Herpes zoster

Herpes zoster
Classification and external resources
Herpes zoster blisters on the neck and shoulder

Herpes zoster (or simply zoster), commonly known as shingles and also known as zona, is a viral disease characterized by apainful skin rash with blisters in a limited area on one side of the body (left or right), often in a stripe. The initial infection with varicella zoster virus (VZV) causes the acute, short-lived illness chickenpox which generally occurs in children and young adults. Once an episode of chickenpox has resolved, the virus is not eliminated from the body and can go on to cause herpes zoster often many years after the initial infection. Herpes zoster is not the same disease as herpes simplex, despite the name similarity; both the varicella zoster virus and herpes simplex virus belong to the same viral subfamily Alphaherpesvirinae.

After the initial episode of chickenpox resolves, the varicella zoster virus remains latent in the nerve cell bodies and, less frequently, the non-neuronal satellite cells of the dorsal root, cranial nerve or autonomic ganglia,^[1] without causing any symptoms.^[2] Years or decades after the initial infection, the virus may break out of nerve cell bodies and travel down nerve axons to cause viral infection of the skin in the region of the nerve. The virus may spread from one or more ganglia along nerves of an affected segment and infect the corresponding dermatome (an area of skin supplied by one spinal nerve) causing a painful rash.^[3][4] Although the rash usually heals within two to four weeks, some sufferers experience residual nerve pain for months or years, a condition called postherpetic neuralgia. Exactly how the virus remains latent in the body, and subsequently re-activates, is not understood.^[1]

Throughout the world, the incidence rate of herpes zoster every year ranges from 1.2 to 3.4 cases per 1,000 healthy individuals, increasing to 3.9–11.8 per year per 1,000 individuals among those older than 65 years.^[5][6][7] Over a lifetime, a large fraction of people develop herpes zoster, though usually only once; a 1965 16-year British study proposed that, of those individuals living to age 85, 50% would likely have had at least one attack, and 1% had at least two attacks.^[8]

The zoster (shingles) vaccine is considered the most effective way to reduce incidence of herpes zoster and postherpetic neuralgia, and to reduce severity of any outbreak.^[9] Antiviral drug treatment is considered a second-line approach, but can reduce the severity and duration of herpes zoster if a seven- to ten-day course of these drugs is started within 72 hours of the appearance of the characteristic rash. 

Signs and symptoms

A case of shingles that demonstrates the typical dermatomal distribution, in this case C8/T1

The earliest symptoms of herpes zoster, which include headache, fever, and malaise, are nonspecific, and may result in an incorrect diagnosis.^[5][11] These symptoms are commonly followed by sensations of burning pain, itching, hyperesthesia (oversensitivity), orparesthesia ("pins and needles": tingling, pricking, or numbness).^[12] The pain may be mild to extreme in the affected dermatome, with sensations that are often described as stinging, tingling, aching, numbing or throbbing, and can be interspersed with quick stabs of agonizing pain.^[13]

Herpes zoster in children is often painless, but older people are more likely to get zoster as they age, and the disease tends to be more severe.^[14]

In most cases after one to two days, but sometimes as long as three weeks, the initial phase is followed by the appearance of the characteristic skin rash. The pain and rash most commonly occurs on the torso, but can appear on the face, eyes or other parts of the body. At first the rash appears similar to the first appearance of hives; however, unlike hives, herpes zoster causes skin changes limited to a dermatome, normally resulting in a stripe or belt-like pattern that is limited to one side of the body and does not cross the midline.^[12] Zoster sine herpete ("zoster without herpes") describes a patient who has all of the symptoms of herpes zoster except this characteristic rash.^[15]

Later the rash becomes vesicular, forming small blisters filled with a serous exudate, as the fever and general malaise continue. The painful vesicles eventually become cloudy or darkened as they fill with blood, and crust over within seven to ten days; usually the crusts fall off and the skin heals, but sometimes, after severe blistering, scarring and discolored skin remain.^[12]

