Epidemiology, clinical manifestations, and

diagnosis of herpes zoster

Authors: Mary A Albrecht, MD, Myron J Levin, MD
Section Editor: Martin S Hirsch, MD
Deputy Editor: Nicole White, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2024. | This topic last updated: Dec 30, 2024.

INTRODUCTION
Varicella-zoster virus (VZV) infection causes two clinically distinct diseases. Primary
infection with VZV results in varicella (chickenpox), which is characterized by
vesicular lesions on an erythematous base in different stages of development;
lesions are most concentrated on the face and trunk. Herpes zoster, also known as
shingles, results from reactivation of latent VZV that gained access to sensory
ganglia during varicella. Herpes zoster is characterized by a painful, unilateral
vesicular eruption, which usually occurs in a single or two contiguous, dermatomes
( picture 1A-J).
This topic will address the epidemiology, clinical manifestations, and diagnosis of
herpes zoster. The treatment and prevention of herpes zoster, and the
epidemiology, pathogenesis, diagnosis, and treatment of varicella, are discussed
elsewhere. (See "Treatment of herpes zoster" and "Diagnosis of varicella-zoster
virus infection" and "Clinical features of varicella-zoster virus infection:
Chickenpox".)

PATHOGENESIS
During the initial phase of varicella, varicella-zoster virus (VZV) infects the
nasopharyngeal lymphoid tissue of a susceptible person. This results in a viremia
consisting of VZV-infected T cells that travel throughout the body [1-3].
VZV enhances infection by inhibiting multiple host defenses, such as
downregulation of major histocompatibility complex class I expression and
inhibition of interferon response genes [1,3,4]. This enables the virus to partially
evade the immune response. The prolonged incubation period prior to the onset of
skin lesions in varicella reflects the time required for VZV to overcome local innate
defenses, such as alpha interferon production by epidermal cells [1,4,5]. VZV
deoxyribonucleic acid (DNA; primarily in T-lymphocytes) is detected 11 to 14 days
before rash [6]; virus can be isolated from blood six to eight days before rash
appears and ceases one to two days later [6].
Once the rash develops, cell-free virus, which is present only in skin vesicles, is
postulated to infect nerve endings in skin and move retrograde along sensory
axons to establish life-long latency in neurons within the regional ganglia [3,7-9].
VZV may also reach and infect neurons as a consequence of the viremia [1,6]. VZV-
specific cell-mediated immune responses that develop during varicella are required
to end the infection. These responses also play a critical role in controlling VZV
latency and limiting the potential for reactivation to cause herpes zoster [10].
During latency, one or a small number of VZV genes are transcribed, but infectious
virus cannot be found in ganglia [11]. If reactivation occurs and is not limited,
infectious VZV can spread within the ganglion to involve multiple sensory neurons
and subsequently spread antegrade down the sensory nerve to establish infection
in the skin and cause the typical rash [12-14].
Following VZV reactivation and if VZV replication continues, the involved sensory
ganglion typically exhibits intense inflammation, accompanied by hemorrhagic
necrosis of nerve cells [15,16]. This neuronal damage is the source of the typical
neuropathic pain of herpes zoster. The ganglion undergoes eventual neuronal loss
with subsequent fibrosis of afferent nerve fibers, particularly type C nociceptors
[17].

