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Chapter 194 :: Varicella and Herpes Zoster :: Kenneth E.

Schmader &
Michael N. Oxman

EPIDEMIOLOGY

Herpes zoster occurs sporadically throughout the year without seasonal


prevalence. The occurrence of herpes zoster is independent of the prevalence of varicella,
and there is no convincing evidence that herpes zoster can be acquired by contact with
other persons with varicella or herpes zoster. Rather, the incidence of herpes zoster is
determined by factors that in uence the host-virus relationship.

One strong risk factor is older age (Fig. 194-1A). The incidence of herpes zoster
is 1.53.0 per 1,000 person- years in all ages and 711 per 1,000 per year in persons over
60 years of age in European and North American studies.1322 It is estimated that there are
more than a million new cases of herpes zoster in the United States each year, more than
half of which occur in persons 60 years of age, and this number will increase as the
population ages.14,17,21,23

Another major risk factor is cellular immune dysfunction. Immunosuppressed


patients have a 20100 times greater risk of herpes zoster than immunocompetent
individuals of the same age. Immunosuppressive conditions associated with high risk of
herpes zoster include HIV infection, bone marrow transplant, leukemia and lymphoma,
use of cancer chemotherapy, and use of corticosteroids. Herpes zoster is a prominent and
early opportunistic infection in persons infected with HIV, in whom it is often the rst
sign of immune deficiency. Thus, HIV infection should be considered in individuals who
develop herpes zoster.

Other factors reported to increase the risk of herpes zoster include female sex,20
physical trauma in the affected dermatome,24 IL-10 gene polymorphisms,25 and white
race.19,20 Exposure to children and contact with cases of varicella have been reported to
increase levels of VZV-CMI and confer protection against herpes zoster.20,26

Second episodes of herpes zoster are uncommon in immunocompetent persons,


and third attacks are very rare. Persons suffering more than one episode may be
immunocompromised. Immunocompetent patients suffering multiple episodes of herpes
zoster-like disease are likely to be suffering from recurrent zosteriform herpes simplex
virus infections.27

Patients with herpes zoster are less contagious than patients with varicella. The
rate at which susceptible household contacts develop varicella after exposure to herpes
zoster appears to be about one-third of the rate observed following exposure to
varicella.14 Virus can be isolated from vesicles and pustules in uncomplicated herpes
zoster for up to 7 days after the appearance of the rash, and for much longer periods in
immunocompromised individuals. Patients with uncomplicated dermatomal zoster appear
to spread the infection by means of direct contact with their lesions. Airborne
transmission has also been documented.28 Patients with disseminated herpes zoster may
also transmit the infection via aerosols, so that airborne precautions, as well as contact
precautions, are required for such patients.

The effect of the marked reduction in the incidence of varicella, due to


widespread varicella vaccination of children, on the epidemiology of herpes zoster is
unclear. In the long term, the incidence of herpes zoster is likely to decline as the cohorts
of children now receiving varicella vaccine become adults; vaccine virus-associated
herpes zoster will probably be less frequent and less severe in older adults than wild-type
virus-associated herpes zoster because the vaccine virus is highly attenuated. In the short
term, the incidence of herpes zoster could increase because a decline in the incidence of
varicella will reduce the adult populations exposure to VZV thereby reducing immune
boosting, hastening the age-related decline in immunity to VZV, and thus increasing the
age-specific risk of herpes zoster. However, recent studies of herpes zoster in populations
with high rates of varicella vaccination have shown little or no increase in the incidence
of herpes zoster.8,15,29,30

ETIOLOGY AND PATHOGENESIS


VZV is a member of the herpesvirus family.31 Other members pathogenic for
humans include herpes simplex viruses type 1 (HSV-1) and type 2 (HSV-2); cytomegalo-
virus (CMV); EpsteinBarr virus (EBV); human herpes- virus-6 (HHV-6) and human
herpesvirus-7 (HHV-7), which cause roseola; and Kaposis sarcoma-associated
herpesvirus, also called human herpesvirus type 8. All herpesviruses are morphologically
indistinguishable and share a number of properties, including the capacity to establish
latent infections that persist for life.

The VZV genome encodes about 70 unique genes, most of which have DNA
sequence and functional homology to genes of the other herpesviruses.32 Immediate early
(IE) gene products regulate VZV replication. Early gene products, such as the virus-
specific thymidine kinase and the viral DNA polymerase, support viral replication. Late
genes encode virus structural proteins that serve as targets for neutralizing antibodies and
cellular immune responses.

