Herpes Zoster

Practice Essentials
Reactivation of varicella-zoster virus (VZV) that has remained dormant within dorsal root
ganglia, often for decades after the patients initial exposure to the virus in the form of varicella
(chickenpox), results in herpes zoster (shingles).[1] Although it is usually a self-limited
dermatomal rash with pain, herpes zoster can be far more serious; in addition, acute cases often
lead to postherpetic neuralgia (PHN) and is responsible for a significant economic burden.[2] See
the image below.

See 15 Rashes You Need to Know: Common Dermatologic Diagnoses, a Critical Images
slideshow, for help identifying and treating various rashes.

Signs and symptoms

The clinical manifestations of herpes zoster can be divided into the following 3 phases:

Preeruptive phase (preherpetic neuralgia)

Acute eruptive phase

Chronic phase (PHN)

The preeruptive phase is characterized by the following:

Sensory phenomena along 1 or more skin dermatomes, lasting 1-10 days

(average, 48 hours)

Phenomena usually are noted as pain or, less commonly, itching or

paresthesias [3]

Pain may simulate headache, iritis, pleurisy, brachial neuritis, cardiac pain,
appendicitis or other intra-abdominal disease, or sciatica

Other symptoms, such as malaise, myalgia, headache, photophobia, and,

uncommonly, fever

The acute eruptive phase is marked by the following:

Patchy erythema, occasionally accompanied by induration, in the dermatomal

area of involvement

Regional lymphadenopathy, either at this stage or subsequently

 Grouped herpetiform vesicles developing on the erythematous base (the
classic finding)

Cutaneous findings that typically appear unilaterally, stopping abruptly at the

midline of the limit of sensory coverage of the involved dermatome

Vesicular involution: Vesicles initially are clear but eventually cloud, rupture,
crust, and involute

After vesicular involution, slow resolution of the remaining erythematous

plaques, typically without visible sequelae

Scarring can occur if deeper epidermal and dermal layers have been
compromised by excoriation, secondary infection, or other complications

Almost all adults experience pain, typically severe

A few experience severe pain without a vesicular eruption (ie, zoster sine
herpete)

Symptoms tend to resolve over 10-15 days

Complete healing of lesions may require up to a month

PHN is characterized by the following:

Persistent or recurring pain lasting 30 or more days after the acute infection
or after all lesions have crusted (9-45% of all cases) [4]

Pain usually is confined to the area of original dermatomal involvement

The pain can be severe and incapacitating

Pain can persist for weeks, months, or years

[5]
Slow resolution of pain is especially common in the elderly

PHN is observed more frequently after cases of herpes zoster ophthalmicus

(HZO) and in instances of upper-body dermatomal involvement

Less common postherpetic sequelae include hyperesthesia or, more rarely,

hypoesthesia or anesthesia in the area of involvement

Common features of herpes zoster ophthalmicus are as follows:

Classic symptoms and lesions of herpes zoster

 Ophthalmic manifestations including conjunctivitis, scleritis, episcleritis,
keratitis iridocyclitis, Argyll-Robertson pupil, glaucoma, retinitis, choroiditis,
optic neuritis, optic atrophy, retrobulbar neuritis, exophthalmos, lid retraction,
ptosis, and extraocular muscle palsies

Other forms of herpes zoster include the following:

Herpes zoster of maxillary branch of cranial nerve (CN) V

Herpes zoster of mandibular branch of CN V

Herpes zoster oticus (Ramsay Hunt syndrome)

Glossopharyngeal and vagal herpes zoster

Herpes occipitocollaris (vertebral nerves C2 and C3 involvement)

Herpes zoster encephalomyelitis

Disseminated herpes zoster

Unilateral herpes zoster involving multiple dermatomes

Recurrent herpes zoster

Herpes zoster involving urinary bladder, bronchi, pleural spaces, or

gastrointestinal tract

Herpes zoster with motor complications

See Clinical Presentation for more detail.

Diagnosis
Diagnosis of herpes zoster is based primarily on the history and physical findings. In most cases,
confirming the diagnosis via laboratory testing has no utility. In select patient populations,
howeverparticularly immunocompromised patientsthe presentation of herpes zoster can be
atypical and may require additional testing.