Development of the shingles rash

Day 1	Day 2	Day 5	Day 6

Herpes zoster may have additional symptoms, depending on the dermatome involved. Herpes zoster ophthalmicus involves the orbit of the eye and occurs in approximately 10% to 25% of cases. It is caused by the virus reactivating in the ophthalmic division of the trigeminal nerve. In a few patients, symptoms may include conjunctivitis, keratitis, uveitis, andoptic nerve palsies that can sometimes cause chronic ocular inflammation, loss of vision, and debilitating pain.^[16] Herpes zoster oticus, also known as Ramsay Hunt syndrome type II, involves the ear. It is thought to result from the virus spreading from the facial nerve to the vestibulocochlear nerve. Symptoms include hearing loss and vertigo (rotational dizziness).^[1]

Pathophysiology

Progression of herpes zoster. A cluster of small bumps (1) turns into blisters (2). The blisters fill with lymph, break open (3), crust over (4), and finally disappear. Postherpetic neuralgia can sometimes occur due to nerve damage (5),

The causative agent for herpes zoster is the varicella zoster virus (VZV)—a double-stranded DNA virus related to the Herpes simplex virus. Most individuals are infected with this virus as children, and suffer from an episode of chickenpox. The immune system eventually eliminates the virus from most locations, but it remains dormant (or latent) in the ganglia adjacent to the spinal cord (called the dorsal root ganglion) or the ganglion semilunare (ganglion Gasseri) in the base of the skull.^[17]

Herpes zoster occurs only in people who have been previously infected with VZV; although it can occur at any age, approximately half of the cases in the USA occur in those aged 50 years or older.^[18] Repeated attacks of herpes zoster are rare,^[12] and it is extremely rare for patients to suffer more than three recurrences.^[17]

The disease results from virus particles in a single sensory ganglion switching from their latent lysogenic cycles to their active lytic cycles.^[4]In contrast to the herpes simplex virus, the latency of VZV is poorly understood. The virus has never been successfully recovered from human nerve cells by cell culture. The complete sequence of the viral genome was published in 1986.^[19] Virus-specific proteins continue to be made by the infected cells during the latent period, so true latency, as opposed to chronic, low-level, active infection, has not been proven to occur in VZV infections.^[2][20] Although VZV has been detected in autopsies of nervous tissue,^[21] there are no methods to find dormant virus in the ganglia of living people.

Unless the immune system is compromised, it suppresses reactivation of the virus and prevents herpes zoster outbreaks. Why this suppression sometimes fails is poorly understood,^[6] but herpes zoster is more likely to occur in people whose immune systems are impaired due to aging, immunosuppressive therapy, psychological stress, or other factors.^[22] Upon reactivation, the virus replicates in neuronal cell bodies, and virions are shed from the cells and carried down the axons to the area of skin innervated by that ganglion. In the skin, the virus causes local inflammationand blistering. The short- and long-term pain caused by herpes zoster outbreaks originates from inflammation of affected nerves due to the widespread growth of the virus in those areas.^[23]

As with chickenpox and/or other forms of herpes, direct contact with an active rash can spread VZV to a person who has no immunity to the virus. This newly infected individual may then develop chickenpox, but will not immediately develop shingles.^[12]

Diagnosis

Herpes zoster on the chest

If the rash has appeared, identifying this disease (making a differential diagnosis) requires only a visual examination, since very few diseases produce a rash in a dermatomal pattern (see map). However, herpes simplex virus (HSV) can occasionally produce a rash in such a pattern (zosteriform herpes simplex).^[24][25] The Tzanck smear is helpful for diagnosing acute infection with a herpes virus, but does not distinguish between HSV and VZV.^[26]

When the rash is absent (early or late in the disease, or in the case of zoster sine herpete), herpes zoster can be difficult to diagnose.^[27]Apart from the rash, most symptoms can occur also in other conditions.

Laboratory tests are available to diagnose herpes zoster. The most popular test detects VZV-specific IgM antibody in blood; this appears only during chickenpox or herpes zoster and not while the virus is dormant.^[28] In larger laboratories, lymph collected from a blister is tested by polymerase chain reaction for VZV DNA, or examined with an electron microscope for virus particles.^[29]

In a recent study, samples of lesions on the skin, eyes, and lung from 182 patients with presumed herpes simplex or herpes zoster were tested with quantitative PCR or with viral culture. In this comparison, viral culture detected VZV with only a 14.3% sensitivity, although the test was highly specific (specificity=100%). By comparison, quantitative PCRresulted in 100% sensitivity and specificity. Overall testing for herpes simplex and herpes zoster using PCR showed a 60.4% improvement over viral culture.^[30]

