Herpes zoster blisters on the neck and shoulder
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Shingles, also known as zoster, herpes zoster, or zona, is a viral disease characterized by a painful skin rash with blisters involving a limited area. Typically the rash occurs on either the left or right of the body or face in a single stripe. Two to four days before the rash occurs there may be pain or tingling in the area. Otherwise there are typically few symptoms. The rash usually heals within two to four weeks; however, some people develop ongoing nerve pain which may last for months or years, a condition called postherpetic neuralgia. In those with poor immune function the rash may occur widely. If the rash involves the eye, vision loss may occur.
Shingles is due to a reactivation of varicella zoster virus (VZV) within a person's body. Chickenpox is due to an initial infection with VZV. Once chickenpox has resolved, the virus may remain inactive in nerve cells. Risk factors for reactivation include older age, poor immune function, and having had chickenpox before 18 months of age. How the virus remains in the body or subsequently re-activates, is not well understood. Exposure to the virus in the blisters can cause chickenpox in someone who has not had it before but will not trigger shingles. Diagnosis is typically based on a person's signs and symptoms. Varicella zoster virus is not the same as herpes simplex virus; however, they belong to the same family of viruses.
The shingles vaccine decreases the chance of shingles by about half in those between the ages of 50 and 80. It also decreases rates of postherpetic neuralgia, and if an outbreak occurs, its severity. After 80 the vaccine is still effective, just less so. It contains the same material as the varicella vaccine, just at a higher dose. If shingles develops, antiviral medications such as aciclovir can reduce the severity and duration of disease if started within 72 hours of the appearance of the rash. Evidence does not show a significant effect of antivirals or steroids on rates of postherpetic neuralgia. Paracetamol, NSAIDs, or opioids may be used to help with the acute pain.
It is estimated that about a third of people develop shingles at some point in their life. While more common among older people, children may also get the disease. The number of new cases per year ranges from 1.2–3.4 per 1,000 among healthy individuals to 3.9–11.8 per 1,000 among those older than 65 years of age. About half of those living to age 85 will have at least one attack, and less than 5% will have more than one attack. The disease has been recognized since ancient times. In Arabic its name means "belt of fire", while in Spanish it means "small snake", and in Hindi it means "big rash".
Signs and symptoms
The earliest symptoms of shingles, 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). Pain can 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.
Shingles in children is often painless, but people are more likely to get shingles as they age, and the disease tends to be more severe.
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, shingles 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 person who has all of the symptoms of shingles 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, 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.
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The ophthalmic division of the trigeminal nerve is most commonly involved branch. When the virus is reactivated in this nerve branch it is termed zoster ophthalmicus. The skin of the forehead, upper eyelid and orbit of the eye may be involved. Zoster ophthalmicus occurs in approximately 10% to 25% of cases. In some people, symptoms may include conjunctivitis, keratitis, uveitis, and optic nerve palsies that can sometimes cause chronic ocular inflammation, loss of vision, and debilitating pain.
Shingles 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).
Shingles may occur in the mouth if the maxillary or mandibular division of the trigeminal nerve is affected, in which the rash may appear on the mucous membrane of the upper jaw (usually the palate, sometimes the gums of the upper teeth) or the lower jaw (tongue or gums of the lower teeth) respectively. Oral involvement may occur alone or in combination with a rash on the skin over the cutaneous distribution of the same trigeminal branch. As with shingles of the skin, the lesions tend to only involve one side, distinguishing it from other oral blistering conditions. In the mouth, shingles appears initially as 1–4 mm opaque blisters (vesicles), which break down quickly to leave ulcers that heal within 10–14 days. The prodromal pain (before the rash) may be confused with toothache. Sometimes this leads to unnecessary dental treatment. Post herpetic neuralgia uncommonly is associated with shingles in the mouth. Unusual complications may occur with intra-oral shingles that are not seen elsewhere. Due the close relationship of blood vessels to nerves, the virus can easily spread to involve the blood vessels and compromise the blood supply, sometimes causing ischemic necrosis. Therefore, oral involvement rarely causes complications such as osteonecrosis, tooth loss, periodontitis (gum disease), pulp calcification, pulp necrosis, periapical lesions and tooth developmental anomalies.
