Herpes simplex

Herpes simplex (ἕρπης - herpes, lit. "creeping") is a viral disease caused by both Herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2). 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 or fever blisters, infects the face and mouth. Oral herpes is the most common form of infection. Genital herpes, known simply as herpes, is the second most common form of herpes. Other disorders such as herpetic whitlow, herpes gladiatorum, ocular herpes (keratitis), cerebral herpes infection encephalitis, Mollaret's meningitis, neonatal herpes, and possibly Bell's palsy are all caused by herpes simplex viruses.

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. Genital herpes, however, is often asymptomatic, though viral shedding may still occur. After initial infection, the viruses are transported along sensory nerves to the sensory nerve cell bodies, where they become latent and reside life-long. Causes of recurrence are uncertain, though some potential triggers have been identified, including immunosuppressant drugs (see below). The previously latent virus then multiplies new virus particles in the nerve cell and these are transported along the axon of each neuron to the nerve terminals in the skin, where they are released. Over time, episodes of active disease reduce in frequency and severity.

Herpes simplex is most easily transmitted by direct contact with a lesion or the body fluid of an infected individual. Transmission may also occur through skin-to-skin contact during periods of asymptomatic shedding. Barrier protection methods are the most reliable method of preventing transmission of herpes, but they merely reduce rather than eliminate risk. Oral herpes is easily diagnosed if the patient presents with visible sores or ulcers. Early stages of orofacial herpes and genital herpes are harder to diagnose; laboratory testing is usually required.

A cure for herpes has not yet been developed. Once infected, the virus remains in the body for life. Recurrent infections (outbreaks) may occur from time to time, especially in times of immune impairment such as HIV and cancer-related immune suppression. However, after several years, some people will become perpetually asymptomatic and will no longer experience outbreaks, though they may still be contagious to others. Treatments with antivirals can reduce viral shedding and alleviate the severity of symptomatic episodes. Vaccines are in clinical trials but have not demonstrated effectiveness. It should not be confused with conditions caused by other viruses in the herpesviridae family such as herpes zoster, which is caused by varicella zoster virus. The differential diagnosis includes hand, foot and mouth disease due to similar lesions on the skin.

Classification
Herpes simplex is divided into two types: HSV type 1 and HSV type 2. HSV1 primarily causes mouth, throat, face, eye, and central nervous system infections, while HSV2 primarily causes anogenital infections. However, each may cause infections in all areas.

Signs and symptoms
HSV infection causes several distinct medical disorders. Common infection of the skin or mucosa may affect the face and mouth (orofacial herpes), genitalia (genital herpes), or hands (herpetic whitlow). More serious disorders occur when the virus infects and damages the eye (herpes keratitis), or invades the central nervous system, damaging the brain (herpes encephalitis). Patients with immature or suppressed immune systems, such as newborns, transplant recipients, or AIDS patients are prone to severe complications from HSV infections. HSV infection has also been associated with cognitive deficits of bipolar disorder, and Alzheimer's disease, although this is often dependent on the genetics of the infected person.

In all cases HSV is never removed from the body by the immune system. Following a primary infection, the virus enters the nerves at the site of primary infection, migrates to the cell body of the neuron, and becomes latent in the ganglion. As a result of primary infection, the body produces antibodies to the particular type of HSV involved, preventing a subsequent infection of that type at a different site. In HSV-1 infected individuals, seroconversion after an oral infection will prevent additional HSV-1 infections such as whitlow, genital herpes, and keratitis. Prior HSV-1 seroconversion seems to reduce the symptoms of a later HSV-2 infection, although HSV-2 can still be contracted. Most indications are that an HSV-2 infection contracted prior to HSV-1 seroconversion will also immunize that person against HSV-1 infection.

Many people infected with HSV-2 display no physical symptoms—individuals with no symptoms are described as asymptomatic or as having subclinical herpes.

Bell's palsy
Although the exact cause of Bell's palsy, a type of facial paralysis, is unknown it may be related to reactivation of herpes simplex virus type 1. This theory has been contested, however since HSV is detected in large numbers of individuals who never experienced facial paralysis, and higher levels of antibodies for HSV are not found in HSV-infected individuals with Bell's palsy compared to those without. Regardless antivirals have been found to not improve outcomes.

Alzheimer's disease
HSV-1 has been proposed as a possible cause of Alzheimer's disease. In the presence of a certain gene variation (APOE-epsilon4 allele carriers), HSV-1 appears to be particularly damaging to the nervous system and increases one’s risk of developing Alzheimer’s disease. The virus interacts with the components and receptors of lipoproteins, which may lead to the development of Alzheimer's disease. 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. Herpes simplex virus type 1 DNA is localized within the beta-amyloid plaques that characterize Alzheimer's disease. It suggests that this virus is a major cause of the plaques and hence probably a significant aetiological factor in Alzheimer's disease.

