Shingles, also known asherpes zoster orzona,[7] is aviral disease characterized by a painfulskin rash with blisters in a localized area.[2][8] Typically the rash occurs in a single, wide mark either on the left or right side of the body or face.[1] Two to four days before the rash occurs, there may betingling or local pain in the area.[1][9] Other common symptoms are fever, headache, and tiredness.[1][10] The rash usually heals within two to four weeks,[2] but some people develop ongoingnerve pain which can last for months or years, a condition calledpostherpetic neuralgia (PHN).[1] In those withpoor immune function therash may occur widely.[1] If the rash involves the eye,vision loss may occur.[2][11]
Shingles is caused by thevaricella zoster virus (VZV) that also causeschickenpox. In the case of chickenpox, also called varicella, the initial infection with the virus typically occurs during childhood or adolescence.[1] Once the chickenpox has resolved, the virus can remaindormant (inactive) in humannerve cells (dorsal root ganglia orcranial nerves)[12] for years or decades, after which it may reactivate and travel along nerve bodies to nerve endings in the skin, producing blisters.[1][9] During an outbreak of shingles, exposure to the varicella virus found in shingles blisters can cause chickenpox in someone who has not yet had chickenpox, although that person will not suffer from shingles, at least on the first infection.[13] How the virus remains dormant in nerve cells or subsequently re-activates is not well understood.[1][14]
The disease has been recognized sinceancient times.[1] Risk factors for reactivation of the dormant virus include old age,poor immune function, and having contracted chickenpox before 18 months of age.[1] Diagnosis is typically based on the signs and symptoms presented.[3]Varicella zoster virus is not the same asherpes simplex virus, although they both belong to the alpha subfamily ofherpesviruses.[15]
Shingles vaccines reduce the risk of shingles by 50 to 90%, depending on the vaccine used.[1][16] Vaccination also decreases rates ofpostherpetic neuralgia, and, if shingles occurs, its severity.[1] If shingles develops, antiviral medications such asaciclovir can reduce the severity and duration of disease if started within 72 hours of the appearance of the rash.[3] Evidence does not show a significant effect of antivirals orsteroids on rates of postherpetic neuralgia.[17][18]Paracetamol,NSAIDs, oropioids may be used to help with acute pain.[3]
It is estimated that about a third of people develop shingles at some point in their lives.[1] While shingles is more common among older people, children may also get the disease.[15] According to the USNational Institutes of Health, thenumber of new cases per year ranges from 1.2 to 3.4 per 1,000 person-years among healthy individuals to 3.9 to 11.8 per 1,000 person-years among those older than 65 years of age.[10][19] About half of those living to age 85 will have at least one attack, and fewer than 5% will have more than one attack.[1][20] Although symptoms can be severe, risk of death is very low: 0.28 to 0.69 deaths per million.[12]
The earliest symptoms of shingles, which include headache, fever, and malaise, are nonspecific, and may result in an incorrect diagnosis.[10][21] These symptoms are commonly followed by sensations of burning pain, itching,hyperesthesia (oversensitivity), orparesthesia ("pins and needles": tingling, pricking, or numbness).[22] Pain can be mild to severe in the affecteddermatome, with sensations that are often described as stinging, tingling, aching, numbing or throbbing, and can be interspersed with quick stabs of agonizing pain.[23]
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.[24]
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 occur 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 ofhives; 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.[22]Zoster sine herpete ("zoster without herpes") describes a person who has all of the symptoms of shingles except this characteristic rash.[25]
Later, the rash becomesvesicular, forming small blisters filled with aserous 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.[22] The blister fluid contains varicella zoster virus, which can be transmitted through contact or inhalation of fluid droplets until the lesions crust over, which may take up to four weeks.[26]
Shingles may have additional symptoms, depending on the dermatome involved. Thetrigeminal nerve is the most commonly involved nerve,[27] of which the ophthalmic division is the most commonly involved branch.[28] When the virus is reactivated in this nerve branch it is termedzoster ophthalmicus. The skin of the forehead, upper eyelid andorbit of the eye may be involved. Zoster ophthalmicus occurs in approximately 10% to 25% of cases. In some people, symptoms may includeconjunctivitis,keratitis,uveitis, andoptic nervepalsies that can sometimes cause chronic ocular inflammation, loss of vision, and debilitating pain.[29]
