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.

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. 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.

Definition
The name herpes zoster comes from Greek zōstēr, meaning "belt" or "girdle", after the characteristic belt-like dermatomal rash. The name shingles represents Latin cingulus, a variant of Latin cingulum meaning "girdle".

Despite the similarity of name, herpes zoster is not the same disease as herpes simplex, although both the varicella zoster virus and herpes simplex virus belong to the same viral subfamily (Alphaherpesvirinae).

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.

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 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, and 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 had chickenpox, and although it can occur at any age, the majority of sufferers are more than 50 years old. 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.

The symptoms of herpes zoster cannot be transmitted to another person. However, during the blister phase, direct contact with the 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). The person is no longer contagious after the rash has disappeared.

Diagnosis
If the rash has appeared, identifying this disease (making a differential diagnosis) only requires 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 only appears during chickenpox or herpes zoster and not while the virus is dormant. In larger laboratories, lymph collected from a blister is tested by the 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. , a controlled study is underway to evaluate the effectiveness on those aged 50–59. Adults also receive an immune boost from contact with children infected with varicella, a boosting method that prevents about a quarter of herpes zoster cases among unvaccinated adults, but which is becoming less common in the U.S. now that children are routinely vaccinated against varicella.

In the United Kingdom and other parts of Europe, population-based immunization is not practised. The rationale is that, until the entire population could be immunized, adults who have previously contracted VZV would 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 pain once the rash has cleared (post herpetic 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
Patients with mild to moderate pain can be treated with over-the-counter analgesics. Topical lotions containing calamine or lard 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 two-fold, 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.

Complications
Although herpes zoster typically resolves within 2 weeks, certain complications may arise:
 * Secondary bacterial infection
 * Motor involvement - incl. 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

Prognosis
The rash and pain usually subside within three to five weeks, but about one in five patients develops 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 multiple 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.

Epidemiology
Varicella zoster virus has a high level of infectivity and is prevalent worldwide, and has a very stable prevalence from generation to generation. VZV is a benign disease in a healthy child in developed countries. However, varicella can be lethal to individuals who are infected later in life or who have low immunity. The number of people in this high-risk group has increased, due to the HIV epidemic and the increase in immunosuppressive therapies. Infections of varicella in institutions such as hospitals are also a significant problem, especially in hospitals that care for these high-risk populations.

In general, herpes zoster has no seasonal incidence and does not occur in epidemics. In temperate zones chickenpox is a disease of children, with most cases occurring during the winter and spring, most likely due to school contact; there is no evidence for regular epidemics. In the tropics chickenpox typically occurs among older people. Incidence is highest in people who are over age 55, as well as in immunocompromised patients regardless of age group, and in individuals undergoing psychological stress. Non-whites may be at lower risk; it is unclear whether the risk is increased in females. Other potential risk factors include mechanical trauma, genetic susceptibility, and exposure to immunotoxins.

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. Similar incidence rates have been observed worldwide. Herpes zoster develops in an estimated 500,000 Americans each year. 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 shinges 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. Additionally, there was a statistically significant increase in adult shingles cases reported to the Antelope Valley Varicella Active Surviellance Project (VASP) from 2000 to 2003. The 56.1% increase from 237 cases in 2000 to 370 cases in 2002 yields a rate ratio of 1.4 (95% C.I. 1.2–1.7). Increases in cases of shingles reported to VASP occurred in every age category (except 70+) from 2000 to 2001. VASP also reported verified cases of shingles among adults aged 50 years and older increased 27.5% from 2006 to 2007. (Annual Summary, 2001, 2002, 2003, 2006, 2007 Antelope Valley Varicella Active Surveillance Project, Los Angeles County Department of Health Services; Centers for Disease Control and Prevention (CDC) Cooperative Agreement No. U66/CCU911165-10; Mascola L, et al.) 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.

A 2008 study revealed that people with close relatives who have had shingles are twice as likely to develop it themselves. The study speculates that there are genetic factors in who is more susceptible to VZV.

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 eighteenth century that William Heberden established a way to differentiate between herpes zoster and smallpox, and only in the late nineteenth 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.