Pathophysiology
Herpes is contracted through direct contact with an active lesion or body fluid of an infected person. Herpes transmission occurs between discordant partners; a person with a history of infection (HSV seropositive) can pass the virus to an HSV seronegative person. The only way to contract Herpes simplex virus 2 is through direct skin-to-skin contact with an infected individual. 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.

HSV asymptomatic shedding occurs at some time in most individuals infected with herpes. It can occur more than a week before or after a symptomatic recurrence in 50% of cases. Virus enters into susceptible cells via entry receptors such as nectin-1, HVEM and 3-O sulfated heparan sulfate. Infected people that show no visible symptoms may still shed and transmit virus through their skin; asymptomatic shedding may represent the most common form of HSV-2 transmission. Asymptomatic shedding is more frequent within the first 12 months of acquiring HSV. Concurrent infection with HIV increases the frequency and duration of asymptomatic shedding. There are 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 one to twelve annual recurrences to those who have no recurrences.

Antibodies that develop following an initial infection with a type of HSV prevents reinfection with the same virus type—a person with a history of orofacial infection caused by HSV-1 cannot contract herpes whitlow or a genital infection caused by HSV-1. In a monogamous couple, a seronegative female runs a greater than 30% per year risk of contracting an HSV 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.

Diagnosis
Primary orofacial herpes is readily identified by clinical examination of persons with no previous history of lesions and contact with an individual with known HSV-1 infection. The appearance and distribution of sores in these individuals typically presents as multiple, round, superficial oral ulcers, accompanied by acute gingivitis. Adults with non-typical presentation are more difficult to diagnose. Prodromal symptoms that occur before the appearance of herpetic lesions help differentiate HSV symptoms from the similar symptoms of other disorders, such as allergic stomatitis. When lesions do not appear inside the mouth, primary orofacial herpes is sometimes mistaken for impetigo, a bacterial infection. Common mouth ulcers (aphthous ulcer) also resemble intraoral herpes, but do not present a vesicular stage.

Genital herpes can be more difficult to diagnose than oral herpes since most HSV-2-infected persons have no classical symptoms. Further confusing diagnosis, several other conditions resemble genital herpes, including fungal infection, lichen planus, atopic dermatitis, and urethritis. Laboratory testing is often used to confirm a diagnosis of genital herpes. Laboratory tests include: culture of the virus, direct fluorescent antibody (DFA) studies to detect virus, skin biopsy, and polymerase chain reaction (PCR) to test for presence of viral DNA. Although these procedures produce highly sensitive and specific diagnoses, their high costs and time constraints discourage their regular use in clinical practice.

Until recently, serological tests for antibodies to HSV were rarely useful to diagnosis and not routinely used in clinical practice. The older IgM serologic assay could not differentiate between antibodies generated in response to HSV-1 or HSV-2 infection. However, the new Immunodot glycoprotein G-specific (IgG) HSV test is more than 98% specific at discriminating HSV-1 from HSV-2. It is the opinion of some modern medical professionals that the new IgG test should always be clinically preferred to the old IgM test, however not all doctors appear to be informed of the availability of the newer, reliable IgG tests.

Prevention


As with almost all sexually transmitted infections, women are more susceptible to acquiring genital HSV-2 than men. 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%. 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. Suppressive antiviral therapy reduces these risks by 50%. Antivirals also help prevent the development of symptomatic HSV in infection scenarios—meaning the infected partner will be seropositive but symptom free—by about 50%. Condom use also reduces the transmission risk by 50%. Condom use is much more effective at preventing male to female transmission than vice-versa. The effects of combining antiviral and condom use is roughly additive, thus resulting in approximately a 75% combined reduction in annual transmission risk. 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. Previous HSV-1 infection appears to reduce the risk for acquisition of HSV-2 infection among women by a factor of 3.

However, asymptomatic carriers of the HSV-2 virus are still contagious. In many infections, the first symptom a person will have of their own infection is the horizontal transmission to a sexual partner or the vertical transmission of neonatal herpes to a newborn at term. Since most asymptomatic individuals are unaware of their infection, they are considered at high risk for spreading HSV.