Shingles may occur in the mouth if the maxillary or mandibular division of the trigeminal nerve is affected,[31] in which the rash may appear on themucous 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.[32] Oral involvement may occur alone or in combination with a rash on the skin over the cutaneous distribution of the same trigeminal branch.[31] As with shingles of the skin, the lesions tend to only involve one side, distinguishing it from other oral blistering conditions.[32] In the mouth, shingles appears initially as 1–4 mm opaque blisters (vesicles),[31] which break down quickly to leaveulcers that heal within 10–14 days.[32] The prodromal pain (before the rash) may be confused withtoothache.[31] Sometimes this leads to unnecessary dental treatment.[32] Post-herpetic neuralgia is uncommonly associated with shingles in the mouth.[32] Unusual complications may occur with intra-oral shingles that are not seen elsewhere. Due to the close relationship of blood vessels to nerves, the virus can spread to involve the blood vessels and compromise the blood supply, sometimes causingischemicnecrosis.[31] In rare cases, oral involvement causes complications such asosteonecrosis,tooth loss,periodontitis (gum disease), pulp calcification,pulp necrosis,periapical lesions and tooth developmental anomalies.[27]
In those with deficits in immune function,disseminated shingles may occur (wide rash).[1] It is defined as more than 20skin lesions appearing outside either the primarily affected dermatome or dermatomes directly adjacent to it. Besides the skin, other organs, such as theliver orbrain, may also be affected (causinghepatitis orencephalitis,[33][34] respectively), making the condition potentially lethal.[35]: 380
Electron micrograph ofvaricella zoster virus. Approximately 150,000× magnification. The virus diameter is 150–200 nm.[36]Progression of shingles. A cluster of small bumps (1) turns into blisters (2). The blisters fill withlymph, break open (3), crust over (4), and finally disappear.Postherpetic neuralgia can sometimes occur due to nerve damage (5).
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 United States occur in those aged 50 years or older.[38] Shingles can recur.[39] In contrast to the frequent recurrence ofherpes simplex symptoms, repeated attacks of shingles are unusual.[40] It is extremely rare for a person to have more than three recurrences.[37]
The disease results from virus particles in a single sensory ganglion switching from their latent phase to their active phase.[41] Due to difficulties in studying VZV reactivation directly in humans (leading to reliance on small-animal models), its latency is less well understood than that of the herpes simplex virus.[40] Virus-specific proteins continue to be made by the infected cells during the latent period, so true latency, as opposed tochronic, low-level, activeinfection, has not been proven to occur in VZV infections.[42][43] Although VZV has been detected in autopsies of nervous tissue,[44] there are no methods to find dormant virus in the ganglia of living people.
Unless theimmune system is compromised, it suppresses reactivation of the virus and prevents shingles outbreaks. Why this suppression sometimes fails is poorly understood,[45] but shingles is more likely to occur in people whose immune systems are impaired due to aging,immunosuppressive therapy,psychological stress, or other factors.[46][47] Upon reactivation, the virus replicates in neuronal cell bodies, andvirions are shed from the cells and carried down theaxons to the area of skin innervated by that ganglion. In the skin, the virus causes localinflammation 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.[48]
As with chickenpox and other forms of alpha-herpesvirus infection, direct contact with an active rash can spread the virus to a person who lacks immunity to it. This newly infected individual may then develop chickenpox, but will not immediately develop shingles.[22]
The complete sequence of the viralgenome was published in 1986.[49]
If the rash has appeared, identifying this disease (making adifferential diagnosis) requires only a visual examination, since very few diseases produce a rash in adermatomal pattern. However,herpes simplex virus (HSV) can occasionally produce a rash in such a pattern (zosteriform herpes simplex).[50][51]
When the rash is absent (early or late in the disease, or in the case ofzoster sine herpete), shingles can be difficult to diagnose.[52] Apart from the rash, most symptoms can also occur in other conditions.
