Herpes zoster

Herpes zoster (or simply zoster), commonly known as shingles and also known as zona, is a viral disease characterized by a painful skin rash with blisters in a limited area on one side of the body, 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 people. Once an episode of chickenpox has resolved, the virus is not eliminated from the body but can go on to cause shingles—an illness with very different symptoms—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).

Varicella zoster virus can become latent in the nerve cell bodies and less frequently in non-neuronal satellite cells of dorsal root, cranial nerve or autonomic ganglion, without causing any symptoms. Years or decades after a chickenpox 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. 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.

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. Over a lifetime, a large fraction of people develop herpes zoster, though usually only once – in a 1960s US study, 50% of individuals living to age 85 had at least one attack, while 1% had at least two attacks. Antiviral drug treatment 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
The earliest symptoms of herpes zoster, which include headache, fever, and malaise, are nonspecific, and may result in an incorrect diagnosis. These symptoms are commonly followed by sensations of burning pain, itching, hyperesthesia (oversensitivity), or paresthesia ("pins and needles": tingling, pricking, or numbness). 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.

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.

In most cases after 1–2 days, but sometimes as long as 3 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. Zoster sine herpete ("zoster without herpes") describes a patient who has all of the symptoms of herpes zoster except this characteristic rash.

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, 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.

Herpes zoster may have additional symptoms, depending on the dermatome involved. Herpes zoster ophthalmicus involves the orbit of the eye and occurs in approximately 10–25% 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, and optic nerve palsies that can sometimes cause chronic ocular inflammation, loss of vision, and debilitating pain. 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).

Pathophysiology


The causative agent for herpes zoster is varicella zoster virus (VZV), a double-stranded DNA virus related to the Herpes simplex virus group. Most people 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. Repeated attacks of herpes zoster are rare, and it is extremely rare for patients to suffer more than three recurrences.

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. The disease results from the virus reactivating in a single sensory ganglion. In contrast to Herpes simplex virus, the latency of VZV is poorly understood. The virus has not been recovered from human nerve cells by cell culture and the location and structure of the viral DNA is not known. Virus-specific proteins continue to be made by the infected cells during the latent period, so true latency, as opposed to a chronic low-level infection, has not been proven. Although VZV has been detected in autopsies of nervous tissue, there are no methods to find dormant virus in the ganglia in living people.

Unless the immune system is compromised, it suppresses reactivation of the virus and prevents herpes zoster. Why this suppression sometimes fails is poorly understood, but herpes zoster is more likely to occur in people whose immune system is impaired due to aging, immunosuppressive therapy, psychological stress, or other factors. Upon reactivation, the virus replicates in the nerve cells, and virions are shed from the cells and carried down the axons to the area of skin served by that ganglion. In the skin, the virus causes local inflammation and blisters. The short- and long-term pain caused by herpes zoster comes from the widespread growth of the virus in the infected nerves, which causes inflammation.

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. Until the rash has developed crusts, a person is extremely contagious. A person is also not infectious before blisters appear, or during postherpetic neuralgia (pain after the rash is gone).

Diagnosis
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. The Tsanck smear is helpful for diagnosing acute infection with a herpes virus, but does not distinguish between HSV and VZV.

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. 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. 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.

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 real-time 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, real-time PCR resulted in 100% sensitivity and specificity. Overall testing for herpes simplex and herpes zoster using PCR showed a 60.4% improvement over viral culture.

Prevention
A live vaccine for VZV exists, marketed as Zostavax. In a 2005 study of 38,000 older adults it prevented half the cases of herpes zoster and reduced the number of cases of postherpetic neuralgia by two-thirds. 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. In October 2007 the vaccine was officially recommended in the U.S. for healthy adults aged 60 and over. 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. The shingles vaccination can cut the risk of the severe disease by 55 percent. 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 post-herpetic neuralgia (pain after the rash is gone) once it develops.

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. 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.