Barrier methods
Condoms offer moderate protection against HSV-2 in both men and women, with consistent condom users having a 30% lower risk of HSV-2 acquisition compared with those who never use condoms A female condom can provide greater protection than the male condom, as it covers the labia. The virus cannot pass through a synthetic condom, but a male condom's effectiveness is limited because herpes ulcers may appear on areas not covered by the male condom. Neither type of condom prevents contact with the scrotum, anus, buttocks, or upper thighs, areas which may come in contact with ulcers or genital secretions during sexual activity. Protection against herpes simplex depends on the site of the ulcer; therefore if ulcers appear on areas not covered by condoms, abstaining from sexual activity until the ulcers are fully healed is one way to limit risk of transmission. The risk is not eliminated, however, as viral shedding capable of transmitting infection may still occur while the infected partner is asymptomatic. 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 a 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. Topical microbicides which contain chemicals that directly inactivate the virus and block viral entry are being investigated.

Vaccine
Vaccines for HSV are undergoing trials. Once developed, they may be used to help with prevention or minimize initial infections as well as treatment for existing infections.

Antivirals
Antivirals may reduce asymptomatic shedding; it is believed asymptomatic genital HSV-2 viral shedding occurs on 20% of days per year in patients not undergoing antiviral treatment, versus 10% of days while on antiviral therapy.

Pregnancy
The risk of transmission from mother to baby is highest if the mother becomes infected at around the time of delivery (30% to 60%), but the risk falls to 3% if it is a recurrent infection, and is less than 1% if there are no visible lesions. 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. A seronegative mother who contracts HSV at this time has up to a 57% chance of conveying the infection to her baby during childbirth, since insufficient time will have occurred for the generation and transfer of protective maternal antibodies before the birth of the child, whereas a woman seropositive for both HSV-1 and HSV-2 has around a 1-3% chance of transmitting infection to her infant. Women who are seropositive for only one type of HSV are only half as likely to transmit HSV as infected seronegative mothers. 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. The use of antiviral treatments, such as acyclovir, given from the 36th week of pregnancy, limits HSV recurrence and shedding during childbirth, thereby reducing the need for caesarean section.

Acyclovir is the recommended antiviral for herpes suppressive therapy during the last months of pregnancy. The use of valaciclovir and famciclovir, while potentially improving compliance have less well determined safety in pregnancy.

Treatment
There is no method to eradicate herpes virus from the body, but antiviral medications can reduce the frequency, duration, and severity of outbreaks. Analgesics such as ibuprofen and acetaminophen can reduce pain and fever. Topical anesthetic treatments such as prilocaine, lidocaine, benzocaine or tetracaine can also relieve itching and pain.

Antiviral


There are several antivirals that are effective for treating herpes including: aciclovir (acyclovir), valaciclovir (valacyclovir), famciclovir, and penciclovir. Aciclovir was the first discovered and is now available in generic.

Evidence supports the use of aciclovir and valaciclovir in the treatment of herpes labialis as well as herpes infections in people with cancer. The evidence to support the use of acyclovir in primary herpetic gingivostomatitis is less strong.

Topical
A number of topical antivirals are effective for herpes labialis including acyclovir, penciclovir, and docosanol. Docosanol can be purchased over the counter in Canada and the USA.

Alternative medicine
Certain dietary supplements and alternative remedies are claimed to be beneficial in the treatment of herpes. There is however insufficient evidence to support use of many of these compounds including echinacea, eleuthero, L-lysine, zinc, bee products and aloe vera.

A single study indicates possible benefit from laser treatment.

Prognosis
Following active infection, herpes viruses 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 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).

Many HSV-infected people experience recurrence within the first year of infection. Prodrome precedes development of lesions. Prodromal symptoms include tingling (paresthesia), itching, and pain where lumbosacral nerves innervate the skin. Prodrome may occur as long as several days or as short as a few hours before lesions develop. Beginning antiviral treatment when prodrome is experienced can reduce the appearance and duration of lesions in some individuals. During recurrence, fewer lesions are likely to develop, lesions are less painful and heal faster (within 5–10 days without antiviral treatment) than those occurring during the primary infection. Subsequent outbreaks tend to be periodic or episodic, occurring on average four to five times a year when not using antiviral therapy.

The causes of reactivation are uncertain, but several potential triggers have been documented. A recent study (2009) showed that the protein VP16 plays a key role in reactivation of the dormant virus. Changes in the immune system during menstruation may play a role in HSV-1 reactivation. Concurrent infections, such as viral upper respiratory tract infection or other febrile diseases, can cause outbreaks. Reactivation due to infection is the likely source of the historic terms cold sore and fever blister.

