Herpes Simplex Virus
Herpes simplex is a viral disease caused by Herpes simplex viruses, herpes simplex virus 1 (HSV–1) and herpes simplex virus 2 (HSV–2). Infection with the herpes virus is categorized according to the site of infection. Oral herpes, the visible symptoms of which are known as cold sores, infects the face and mouth. Oral herpes is the most common form of herpes infection. Infection of the genitals, commonly known as genital herpes, is the second most common form of herpes. Other disorders caused by the herpes viruses are herpetic whitlow, herpes gladiatorum, ocular herpes (keratitis), herpes encephalitis, Mollaret's meningitis, neonatal herpes, and possibly Bell's palsy are all caused by herpes simplex viruses. Most individual disorders may be caused by HSV–1 or HSV–2, though some disorders have significantly different rates of infection by type. Herpes simplex is not typically life-threatening for immunocompetent people.
In both oral and genital herpes, after initial infection, the viruses move to sensory nerves, where they continue living in a latent form for the rest of the life of the host. Recurrence decline in frequency as the immune system comes to equilibrium with the presence of the viruses.
Herpes simplex is most easily transmitted by direct contact with a lesion or with the body fluid of an infected individual although transmission may also occur through skin-to-skin contact during periods of asymptomatic shedding. Barrier protection methods are the most reliable method of prevention, but they are not failsafe.
Herpes viruses cycle between periods of active disease beginning as blisters containing infectious virus particles lasting 2–21 days followed by a remission during which the sores disappear. Genital herpes, however, is often asymptomatic, although viral shedding may still occur during periods of remission and therefore it is possible to transmit the disease during remission.
Oral herpes is easily diagnosed by simple inspection when visible sores or ulcers are present. Early stages of orofacial herpes and genital herpes are harder to diagnose and laboratory testing is usually required.
Prevalence of herpes simplex virus (HSV) infections varies throughout the world with poor hygiene, overcrowding, lower socioeconomic status, and birth in an undeveloped country identified as risk factors associated with increased HSV-1 childhood infection.
Herpes infections are often asymptomatic and when there are symptoms they typically disappear within two weeks. The main symptom of oral infection is acute herpetic gingivo-stomatitis (inflammation of the mucosa of the cheek and gums), which occurs within 5 to 10 days of infection. Other symptoms may also occur, to wit: painful ulcers (sometimes confused with canker sores) fever, and sore throat. 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).
There is currently no cure for herpes and no vaccine is currently available to prevent or eliminate the disease. Treatments are available to reduce viral reproduction and shedding, prevent the virus from entering the skin, and alleviate the severity of symptomatic episodes.
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 (herpes whitlow). More serious disorders occur when the virus infects the eye (herpes keratitis), or invades the central nervous system, damaging the brain (herpes encephalitis). Patients with immature or suppressed immune systems, for example newborn infants, transplant recipients, and AIDS patients are prone to severe complications from HSV infections.
In the case of oral herpes, following a primary infection, the virus enters the nerves at the site of primary infection, migrating to the ganglion associated with the local nerve (trigeminal, or 5th cranial nerve) supply (the trigeminal ganglion). The body produces antibodies to the particular type of HSV, 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, and keratitis. Prior HSV-1 seroconversion ameliorates the symptoms of a later HSV-2 infection, although HSV-2 can still be contracted. On the other hand, it appears that if an HSV-2 infection is contracted prior to HSV-1 seroconversion, that person cannot contract an HSV-1 infection later.
Orofacial herpes affects the face and mouth. Infection occurs when the virus comes into contact with oral mucosa or abraded skin. Infection by HSV-1 is the most common cause of orofacial herpes, though cases of oral infection by the HSV-2 strain are well documented and increasing.
Infections in adults often result in pharyngitis similar to that observed in infectious mononucleosis, but gingivostomatitis (infection of gums and mouth) is less likely. Recurrent oral infection is more common with HSV-1 infections than with HSV-2. Prodromal symptoms such as tingling, itching and reddening of the skin around the infected site often precede a recurrence. Eventually, fluid-filled blisters (lesions) form on the lip (labial) tissue and the area between the lip and skin (vermilion border). The recurrent infection is 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, possibly accompanied by herpes labialis.
The typical symptom of a primary HSV-1 or HSV-2 genital infection is clusters of inflamed papules and vesicles on the outer surface of the genitals which resemble cold sores. These usually appear 4–7 days after first time sexual exposure to HSV. The incidence of genital HSV-1 infection is about one sixth of that of genital HSV-2. 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. Common symptoms include pain, itching, and burning. Less frequent symptoms include discharge from the penis or vagina, fever, headache, muscle pain, enlarged lymph nodes and malaise. Women often experience symptoms that include painful urination and inflamation of the cervix. Inflamation of the anus and rectum is common for individuals participating in anal intercourse. After 2–3 weeks, existing lesions progress into ulcers and then crust and heal, although lesions on mucosal surfaces may never form crusts.
