Herpes

• 1. Introduction

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  Herpes simplex infects somewhere between 60 and 95 percent of adults worldwide, and it never leaves the body once it arrives. The virus comes in two types, called HSV-1 and HSV-2. Most people who carry the second type do not even know it.

  The name sounds modern and clinical, yet people have been recording its blisters for at least 2,000 years. How did a virus that the immune system cannot clear learn to hide so well? Why can it spread when there is nothing to see? And why does a condition this common still carry such heavy silence around it?

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• 2. A Creeping Name

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  The word herpes comes from the Greek herpēs, a term linked to the idea of creeping. It describes blisters that spread across the skin. It was never a reference to the virus lying dormant, though that later turned out to be its most remarkable trick.

  The Roman emperor Tiberius is said to have banned kissing in Rome for a time, because so many people had cold sores. That tale is the oldest hint of how long the infection has circulated among people.

  In the 16th century, Romeo and Juliet mentions blisters on ladies' lips. By the 18th century, the infection was so common among prostitutes that it was called "a vocational disease of women".

  The medical term herpes simplex appeared in Richard Boulton's book A System of Rational and Practical Chirurgery in 1713. The same book used the phrases herpes miliaris and herpes exedens.

  The virus itself has older roots than any book. Herpes appears to have originated and evolved in Africa. It may have begun as a cross-species transmission from gibbons, orangutans or gorillas. A genomic study of HSV-1 lines up with the out-of-Africa theory of human migration, which suggests the virus traveled with our ancestors.

  For all those centuries, no one knew what caused the blisters. Only in the 1940s did researchers establish that herpes was a virus.

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• 3. Hiding In The Nerve

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  In 1971, Margery L Cook and Jack G Stevens published the first direct evidence that herpes simplex can settle into a lasting latent infection and later reactivate. That finding explained why a cold sore can return in the same spot after years of calm.

  The route is surprisingly simple. After the first infection, the virus enters the nerves at the site of contact. It travels to the cell body of the neuron and becomes latent in a cluster of nerve cells called a ganglion. The immune system never removes it.

  Inside the nerve cell, the virus's double-stranded DNA becomes part of the cell's own workings. Latency is static. No new virus is produced, and a handful of viral genes keep it that way, including one called latency-associated transcript.

  A 2009 study showed that a viral protein named VP16 plays a key role in waking the dormant virus. Beyond that single protein, the causes of reactivation remain uncertain, but many triggers have been documented. Weakened immunity, stress and sunlight are on the list. So are changes in the immune system during menstruation, injury to the face, lips, eyes or mouth, surgery, radiotherapy, and exposure to wind or ultraviolet light.

  Other infections can also set it off. A viral upper respiratory infection or any febrile illness may trigger an outbreak. That is the likely origin of the old names cold sore and fever blister.

  Outbreaks usually announce themselves early. Doctors call this warning phase the prodrome. It brings tingling, itching or pain in the skin supplied by the affected nerves. It can start several days before the lesions or only a few hours before. Starting antiviral treatment at that moment can reduce how many lesions appear and how long they last in some people.

  The first outbreak is typically the worst. The first episode is often marked by fever, muscle pains, swollen lymph nodes and headaches. Recurrences usually bring fewer lesions, less pain, and healing within 5 to 10 days without treatment. Without antivirals, subsequent outbreaks arrive on average four or five times a year.

  People differ enormously. Some have large, painful lesions that last for weeks, while others feel only minor itching or burning for a few days. Genetics seems to matter. An area of human chromosome 21 containing six genes has been linked to frequent oral herpes outbreaks.

  Immunity builds with time, so most people have fewer and milder outbreaks as the years pass. After several years, some become permanently free of symptoms yet remain able to infect others. Immunocompromised people can face longer, more frequent and more severe episodes.

  The location of a recurrence is not random either. In a genital infection, sores can appear at the original site, but they can also show up near the base of the spine, on the buttocks, or on the back of the thighs.

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• 4. Many Faces

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  A single virus produces a surprisingly wide gallery of illnesses. Herpetic gingivostomatitis is often the first sign of a first infection, and it is more severe than the cold sore that usually follows. The cold sore is called herpes labialis. It is the most common form of recurrent HSV-1 infection, and the virus re-emerges from the trigeminal nerve to cause it.

  When symptoms do appear in genital infection, they take the form of clusters of inflamed bumps and fluid-filled blisters on the outer surface of the genitals. These resemble cold sores.

  The fingers and thumbs can be affected too. Herpetic whitlow is a painful infection that typically strikes there, and now and then the toes or the nail cuticle. Athletes in contact sports such as wrestling, rugby and football can pick up a related HSV-1 condition. It is called herpes gladiatorum, scrumpox, wrestler's herpes or mat herpes, and it causes skin ulceration on the face, ears and neck.

  The eye is vulnerable as well. Herpes keratitis damages it, and a first infection there can swell the conjunctiva and eyelids and leave small, white, itchy lesions on the surface of the cornea.

