Oral herpes involves the face or mouth. It may result in small blisters in groups, often called cold sores or fever blisters, or may just cause a sore throat.^[2][6] Genital herpes involves the genitalia. It may have minimal symptoms or form blisters that break open and result in small ulcers.^[1] These typically heal over two to four weeks.^[1] Tingling or shooting pains may occur before the blisters appear.^[1]


Herpes cycles between periods of active disease followed by periods without symptoms.^[1] The first episode is often more severe and may be associated with fever, muscle pains, swollen lymph nodes and headaches.^[1] Over time, episodes of active disease decrease in frequency and severity.^[1]


Herpetic whitlow typically involves the fingers or thumb,^[7] herpes simplex keratitis involves the eye,^[8] herpesviral encephalitis involves the brain,^[9] and neonatal herpes involves any part of the body of a newborn, among others.^[10]


There are two types of herpes simplex virus, type 1 (HSV-1) and type 2 (HSV-2).^[1] HSV-1 more commonly causes infections around the mouth while HSV-2 more commonly causes genital infections.^[2] They are transmitted by direct contact with body fluids or lesions of an infected individual.^[1] Transmission may still occur when symptoms are not present.^[1] Genital herpes is classified as a sexually transmitted infection.^[1] It may be spread to an infant during childbirth.^[1] After infection, the viruses are transported along sensory nerves to the nerve cell bodies, where they reside lifelong.^[2] Causes of recurrence may include: decreased immune function, stress, and sunlight exposure.^[2][3] Oral and genital herpes is usually diagnosed based on the presenting symptoms.^[2] The diagnosis may be confirmed by viral culture or detecting herpes DNA in fluid from blisters.^[1] Testing the blood for antibodies against the virus can confirm a previous infection but will be negative in new infections.^[1]


The most effective method of avoiding genital infections is by avoiding vaginal, oral, manual, and anal sex.^[1][11] Condom use decreases the risk.^[1] Daily antiviral medication taken by someone who has the infection can also reduce spread.^[1] There is no available vaccine^[1] and once infected, there is no cure.^[1] Paracetamol (acetaminophen) and topical lidocaine may be used to help with the symptoms.^[2] Treatments with antiviral medication such as aciclovir or valaciclovir can lessen the severity of symptomatic episodes.^[1][2]


Worldwide rates of either HSV-1 or HSV-2 are between 60% and 95% in adults.^[4] HSV-1 is usually acquired during childhood.^[1] Since there is no cure for either HSV-1 or HSV-2, rates of both inherently increase as people age.^[4] Rates of HSV-1 are between 70% and 80% in populations of low socioeconomic status and 40% to 60% in populations of improved socioeconomic status.^[4] An estimated 536 million people worldwide (16% of the population) were infected with HSV-2 as of 2003 with greater rates among women and those in the developing world.^[12] Most people with HSV-2 do not realize that they are infected.^[1]

Etymology

The name is from Greek: ἕρπης herpēs, which is related to the meaning 'to creep', referring to spreading blisters.^[13] The name does not refer to latency.^[14]

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.^[74]


Many HSV-infected people experience recurrence within the first year of infection.^[16] 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 and are less painful and heal faster (within 5–10 days without antiviral treatment) than those occurring during the primary infection.^[16] Subsequent outbreaks tend to be periodic or episodic, occurring on average four or five times a year when not using antiviral therapy.


The causes of reactivation are uncertain, but several potential triggers have been documented. A 2009 study showed the protein VP16 plays a key role in reactivation of the dormant virus.^[75] Changes in the immune system during menstruation may play a role in HSV-1 reactivation.^[76][77] Concurrent infections, such as viral upper respiratory tract infection or other febrile diseases, can cause outbreaks. Reactivation due to other infections 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.^{[78][79][80][81][82]}


The frequency and severity of recurrent outbreaks vary greatly between people. Some individuals' outbreaks can be quite debilitating, with large, painful lesions persisting for several weeks, while others experience only minor itching or burning for a few days. Some evidence indicates genetics play a role in the frequency of cold sore outbreaks. An area of human chromosome 21 that includes six genes has been linked to frequent oral herpes outbreaks. An immunity to the virus is built over time. Most infected individuals experience fewer outbreaks and outbreak symptoms often become less severe. After several years, some people become perpetually asymptomatic and no longer experience outbreaks, though they may still be contagious to others. Immunocompromised individuals may experience longer, more frequent, and more severe episodes. Antiviral medication has been proven to shorten the frequency and duration of outbreaks.^[83] 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, in particular during an outbreak with active lesions.^[84]

History

Herpes originated and evolved in Africa and could be the result of a cross-species transmission event from gibbons, orangutans, or gorillas.^[95]


Herpes has been known for at least 2,000 years. Emperor Tiberius is said to have banned kissing in Rome for a time due to so many people having cold sores. In the 16th century Romeo and Juliet, blisters "o'er ladies' lips" are mentioned. In the 18th century, it was so common among prostitutes that it was called "a vocational disease of women".^[96] 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.^[96]


Herpes antiviral therapy began in the early 1960s with the experimental use of medications that interfered with viral replication called deoxyribonucleic acid (DNA) inhibitors. The original use was against normally fatal or debilitating illnesses such as adult encephalitis,^[97] keratitis,^[98] in immunocompromised (transplant) patients,^[99] or disseminated herpes zoster (also known as disseminated shingles).^[100] The original compounds used were 5-iodo-2'-deoxyuridine, AKA idoxuridine, IUdR, or(IDU) and 1-β-D-arabinofuranosylcytosine or ara-C,^[101] later marketed under the name cytosar or cytarabine. The usage expanded to include topical treatment of herpes simplex,^[102] zoster, and varicella.^[103] Some trials combined different antivirals with differing results.^[97] The introduction of 9-β-D-arabinofuranosyladenine, (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 in 1977. Other experimental antivirals of that period included: heparin,^[104] trifluorothymidine (TFT),^[105] Ribivarin,^[106] interferon,^[107] Virazole,^[108] and 5-methoxymethyl-2'-deoxyuridine (MMUdR).^[109] The introduction of 9-(2-hydroxyethoxymethyl)guanine, AKA aciclovir, in the late 1970s^[110] raised antiviral treatment another notch and led to vidarabine vs. aciclovir trials in the late 1980s.^[111] The lower toxicity and ease of administration over vidarabine has led to aciclovir becoming the drug of choice for herpes treatment after it was licensed by the FDA in 1998.^[112] Another advantage in the treatment of neonatal herpes included greater reductions in mortality and morbidity with increased dosages, which did not occur when compared with increased dosages of vidarabine.^[112] However, aciclovir seems to inhibit antibody response, and newborns on aciclovir antiviral treatment experienced a slower rise in antibody titer than those on vidarabine.^[112]