rates in Europe and North America with levels estimated at 20–60%.^[63][78] During the mid 1980s, HSV-2 prevalence was 33% in 25–29 years old women and 45% in those aged 40 and over in Costa Rica, and, in the early 1990s, was approximately 45% among women over 60 in Mexico.^[63] The highest HSV-2 prevalence (60%) in Central or South America has been found Colombian middle-aged women although similar HSV-2 prevalence (54%) has been observed in younger women in Haiti.^[63] HSV-2 infects about 30% in women more than 30 years old from Colombia, Costa Rica, Mexico, and Panama and steadily increases to 52% in an age-associated manner in those aged 50–59. HSV-2 antibodies were found in more than 41% of women of childbearing age in Brazil.^[63] However, no increase in seroprevalence was associated with age in women over 40 years old in this country - HSV-2 prevalence was estimated at 50% among women aged 40–49 years, 33% among women 50–59, and 42% among women over 60. Women in Brazil are more likely to acquire an HSV-2 infection if their male partners had history of anal sex and had many sexual partners in his lifetime.^[64] In Peru, HSV-2 prevalence is also high among women in their 30s but is lower in men.^[63]

Asia

Eastern and South East Asia

HSV-2 seroprevalence in developing Asian countries is comparable (10-30%) to that observed in North America and Northern Europe.^[78] HSV-1 seroprevalence in some Asian countries is low, relative to other countries worldwide, with only 51% women in Thailand and between 50-60% in Japan possessing antibodies against this virus.^[64][63] However, estimates of HSV-2 infectivity, in Thailand, is higher than observed in other Eastern Asian countries - total HSV-2 seroprevalence is approximately 37% in this country.^[64] HSV-2 seroprevalence is low in women in the Philippines (9%), although commencing activity while young is associated with an increase risk of acquiring HSV-2 infection; woman starting sexual activity by the time they reach 17 are seven times more likely to be HSV-2 seropositive that those starting sexual activity when over 21.^[81] In South Korea, incidence of HSV-2 infection in those under the age of 20 is low at only 2.7% in men and 3.0% in women.^[65] Seroprevalence levels increase in older South Koreans, however, such that the population over 20 that has antibodies against HSV-2 is 21.7% of men and 28% of women, with increasing HSV-2 prevalence becoming significant once individuals reached their 30's.^[65]

Southern Asia

In India, 33.3% of individual are seropositive for just HSV-1 and 16.6% are seropositive for only HSV-2. Those with both HSV-1 and HSV-2 antibodies are estimated at 13.3% of the population. Indian men are more likely to be infected with HSV-2 than women, and increasing seroprevalence of this virus is associated with an increasing age.^[82]

Middle East

High levels of HSV-2 (42%) and HSV-1 (97%) were found amongst pregnant women in the city of Erzurum in Eastern Anatolia Region, Turkey.^[63] In Istanbul, a city in the Marmara Region in North West Turkey, however, lower HSV-2 seroprevalence was observed; HSV-2 antibodies were found in 4.8% of sexually active adults, and HSV-1 antibodies were found in 85.3%.^[83] Only 5% of pregnant women were infected with HSV-2, and 98% were infected with HSV-1. Prevalence of these viruses was higher in sex workers of Istanbul, reaching levels of 99% and 60% for HSV-1 and HSV-2 prevalence respectively.^[83] The prevalence of HSV-2 in Jordan is 52.8% for men and 41.5% for women.^[84] HSV-1 seroprevalence is 59.8% in the population of Israel and increases with age in both genders. An estimated 9.2% of Israeli adults are infected with HSV-2. Infection of either HSV-1 or HSV-2 is higher in females; HSV-2 seroprevalence reaches 20.5% in females in their 40s. These values are similar to levels in HSV infection in Europe.^[85] Antibodies for HSV-1 or HSV-2 are also more likely to be found individuals born outside of Israel, and individuals residing in Jerusalem and Southern Israel. People from Jewish origin, living in Israel, are less likely to possess antibodies against herpes.^[85] HSV-1 causes 66.3% of genital herpes in individuals living in Tel Aviv, Israel.^[86] Genital herpes infection from HSV-2 is predicted to be low in Syria although HSV-1 levels are high. HSV-1 infections is common (95%) among healthy Syrians over the age of 30, whilst HSV-2 prevalence is low in healthy individuals (0.15%), and persons infected with other sexually transmitted diseases (9.5%). High risk groups for acquiring HSV-2, in Syria, include prostitutes and bar girls that have 34% and 20% seroprevalence respectively.^[87]

Australasia

In Australia, the seroprevalence of HSV-1 is 76%, with differences associated with age, gender and Indigenous status.^[88] An estimated 12% of Australian adults are seropositive for HSV-2, with higher prevalence in women (16%) than in men (8%).^[88] Larger cities have higher HSV-2 seroprevalence (13%) than rural populations (9%) in this country. Higher prevalence is found in Indigenous Australians (18%) than non-Indigenous Australians (12%) but is lower than HSV-2 prevalence observed in the United States.^[88] As in the U.S., HSV-1 is increasingly identified as the cause of genital herpes in Australians; HSV-1 was identified in the anogenital area of only 3% of the population in 1980, but had risen to 41% in 2001.^[89] This was most common in females and persons under 25.^[89]