  The most dangerous form reaches the brain. Herpes simplex encephalitis is rare, but it is the most common sporadic fatal encephalitis in the world. It is thought to arise when HSV-1 travels from the nasal cavity to the temporal lobe, or along the trigeminal nerve from the face to the brainstem. HSV-2 is the most common cause of Mollaret's meningitis, a recurrent viral meningitis. In people with weakened immunity, the virus can also inflame the esophagus and make swallowing painful.

  Some of its skin effects are odd and dramatic. In immunodeficiency, the virus can carve clean linear erosions into skin creases that look like knife cuts. In people with chronic atopic dermatitis, it can spread across the eczema in a condition called eczema herpeticum.

  Newborns, transplant recipients and people with AIDS are especially prone to severe complications.

  Some links remain unsettled. Bell's palsy, a type of facial paralysis, may be related to reactivation of HSV-1, but that theory is contested. The virus is found in many people who have never had paralysis, and antibody levels are no higher in those who have.

  The Alzheimer's connection is also debated. HSV-1 has been proposed as a possible cause, and it appears especially damaging to the nervous system in carriers of the APOE-epsilon4 gene variant. A 2019 systematic review found only low-quality evidence tying recent infection or reactivation to dementia or mild cognitive impairment.

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• 5. Silent Spread

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  On roughly one day in five, a person with genital HSV-2 who takes no antivirals is shedding virus from the skin without any sign of it. The estimate is 15 to 25 percent of days. Oral HSV-1 sheds on 6 to 33 percent of days, genital HSV-1 on about 5 percent, and oral HSV-2 on about 1 percent.

  This silent shedding may be the most common route of HSV-2 transmission. It occurs at some point in most infected people. In half of cases it can happen more than a week before or after a visible recurrence. It is more frequent in the first 12 months after infection, and concurrent HIV makes it more frequent and longer lasting.

  To get in, the virus needs only the smallest opening. It passes through tiny breaks in the skin or mucous membranes of the mouth or genital area. Even microscopic abrasions are enough. Receptors such as nectin-1, HVEM and 3-O sulfated heparan sulfate let it enter susceptible cells.

  The risk is uneven between partners. Among monogamous couples, a woman without antibodies who has a male partner with HSV-2 faces more than a 30 percent chance per year of catching it. Without antivirals or condoms, the yearly transmission risk is about 8 to 11 percent from man to woman. From woman to man it is around 4 to 5 percent. The difference is believed to come from the greater exposure of mucosal tissue.

  Antibodies from one infection offer partial protection. Previous HSV-1 infection may cut the risk of catching HSV-2 among women by a factor of three. That claim rests on a small study of 214 couples with 14 transmissions, so it deserves caution.

  Protection comes in layers. Daily suppressive antiviral therapy reduces transmission risk by 50 percent. It also lowers asymptomatic shedding on genital HSV-2 from about 20 percent of days to about 10 percent. Consistent condom users have a 30 percent lower risk of acquiring HSV-2 than people who never use them.

  Condoms have limits. The virus cannot pass through a synthetic condom, but ulcers can appear on the scrotum, anus, buttocks or upper thighs, where no condom reaches. A female condom can offer more protection because it covers the labia. Condoms or dental dams also limit spread between the genitals of one partner and the mouth of the other.

  In October 2011, researchers reported that tenofovir, an anti-HIV drug, reduced sexual transmission of herpes by 51 percent when used as a vaginal gel. Other topical microbicides that directly inactivate the virus are still under investigation.

  The silence has a human cost. For many people, the first sign of their own infection is passing it to a partner.

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• 6. Newborns And Pregnancy

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  A woman who first catches herpes around the time of delivery gives her baby a 30 to 60 percent chance of infection. The reason is timing. There has not been enough time for protective maternal antibodies to form and cross to the child before birth.

  The odds fall sharply in other situations. If the mother's infection is a recurrence, the risk drops to 3 percent. It is 1 to 3 percent if she carries antibodies to both HSV-1 and HSV-2. It is under 1 percent if no lesions are visible. Women with antibodies to only one type are half as likely to pass it on as infected women with none.

  Neonatal herpes simplex is rare, but it is serious. It is usually caused by transmission from mother to newborn, and it can involve any part of the baby's body.

  The advice for pregnant women follows from this. Women without antibodies are recommended to avoid unprotected oral-genital contact with a partner who has HSV-1, and conventional sex with a partner who has a genital infection, during the last trimester. Infected mothers are advised to avoid procedures that could injure the baby during birth. Those include fetal scalp electrodes, forceps and vacuum extractors. If lesions are present, a caesarean section is recommended to keep the child away from infected secretions in the birth canal.

  Antivirals can lessen the need for surgery. Aciclovir given from the 36th week of pregnancy limits recurrence and shedding during childbirth. It is the recommended drug for suppressive therapy in the last months. Valaciclovir and famciclovir might make it easier for patients to keep taking their medication, but their safety in pregnancy is less well established.

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• 7. Tests And Treatments

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  A herpes diagnosis often rests on nothing more than how the sores look. Primary oral herpes shows up as multiple round, shallow ulcers inside the mouth along with inflamed gums. Even so, mistakes happen. When lesions form outside the mouth, doctors sometimes confuse them with impetigo, a bacterial infection. Common mouth ulcers look similar but never pass through a blister stage.