EPIDEMIOLOGY
Incidence — In the United States, herpes zoster occurs in more than 1.2 million
individuals annually, causing substantial morbidity [18]. The United States Centers
for Disease Control and Prevention (CDC) estimates that approximately 30 percent
of persons in the United States will experience herpes zoster during their lifetime
[19,20]. Incidence rates progressively increase with age, presumably due to the
decline in virus (VZV)-specific cell-mediated immunity ( figure 1) [18,21-25]. The
epidemiology is similar worldwide.
The incidence of herpes zoster has been increasing throughout the world [18,23,26-
28]. In a large database analysis that evaluated trends in herpes zoster cases from
1993 to 2016 in over 27 million persons aged ≥35 years, the incidence of herpes
zoster increased from 2.5 per 1000 person-years in 1993 to 7.2 per 1000 person-
years in 2016 [29]. In that study, the incidence continued to increase in a relatively
steady manner among those aged 35 through 55 years over this period. Among
those aged >55 years, there was a similar rise in herpes zoster incidence through
2006, but this rate subsequently decelerated. The reason for the overall increase in
herpes zoster incidence, as well as these age-specific findings, is unclear.
Some experts raised the possibility that widespread varicella immunization in
childhood may increase the age-specific incidence of herpes zoster in adults [30].
Their concern was based on evidence that exposure to endemic varicella boosts
VZV-specific immunity in adults and that cessation of varicella in the community
would result in a decline in the T cell-mediated immunity required to maintain
latency of VZV in neurons [31]. However, numerous epidemiologic studies have
failed to document this effect [27,30,32,33]. In addition, the rise in herpes zoster
incidence has occurred equally in countries without varicella immunization, and in
the United States, the rise in incidence occurred equally in states with or without
good uptake of the varicella vaccine.
There have also been concerns that varicella immunization might lead to an
increased risk of vaccine-associated herpes zoster, particularly in
immunocompromised children. The incidence of postvaccination herpes zoster was
examined in a study of 346 children with acute lymphocytic leukemia who received
the Oka live attenuated varicella vaccine. Herpes zoster developed in five subjects
(1.45 percent) after 10,878 months of observation [34]. In a substudy that matched
84 vaccinated subjects to those who had prior natural varicella infection, herpes
zoster was less frequent in the immunized group (3 versus 11 cases). Reduction in
herpes zoster among children was also reported in a population-based study
evaluating persons vaccinated in a community-based setting [35,36]. In a database
analysis of 13.08 million children aged <18 years from 1998 to 2016, there was an
initial increase in incidence of herpes zoster among those aged 6 to 17 years, but
this was followed by a dramatic reduction, with the incidence declining from peak
values by approximately 70 to 80 percent in children of all ages [37]. (See
"Vaccination for the prevention of chickenpox (primary varicella infection)".)
Risk factors — The natural history of herpes zoster is influenced by the immune
status of the host. Reactivation is influenced by age-related immunosenescence,
disease-related immunocompromise, or iatrogenic immunosuppression.
Age — Increasing age is the most important risk factor for developing herpes
zoster ( figure 1) [18,19,23,38]. A dramatic increase in the age-specific incidence of
herpes zoster begins at approximately 50 years of age. Twenty percent of cases
occur between ages of 50 and 59 years, and 40 percent occur in people at least 60
years of age. It is estimated that approximately 50 percent of persons who live to
85 years of age will have had an episode of herpes zoster [21]. Globally, older
patients account for the majority of medical consultations and hospitalizations for
herpes zoster [39-43].
The severity of disease and the likelihood of complications, including postherpetic
neuralgia (PHN), also increase with age ( figure 1) [18]. In one study, the risk for
experiencing PHN increased 27-fold among patients aged >50 years compared with
those <50 years [44]. In another study, PHN occurred in 18 percent of adult patients
with herpes zoster overall but in more than one-third of those aged ≥79 years [18].
(See "Postherpetic neuralgia".)
Immunocompromised patients — Immunocompromised patients are at
increased risk of VZV reactivation because of reduced T cell-mediated immunity.
This includes transplant recipients [45-52], patients receiving selected
immunomodulator therapies [51,53-60], patients treated with chemotherapy
and/or corticosteroids, and patients with human immunodeficiency virus (HIV)
[51,60-63]. The rate of complications is also significantly higher in
immunocompromised patients [18].
Transplant patients — The risk of developing herpes zoster is increased in
hematopoietic stem cell (HCT) and organ transplant recipients compared with the
general population [51,52,64,65]. The risk is higher in those undergoing HCT [66].
In a large database analysis that evaluated data from 51 million individuals
between 2005 and 2009, the incidence of herpes zoster in the total study
population was 4.82 per 1000 person-years, compared with a very high incidence
among bone marrow or stem cell transplant recipients (43 per 1000 person-years)
[51]. Among HCT recipients, the risk of developing herpes zoster remained
increased even with reduced-intensity regimens. In this study, the risk of
developing herpes zoster in those who underwent solid organ transplant was 17
per 1000 person-years and depended in part on the immunosuppressive regimen.
In patients undergoing HCT, disseminated VZV remains one of the most frequent
late infections of allogeneic bone marrow transplant recipients [67,68]. In one
study, herpes zoster occurred in 35 percent of allogeneic HCT recipients at one
year, and almost 50 percent of those patients developed disseminated VZV [69].
Concurrent graft versus host disease (GVHD), which requires additional immune
suppression, is a major risk factor for dissemination [68]. However, when antiviral
therapy is used in transplant settings, it can prevent herpes zoster [70,71]. Topic
reviews that discuss the use of antiviral prophylaxis in transplant recipients are
found elsewhere. (See "Prevention of viral infections in hematopoietic cell