Individuals who participate in contact sports (e.g. 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 provides an the point of entry of HSV-1. Symptoms present within 2 weeks of direct skin-to-skin contact with an infected person including skin ulceration on the face, ears, and neck, fever, headache, sore throat and swollen glands. It occasionally affects the eyes.
Herpes whitlow (herpetic whitlow) is a painful infection that typically affects the fingers or thumbs. Occasionally it occurs on the toes or on the nail cuticle. Herpes whitlow can be caused by infection by HSV-1 or HSV-2. HSV-1 whitlow is often contracted by health care workers who come in contact with the virus. It is most commonly contracted by dental workers and medical workers exposed to oral secretions. It is also often observed in thumb-sucking children with primary HSV-1 oral infection (autoinoculation) prior to seroconversion, and in adults aged 20 to 30 following contact with HSV-2-infected genitals.
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 individually, then merge and become cloudy. Associated pain often seems large relative to the physical symptoms. The herpes whitlow lesion usually heals in two to three weeks.
Herpes Infection of the Cornea
Ocular herpes is a special case of facial herpes infection, known as herpes keratitis. Ocular herpes is usually caused by HSV-1. It begins with infection of epithelial cells on the surface of the eye and moves to the nerves serving the cornea. A primary infection commonly presents as swelling of the conjunctiva and eye-lids (blepharoconjunctivitis), with small white itchy lesions on the surface of the cornea. The effect of the lesions varies, from minor damage to the epithelium (superficial punctate keratitis), to formation of ulcers. Infection affects one eye at a time. Other symptoms include dull pain deep inside the eye, mild to acute dryness, and sinusitis. Most primary infections resolve without treatment in a few weeks. Healing can be accelerated by the use of oral and topical antivirals.
Recurrences may be more severe, with infected epithelial cells showing larger ulceration, and the formation of white plaques. The epithelial layer is sloughed off as the ulcer grows, and mild inflammation (iritis) may occur in the underlying stroma of the iris. Loss of local sensation occurs producing generalized corneal anaesthesia with repeated recurrences. Recurrence can be accompanied by chronic dry eye, intermittent conjunctivitis, or chronic unexplained sinusitis. Following persistent infection the concentration of viral DNA reaches a critical limit and antibody responses against the viral antigen can trigger a massive autoimmune response in the eye. The response may result in the destruction of the corneal stroma resulting in loss of vision due to opacification of the cornea. This is known as immune-mediated stromal keratitis. Treatment with corneal transplants was once ineffective (as low as 14% rate of success before antiviral therapy). However, with concurrent use of antivirals the chance of graft acceptance has improved dramatically.
Herpes Simplex Encephalitis
Herpes simplex encephalitis (HSE) is one of the most severe viral infections of the human central nervous system estimated to affect at least 1 in 500,000 individuals per year. About 1 in 3 cases of HSE result from primary HSV-1 infection, predominantly occurring in individuals under the age of 18.
HSE is thought to be caused by the retrograde transmission of virus from a peripheral site on the face following HSV-1 reactivation, along a nerve axon, to the brain. The virus lies dormant in the ganglion of the trigeminal cranial nerve, but the reason for reactivation, and its pathway to gain access to the brain, remains unknown. The olfactory nerve may also be involved in HSE. The virus seems to target the temporal lobes of the brain.
Most individuals with HSE show a decrease in level of consciousness and an altered mental state with confusion, and changes in personality. Increased numbers of white blood cells can be found in patient's cerebrospinal fluid. Patients typically have a fever and may have seizures. The electrical activity of the brain changes as the disease progresses, first showing abnormalities in one temporal lobe of the brain, then spread to the other temporal lobe 7–10 days later.
Without treatment, HSE results in rapid death in approximatley 70% of cases. HSE is fatal in around 20% of cases treated, and causes serious long-term neurological damage in over half of survivors. Only a small population of survivors (2.5%) regain completely normal brain function.
Herpes Viral Meningitis
HSV-2 is the most common cause of Mollaret's meningitis, a type of recurrent viral meningitis first described in 1944 by French neurologist Pierre Mollaret. Recurrences usually last a few days or a few weeks, and resolve without treatment. They tend to recur weekly or monthly for approximately 5 years following primary infection.