  Genital herpes is harder to identify. Most people have none of the classic symptoms, and fungal infection, lichen planus, atopic dermatitis and urethritis can all look alike. Herpes must also be told apart from shingles, which belongs to the same virus family but is caused by varicella zoster. Hand, foot and mouth disease can produce similar skin lesions as well.

  For fresh blisters, the preferred test is PCR, which detects viral DNA with high sensitivity and rapid results. Viral culture is less sensitive and takes several days. The older bedside Tzanck smear finds giant multinucleated cells in about 60 to 75 percent of samples. It cannot separate HSV-1 from HSV-2, so it is used less often.

  Blood tests are trickier. IgG tests can show past exposure, but they cannot tell active from latent infection. The HSV-2 version has roughly 92 percent sensitivity, but its specificity can fall as low as 57.4 percent. That produces many false positives where infection is uncommon. Because of this, the US CDC and several professional bodies advise against routine blood screening in people without symptoms. The Western blot is the gold standard at 99 percent sensitivity and specificity, but it is costly and hard to find.

  Until the 1980s, serological tests for herpes were rarely useful. The older IgM assay could not distinguish antibodies to HSV-1 from those to HSV-2. A glycoprotein G-specific IgG test introduced in the 1980s is more than 98 percent specific at telling them apart.

  No treatment removes the virus from the body. Antivirals reduce the frequency, duration and severity of outbreaks. Ibuprofen and paracetamol ease pain and fever, and topical anesthetics such as lidocaine relieve itching and pain.

  The drug story began in the early 1960s with experimental DNA inhibitors, such as idoxuridine and ara-C. They were used first against deadly or disabling illnesses, including adult encephalitis and keratitis. Vidarabine, introduced in the mid-1970s, was considerably less toxic than ara-C. It was the first systemic antiviral whose benefit outweighed its toxicity in life-threatening HSV disease, and the US Food and Drug Administration licensed the intravenous form in 1977.

  Then came aciclovir in the late 1970s. After the FDA licensed it in 1982, its lower toxicity and easier administration made it the drug of choice. In neonatal herpes, higher doses of aciclovir also brought greater drops in mortality and illness, which vidarabine had not delivered. One drawback emerged. Newborns on aciclovir saw antibody levels rise more slowly than those on vidarabine.

  Today aciclovir is available as a generic. Valaciclovir is also generic and is slightly more effective at shortening lesion healing time. Famciclovir and penciclovir are other options, and foscarnet is approved for infections that resist first-line drugs in immunocompromised patients. Cream treatments for cold sores include aciclovir, penciclovir and docosanol.

  Herbal and supplement remedies fare worse. Echinacea, L-lysine, zinc, aloe vera and others lack enough evidence, and small early studies have never been confirmed by higher-quality trials.

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• 8. Counting And Silence

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  In the United States, 58 percent of the population carries HSV-1 and 16 percent carries HSV-2. Among those with HSV-2, only 19 percent knew they were infected. In Canada, a study suggested as many as one in seven people aged 14 to 59 may have HSV-2, with more than 90 percent unaware.

  Globally, HSV-1 is usually picked up in childhood. Rates run from 70 to 80 percent in low-income populations and 40 to 60 percent in better-off ones. An estimated 536 million people, or 16 percent of the world, had HSV-2 as of 2003. Women and people in the developing world have higher rates.

  Local studies show how the picture shifts. In British Columbia in 1999, HSV-2 antibodies were found in 17 percent of leftover blood samples from antenatal testing. The figure climbed from 7 percent among women aged 15 to 19 to 28 percent among those aged 40 to 44. A study published in 2000 found that up to 70 to 90 percent of first genital infections in Norway were due to HSV-1. In Nova Scotia, 58 percent of 1,790 isolates from women's genital lesions were HSV-1, versus 37 percent of 468 from men.

  In the United States, about 1,640,000 new HSV-2 infections are estimated each year, 730,000 in men and 910,000 in women.

  Numbers like these hide the emotional weight. After a diagnosis, particularly of the genital form, people can feel depression, fear of rejection, isolation and fear of being found out. Many hesitate to tell friends, family or casual partners. In a 2007 study of 1,900 people, a quarter of whom had herpes, genital herpes ranked second for stigma among all sexually transmitted diseases, behind HIV.

  Support groups grew out of that need. The American Sexual Health Association was created in 1914 in response to sexually transmitted diseases spreading during World War I. When infections rose in the 1970s and genital herpes increased dramatically, it set up the National Herpes Resource Center in 1979. One of the center's projects was a network of local HELP groups, meant as confidential places to share experiences and fears.

  In the UK, the Herpes Association, now the Herpes Viruses Association, began in 1982. It became a registered charity with a Department of Health grant in 1985, after starting as a string of local meetings.

  Research continues toward a vaccine for both prevention and treatment. As of October 2022, the US FDA had not approved one. Moderna's mRNA-1608 is among the candidates in clinical trials.

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