transplant recipients", section on 'Varicella-zoster virus' and "Prophylaxis of
infections in solid organ transplantation", section on 'Herpes simplex and varicella-
zoster'.)
Autoimmune disease — The incidence of herpes zoster is increased in
patients with autoimmune diseases (eg, rheumatoid arthritis, inflammatory bowel
disease), primarily related to the use of immunosuppressive therapies such as
glucocorticoids, nonbiologic disease-modifying antirheumatic drugs (DMARDs),
tumor necrosis factor (TNF)-alpha inhibitors, sphingosine 1-phosphate receptor
inhibitors, and Janus kinase (JAK) inhibitors [54-58,60,72-79].
In a nested retrospective case-control study that included 18,000 patients with
inflammatory bowel disease treated with glucocorticoids and/or the nonbiologic
DMARDs azathioprine or 6-mercaptopurine, the incidence of herpes zoster was
significantly increased with both glucocorticoids and azathioprine/6-
mercaptopurine (adjusted odds ratio 1.5 and 3.1, respectively) [73]. In a
retrospective Veterans Affairs cohort study involving 20,357 patients with
rheumatoid arthritis, those who received treatment for either moderate disease
(eg, methotrexate, azathioprine, cyclosporin) or severe disease (eg, TNF-alpha
inhibitors) were at increased risk of developing herpes zoster [80].
There are conflicting data regarding the question of whether biologic agents confer
a greater risk of herpes zoster compared with nonbiologic therapies for
autoimmune diseases. In one study, the rate of herpes zoster associated with
tofacitinib, a JAK inhibitor, was approximately double that observed in patients
using the selective T-cell costimulation blocker, abatacept (hazard ratio [HR] 2.01,
95% CI 1.40-2.88) [76]. By contrast, no difference in risk was seen in a multicenter
cohort study that compared the incidence of herpes zoster in 25,742 patients with
rheumatoid arthritis or another autoimmune disease initiating nonbiologic
DMARDs with 33,324 patients initiating a TNF-alpha inhibitor [75]. In that study,
baseline use of glucocorticoids at a dose of ≥10 mg per day prednisone equivalents
was associated with an increased risk of herpes zoster (adjusted HR 2.13, 95% CI
1.64-2.75) compared with no baseline use, but patients who initiated a TNF-alpha
inhibitor were not at higher risk for herpes zoster than patients initiating
nonbiologic DMARDs. No differences in risk were observed among infliximab,
etanercept, and adalimumab recipients [75,76].
More detailed information on the risk of developing herpes zoster in patients
receiving TNF-alpha inhibitors is presented elsewhere. (See "Tumor necrosis factor-
alpha inhibitors: Bacterial, viral, and fungal infections", section on 'Herpes zoster'.)
HIV infection
● Adults – Adults with HIV are at greater risk of developing herpes zoster
compared with those without HIV [61,62]. This was most evident prior to the
introduction of potent antiretroviral therapy (ART), when a prospective study of
966 men who have sex with men found a higher incidence of herpes zoster
versus men without HIV (51.51 per 1000 person-years versus 3.31 per 1000
person-years), and second cases were only documented in individuals with HIV
(26 percent) [62]. In this study, the incidence of herpes zoster increased with
decreasing CD4 cell counts (31.2 per 1000 person-years for CD4 count >500
cells/microL, 47.2 per 1000 person-years for CD4 count 200 to 499 cells/microL,
and 97.5 per 1000 person-years for CD4 count <200 cells/microL),
demonstrating the importance of T cell-mediated immunity in maintaining
latency. (See 'Pathogenesis' above.)
With the widespread availability of potent ART, the incidence of herpes zoster
has decreased in persons with HIV, but remains greater than the general
 population. In adults, this was illustrated in a study evaluating 7167 cases of
herpes zoster among 91,044 individuals [81]. Although there was an overall
decline in the incidence of herpes zoster that was attributed to ART (2955 cases
per 100,000 person-years between 1992 and 1996 versus 628 cases per
100,000 person-years between 2009 and 2011), the incidence of herpes zoster
remained significantly higher in patients with HIV compared with the general
population (overall standardized incidence ratio 2.7, 95% CI 2.6-2.9).
● Children – The incidence of herpes zoster in children with prior varicella is
estimated to be 2.6 per 1000 person-years [82]. However, the incidence is
higher in children with HIV. Prior to the availability of effective ART, the natural
history of varicella infection was observed in 30 children, of whom 8 developed
herpes zoster [63]. The incidence of herpes zoster was 467 cases per 1000
person-years in those with CD4 cells <15 percent at the time they developed
chickenpox. Half of the children who developed herpes zoster had a
recurrence.
Similar to adults, herpes zoster is less common in children after the
introduction of potent ART. One study evaluated 536 perinatally infected
children with HIV and a history of prior varicella over a 13-year period (from
1993 to 2006) [83]. Although the incidence of herpes zoster increased from
1993 to 1996 (prior to the introduction of potent ART) and then declined by
more than half through 2006, an incidence rate of 14 to 31 herpes zoster
episodes per 1000 person-years persisted from 2001 to 2006. The incidence of
herpes zoster declined significantly after more than 90 days of potent ART.
Other risk factors — Other risk factors for developing herpes zoster include:
● Sex – Rates of herpes zoster are greater in women, even when controlling for
age [84].
● Physical trauma – Physical trauma may be a risk factor for herpes zoster,
particularly cranial herpes zoster [85]. As an example, in an age-matched case-
control study that used Medicare data, patients ≥65 years of age who
developed herpes zoster were 3.4 times more likely than controls to have
experienced trauma during the week prior to herpes zoster onset [86]. Patients
who had cranial herpes zoster were more than 25 times as likely as controls to
have had cranial trauma during the week prior to herpes zoster onset.
 ● Comorbid conditions – Certain conditions other than those described above
(eg, transplant, autoimmune disease, HIV) may be associated with herpes
zoster. These include underlying malignancy and chemotherapy, disorders of
cell-mediated immunity, and chronic lung or kidney disease [80,87,88]. Some
studies have suggested that depression is a risk factor for herpes zoster
[89,90], although this association has not been observed in others [91].