In those with poor immune function, disseminated shingles may occur (wide rash). It is defined as more than twenty skin lesions appearing outside either the primarily affected dermatome or dermatomes directly adjacent to it. Besides the skin, other organs, such as the liver or brain, may also be affected (causing hepatitis or encephalitis respectively), making the condition potentially lethal.:380
The causative agent for shingles 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 which causes 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 trigeminal ganglion in the base of the skull.
Shingles 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. Repeated attacks of shingles are rare, and it is extremely rare for a person to have more than three recurrences.
The disease results from virus particles in a single sensory ganglion switching from their latent lysogenic cycles to their active lytic cycles. 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. 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. Although VZV has been detected in autopsies of nervous tissue, 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 shingles outbreaks. Why this suppression sometimes fails is poorly understood, but shingles is more likely to occur in people whose immune systems are impaired due to aging, immunosuppressive therapy, psychological stress, or other factors. 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 inflammation and blistering. The short- and long-term pain caused by shingles outbreaks originates from inflammation of affected nerves due to the widespread growth of the virus in those areas.
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.
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). The Tzanck 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), shingles can be difficult to diagnose. Apart from the rash, most symptoms can occur also in other conditions.
Laboratory tests are available to diagnose shingles. The most popular test detects VZV-specific IgM antibody in blood; this appears only during chickenpox or shingles 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.
Samples of lesions on the skin, eyes, and lung from 182 people with presumed herpes simplex or shingles 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 PCR resulted in 100% sensitivity and specificity. Overall testing for herpes simplex and shingles using PCR showed a 60.4% improvement over viral culture.
There is a live vaccine for VZV, known as the zoster vaccine. 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.
A systematic review by Cochrane concluded that the herpes zoster vaccine was useful for preventing herpes zoster for at least three years. This equates to about 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.
As of 2013, the duration of protection was unknown. 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. An episode of HZ has an immunizing effect, greatly reducing the probability of a subsequent recurrence. However, individuals with a history of severe HZ are often insistent on receiving the vaccine, and there have been concerns about the validity of people's 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.
It has been recommended that people with primary or acquired immunodeficiency should not receive the vaccine.
The likelihood of vaccination causing a case of HZ appears to be very low.
A 2007 study found that the shingles 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. 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. Adults also receive an immune boost from contact with children infected with varicella (chicken pox), a boosting method that prevents about a quarter of shingles cases among unvaccinated adults, but that 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 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.
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. 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.
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 shingles 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.
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. Topical lidocaine and nerve blocks may also reduce pain. Administering gabapentin along with antivirals may offer relief of postherpetic neuralgia.
Antiviral drugs may reduce the severity and duration of shingles; however, they do not 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 for prevention (for example in HIV/AIDS) and as therapy during the acute phase. Complications in immunocompromised individuals with shingles 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.
Treatment for zoster ophthalmicus is similar to standard treatment for shingles at other sites. A recent trial comparing acyclovir 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 people and improve adherence with therapy.
The rash and pain usually subside within three to five weeks, but about one in five people develop a painful condition called postherpetic neuralgia, which is often difficult to manage. In some people, shingles 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 shingles 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 shingles 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.
- Postherpetic neuralgia, a condition of chronic pain following shingles
Varicella zoster virus (VZV) has a high level of infectivity and has a worldwide prevalence. Shingles is a re-activation of latent VZV infection: zoster can only occur in someone who has previously had chickenpox (varicella).
Shingles has no relationship to season and does not occur in epidemics. There is, however, a strong relationship with increasing age. The incidence rate of shingles 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, 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 immunosuppression, as in people with HIV. Other risk factors include psychological stress. According to a study in North Carolina, "black subjects were significantly less likely to develop zoster than were white subjects." It is unclear whether the risk is different by gender. 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 had had shingles were 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 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. 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 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. 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%. 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 those who contract shingles eventually present complications. Postherpetic neuralgia arises in approximately 20% of people with shingles. 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.