Prevention

There is a live vaccine for VZV, marketed as Zostavax.^[31] It must be maintained at a temperature not exceeding -15 °C during shipping and storage, although it can be stored and transported at refrigerator temperature for up to 72 continuous hours before reconstitution. The incidence of side effects is low. There is no recommended upper age limit.^[32]

A systematic review by the Cochrane Library concluded that Zostavax can reduce the absolute risk of shingles by 1.75%, i.e. 1 episode of shingles prevented for every 70 patients vaccinated.^[33] This equates to a 50% relative risk reduction. The vaccine reduced incidence of persistent, severe pain after shingles (i.e., PHN) by 66% in people who contracted shingles despite vaccination.^[32]

Duration of protection was not known as of 2013. In the Shingles Prevention Study (SPS), vaccine efficacy was maintained through four years of follow-up, and a larger and longer study was in progress; evidence suggested that protection persists for up to 7 years. The need for revaccination had not been defined.^[32] An episode of HZ has an immunizing effect, greatly reducing the probability of a subsequent recurrence. However, patients with a history of severe HZ are often insistent on receiving the vaccine, and there have been concerns about the validity of patient histories of HZ. Both the Centers for Disease Control and Prevention and the ACIP recommended the vaccination of adults regardless of a previous episode of HZ.^[32]

It has been recommended that people with primary or acquired immunodeficiency should not receive the vaccine.^[32]

The likelihood of vaccination causing a case of HZ appears to be very low.^[32]

A 2007 study found that the zoster vaccine is likely to be cost-effective in the U.S., projecting an annual savings of $82 to $103 million in healthcare costs with cost-effectiveness ratios ranging from $16,229 to $27,609 per quality-adjusted life year gained.^[34] In October 2007 the vaccine was officially recommended in the U.S. for healthy adults aged 60 and over.^[31][35] The Centers for Disease Control and Prevention recommends shingle vaccine for use in people 60 years old and older to prevent shingles, but it is not recommended to treat active shingles or postherpetic neuralgia (pain after the rash is gone) once it develops.^[36] Adults also receive an immune boost from contact with children infected with varicella (chicken pox), a boosting method that prevents about a quarter of herpes zoster cases among unvaccinated adults, but that is becoming less common in the U.S. now that children are routinely vaccinated against varicella.^[10][37]

In the United Kingdom and other parts of Europe, population-based varicella immunization is not practiced. The rationale is that until the entire population could be immunized, adults who have previously contracted VZV would instead derive benefit from occasional exposure to VZV (from children), which serves as a booster to their immunity to the virus, and may reduce the risk of shingles later on in life.^[38] The UK Health Protection Agency states that, while the vaccine is licensed in the UK, there are no plans to introduce it into the routine childhood immunization scheme, although it may be offered to healthcare workers who have no immunity to VZV.^[39]

From 2013 the UK National Health Service started offering shingles vaccination, with Zostavax, to elderly people. People aged either 70 or 79 on 1 September 2013 were offered the vaccine. People aged 71 to 78 on that date would only have an opportunity to have the shingles vaccine after reaching the age of 79.^[40] The original intention was for people aged between 70 and 79 to be vaccinated, but the NHS later said that the vaccination programme was being staggered as it would be impractical to vaccinate everyone in their 70s in a single year.^[41]

Treatment

The aims of treatment are to limit the severity and duration of pain, shorten the duration of a shingles episode, and reduce complications. Symptomatic treatment is often needed for the complication of postherpetic neuralgia.^[42] However, a study on untreated herpes zoster shows that, once the rash has cleared, postherpetic neuralgia is very rare in people under 50 and wears off in time; in older people the pain wore off more slowly, but even in people over 70, 85% were pain free a year after their shingles outbreak.^[43]

Analgesics

People with mild to moderate pain can be treated with over-the-counter pain medications. Topical lotions containing calamine can be used on the rash or blisters and may be soothing. Occasionally, severe pain may require an opioid medication, such as morphine. Once the lesions have crusted over, capsaicin cream (Zostrix) can be used. Topicallidocaine and nerve blocks may also reduce pain.^[44] Administering gabapentin along with antivirals may offer relief of postherpetic neuralgia.^[42]