Laboratory studies for VZV include the following:

Direct fluorescent antibody (DFA) testing of vesicular fluid or a corneal lesion

Polymerase chain reaction (PCR) testing of vesicular fluid, a corneal lesion, or

blood
 Tzanck smear of vesicular fluid (lower sensitivity and specificity than DFA or
PCR)

See Workup for more detail.

Management
Episodes of herpes zoster are generally self-limited and resolve without intervention; they tend to
be more benign and mild in children than in adults.

Conservative therapy includes the following:

Nonsteroidal anti-inflammatory drugs (NSAIDs)

Wet dressings with 5% aluminum acetate (Burrow solution), applied for 30-60
minutes 4-6 times daily

Lotions (eg, calamine)

Primary medications for acute zosterassociated pain include the following:

Narcotic and nonnarcotic analgesics (both systemic and topical)

Neuroactive agents (eg, tricyclic antidepressants [TCAs])

Anticonvulsant agents

Steroid treatment for herpes zoster is traditional but controversial. Typically, a substantial dose
(eg, 40-60 mg of oral prednisone every morning) typically is administered as early as possible in
the course of the disease and is continued for 1 week, followed by a rapid taper over 1-2 weeks.

Antiviral therapy for herpes zoster may decrease the length of time for new vesicle formation,
the number of days to attain complete crusting, and the days of acute discomfort. Usually, the
earlier antiviral medications are started, the more effective they are in shortening the duration of
zoster and in preventing or decreasing the severity of PHN. Ideally, therapy should be initiated
within 72 hours of symptom onset.

Oral treatment with the following has been found beneficial:

Acyclovir

Famciclovir

Valacyclovir

Hospital admission should be considered for patients with any of the following:
 Severe symptoms

Immunosuppression

Atypical presentations (eg, myelitis)

Involvement of more than 2 dermatomes

Significant facial bacterial superinfection

Disseminated herpes zoster

Ophthalmic involvement

Meningoencephalopathic involvement

Prevention and treatment of postherpetic neuralgia

Prompt treatment of acute zoster and its associated pain (eg, with antiviral therapy) can prevent
the development of PHN. Once PHN has developed, various treatments are available, including
the following:

[6]
Neuroactive agents (eg, TCAs)

[7]
Anticonvulsant agents (eg, gabapentin, pregabalin)

Narcotic and nonnarcotic analgesics, both systemic (eg, opioids) and topical

A live attenuated VZV vaccine introduced in 2005 (Zostavax) has demonstrated a reduction in
the incidence rate of herpes zoster. It is approved for use in patients 50 years of age and older and
has been judged to be cost-effective.[8]

See Treatment and Medication for more detail.

Background
Herpes zoster (shingles) is an acute, cutaneous viral infection caused by the reactivation of
varicella-zoster virus (VZV), a herpesvirus that is the cause of varicella (chickenpox).
Differences in clinical manifestations between varicella and herpes zoster apparently depend on
an individual's immune status; those with no previous exposure to VZV, most commonly
children, develop the clinical syndrome of varicella, whereas those with circulating varicella
antibodies develop a localized recrudescence, zoster.

Zoster probably results most often from a failure of the immune system to contain latent VZV
replication. Whether other factors, such as radiation, physical trauma, certain medications, other
infections, and stress, also can trigger zoster has not been determined with certainty. Nor is it
entirely clear why circulating varicella antibodies and cell-mediated immune mechanisms do not
prevent recurrent overt disease, as is common with most other viral illnesses.

The incidence of zoster appears to be inversely correlated with the hosts capacity to mount a
cellular immune response. However, many patients with zoster apparently have normal
immunity. In these patients, zoster is postulated to occur when VZV antibody titers and cellular
immunity drop to levels that no longer are completely effective in preventing viral invasion.
Evidence for this hypothesis includes the observation that pediatricians, who presumably are
routinely reexposed to VZV and thus maintain high levels of immunity, seldom develop zoster.