TRANSMISSION
People with herpes zoster can transmit varicella-zoster virus (VZV), causing varicella
(chickenpox) in contacts who are varicella naïve (ie, never had varicella or the
varicella vaccine).
In patients with herpes zoster, VZV is spread by direct contact with active herpes
zoster lesions or through inhalation of aerosolized virus from skin lesions [92-95].
Lesions are considered infectious until they have fully crusted [93-95].
A more detailed discussion of VZV transmission is found elsewhere. (See
"Prevention and control of varicella-zoster virus in health care facilities".)

CLINICAL MANIFESTATIONS
Uncomplicated herpes zoster — The presenting clinical manifestations of herpes
zoster are usually rash and acute neuritis. Fewer than 20 percent of patients who
develop a rash have significant systemic symptoms, such as headache, fever,
malaise, or fatigue [2].
Rash — The rash starts as erythematous papules, typically in a single dermatome
or several contiguous dermatomes ( figure 2A-B and picture 1A-B, 1K-L). The
dermatomal distribution of the vesicular rash of herpes zoster corresponds to the
sensory fields of the ganglion (or neighboring ganglia) involved.
Within several days, grouped vesicles or bullae are the predominant manifestation
( picture 1C-F, 1M). Within three to four days, the rash becomes pustular
( picture 1G). The rash can be hemorrhagic in immunosuppressed people and
people of advanced age ( picture 2).
In immunocompetent hosts, the lesions crust by 7 to 10 days and are no longer
considered infectious ( picture 1J). Scarring and hypo- or hyperpigmentation may
persist months to years after herpes zoster has resolved ( picture 3) [96]. The
development of new lesions more than a week after presentation should raise
concerns regarding possible underlying immunodeficiency [2]. (See 'Approach to
diagnosis' below.)
Although the rash can occur in any dermatome, the thoracic and lumbar
dermatomes are most commonly involved ( figure 2A) [18]. Herpes zoster occurs
on the face in 10 percent or more of cases. Some patients may also have a few
scattered vesicles located at some distance away from the involved dermatome,
probably reflecting the presence of varicella-zoster virus (VZV) viremia early in
herpes zoster [2,12].
Herpes zoster keratitis or herpes zoster ophthalmicus can result from involvement
of the ophthalmic branch of the trigeminal cranial nerve [96,97]. These
complications can be sight-threatening. (See 'Complicated disease' below.)
Acute neuritis — Pain is the most common symptom of herpes zoster. Most
patients describe a deep "burning," "throbbing," or "stabbing" sensation [43,98]. In
a study of 1669 patients with confirmed herpes zoster, 18 percent had pain in the
area of rash for at least 30 days, and the duration and severity of pain increased
with age [18]. Acute neuritis should not be confused with postherpetic neuralgia
(PHN), which is discussed below. (See 'Postherpetic neuralgia' below.)
Approximately 75 percent of patients have prodromal pain that precedes the rash
in the affected dermatome [2]. Prodromal pain may be constant or intermittent and
typically precedes the rash by two to three days, but this interval can be longer [98].
Prior to the development of rash, the prodromal pain is often misinterpreted as
another disease, such as angina, cholecystitis, appendicitis, spinal disc diseases, or
renal colic, depending on the involved dermatome [18,99].
The concept that some atypical pain syndromes may be related to herpes zoster
without rash, or "zoster sine herpete," has been raised. Clinical data, paired with
serologic and polymerase chain reaction (PCR) evidence of concurrent VZV
reactivation, support this theory [100]. (See "Varicella zoster virus vasculopathy".)
Postherpetic neuralgia — The most common complication of herpes zoster is
postherpetic neuralgia (PHN). PHN is frequently defined as significant pain
persisting for 90 days after the onset of rash. Significant pain is considered a pain
level 3 or higher on a pain scale of 1 to 10. Sensory symptoms can also include
numbness, dysesthesias, pruritus, and allodynia in the affected dermatome. A
more detailed discussion of the clinical manifestations and diagnosis of PHN is
presented in a separate topic review. (See "Postherpetic neuralgia".)
Approximately 10 to 15 percent of patients with herpes zoster will go on to develop
PHN [101,102]. Individuals older than 60 years of age account for 50 percent of
these cases [44]. In one study, the percentage of patients with herpes zoster who
developed PHN increased from 5 percent in those younger than 60 years to 20
percent in those aged 80 years or older [103]. Immunosuppressed patients also
have a higher incidence. By contrast, patients who receive a herpes zoster vaccine
are less likely to develop PHN, even if herpes zoster occurs. (See "Vaccination for
the prevention of shingles (herpes zoster)".)
Complicated disease — Some patients may develop ocular, otic, or neurologic
disease ( table 1). Disseminated infection, which includes extensive cutaneous or
visceral involvement (pneumonia, hepatitis, or encephalitis), can also occur but
typically presents in immunocompromised patients [18,96,97,104,105].
Herpes zoster ophthalmicus — Herpes zoster ophthalmicus (HZO)
( picture 1H-I, 1N), a potentially sight-threatening condition, is defined as herpes
zoster involvement of the ophthalmic division of the fifth cranial nerve [106].
Incidence rates of HZO complicating herpes zoster in various surveys have ranged
from 8 to 20 percent [106-108]. Approximately 50 percent of patients with HZO