A 2006 study of 243 cases and 483 matched controls found that fresh fruit is associated with a reduced risk of developing shingles–people who consumed less than one serving of fruit a day had a risk three times as great as those who consumed more than three servings, after adjusting for other factors such as total energy intake. For those aged 60 or more, vitamins and vegetable intake had a similar association.

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. 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 one year after their shingles outbreak.

Analgesics
People with mild to moderate pain can be treated with over-the-counter analgesics. 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. Topical lidocaine and nerve blocks may also reduce pain. Administering gabapentin along with antivirals may offer relief of postherpetic neuralgia.

Antivirals
Antiviral drugs inhibit VZV replication and reduce the severity and duration of herpes zoster with minimal side effects, but do not reliably prevent postherpetic neuralgia. 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. The drugs are used both as prophylaxis (for example in AIDS patients) and as therapy during the acute phase. Antiviral treatment is recommended for all immunocompetent individuals with herpes zoster over 50 years old, preferably given within 72 hours of the appearance of the rash. Complications in immunocompromised individuals with herpes zoster may be reduced with intravenous acyclovir. In people who are at a high risk for repeated attacks of shingles, five daily oral doses of acyclovir are usually effective.

Steroids
Orally administered corticosteroids are frequently used in treatment of the infection, despite clinical trials of this treatment being unconvincing. Nevertheless, one trial studying immunocompetent patients older than 50 years of age with localized herpes zoster, suggested that administration of prednisone with aciclovir improved healing time and quality of life. Upon one-month evaluation, aciclovir with prednisone increased the likelihood of crusting and healing of lesions by about twofold, when compared to placebo. This trial also evaluated the effects of this drug combination on quality of life at one month, showing that patients had less pain, and were more likely to stop the use of analgesic agents, return to usual activities and have uninterrupted sleep. However, when comparing cessation of herpes zoster-associated pain or post herpetic neuralgia, there was no difference between aciclovir plus prednisone and simply aciclovir alone. Because of the risks of corticosteroid treatment, it is recommended that this combination of drugs only be used in people more than 50 years of age, due to their greater risk of postherpetic neuralgia.

Herpes zoster ophthalmicus
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. 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.

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, or encephalitis. 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.

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. Instead, the increased risk may result from the immune suppression that allows the reactivation of the virus.

Although herpes zoster typically resolves within 2 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.
 * Postherpetic neuralgia – a condition of chronic pain following herpes zoster

Epidemiology


Varicella zoster virus (VZV) has a high level of infectivity and has a worldwide prevalence. Herpes zoster is a re-activation of latent VZV infection: this means that 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. The incidence rate of herpes zoster ranges from 1.2 to 3.4 per 1,000 person-years among healthy individuals, increasing to 3.9–11.8 per 1,000 person‐years among those older than 65 years, and incidence rates worldwide are similar. This relationship with age has been demonstrated in many countries,    and is attributed to the fact that cellular immunity declines as people grow older.

Another important risk factor is immunocompromise: HIV is an important example of immune compromise ). Other risk factors include psychological stress. Blacks are at lower risk of shingles than caucasians.   It is unclear whether the risk is increased in females. Other potential risk factors include mechanical trauma and exposure to immunotoxins.

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 have had shingles are twice as likely to develop it themselves, but a 2010 study found no such link.

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

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. 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. A recent study by Patel et al. concluded that since the introduction of the chickenpox vaccine, hospitalization costs for complications of shingles have increased by more than $700 million annually for those over 60 years. 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 90%. The results of a further study by Yawn et al. showed a 28% increase in shingles incidence from 1996 to 2001. 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.

In one study, it was estimated that 26% of patients who contract herpes zoster eventually present with complications. Postherpetic neuralgia arises in approximately 20% of patients. 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. 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.

History
Herpes zoster has a long recorded history, although historical accounts fail to distinguish the blistering caused by VZV and those caused by smallpox, ergotism, and erysipelas. It was only in the late 18th century that William Heberden established a way to differentiate between herpes zoster and smallpox, 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 by Felix von Bärunsprung.

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.

Until the 1940s, the disease was considered benign, and serious complications were thought to be very rare. 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. 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.

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.” 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. 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.

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