Herpes zoster manifests in many ways. It should not be considered simply a self-limited
dermatomal rash with pain. VZV infection is an acute neurologic disease that warrants
immediate evaluation. That VZV is always a benign disorder is a common misperception. Once
VZV infection resolves, many individuals continue to suffer paina condition known as
postherpetic neuralgia (PHN).

Pathophysiology
VZV infection gives rise to 2 distinct syndromes. The primary infection, chickenpox, is a
contagious and usually benign febrile illness. After this infection resolves, viral particles remain
in the dorsal root or other sensory ganglia, where they may lay dormant for years to decades.

In this latent period, host immunologic mechanisms suppress replication of the virus, but VZV
reactivates when the host mechanisms fail to contain the virus. Such failure may result from a
wide spectrum of conditions, ranging from stress to severe immunosuppression; occasionally, it
follows direct trauma. VZV viremia occurs frequently with chickenpox but also may arise with
herpes zoster, albeit with a lower viral load.

Once VZV is activated at the spinal root or cranial nerve neurons, an inflammatory response
occurs that also encompasses the leptomeninges; both plasma cells and lymphocytes are noted.
This inflammation in the dorsal root ganglion can be accompanied by hemorrhagic necrosis of
nerve cells. The result is neuronal loss and fibrosis.

The frequency of dermatologic involvement is correlated with the centripetal distribution of the
initial varicella lesions. This pattern suggests that the latency may arise from contiguous spread
of the virus during varicella from infected skin cells to sensory nerve endings, with subsequent
ascent to the ganglia. Alternatively, the ganglia may become infected hematogenously during the
viremic phase of varicella, and the frequency of the dermatome involvement in herpes zoster
may reflect the ganglia most often exposed to reactivating stimuli.
The appearance of the cutaneous rash due to herpes zoster coincides with a profound VZV-
specific T-cell proliferation. Production of interferon alfa appears with the resolution of herpes
zoster. In immunocompetent patients, specific antibodies (immunoglobulins G, M, and A [IgG,
IgM, and IgA]) appear more rapidly and reach higher titers during reactivation (herpes zoster)
than during the primary infection. The patient has a long-lasting, enhanced, cell-mediated
immunity response to VZV.[9, 10, 11]

The anatomic location of the involved dermatome often determines the specific manifestations.
When cervical and lumbar roots are involved, motor involvement, which is often overlooked,
may be evident, depending on the virulence or extent of migration. In at least 1 case of motor
neuron involvement, lymphocytic infiltration and myelin breakdown were observed with
preservation of axons.

Herpes zoster infections are contagious to persons with no previous immunity to VZV. However,
herpes zoster is estimated to be only one third as contagious as primary varicella. It is transmitted
either via direct contact with the lesions or via the respiratory route.

Organ system involvement

Central nervous system

Whereas herpes zoster is classically described in sensory (dorsal root) ganglia, it can spread to
affect any portion of the central nervous system (CNS). Involvement of the anterior horn cells
can produce muscular weakness, cranial nerve palsies, diaphragmatic paralysis, neurogenic
bladder, and colonic pseudo-obstruction. Wider involvement of the spinal cord can produce
Guillain-Barr syndrome, transverse myelitis, and myositis.

In severely ill or immunocompromised patients, general CNS involvement can be observed in

the form of meningoencephalitis or encephalitis. Such presentations may be indistinguishable
from those of other forms of meningoencephalitis, though other evidence of acute zoster usually
is present.[12] Cerebrospinal fluid (CSF) studies frequently reveal pleocytosis without elevated
protein. These infections can be life-threatening.

Optical system

Herpes zoster ophthalmicus (HZO), a potentially devastating form of acute herpes zoster, results
from the reactivation of VZV in the trigeminal (fifth cranial) nerve. Any branch of the nerve may
be affected, though the frontal branch within the first division of the trigeminal nerve is most
commonly involved. This branch innervates nearly all of the ocular and periocular structures.

Polymerase chain reaction (PCR) nerve studies have detected latent trigeminal VZV in as many
as 87% of patients.[13] Clinical disease has been reported in as few as 8% and as many as 56% of
patients in studies focused on ophthalmic involvement.[14]
Auditory system

Herpes zoster oticus (also known as Ramsay Hunt syndrome, geniculate neuralgia, or herpes
zoster auricularis) is caused by VZV reactivation involving the facial and auditory nerves. This
syndrome may go unnoticed and be difficult to diagnose, especially in elderly patients.