experience direct ocular involvement if antiviral therapy is not used [106,107].
● HZO begins with a prodrome of headache, malaise, and fever. Unilateral pain
or hypesthesia in the affected eye, forehead, and top of the head may precede
or follow the prodrome.
● With the onset of the rash, hyperemic conjunctivitis, uveitis, episcleritis, and
keratitis may occur [104,107,109,110]; ptosis is rare.
● Acute keratitis typically involves the epithelial, stromal, or endothelial layers of
the cornea [111]. Patients who develop epithelial or stromal keratitis are most
at risk for vision loss.
Vesicular lesions on the side or tip of the nose correlate highly with eye
involvement ( picture 1N) [112]. Lesions in this area of the face signify
involvement of the nasociliary branch of the trigeminal nerve, which also
innervates the globe [113].
Early diagnosis and treatment is critical to prevent progressive corneal involvement
and potential loss of vision [114]. (See "Treatment of herpes zoster", section on
'Ocular disease'.)
Acute retinal necrosis — VZV is the leading cause of acute retinal necrosis (ARN)
[115-118]. ARN occurs in both immunocompetent and immunocompromised hosts
[119-121]. In one study, VZV DNA was detected in aqueous humor in seven of nine
patients with necrotizing retinopathies of suspected viral origin and in four of six
patients with ARN [119]. Herpes simplex virus (HSV) is another cause of ARN and
has been described in patients with a history of herpes encephalitis [122]. (See
"Retinal vasculitis associated with systemic disorders and infections".)
The clinical features of ARN are acute iridocyclitis, vitritis, necrotizing retinitis,
occlusive retinal vasculitis with rapid loss of vision, and eventual retinal detachment
[104,116,119-121]. Blurred vision is characteristic and pain is present in the affected
eye due to progressive necrotizing retinitis.
Initial disease is usually unilateral, but can subsequently involve the other eye in 33
to 50 percent of patients [116]. The mechanism of bilateral involvement is not clear,
but one study found a diminished or absent VZV-specific delayed hypersensitivity
reaction in patients with ARN compared with patients with herpes zoster involving
only the skin [123]. This is suggested by the frequency of bilateral disease in
patients with advanced acquired immunodeficiency syndrome (AIDS).
Patients with advanced AIDS and ARN are subject to rapid progression and severe
disease. In one report of ARN in patients with AIDS prior to the introduction of
potent ART, only 4 of 20 involved eyes retained useful vision at two-month follow-
up, and 70 percent had no light perception at the conclusion of the study [121]. In
addition, 82 percent of patients had bilateral eye involvement, and 73 percent had
accompanying central nervous system (CNS) disease (eg, confusion,
encephalopathy), presumably due to VZV. ARN is now rare in patients with HIV,
reflecting the near normal immune status of patients receiving ART.
Patients with ARN must be managed in conjunction with an ophthalmologist. (See
"Treatment of herpes zoster", section on 'Ocular disease'.)
 Ramsay Hunt syndrome (herpes zoster oticus) — The major otologic
complication of VZV reactivation is the Ramsay Hunt syndrome, which typically
includes the triad of ipsilateral facial paralysis, ear pain, and vesicles in the auditory
canal or on the auricle ( picture 4) [124,125]. Ipsilateral altered taste perception
and tongue lesions, hearing abnormalities (decreased hearing, tinnitus,
hyperacusis), and lacrimation occur in some patients; vestibular disturbances
(vertigo) are also frequently reported [125].
Ramsay Hunt syndrome reflects reactivation of latent VZV in the geniculate
ganglion [126,127], with subsequent spread of the infection to the eighth cranial
nerve. Ramsay Hunt syndrome may rarely occur as a component of multiple cranial
nerve involvement, especially cranial nerves V, IX, and X [124].
The facial paralysis seen in Ramsay Hunt syndrome is often more severe than Bell's
palsy attributed to HSV, with increased rates of late neural denervation and a
decreased probability of complete recovery [128,129]. Antiviral therapy is
prescribed, although there are few data on the management of this complication
[130]. (See "Treatment of herpes zoster", section on 'Ramsay Hunt syndrome'.)
Other neurologic complications — Herpes zoster is not always limited to a spinal
nerve distribution; it may also extend centrally, which can result in meningeal
inflammation and clinical meningitis. Occasionally, VZV reactivation affects motor
neurons in the spinal cord and brainstem, resulting in motor neuropathies.
Aseptic meningitis — A subset of immunocompetent patients with herpes
zoster develop clinically evident aseptic meningitis [131,132]; lumbar puncture
typically confirms a brisk cerebrospinal fluid (CSF) pleocytosis and an elevated
protein concentration [133,134]. Most patients will have a rash at the time of
diagnosis, although in some cases, the rash can appear after the onset of
meningitis. In a Finnish epidemiologic study of 144 patients with aseptic meningitis
without an obvious cause, 8 percent had VZV infection [131].
Aseptic meningitis differs from subclinical meningeal irritation, evidenced by a
reactive CSF pleocytosis, which occurs in 40 to 50 percent of cases [135,136].
Patients with subclinical meningeal irritation can also have VZV DNA detected in the
CSF.
Encephalitis — Herpes zoster-associated encephalitis typically presents with
delirium within days following the vesicular eruption, but may occur prior to the
onset of rash or following an episode of herpes zoster [135,137]. Although VZV