Laboratory tests are available to diagnose shingles. The most popular test detects VZV-specificIgMantibody in blood; this appears only during chickenpox or shingles and not while the virus is dormant.[53] In larger laboratories,lymph collected from a blister is tested bypolymerase chain reaction (PCR) for VZV DNA, or examined with an electron microscope for virus particles.[54] Molecular biology tests based onin vitro nucleic acid amplification (PCR tests) are currently considered the most reliable.Nested PCR test has highsensitivity, but is susceptible to contamination leading tofalse positive results. The latestreal-time PCR tests are rapid, easy to perform, and as sensitive as nested PCR, and have a lower risk of contamination. They also have more sensitivity thanviral cultures.[55]
Shingles risk can be reduced in children by thechickenpox vaccine if the vaccine is administered before the individual gets chickenpox.[5] If primary infection has already occurred, there areshingles vaccines that reduce the risk of developing shingles or developing severe shingles if the disease occurs.[1][16] They include alive attenuated virus vaccine, Zostavax, and anadjuvantedsubunit vaccine, Shingrix.[39][57][58]
A review byCochrane concluded that Zostavax was useful for preventing shingles for at least three years.[9] This equates to about 50%relative risk reduction. The vaccine reduced rates of persistent, severe pain after shingles by 66% in people who contracted shingles despite vaccination.[59] Vaccine efficacy was maintained through four years of follow-up.[59] It has been recommended that people with primary or acquired immunodeficiency should not receive the live vaccine.[59]
Two doses of Shingrix are recommended, which provide about 90% protection at 3.5 years.[39][58] As of 2016, it had been studied only in people with an intact immune system.[16] It appears to also be effective in the very old.[16]
In the UK, shingles vaccination is offered by theNational Health Service (NHS) to all people in their 70s. As of 2021[update], Zostavax is the usual vaccine, but the Shingrix vaccine is recommended if Zostavax is unsuitable, for example, for those with immune system issues. Vaccination is not available to people over 80 as "it seems to be less effective in this age group".[60][61] By August 2017, just under half of eligible 70–78 year olds had been vaccinated.[62] About 3% of those eligible by age have conditions that suppress their immune system, and should not receive Zostavax.[63] There had been 1,104 adverse reaction reports by April 2018.[63] In the US, it is recommended that healthy adults 50 years and older receive two doses of Shingrix, two to six months apart.[39][64]
Treatment aims 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 ofpostherpetic neuralgia.[65]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 free from pain a year after their shingles outbreak.[66]
People with mild to moderate pain can be treated withover-the-counterpain medications. Topical lotions containingcalamine can be used on the rash or blisters and may be soothing. Occasionally, severe pain may require an opioid medication, such asmorphine. Once the lesions have crusted over,capsaicin cream (Zostrix) can be used. Topicallidocaine and nerve blocks may also reduce pain.[67] Administeringgabapentin along with antivirals may offer relief of postherpetic neuralgia.[65]
Antiviral drugs may reduce the severity and duration of shingles;[68] however, they do not preventpostherpetic neuralgia.[69] Of these drugs,aciclovir has been the standard treatment, but the newer drugsvalaciclovir andfamciclovir demonstrate similar or superior efficacy and good safety and tolerability.[65] The drugs are used both forprevention (for example in people withHIV/AIDS) and as therapy during theacute phase. Complications inimmunocompromised individuals with shingles may be reduced withintravenous aciclovir. In people who are at a high risk for repeated attacks of shingles, five daily oral doses of aciclovir are usually effective.[30]
Zoster ophthalmicus. Labels inSerbian, from top:exudativeerythema, scabs, blister, eyelid swelling
Treatment forzoster ophthalmicus is similar to standard treatment for shingles at other sites.[medical citation needed] A trial comparing aciclovir with itsprodrug, valaciclovir, demonstrated similar efficacies in treating this form of the disease.[71]
The rash and pain usually subside within three to five weeks, but about one in five people develop a painful condition calledpostherpetic neuralgia, which is often difficult to manage. In some people, shingles can reactivate, presenting aszoster sine herpete: pain radiating along the path of a single spinal nerve (adermatomal distribution), but without an accompanyingrash. This condition may involve complications that affect several levels of thenervous system and cause manycranialneuropathies,polyneuritis,myelitis, oraseptic meningitis. Other serious effects that may occur in some cases include partialfacial paralysis (usually temporary), ear damage, orencephalitis.[30] Although initial infections with VZV during pregnancy, causing chickenpox, may lead to infection of the fetus and complications in the newborn, chronic infection or reactivation in shingles are not associated with fetal infection.[72][73]
There is a slightly increased risk of developingcancer after a shingles episode. However, the mechanism is unclear, and mortality from cancer did not appear to increase as a direct result of the presence of the virus.[74] Instead, the increased risk may result from the immune suppression that allows the reactivation of the virus.[75]
Although shingles typically resolves within 3–5 weeks, certain complications may arise:
Motor involvement,[11] including weakness especially in "motor herpes zoster".[76]
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.[77]
Varicella zoster virus (VZV) has a high level ofinfectivity and has a worldwide prevalence.[78] Shingles is a reactivation 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.[24][46] 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,[10][24] and incidence rates worldwide are similar.[10][79]This relationship with age has been demonstrated in many countries,[10][79][80][81][82][83] and is attributed to the fact that cellular immunity declines as people grow older.