Antivirals

Antiviral drugs may reduce the severity and duration of herpes zoster.^[45] They however do not prevent postherpetic neuralgia.^[46] Of these drugs, acyclovir has been the standard treatment, but the new drugs valaciclovir and famciclovir demonstrate similar or superior efficacy and good safety and tolerability.^[42] The drugs are used both forprevention (for example in HIV/AIDS) and as therapy during the acute phase. Complications in immunocompromised individuals with herpes zoster may be reduced withintravenous acyclovir. In people who are at a high risk for repeated attacks of shingles, five daily oral doses of acyclovir are usually effective.^[1]

Steroids

Corticosteroids have been recommended to help with acute pain but do not appear to decrease the risk of long term pain.^[47] Their use in Ramsay Hunt syndrome has not been properly studied as of 2008.^[48]

Herpes zoster ophthalmicus

Herpes zoster ophthalmicus.

Trigeminal herpes zoster withuveitis and keratitis.

Treatment for herpes zoster ophthalmicus is similar to standard treatment for herpes zoster at other sites. A recent trial comparing aciclovir with its prodrug, valaciclovir, demonstrated similar efficacies in treating this form of the disease.^[49] The significant advantage of valciclovir over aciclovir is its dosing of only 3 times/day (compared with aciclovir's 5 times/day dosing), which could make it more convenient for patients and improve adherence with therapy.^[50]

Prognosis

The rash and pain usually subside within three to five weeks, but about one in five patients develop a painful condition called postherpetic neuralgia, which is often difficult to manage. In some patients, herpes zoster can reactivate presenting as zoster sine herpete: pain radiating along the path of a single spinal nerve (a dermatomal distribution), but without an accompanying rash. This condition may involve complications that affect several levels of the nervous system and cause many cranial neuropathies, polyneuritis, myelitis, or aseptic meningitis. Other serious effects that may occur in some cases include partial facial paralysis (usually temporary), ear damage, orencephalitis.^[1] During pregnancy, first infections with VZV, causing chickenpox, may lead to infection of the fetus and complications in the newborn, but chronic infection or reactivation in shingles are not associated with fetal infection.^[51][52]

There is a slightly increased risk of developing cancer after a herpes zoster infection. However, the mechanism is unclear and mortality from cancer did not appear to increase as a direct result of the presence of the virus.^[53] Instead, the increased risk may result from the immune suppression that allows the reactivation of the virus.^[54]

Although herpes zoster typically resolves within 3–5 weeks, certain complications may arise:

• Secondary bacterial infection
• Motor involvement, including weakness especially in "motor herpes zoster"
• Eye involvement: trigeminal nerve involvement (as seen in herpes ophthalmicus) should be treated early and aggressively as it may lead to blindness. Involvement of the tip of the nose in the zoster rash is a strong predictor of herpes ophthalmicus.^[55]
• Postherpetic neuralgia, a condition of chronic pain following herpes zoster

Epidemiology

Electron micrograph of Varicella zoster virus. Approx. 150,000-fold magnification.

Varicella zoster virus (VZV) has a high level of infectivity and has a worldwide prevalence.^[56] Herpes zoster is a re-activation of latent VZV infection: zoster can only occur in someone who has previously had chickenpox (varicella).

Herpes zoster has no relationship to season and does not occur in epidemics. There is, however, a strong relationship with increasing age.^[14][22] The incidence rate of herpes zoster ranges from 1.2 to 3.4 per 1,000 person-years among younger healthy individuals, increasing to 3.9–11.8 per 1,000 person‐years among those older than 65 years,^[5][14] and incidence rates worldwide are similar.^[5][7] This relationship with age has been demonstrated in many countries,^{[5][7][57][58][59][60]} and is attributed to the fact that cellular immunity declines as people grow older.

Another important risk factor is immunocompromise, as in people with HIV.^[61][62] Other risk factors include psychological stress.^[13][63][64]According to a study in North Carolina, "black subjects were significantly less likely to develop zoster than were white subjects."^[65][66] It is unclear whether the risk is increased in females. Other potential risk factors include mechanical trauma and exposure toimmunotoxins.^[22][64]

There is no strong evidence for a genetic link or a link to family history. A 2008 study showed that people with close relatives who had had shingles were twice as likely to develop it themselves,^[67] but a 2010 study found no such link.^[64]

Adults with latent VZV infection who are exposed intermittently to children with chickenpox receive an immune boost.^[14][64] This periodic boost to the immune system helps to prevent shingles in older adults. When routine chickenpox vaccination was introduced in the United States, there was concern that, because older adults would no longer receive this natural periodic boost, there would be an increase in the incidence of shingles.