Vesicular eruptions may manifest on the pinna, tragus, or tympanic membrane or in the auditory
canal, as well as anywhere in the facial nerve distribution. The patient may experience hearing
impairment, nystagmus, vertigo, or a facial nerve palsy mimicking Bell palsy.[15] Patients may
lose taste sensation in the anterior two thirds of the tongue.[15]

Clinical phases of disease

The clinical manifestations of herpes zoster can be divided into the following 3 phases:

Preeruptive phase (preherpetic neuralgia)

Acute eruptive phase

Chronic phase (PHN)

The preeruptive phase is characterized by unusual skin sensations or pain within the affected
dermatome that heralds the onset of lesions by 48-72 hours. During this time, patients may also
experience other symptoms, such as malaise, myalgia, headache, photophobia, and,
uncommonly, fever.

The acute eruptive phase is marked by the emergence of vesicular eruptions. Patients may also
experience some of the other symptoms seen in the preeruptive phase. Lesions begin as
erythematous macules and papules that quickly develop into vesicles. New lesions tend to form
over a period of 3-5 days, sometimes coalescing to form bullae. After they form vesicles, lesions
progress through stages in which they rupture, release their contents, ulcerate, and finally crust
over and become dry. Patients remain infectious until the lesions have dried.

During this phase, almost all adult patients experience pain (ie, acute neuritis). A few experience
severe pain without any evidence of a vesicular eruption (ie, zoster sine herpete), and a small
number have a characteristic eruption but do not experience pain. Symptoms and lesions in the
acute eruptive phase tend to resolve over 10-15 days. However, lesions may require up to a
month to completely heal, and the associated pain may become chronic.

PHN, the chronic phase, is characterized by persistent or recurring pain lasting 30 or more days
after the acute infection or after all lesions have crusted. It is the most frequent complication of
herpes zoster, observed in 9-45% of all cases.[4] Most people report a deep burning or aching
pain, paresthesia, dysesthesia, hyperesthesia, or electric shocklike pains. The pain can be severe
and incapacitating, and may take a long time to resolve, especially in the elderly; it lasts longer
than 12 months in nearly 50% of patients older than 70 years.[5]

Etiology
Herpes zoster is caused by VZV infection. VZV is an enveloped, double-stranded DNA virus
belonging to the Herpesviridae family; its genome encodes approximately 70 proteins. In
humans, primary infection with VZV occurs when the virus comes into contact with the mucosa
of the respiratory tract or conjunctiva. From these sites, it is distributed throughout the body.
After primary infection, the virus migrates along sensory nerve fibers to the satellite cells of
dorsal root ganglia where it becomes dormant.

Reactivation of VZV that has remained dormant within dorsal root ganglia, often for decades
after the patients initial exposure to the virus in the form of varicella (chickenpox), results in
herpes zoster.[1] Exactly what triggers this reactivation has not yet been determined precisely, but
likely candidates (alone, or in combination) include the following:

External reexposure to the virus

Acute or chronic disease processes (particularly malignancies and infections)

Medications of various types

Emotional stress

The reason why one dorsal root ganglion experiences reactivation of its stored viral load
preferentially over another ganglia is unclear. Diminished cellular immunity seems to increase
the risk of reactivation, in that the incidence increases with age and in immunocompromised
persons.[16]

Zoster can be a presenting symptom of hyperparathyroidism, and it occurs twice as often

(frequency, 3.7%) among patients with hypercalcemia as it does among age-matched cohorts of
patients older than 40 years who have normal calcium levels.[17]

The cause of PHN also remains a mystery. Rapid initiation of treatment decreases the incidence
of PHN substantially, an effect that can be explained by the theory that incessant pain of active
zoster sets up a positive feedback loop within the thalamus and the cortex, creating a central pain
syndrome similar to phantom leg pain. According to this theory, prompt treatment breaks the
loop by providing pain-free periods early in the disease course.