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 shingles were twice as likely to develop it themselves,[91] but a 2010 study found no such link.[88]
Adults with latent VZV infection who are exposed intermittently to children with chickenpox receive an immune boost.[24][88] 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.[92] 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.[93][94] A later study by Patelet 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.[95] Another study by Yihet 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%.[96] The results of a further study by Yawnet al. showed a 28% increase in shingles incidence from 1996 to 2001.[97] 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.[10]
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.[98] 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.[99] An earlier Connecticut study found a higher hospitalization rate; the difference may be due to the prevalence ofHIV in the earlier study, or to the introduction of antivirals in California before 1994.[100]
Shingles has a long recorded history, although historical accounts fail to distinguish the blistering caused by VZV and those caused bysmallpox,[38]ergotism, anderysipelas.Aulus Cornelius Celsus, around 25 BC to 50 AD, first used the term herpes zoster.[101] In the late 18th centuryWilliam Heberden established a way to differentiate shingles and smallpox,[102] and in the late 19th century, shingles was differentiated from erysipelas. In 1831Richard Bright hypothesized that the disease arose from the dorsal root ganglion, and an 1861 paper byFelix von Bärensprung confirmed this.[103]
Recognition that chickenpox and shingles were caused by the same virus came at the beginning of the 20th century. Physicians began to report that cases of shingles were often followed by chickenpox in 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 incell cultures, by the Nobel laureateThomas Huckle Weller, in 1953.[104] Some sources also attribute the first isolation of the herpes zoster virus toEvelyn Nicol.[105]
Until the 1940s, the disease was considered benign, and serious complications were thought to be very rare.[106] 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.[107] 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.[108]
In historical shingles studies, shingles incidence generally increased with age. However, in his 1965 paper,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".[24]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 Thomaset al. reported that adults in households with children had lower rates of shingles than households without children.[109] Also, the study by Teradaet al. indicated that pediatricians reflected incidence rates from 1/2 to 1/8 that of the general population their age.[110]
The family name of all theherpesviruses derives from the Greek wordέρπης herpēs,[111] fromέρπω herpein ("to creep"),[112][113][114] referring to the latent, recurring infections typical of this group of viruses.Zoster comes from Greekζωστήρ zōstēr,[115] meaning "belt" or "girdle", after the characteristic belt-like dermatomal rash.[116] The common name for the disease,shingles, derives from the Latincingulus, a variant of Latincingulum,[117] meaning "girdle".[118][119]
Until the mid-1990s, infectious complications of thecentral nervous system (CNS) caused by VZV reactivation were regarded as rare. The presence of rash, as well as specific neurological symptoms, was 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.[120]
Classic textbook descriptions state that VZV reactivation in the CNS is restricted to immunocompromised individuals and the elderly; however, studies have found that most participants are immunocompetent and younger than 60 years old. Historically, vesicular rash was considered a characteristic finding, but studies have found that rash is only present in 45% of cases.[120]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 participants with VZV meningitis.[121]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 people diagnosed with VZV encephalitis by PCR.[120]
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 not to be reliable in diagnosing VZV infections in the CNS, PCR is the recommended method of testing for VZV. 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).[120]
The introduction of DNA analysis techniques has shown that some complications of varicella-zoster are more common than previously thought. For example, sporadic meningoencephalitis (ME) caused by varicella-zoster was regarded as a 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.[122]
Diagnosis of complications of varicella-zoster, particularly in cases where the disease reactivates after years or decades of latency, is difficult. A rash (shingles) can be present or absent. Symptoms vary, and there is a significant overlap in symptoms with herpes simplex symptoms.[122]
Although DNA analysis techniques such aspolymerase chain reaction (PCR) 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.[123] 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 thatencephalitis was caused byherpes simplex and that people always died or developed serious long-term functional problems. People were diagnosed atautopsy or bybrain 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 people are decreasing.[122]
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