encephalitis is a more common complication in immunocompromised patients, it is
also seen in previously healthy hosts [104,135,137-139]. Major risk factors identified
for the development of zoster encephalitis include cranial or cervical dermatomal
involvement, two or more prior episodes of herpes zoster, disseminated herpes
zoster, and impaired cell-mediated immunity [135,138].
Patients with AIDS may develop a leukoencephalitis associated with CNS white
matter demyelination and cerebral vasculopathy due to ongoing VZV replication
within the brain parenchyma [135,138-140]. CSF PCR assays, in conjunction with
magnetic resonance imaging (MRI) brain imaging studies, provide rapid diagnosis
of VZV encephalitis [141,142].
Peripheral motor neuropathy — Segmental motor paresis develops in
approximately 3 percent of patients with herpes zoster [135,143]. Peripheral motor
weakness results from spread of VZV from the dorsal root ganglia to the anterior
root/horn of the spinal cord. Although the onset is typically coincident with the
development of pain and cutaneous eruption in a dermatomal distribution
[135,143,144], there are reports of delayed onset with neurologic symptoms
presenting two to three weeks after the onset of rash [145,146]. Muscle atrophy
may result in the affected region, but approximately 75 percent of patients
experience gradual recovery of motor strength [135]. Involvement of sacral sensory
ganglia may cause bladder or bowel dysfunction.
Myelitis — Transverse myelitis is a rare complication of herpes zoster (usually
involving thoracic dermatomes ( figure 2A)) and typically occurs within days to
weeks following the initial onset of the vesicular rash [135,147]. There are several
reports of myelitis occurring in untreated persons with HIV [148,149]. One report
described herpes zoster myelitis in the absence of rash, but with documented VZV
DNA in spinal cord specimens at autopsy [148].
Guillain-Barré syndrome — There is an association between herpes zoster
and Guillain-Barré syndrome (GBS). Data from a Taiwan health registry indicated an
increased risk of GBS in people with herpes zoster within the prior two months of
GBS [150]. Of 315,595 patients with herpes zoster, 0.03 percent developed GBS.
Although GBS was a relatively rare event, the risk of developing this syndrome was
significantly higher among patients with a recent history of herpes zoster
compared with controls, who were matched by age and sex. (See "Guillain-Barré
syndrome in adults: Pathogenesis, clinical features, and diagnosis".)
Stroke syndromes — VZV infection can produce stroke syndromes secondary
to infection of cerebral arteries. In a series of 30 patients with VZV vasculopathy,
diagnosed by either VZV-specific antibodies or VZV DNA in the CSF, rash occurred in
19 (63 percent), and CSF pleocytosis occurred in 20 (67 percent) [151]. Angiography
demonstrated the involvement of both large and small arteries in approximately
half of the patients. HZO can be complicated by contralateral thrombotic stroke
syndrome [135,152,153]. A more detailed discussion of stroke syndromes and other
forms of vasculopathy associated with VZV is presented in a separate topic review.
(See "Varicella zoster virus vasculopathy".)
Disseminated infection in immunocompromised
hosts — Immunocompromised hosts are at risk of having more frequent episodes
of herpes zoster and/or severe VZV-related complications [104,135,148,149,154-
157]. Severe complications include cutaneous dissemination and visceral
involvement.
● Cutaneous dissemination is defined by multiple vesicular skin lesions in a
generalized distribution distant from the dermatomes affected by the herpes
zoster rash ( picture 5A-B). This has been reported in solid organ and
hematopoietic cell transplant recipients and in patients with hematologic
malignancies undergoing chemotherapy [67,69,155]. Cutaneous dissemination
may be accompanied by visceral involvement [69,158]. Patients with cutaneous
dissemination are at high risk of transmitting VZV to nonimmune patients.
● Visceral organ involvement may present as a fulminant and rapidly evolving
syndrome with pneumonia, hepatitis, or encephalitis and may occasionally
develop in the absence of rash [159]. When cutaneous lesions are present, they
may be delayed or atypical with hemorrhage [45]. In hematopoietic stem cell
transplant patients, reactivation of VZV typically occurs later than
cytomegalovirus or HSV (>3 months after immune compromise) [160].
Hematopoietic stem cell and organ transplant recipients can have acute, severe
abdominal pain as the initial manifestation of visceral reactivated VZV in the
absence of antecedent cutaneous rash, hepatitis, or pneumonitis [67,161]. The
appearance of a herpes zoster rash as long as 10 to 14 days after the
 abdominal pain begins delays the diagnosis, which results in a poor outcome
despite the institution of appropriate antiviral therapy.
Visceral dissemination is a life-threatening emergency [45]. VZV pneumonitis in
transplant recipients has been associated with a high mortality despite prompt
diagnosis and the empiric institution of antiviral therapy [162].
Bacterial superinfections — Patients with localized herpes zoster are at risk for
developing soft tissue infections with bacterial pathogens, particularly if they are
immunocompromised. Common pathogens include Staphylococcus and
Streptococcus [163,164]. In addition to antiviral therapy, antibiotic therapy
targeting these bacterial pathogens is indicated when this occurs. (See "Acute
cellulitis and erysipelas in adults: Treatment".)