Other identified triggers include: local injury to the face, lips, eyes, or mouth, trauma, surgery, radiotherapy, and exposure to wind, ultraviolet light, or sunlight.

The frequency and severity of recurrent outbreaks vary greatly between patients. Some individuals' outbreaks can be quite debilitating with large, painful lesions persisting for several weeks, while others will experience only minor itching or burning for a few days. There is some evidence that genetics plays a role in the frequency of cold sore outbreaks. An area of human chromosome 21 that includes 6 genes has been linked to frequent oral herpes outbreaks. An immunity to the virus is built over time. Most infected individuals will experience fewer outbreaks and outbreak symptoms will often become less severe. After several years, some people will become perpetually asymptomatic and will no longer experience outbreaks, though they may still be contagious to others. Immuno-compromised individuals may experience episodes that are longer, more frequent, and more severe. Antiviral medication has been proven to shorten the frequency and duration of outbreaks. Outbreaks may occur at the original site of the infection or in proximity to nerve endings that reach out from the infected ganglia. In the case of a genital infection, sores can appear at the original site of infection or near the base of the spine, the buttocks, or the back of the thighs. HSV-2 infected individuals are at higher risk for acquiring HIV when practicing unprotected sex with HIV-positive persons, particularly during an outbreak with active lesions.

Epidemiology
Worldwide rates of HSV infection are between 65% and 90%. HSV1 is more common than HSV2 with rates of both increasing as people age. Rates of infection are determined by the presence of antibodies against either viral species.

In the US, 57.7% of the population is infected with HSV-1 and 16.2% are infected with HSV-2. Among those HSV-2 seropositive, only 18.9% were aware that they were infected.

History
Herpes has been known for at least 2,000 years. It is said that Emperor Tiberius banned kissing in Rome for a time due to so many people having cold sores. In the 16th century Romeo and Juliet, it is mentioned that there are blisters "o'er ladies' lips." In 18th century it was so common among prostitutes that it was called "a vocational disease of women."

The term Herpes Simplex appeared in Richard Boulton's A System of Rational and Practical Chirurgery in 1713, where the terms Herpes miliaris and Herpes exedens also appeared.

Herpes was not found to be a virus until the 1940s.

Herpes antiviral therapy began in the early 1960s with the experimental use of medication that interfered with viral replication called deoxyribonucleic acid (DNA) inhibitors. The original use was against normally fatal or disabilitating illness such as adult encephalitis, keratitis, in immunocompromised (transplant) patients, or disseminated herpes zoster. The original compounds used were 5-iodo-2'-deoxyuridine, AKA idoxuridine, IUdR, or(IDU) and 1-β-D-arabinofuranosylcytosine or ara-C, later marketed under the name cytosar or cytorabine. The usage expanded to include topical treatment of herpes simplex, zoster, and varicella. Some trials combined different antivirals with differing results. The introduction of 9-β-D-arabinofuranosyladenine, AKA ara-A or vidarabine, considerably less toxic than Ara-C, in the mid 1970s, heralded the way for the beginning of regular neonatal antiviral treatment. Vidarabine was the first systemically administered antiviral medication with activity against HSV for which therapeutic efficacy outweighed toxicity for the management of life-threatening HSV disease. Intravenous vidarabine was licensed for use by the U.S. Food and Drug Administration (FDA) in 1977. Other experimental antivirals of that period included: Heparin, trifluorothymidine (TFT), Ribivarin, interferon, Virazole, and 5-methoxymethyl-2'-deoxyuridine (MMUdR). The introduction of 9-(2-hydroxyethoxymethyl)guanine, AKA acyclovir, in the late 1970s raised antiviral treatment another notch and led to vidarabine vs. acyclovir trials in the late 1980s. The lower toxicity and ease of administration over vidarabine has led to acyclovir becoming the drug of choice for herpes treatment after it was licensed by the FDA in 1998. Another advantage in the treatment of neonatal herpes included greater reductions in mortality and morbidity with increased dosages, something that did not occur when compared with increased dosages of vidarabine. On the other side of the equation, acyclovir seems to inhibit antibody response and newborns on acyclovir antiviral treatment experienced a slower rise in antibody titer than those on vidarabine.

Society and culture
Herpes simplex was not always stigmatised. It was merely a cold sore in an unusual place until the 1970s. As late as 1975, a study of “Psychological morbidity in a clinic for sexually-transmitted disease” (Richard Mayou, The London Hospital) does not mention herpes simplex because at that time, there was no significant morbidity problem (i.e. mental anxiety or illness) associated with the virus.