Risk factors
Known risk factors for developing herpes zoster relate to the status of cell-mediated immunity to
VZV. Risk factors in children and adults include the following:
 VZV-specific immunity and cell-mediated immunity, which generally declines
with age

[16, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28,
Immunosuppression (eg, by HIV infection or AIDS)
29, 30]

[31, 32]
Immunosuppressive therapy

Primary VZV infection in utero or in early infancy, when the normal immune
response is decreased

[33]
Anti-tumor necrosis factor (TNF)-a agents (may pose an increased risk)

Immune reconstitution inflammatory syndrome (IRIS)

Acute lymphocytic leukemia and other malignancies

IRIS is a paradoxical deterioration in clinical status that develops in a patient receiving

antiretroviral treatment despite satisfactory control of viral replication and improvement of the
patients CD4 count. Such patients may have signs and symptoms of a previously subclinical and
unrecognized herpes zoster infection, as a paradoxical worsening of treatment response several
weeks into therapy in the context of immune recovery on antiretroviral therapy (ART).

The appearance of herpes zoster within an 8- to 12-week period after initiation of ART should
prompt consideration of IRIS. Early recognition and prompt treatment, along with continuation
of highly active ART, are especially important in such cases.[34]

Research indicates that patients with inflammatory bowel disease (IBD) are at significantly
increased risk for herpes zoster.[9] In an analysis of more than 108,000 IBD patients and 430,000
matched controls, the overall annual incidence of herpes zoster per 100,000 person-years was
734 among IBD patients, compared with 437 in non-IBD patients. The elevated risk in IBD
patients remained after adjustment for comorbidities and other factors. Treatment with
thiopurines, corticosteroids, and biologic antitumor necrosis factoralpha (anti-TNF) agents was
independently associated with an increased risk of herpes zoster.[35, 36]

Patients with multiple myeloma and colon cancer treated with arsenic trioxide may have a
propensity to develop herpes zoster (shingles). Arsenic compounds have been suggested as a
possible predisposing factor for herpes viral reactivation in these patients.[37]

Ambilateral reactivation of herpes zoster after cataract operations on both eyes has been
described.[38]

In a population-based case-control study from the United Kingdom aimed at quantifying the
effects of herpes zoster risk factors at various ages, 144,959 adults diagnosed with herpes zoster
between 2000 and 2011 were compared with 549,336 age-, sex-, and practice-matched control
subjects (median age, 62 years).[39] The following factors were associated with increased risk of
zoster:

Rheumatoid arthritis (2.1% vs 1.5%)

Inflammatory bowel disease (1.3% vs 0.9%)

Chronic obstructive pulmonary disease (4.7% vs 3.7%)

Asthma (7.1% vs 5.8%)

Chronic kidney disease (6.0% vs 5.4%)

Depression (4.7% vs 4.0%)

For many of the risk factors evaluated, the relative effects were greater in younger individuals.[39]
The greatest risk of zoster was observed in patients with severely immunosuppressive conditions
(eg, lymphoma and myeloma), but current vaccines are contraindicated in these individuals.

Epidemiology
United States statistics
In the United States, approximately 95% of adultsand 99.5% of adults aged 40 years or older
have antibodies to VZV and thus are vulnerable to reactivation of infection.[40] A person of any
age with a previous varicella infection may develop zoster, but the incidence increases with
advancing age as a consequence of declining immunity.

Approximately 4% of patients with herpes zoster will develop a recurrent episode later in life.[41]
Recurrent zoster occurs almost exclusively in people who are immunosuppressed.
Approximately 25% of patients with HIV and 7-9% of those receiving renal transplantation or
cardiac transplantation experience a bout of zoster.

HZO represents 10-15% of all cases of HZ. Approximately half of these patients develop
complications of HZO. The risk of ophthalmic complications in patients with herpes zoster does
not seem to correlate with age, sex, or severity of the rash.