DIAGNOSIS
Approach to diagnosis — The diagnosis of herpes zoster is usually based solely on
the clinical presentation (unilateral, usually painful vesicular eruption with a well-
defined dermatomal distribution) ( picture 1M and picture 1A). (See 'Rash'
above.)
Laboratory confirmation should be attempted when the clinical presentation is
uncertain, including when complicated disease is a possibility ( table 1). As an
example, herpes zoster may occasionally present with atypical skin lesions (eg,
hemorrhagic), especially in immunocompromised individuals. In addition, patients
with herpes simplex virus infection may develop vesicular lesions in a distribution
that can be confused with herpes zoster ("zosteriform herpes simplex"); this is most
likely to occur on the face or genital/buttock areas, which are characteristic
locations for herpes simplex reactivation, and there is often a history of prior
episodes in the same area. (See "Approach to the patient with cutaneous blisters".)
Patients with signs or symptoms of eye involvement (eg, tearing, ocular pain,
blurred vision, conjunctival injection, swelling/erythema of the lid and periorbital
structures) should be evaluated by an ophthalmologist.
Diagnostic tests — Diagnostic techniques include polymerase chain reaction (PCR)
testing, direct fluorescent antibody (DFA) testing, and viral culture [165].
 ● PCR testing is preferred since PCR is the most sensitive laboratory test to
diagnose herpes zoster (>95 percent) and is more rapid (≤1 day) compared with
conventional culture techniques [166,167]. PCR testing can be used to test
lesions of all stages, including late-stage (ulcers and crusts) lesions. PCR is also
useful for cerebrospinal fluid (CSF), blood, and other noncutaneous specimens,
such as vitreous humor, and bronchoalveolar lavage [166,168,169].
In a study that evaluated 1479 clinical specimens from 1220 patients with
suspected herpes zoster, real-time PCR testing was highly sensitive compared
with culture (92 versus 53 percent) [167]. In addition, PCR-based testing was
highly specific, and no cross-reactivity was identified when tested against
several other viruses.
● When PCR testing is not available, we either do DFA testing on scrapings from
vesicular skin lesions that have not yet crusted or viral culture. Both of these
tests are best done from unroofed or recently ruptured vesicles. Viral culture
can also be performed on sterile body fluid, such as CSF. DFA testing can
provide results in approximately two hours. However, specific VZV culture
isolation typically requires prolonged incubation with a turnaround time of
approximately one week [170].
The sensitivity of DFA and viral culture are significantly lower than PCR testing
[105,167,171,172]. In one study, the sensitivity of DFA was approximately 55
percent compared with PCR testing [171]. DFA is often limited by the quality of
the specimen since sufficient infected skin cells must be present on the slide to
ensure a valid test. Virus isolation by culture is associated with a yield of 50 to
75 percent in PCR-positive samples [167,172,173]. The sensitivity of culture is
very dependent on the age of the lesion (the closer a lesion is to healing, the
less likely there will be culturable virus in the lesion); in addition, culture can be
falsely negative if antiviral therapy has been initiated.
● Viral cultures must be performed if testing an isolate for antiviral drug
resistance is required to guide treatment decisions. (See "Treatment of herpes
zoster".)