In the Journal of Clinical Investigation, Pedro Cuatrecasas states, “during the R&D of acyclovir (Zovirax), marketing [department of Burroughs Wellcome] insisted that there were ‘no markets’ for this compound. Most had hardly heard of genital herpes...” Thus marketing the medical condition – separating the ‘normal cold sore’ from the ‘stigmatized genital infection’ was to become the key to marketing the drug, a process now known as ‘disease mongering’

Since the creation of the herpes hype, some people experience negative feelings related to the condition following diagnosis, particularly if they have acquired the genital form of the disease. Feelings can include depression, fear of rejection, feelings of isolation, fear of being found out, self-destructive feelings, and fear of masturbation. These feelings usually lessen over time. Much of the hysteria and stigma surrounding herpes stems from a media campaign beginning in the late 1970s and peaking in the early 1980s. There were multiple articles worded in fear-mongering and anxiety-provoking terminology, such as the now ubiquitous "attacks," "outbreaks," "victims," and "sufferers." At one point the term "herpetic" even entered the popular lexicon. The articles were published by Reader's Digest, U.S. News, and Time magazine, among others. A made-for-TV movie was named Intimate Agony. The peak was when Time magazine had 'Herpes: The New Scarlet Letter' on the cover in August 1982, forever stigmatizing the word in the public mind. The scientific reality is that most people are asymptomatic, the virus causes no real health problems for a vast majority of people, and a vast majority (around 90%) of the Earth's population carries HSV-1, 2, or both. Herpes support groups have been formed in the United States and the UK, providing information about herpes and running message forums and dating websites for "sufferers." People with the herpes virus are often hesitant to divulge to other people, including friends and family, that they are infected. This is especially true of new or potential sexual partners whom they consider casual.

Research
Researchers at the University of Florida have made a hammerhead ribozyme that targets and cleaves the mRNA of essential genes in HSV-1. The hammerhead which targets the mRNA of the UL20 gene greatly reduced the level of HSV-1 ocular infection in rabbits and reduced the viral yield in vivo. The gene-targeting approach uses a specially designed RNA enzyme to inhibit strains of the herpes simplex virus. The enzyme disables a gene responsible for producing a protein involved in the maturation and release of viral particles in an infected cell. The technique appears to be effective in experiments with mice and rabbits, but further research is required before it can be attempted in people who are infected with herpes.

Another possibility to eradicate the HSV-1 variant is being pursued by a team at Duke University. By figuring out how to switch all copies of the virus in the host from latency to their active stage at the same time, rather than the way the virus copies normally stagger their activity stage, leaving some dormant somewhere at all times, it is thought that conventional anti-viral drugs can kill the entire virus population completely, since they can no longer hide in the nerve cells. One class of drugs called antagomir could serve this purpose. These are chemically engineered oligonucleotides or short segments of RNA, that can be made to mirror their target genetic material, namely herpes microRNAs. They could be engineered to attach and thus 'silence' the microRNA, thus rendering the virus incapable to keep latent in their host. Professor Cullen believes a drug could be developed to block the microRNA whose job it is to suppress HSV-1 into latency.

One vaccine that was under trial was Herpevac, a vaccine against HSV-2. The National Institutes of Health (NIH) in the United States conducted phase III trials of Herpevac. In 2010, it was reported that, after 8 years of study in more than 8000 women in the United States and Canada, there was no sign of positive results against the sexually transmitted disease caused by HSV-2 (and this despite earlier favorable interim reports ).

A laboratory at Harvard Medical School has developed dl5-29 (now known as ACAM-529), a replication-defective mutant virus that has proved successful both in preventing HSV-2/HSV-1 infections, and in combating the virus in already infected hosts, in animal models. It has been shown that the replication-defective vaccine induces strong HSV-2-specific antibody and T-cell responses; protects against challenge with a wild-type HSV-2 virus; greatly reduces the severity of recurrent disease; provides cross-protection against HSV-1, and renders the virus unable to revert to a virulent state or to become latent. His vaccine is now being researched and developed by Accambis (acquired by Sanofi Pasteur in September 2008), and is due to be applied as an Investigational New Drug in 2009. However, the status of ACAM-529 became after the acquisition somewhat unclear. According to Jim Tartaglia, a company representative of Sanofi Pasteur, ACAM-529 is still under development and should be enter phase I clinical testing in 2012.

A private company called BioVex began Phase I clinical trials for ImmunoVEX, another proposed vaccine, in March 2010. A completely new approach has the "HSV-2 ICP0 live-attenuated HSV-2 vaccine" investigated by Dr. William Halford at the Southern Illinois University (SIU) School of Medicine.