Before the advent of widespread vaccination, an estimated 4 million cases of primary VZV
infection occurred annually in the United States alone.[40] Infection was nearly universal by the
end of the teenage years, with studies showing only 10% of persons older than age 15 years as
remaining susceptible to infection.[41]
Over the period of a lifetime, 10-20% of those with primary infections went on to experience
episodes of herpes zoster.[42] High-risk groups, such as elderly populations and
immunocompromised people, might experience cumulative incidences as high as 50%.[43] The
estimated annual number of herpes zoster cases in the United States is approximately 1 million.
[17]

Since the introduction of widespread vaccination for varicella in 1995, the incidence of primary
VZV infection in the United States has been reduced by up to 90%.[40] However, the effect of this
vaccination, as well as that of the subsequently approved vaccination for herpes zoster, on the
current and future incidence of herpes zoster remains to be determined.

International statistics
Internationally, the incidence of zoster has not been well studied, but it is probably in the same
range as that reported in the United States.[44] A German study of data on patients in the countrys
statutory health system (SHI) for the year 2010 estimated that the mean annual incidence of
herpes zoster was 5.79 cases per 1000 person-years, equivalent to 403,625 cases annually in the
SHI population (which comprised about 85% of the total German population).[45]

Age-related demographics
Herpes zoster is rare in children and young adults, except in younger patients with AIDS,
lymphoma, other malignancies, and other immune deficiencies and in patients who have received
bone marrow or kidney transplants. Fewer than 10% of zoster patients are younger than 20 years,
and only 5% are younger than 15 years. Even though zoster is primarily a disease of adults, it has
been noted as early as the first week of life, occurring in infants born to mothers who had
primary VZV infection (chickenpox) during pregnancy.

The incidence of herpes zoster increases with age.[46] In the general population, the lifetime
incidence rate of herpes zoster is 10-20%, which rises to 50% in those individuals surviving to
age 85 years.[16] More than 66% of patients are older than 50 years. The incidence of PHN also
rises with advancing age.[47]

Sex-related demographics
Herpes zoster generally has not been considered to have a sex predilection. However, one study
reported a higher prevalence in women than in men.[48] Ertunc et al suggested both that zoster
frequency is higher in right-handed patients and that the rash appears more frequently on the left
side in females.[49] The pathophysiology for these differences is uncertain.

Race-related demographics
Blacks are reported to have a significantly lower risk of developing zoster than whites do;
however, zoster has been reported as an early manifestation of HIV infection in young Africans.
Research has shown that elderly blacks are up to 75% less likely to develop herpes zoster than
elderlys.[43] Similar findings have been demonstrated in children.[50] In a meta-analysis of
controlled herpes zoster clinical trials, a nonwhite racial group was found to be associated with a
younger age at zoster onset.[46]

Prognosis
The rash usually resolves within 10-15 days. The prognosis for younger and otherwise healthy
patients is excellent. Elderly people have a significantly increased risk of complications.

Herpes zoster rarely causes fatalities in patients who are immunocompetent, but it can be life-
threatening in severely debilitated or immunocompromised patients. Disseminated zoster in
immunocompromised patients can lead to death from encephalitis, hepatitis, or pneumonitis.
Patients with active lymphoproliferative malignancies are at particular risk. Mortality rate from
disseminated herpes zoster is between 5% and 15%.[42]

Morbidity usually is confined to pain within the affected dermatome, which can range in
intensity from uncomfortable to debilitating. PHN can persist well beyond the duration of active
disease, though most cases eventually resolve.

Variant presentations of zoster (eg, keratitis and myelitis) may carry additional morbidity. Eye
involvement (HZO) can cause temporarily or permanently decreased visual acuity or blindness.
Complications such as secondary infection and meningeal or visceral involvement can produce
further morbidity in the form of infections and scarring.

Patient Education
Patients should be informed about the natural progression of herpes zoster and its potential
complications.

During the acute phase, patients are infective to others and should be instructed to avoid contact
with elderly people, people who are immunocompromised, pregnant women, or people with no
history of chickenpox infection.

In regard to treatment, patients should be instructed that treatment should be started within 72
hours of onset if at all possible, not only to speed resolution of the shingles itself but also to
prevent PHN. Once PHN begins, treatment is much more difficult and often unsuccessful.
Patients should also be told not to scratch the lesions; doing so may predispose them to
secondary bacterial infections.

For patient education resources, see the Infections Center, as well as Shingles and Chickenpox.