Multiple studies and surveillance data, at least when viewed superficially, demonstrate no consistent trends in incidence in the U.S. since the chickenpox vaccination program began in 1995.^[68] However, upon closer inspection, the two studies that showed no increase in shingles incidence were conducted among populations where varicella vaccination was not as yet widespread in the community.^[69][70] A later study by Patel et al. concluded that since the introduction of the chickenpox vaccine, hospitalization costs for complications of shingles increased by more than $700 million annually for those over age 60.^[71] Another study by Yih et al. reported that as varicella vaccine coverage in children increased, the incidence of varicella decreased, and the occurrence of shingles among adults increased by 90%.^[72] The results of a further study by Yawn et al. showed a 28% increase in shingles incidence from 1996 to 2001.^[73] It is likely that incidence rate will change in the future, due to the aging of the population, changes in therapy for malignant and autoimmune diseases, and changes in chickenpox vaccination rates; a wide adoption of zoster vaccination could dramatically reduce the incidence rate.^[5]

In one study, it was estimated that 26% of patients who contract herpes zoster eventually present complications. Postherpetic neuralgia arises in approximately 20% of patients.^[74]A study of 1994 California data found hospitalization rates of 2.1 per 100,000 person-years, rising to 9.3 per 100,000 person-years for ages 60 and up.^[75] An earlier Connecticut study found a higher hospitalization rate; the difference may be due to the prevalence of HIV in the earlier study, or to the introduction of antivirals in California before 1994.^[76]

History

Herpes zoster has a long recorded history, although historical accounts fail to distinguish the blistering caused by VZV and those caused by smallpox,^[18] ergotism, and erysipelas. It was only in the late 18th century that William Heberden established a way to differentiate between herpes zoster and smallpox,^[77] and only in the late 19th century that herpes zoster was differentiated from erysipelas. In 1831, Richard Bright hypothesized that the disease arose from the dorsal root ganglion, and this was confirmed in an 1861 paper byFelix von Bärensprung.^[78]

The first indications that chickenpox and herpes zoster were caused by the same virus were noticed at the beginning of the 20th century. Physicians began to report that cases of herpes zoster were often followed by chickenpox in the younger people who lived with the shingles patients. The idea of an association between the two diseases gained strength when it was shown that lymph from a sufferer of herpes zoster could induce chickenpox in young volunteers. This was finally proved by the first isolation of the virus in cell cultures, by the Nobel laureate Thomas Huckle Weller, in 1953.^[79]

Until the 1940s, the disease was considered benign, and serious complications were thought to be very rare.^[80] However, by 1942, it was recognized that herpes zoster was a more serious disease in adults than in children, and that it increased in frequency with advancing age. Further studies during the 1950s on immunosuppressed individuals showed that the disease was not as benign as once thought, and the search for various therapeutic and preventive measures began.^[81] By the mid-1960s, several studies identified the gradual reduction in cellular immunity in old age, observing that in a cohort of 1,000 people who lived to the age of 85, approximately 500 (i.e., 50%) would have at least one attack of herpes zoster, and 10 (i.e., 1%) would have at least two attacks.^[8]

In historical shingles studies, shingles incidence generally increased with age. However, in his 1965 paper, Dr. Hope-Simpson was first to suggest, “The peculiar age distribution of zoster may in part reflect the frequency with which the different age groups encounter cases of varicella and because of the ensuing boost to their antibody protection have their attacks of zoster postponed.”^[14] Lending support to this hypothesis that contact with children with chickenpox boosts adult cell-mediated immunity to help postpone or suppress shingles, is the study by Thomas et al., which reported that adults in households with children had lower rates of shingles than households without children.^[82] Also, the study by Terada et al. indicated that pediatricians reflected incidence rates from 1/2 to 1/8 that of the general population their age.^[83]

Etymology

The family name of all the herpesviridae is derived from the Greek word herpein ("to creep"),^[84] referring to the latent, recurring infections typical of this group of viruses. Zostercomes from Greek zōstēr, meaning "belt" or "girdle", after the characteristic belt-like dermatomal rash.^[85] The common name for the disease, shingles, derives from the Latincingulus, a variant of Latin cingulum meaning "girdle".