The number of genital herpes infections appears to be rising in New Zealand with three times more cases in 1993 compared to 1977.^[90] In this country, HSV-2 affects 60% more women than men of similar age.^[63]

Treatment

Currently, there is no treatment that can eradicate any of the herpes viruses from the body. Non-prescription analgesics can reduce pain and fever during initial outbreaks. Topical anesthetic treatment (such as prilocaine, lidocaine or tetracaine) can relieve itching and pain.^[91][92]

Antiviral Medication

Antiviral medications used against herpes viruses work by interfering with viral replication, effectively slowing the replication rate of the virus and providing a greater opportunity for the immune response to intervene. All drugs in this class depend on the activity of the viral enzyme, thymidine kinase, to convert the drug sequentially from its prodrug form to a monophosphate (with one phosphate group), diphosphate (with two phosphate groups) and, finally, triphosphate (with three phosphate groups) form that interferes with viral DNA replication.^[93]

There are several prescription antiviral medications for controlling herpes simplex outbreaks, including aciclovir (Zovirax), valaciclovir (Valtrex), famciclovir (Famvir), and penciclovir. Aciclovir was the original and prototypical member of this drug class and is now available in generic brands at a greatly reduced cost. Valaciclovir and famciclovir are prodrugs of aciclovir and penciclovir respectively, which have improved solubility in water and better bioavailability when taken orally.^[93] Aciclovir is the recommended antiviral for suppressive therapy in the last months of pregnancy to prevent transmission of herpes simplex to the neonate.^[94] The use of valaciclovir and famciclovir, while potentially improving treatment compliance and efficacy, are still undergoing safety evaluation in this context. There is evidence in mice that treatment with famciclovir, rather than aciclovir, during an initial outbreak can help lower the incidence of future outbreaks by reducing the amount of latent virus in the neural ganglia. This potential effect on latency over aciclovir drops to zero a few months post-infection.^[95] Antiviral medications are also available as topical creams for treating recurrent outbreaks on the lips although their effectiveness is disputed.^[96] Penciclovir cream has a far longer cellular half-life than aciclovir cream – 10-20 hours for penciclovir versus 3 hours for aciclovir - increasing its effectiveness relative to aciclovir when topically applied.^[97]

Topical treatments

Docosanol is available as a cream for direct application to the affected area of skin. It prevents HSV from fusing to cell membranes, thus barring the entry of the virus into the skin. Docosanol was approved for use after clinical trials by the FDA in July 2000.^[98] Marketed by Avanir Pharmaceuticals under the brand name Abreva, it was the first over-the-counter antiviral drug approved for sale in the United States and Canada and was the subject of a US nationwide class-action suit in March, 2007 due to the misleading claim that it cut recovery times in half.^[99] Tromantadine is available as a gel that inhibits entry and spreading of the virus by altering the surface composition of skin cells and inhibiting release of viral genetic material. Zilactin is a topical analgesic barrier treatment, which forms a "shield" at the area of application to prevents a sore from increasing in size and decrease viral spreading during the healing process.

Other drugs

Cimetidine, a common component of heartburn medication, has been shown to lessen the severity of herpes zoster outbreaks in several different instances, and offered some relief from herpes simplex.^{[100][101][102]} This is an off-label use of the drug. It and probenecid have been shown to reduce the renal clearance of aciclovir.^[103] These compounds also reduce the rate, but not the extent, at which valaciclovir is converted into aciclovir.

Limited evidence suggests that low dose aspirin (125 mg daily) might be beneficial in patients with recurrent HSV infections. Aspirin (also called acetylsalicylic acid) is an non-steroidal anti-inflammatory drug, which reduces the level of prostaglandins - naturally occurring lipid compounds - that are essential in creating inflammation.^[104] A recent study in animals showed inhibition of thermal (heat) stress-induced viral shedding of HSV-1 in the eye by aspirin, and a possible benefit in reducing the frequency of recurrences.^[105]

Vaccines

The National Institutes of Health (NIH) in the United States is currently in the midst of phase III trials of a vaccine against HSV-2, called Herpevac.^[106] The vaccine has only been shown to be effective for women who have never been exposed to HSV-1. Overall, the vaccine is approximately 48% effective in preventing HSV-2 seropositivity and about 78% effective in preventing symptomatic HSV-2.^[106] Assuming FDA approval, a commercial version of the vaccine is estimated to become available around 2008. During initial trials, the vaccine did not exhibit any evidence in preventing HSV-2 in males.^[106] Additionally, the vaccine only reduced the acquisition of HSV-2 and symptoms due to newly acquired HSV-2 among women who did not have HSV-2 infection at the time they got the vaccine.^[106] Because about 20% of persons in the United States have HSV-2 infection, this further reduces the population for whom this vaccine might be appropriate.^[106]

Natural compounds

Certain dietary supplements and alternative remedies are believed beneficial in the treatment of herpes when used in conjunction with conventional antiviral therapy. However, there is currently insufficient scientific and clinical evidence to support the safe or effective use of these compounds to treat herpes in humans.^[107]

Aloe vera is available as cream or gel which makes an affected area heal faster, and may even prevent recurrences.^[108] Lemon balm (Melissa officinalis), has antiviral activity against HSV-2 in cell culture, and may reduce HSV symptoms in herpes infected people.^{The content on this page was obtained from the Wikipedia and is therefore licensed under the GNU Free Documentation License.}

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