Shingles has a long recorded history, although historical accounts fail to distinguish the blistering caused by VZV and those caused by smallpox, ergotism, and erysipelas. In the late 18th century William Heberden established a way to differentiate between shingles and smallpox, and in the late 19th century shingles was differentiated from erysipelas. In 1831 Richard Bright hypothesized that the disease arose from the dorsal root ganglion, and an 1861 paper by Felix von Bärensprung confirmed this.
The first indications that chickenpox and shingles were caused by the same virus were noticed at the beginning of the 20th century. Physicians began to report that cases of shingles were often followed by chickenpox in the younger people who lived with the person with shingles. The idea of an association between the two diseases gained strength when it was shown that lymph from a person with shingles 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 shingles 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 shingles, 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 suggested that 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, a study by Thomas et al. 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.
The family name of all the herpesviridae derives 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".
Advances in research and diagnosis
Until the mid 1990s, infectious complications of the Central Nervous System (CNS) caused by VZV reactivation were regarded as rare. The presence of rash, as well as speciﬁc neurological symptoms, were required to diagnose a CNS infection caused by VZV. Since 2000, PCR testing has become more widely used, and the number of diagnosed cases of CNS infection has increased.
Classic textbook descriptions state that VZV reactivation in the CNS is restricted to immunocompromised individuals and the elderly, however, recent studies have found that most patients are immunocompetent, and less than 60 years old. Old references cite vesicular rash as a characteristic finding, however, recent studies have found that rash is only present in 45% of cases. In addition, systemic inflammation is not as reliable an indicator as previously thought: the mean level of C-reactive protein and mean white blood cell count are within the normal range in patients with VZV meningitis. MRI and CT scans are usually normal in cases of VZV reactivation in the CNS. CSF pleocytosis, previously thought to be a strong indicator of VZV encephalitis, was absent in half of a group of patients diagnosed with VZV encephalitis by PCR.
The frequency of CNS infections presented at the emergency room of a community hospital is not negligible, so a means of diagnosing cases is needed. PCR is not a foolproof method of diagnosis, but because so many other indicators have turned out to not be reliable in diagnosing VZV infections in the CNS, screening for VZV by PCR is recommended. Negative PCR does not rule out VZV involvement, but a positive PCR can be used for diagnosis, and appropriate treatment started (for example, antivirals can be prescribed rather than antibiotics).
The introduction of DNA analysis techniques has shown some complications of varicella-zoster to be more common than previously thought. For example, sporadic meningoencephalitis (ME) caused by varicella-zoster was regarded as rare disease, mostly related to childhood chickenpox. However, meningoencephalitis caused by varicella-zoster is increasingly recognized as a predominant cause of ME among immunocompetent adults in non-epidemic circumstances.
Diagnosis of complications of varicella-zoster, particularly in cases where the disease reactivates after years or decades of latency, are difficult. A rash (shingles) can be present or absent. Symptoms vary, and there is significant overlap in symptoms with herpes-simplex symptoms.
Although DNA analysis techniques such as polymerase chain reaction can be used to look for DNA of herpesviruses in spinal fluid or blood, the results may be negative, even in cases where other definitive symptoms exist. Notwithstanding these limitations, the use of PCR has resulted in an advance in the state of the art in our understanding of herpesviruses, including VZV, during the 1990s and 2000s. For example, in the past, clinicians believed that encephalitis was caused by herpes simplex, and that patients always died or developed serious long term function problems. People were diagnosed at autopsy or by brain biopsy. Brain biopsy is not undertaken lightly: it is reserved only for serious cases that cannot be diagnosed by less invasive methods. For this reason, knowledge of these herpes virus conditions was limited to severe cases. DNA techniques have made it possible to diagnose “mild” cases, caused by VZV or HSV, in which the symptoms include fever, headache, and altered mental status. Mortality rates in treated patients are decreasing.
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