Bell's palsy (sudden unilateral facial paralysis) has been linked to the presence and reactivation of latent HSV-1 inside the sensory nerves of the face (the geniculate ganglia). The presence of HSV-1 DNA in saliva occurs at a higher frequency in patients with Bell's palsy than in people without the condition. However, since HSV-1 can also be detected in these ganglia in large numbers of individuals who have never had facial paralysis, and high titers of antibodies for HSV-1 are not found in HSV-1 infected individuals with Bell's palsy relative to those without, this theory is in question. Neonatal Herpes Simplex
Neonatal HSV (NHSV) infection is a rare but serious condition, with 90% caused by transmission of HSV from mother to newborn. Only 10% of cases are acquired postnatally. Neonatal HSV rates in the U.S. are estimated to be between 1 in 3,000 and 1 in 20,000 live births. Approximately 22% of pregnant women in the U.S. have had previous exposure to HSV-2, and an additional 2% acquire the virus during pregnancy. The risk of transmission to the newborn is 30-57% in cases where the mother acquired a primary infection 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 transfer of protective antibodies to the fetus from about the seventh month of pregnancy. Neonatal herpes manifests itself in three forms: skin, eyes, mouth SEM), disseminated herpes (DIS), and central nervous system herpes. SEM involves external lesions but no internal organ involvement.
Reductions in morbidity and mortality are due to the use of antiviral treatments such as vidarabine and acyclovir. 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 the 20-40% of infected neonates that have no visible lesions. Herpes simplex virus infection in the newborn carries high mortality and morbidity rates from central nervous system involvement. Most obstetricians believe that pregnant women with active genital herpes lesions at the time of labor should be delivered by cesarean section. Women whose herpes is not active can be managed with acyclovir.
A link between HSV-1 and Alzheimer's disease was demonstrated in 1979. In the presence of a certain gene variation (APO-E-epsilon4 allele carriers), HSV-1 appears to be particularly damaging to the nervous system of these people and increases the risk of developing Alzheimer's disease. The virus seems to interacts with the components and receptors of lipoproteins, which may lead to the development of Alzheimer's. Some research identifies HSVs as the pathogens most clearly linked to Alzheimer's. Without the presence of the gene allele, HSV type 1 does not appear to be associated with any neurological damage.
Following active infection herpes virus establishes a latent presence in sensory and autonomic ganglia of the nervous system. HSV latency is static, that is no virus is produced, and is controlled by a number of viral genes. Many HSV infected people experience recurrence within the first year of infection with a prodrome preceding the 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 the prodrome is experienced can sometimes reduce the appearance and duration of lesions. During recurrence fewer lesions are likely to develop, they are less painful and heal faster (within 5–10 days without antiviral treatment) than those during the primary infection. Subsequent outbreaks tend to be periodic or episodic, occurring on average 4-5 times a year when not using antiviral therapy.
Several potential triggers have been documented to explain reactivation. Physical or psychological stress can trigger an outbreak, changes in the immune system during menstruation and concurrent infections such as viral URI or other febrile diseases may play a role Reactivation due to infection is the likely source of the historic terms cold sore and fever blister. Other triggers include: local injury to the face, lips, eyes, or mouth, trauma, surgery, exposure to wind, radiotherapy, and ultraviolet or sunlight.
The frequency and severity of recurrent outbreaks varies between patients. Immunity to the virus is built over time. Immunologically compromised individuals may experience longer, more frequent and severe episodes. Antiviral medication has been proven to shorten the frequency and duration of outbreaks.
Prevention and Transmission
We know that herpes is contracted through direct contact with an active lesion or body fluid of an infected person. A person with a history of infection (HSV seropositive) can pass the virus to an HSV seronegative person. 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.
Viral shedding occurs at some time in most individuals infected with herpes. It can occur more than a week before or after a symptomatic recurrence. Infected people who 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.
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-1 infection from a seropositive male partner.
Barrier protection, such as a condom, can reduce the risk of herpes transmission in some cases. For genital herpes, condoms are highly effective in limiting transmission of herpes simplex infection. However condoms are not completely effective. The virus cannot pass through latex, but a condom's effectiveness is somewhat limited on a public health scale by their limited use. and on at individual level because the condom may not completely cover blisters on the penis of an infected male, or the 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, but placement of a dental dam practically requires going to dental school, not to mention the deromanticizing effects of such a procedure.
When one partner has a herpes simplex infection and the other does not, the use of antiviral medication along with a condom, further decreases the chances of transmission to the uninfected partner.
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 thought to be approximately 8-10% due to the increased exposure of mucosal tissue. Transmission risk from infected female to male is thought to be approximately 4-5% annually. Suppressive antiviral therapy may reduce these risks by about 50%. Antivirals also help prevent the development of symptomatic HSV. The infected partner will be seropositive but symptom free about 50% of the time. Condom use also reduces transmission risk by about 50%. Condom use is much more effective in 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.