ASSESSING FOR COMORBID CONDITIONS

Although herpes zoster is seen with increased frequency in immunocompromised
individuals, an episode of herpes zoster itself should not prompt a detailed
evaluation for an underlying disease (eg, occult cancer) in an otherwise healthy
individual. However, a careful history and physical examination should be
performed. In addition, HIV serologic testing should be performed on patients who
have never had routine testing, as well as on those with significant risk factors for
HIV acquisition [174]. (See "Screening and diagnostic testing for HIV infection in
adults", section on 'Indications for testing'.)

RECURRENT HERPES ZOSTER

Approximately 1 to 6 percent of individuals will experience a second episode of
herpes zoster [18,40,175-178]. Recurrent herpes zoster is more frequent in women.
Three or more episodes recurring in the same individual are very rare [165]. If
recurrent herpes zoster is suspected, laboratory confirmation may be reasonable to
rule out other etiologies [178], such as recurrent zosteriform herpes simplex, or a
noninfectious etiology, such as contact dermatitis.
Recurrences are more common in immunocompromised hosts [175,179]. In one
study of patients with HIV (mean age 41 years), 282 episodes of herpes zoster were
identified in 239 patients. Of these episodes, 158 were new occurrences of herpes
zoster and 124 were recurrent herpes zoster events [179].

SOCIETY GUIDELINE LINKS

Links to society- and government-sponsored guidelines from selected countries
and regions around the world are provided separately. (See "Society guideline links:
Varicella-zoster virus".)

INFORMATION FOR PATIENTS

UpToDate offers two types of patient education materials, "The Basics" and
"Beyond the Basics." The Basics patient education pieces are written in plain
language, at the 5th to 6th grade reading level, and they answer the four or five key
questions a patient might have about a given condition. These articles are best for
patients who want a general overview and who prefer short, easy-to-read materials.
Beyond the Basics patient education pieces are longer, more sophisticated, and
more detailed. These articles are written at the 10th to 12th grade reading level and
are best for patients who want in-depth information and are comfortable with
some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage
you to print or e-mail these topics to your patients. (You can also locate patient
education articles on a variety of subjects by searching on "patient info" and the
keyword(s) of interest.)
● Basics topic (see "Patient education: Shingles (The Basics)")
● Beyond the Basics topic (see "Patient education: Shingles (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

● Infections caused by varicella-zoster virus (VZV) – Varicella-zoster virus (VZV)
infection causes two distinct diseases. Primary infection with VZV results in
varicella (chickenpox), characterized by vesicular lesions in different stages of
development on the face, trunk, and extremities. Herpes zoster, also known as
shingles, results from reactivation of latent VZV infection within the sensory
ganglia. (See 'Introduction' above and 'Pathogenesis' above.)
● Risk factors for herpes zoster infection – The incidence of herpes zoster is
influenced by the immune status of the host, age-related immunosenescence,
disease-related immunocompromise, or iatrogenic immunosuppression, with
age being the major risk factor for 90 percent of cases of herpes zoster in
adults. (See 'Epidemiology' above.)
● Risk of transmitting VZV to others – People with herpes zoster can spread
VZV to those who have not had varicella and have never received the varicella
vaccine. VZV is primarily spread by direct contact with active herpes zoster
lesions; inhalation of aerosolized virus from skin lesions can also occur. Lesions
are considered infectious until they have fully crusted. (See 'Transmission'
above.)
● Clinical manifestations
 • Uncomplicated herpes zoster – Patients with herpes zoster typically
present with a unilateral dermatomal rash and acute neuritis
( picture 1A-J). Although the rash can develop in any dermatome, the
thoracic and lumbar dermatomes are most commonly involved ( figure 2B
and figure 2A and figure 3). (See 'Uncomplicated herpes zoster' above.)
Approximately 10 to 15 percent of patients with uncomplicated herpes
zoster develop postherpetic neuralgia (PHN), which is typically defined as
significant pain persisting for 90 days after the onset of rash. Symptoms can
also include numbness, dysesthesias, pruritus, and allodynia in the affected
dermatome. (See 'Postherpetic neuralgia' above.)
• Complicated disease – Some patients may develop herpes zoster
ophthalmicus or oticus, and less commonly acute retinal necrosis, or aseptic
meningitis ( table 1). (See 'Complicated disease' above.)
Disseminated disease, which includes extensive cutaneous or visceral
involvement (pneumonia, hepatitis, or encephalitis), typically occurs in
immunocompromised patients. (See 'Disseminated infection in
immunocompromised hosts' above.)
● Approach to diagnosis – In immunocompetent individuals, the diagnosis of
herpes zoster is usually based on the clinical presentation (ie, unilateral, usually
painful, vesicular eruption with a well-defined dermatomal distribution). (See
'Approach to diagnosis' above.)
Laboratory confirmation should be attempted when the diagnosis is uncertain.
Diagnostic techniques include polymerase chain reaction (PCR) testing (which is
the most sensitive test), direct fluorescent antibody testing, and viral culture.
(See 'Diagnostic tests' above.)
Patients with signs or symptoms of eye involvement (eg, tearing, ocular pain,
blurred vision, conjunctival injection, swelling/erythema of the lid and
periorbital structures) should be evaluated by an ophthalmologist.
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