To prevent neonatal infections, seronegative women are recommended to avoid unprotected oral-genital contact with an HSV-1 seropositive partner and also to avoid 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, if 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, thus reducing the need for C-section.
Primary orofacial herpes is readily identified by examination. 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 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 can be 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 as most HSV-2-infected persons have no classical symptoms. Further confusing diagnosis, several other conditions resemble genital herpes: lichen planus, atopic dermatitis, and urethritis. Laboratory testing can be used to confirm a diagnosis of genital herpes and includes culture of the virus, direct fluorescent antibody studies to detect virus, skin biopsy, and polymerase chain reaction (PCR) to test for presence of viral DNA. A Tzanck test (smear) can also be performed, although this cannot differentiate between herpes simplex and varicella (chicken pox) or the primary infection of varicella zoster virus (shingles). The high costs and time constraints of these tests discourage their regular use in clinical practice.
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. 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. This information provides population prevalence of HSV viral infections in individuals with or without active disease.
No treatment that can eradicate herpes virus from the body currently exists. Antiviral medications can reduce the frequency, duration, and severity of outbreaks as well as asymptomatic shedding of virus. It is believed asymptomatic shedding occurs on about 10% of days in patients not undergoing antiviral treatment, versus 3% of days while on antiviral therapy. Non-prescription analgesics can reduce pain and fever during initial outbreaks. Topical anesthetic treatments such as prilocaine, lidocaine or tetracaine can relieve itching and pain. Antiviral medications are also available as topical creams for treating recurrent outbreaks on the lips, although their effectiveness is disputed. Penciclovir cream has a 7-17 hour longer cellular half-life than aciclovir cream, increasing its effectiveness relative to aciclovir when topically applied. 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. Tromantadine is available as a gel that inhibits the entry and spread 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 prevent a sore from increasing in size, and decrease viral spreading during the healing process. Cimetidine, a common component of heartburn medication, has been shown to lessen the severity of herpes zoster outbreaks in several different instances.This is an off-label use of the drug. There is some evidence suggesting that low dose aspirin (125 mg daily) might be beneficial in patients with recurrent HSV infections. Aspirin (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. Another treatment is the use of petroleum jelly. Healing of cold sores is accelerated by barring water or saliva from reaching the sore.
Antiviral medications used against herpes viruses work by interfering with viral replication, slowing the replication rate and providing greater opportunity for the immune response to intervene. There are several prescription antiviral medications for controlling herpes simplex outbreaks, including aciclovir (Zovirax), valaciclovir (Valtrex), famciclovir (Famvir), and penciclovir. Aciclovir was the original medication, and prototypical member of this drug class. It is now available in generic brands at a greatly reduced cost. Aciclovir is the recommended antiviral for suppressive therapy for use during the last months of pregnancy to prevent transmission of herpes simplex to the neonate. Valaciclovir and famciclovir, while potentially improving treatment compliance and efficacy, are still undergoing safety evaluation in pregnancy.
Certain natural compounds, dietary adjustments, dietary supplements, and alternative remedies are believed to be beneficial in the treatment of herpes, either alone, or in conjunction with prescribed antiviral therapy. There is currently insufficient scientific and clinical evidence to support the effective use of many of these compounds to treat herpes in humans. Lysine supplementation has been used for the prophylaxis and treatment of herpes simplex Doses smaller than 1 gram per day appear to be ineffective. The optimal dose is said to be four grams per day in two divided doses. Aloe vera, available as a cream or gel, makes an affected area heal faster and may prevent recurrences. Lemon balm has antiviral activity against HSV-2 in cell culture and may reduce HSV symptoms.There is conflicting evidence on a possible benefit from extracts from the plant echinacea in treating oral, but not genital, herpes. Resveratrol, a compound naturally produced by plants and a component of red grapes and thus red wine, prevents HSV replication in cultured cells and reduces cutaneous HSV lesion formation in mice. It is not considered potent enough to be an effective treatment on its own. It is available as capsules. Some dietary supplements have been suggested to positively treat herpes: vitamin C, vitamin A, vitamin E, and zinc.
While no vaccine is currently available to prevent herpes illnesses, there is a large market for such an invention and therefore research is intense.
Psychological and Social Effects
Some people experience negative feelings related to the condition following diagnosis, particularly if they have acquired the genital form of the disease. Feelings of depression, isolation, fear of rejection, fear of being found out, self-destructive feelings, and fear of masturbation are not uncommon, These concerns usually lessen over time. 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.
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