There is only one VZV serotype. However, there are multiple VZV genotypes that
display geographic segregation and recombination, and minor variations in their
nucleotide sequences allow one to distinguish wild type from vaccine virus strains, and to
fingerprint viruses isolated from individual patients.32,33

PATHOGENESIS

During the course of varicella, VZV passes from lesions in the skin and mucosal
surfaces into the contiguous endings of sensory nerves and is transported centripetally up
the sensory fibers to the sensory ganglia. Infected T cells may also carry virus to sensory
ganglia hematogenously. In the ganglia, the virus establishes a latent infection that
persists for life. Herpes zoster occurs most often in dermatomes in which the rash of
varicella achieves the highest densitythose innervated by the first (ophthalmic) division
of the trigeminal nerve and by spinal sensory ganglia from T1 to L2.39

Although the latent virus in the ganglia retains its potential for full infectivity,
reactivation is sporadic and infrequent, and infectious virus does not appear to be present
during latency. The mechanisms involved in reactivation of latent VZV are unclear, but
reactivation has been associated with immunosuppression; emotional stress; irradiation of
the spinal column; tumor involvement of the cord, dorsal root ganglion, or adjacent
structures; local trauma; surgical manipulation of the spine; and frontal sinusitis (as a
precipitant of ophthalmic zoster). Most important, though, is the decline in VZV-spesific
cellular immunity that occurs with increasing age.40

VZV may also reactivate without producing overt disease. The small quantity of
viral antigens released during such contained reactivations would be expected to
stimulate and sustain host immunity to VZV.14,41

When VZV-specific cellular immunity falls below some critical level, reactivated
virus can no longer be contained.14 Virus multiplies and spreads within the ganglion,
causing neuronal necrosis and intense inflammation, a process that is often accompanied
by severe neuralgia.42,43 Infectious VZV then spreads antidromically down the sensory
nerve, causing intense neuritis, and is released from the sensory nerve endings in the skin,
where it produces the characteristic cluster of zoster vesicles. Spread of the ganglionic
infection proximally along the posterior nerve root to the meninges and cord may result
in local leptomeningitis, cerebrospinal fluid pleocytosis, and segmental myelitis.
Infection of motor neurons in the anterior horn and inflammation of the anterior nerve
root account for the local palsies that may accompany the cutaneous eruption, and
extension of infection within the central nervous system (CNS) may result in rare
complications of herpes zoster (e.g., meningoencephalitis, transverse myelitis). Viremia
also occurs during herpes zoster.44

PATHOGENESIS OF PAIN IN HERPES ZOSTER AND POSTHERPETIC


NEURALGIA

Pain is a major symptom of herpes zoster. It often precedes and generally


accompanies the rash, and it frequently persists after the rash has healeda complication
known as postherpetic neuralgia (PHN). A number of different but overlapping
mechanisms appear to be involved in the pathogenesis of pain in herpes zoster and PHN
(Fig. 194-2).45,46

Injury to the peripheral nerve and to neurons in the ganglion triggers afferent pain
signals. Inflammation in the skin triggers nociceptive signals that further amplify
cutaneous pain. The abundant release of excitatory amino acids and neuropeptides
induced by the sustained barrage of afferent impulses during the prodrome and acute
phase of herpes zoster may cause excitotoxic injury and the loss of inhibitory
interneurons in the spinal dorsal horn. Damage to neurons in the spinal cord and
ganglion, and to the peripheral nerve, is important in the pathogenesis of PHN. Damaged
primary afferent nerves may become spontaneously active and hypersensitive to
peripheral stimuli, and also to sympathetic stimulation. Excessive nociceptor activity and
ectopic impulse generation may, in turn, sensitize CNS neurons, augmenting and
prolonging central responses to innocuous as well as noxious stimuli. Clinically, these
mechanisms result in allodynia (pain and/or unpleasant sensations elicited by stimuli that
are normally not painful, e.g., light touch) with little or no sensory loss.

The anatomic and functional changes responsible for PHN appear to be


established early in the course of herpes zoster. This would explain the correlation of
initial pain severity and the presence of prodromal pain with the subsequent development
of PHN, and the failure of antiviral therapy to fully prevent PHN (see below).

CLINICAL FINDING

PRODROME OF HERPES ZOSTER.

Pain and paresthesia in the involved dermatome often precede the eruption by
several days and vary from superficial itching, tingling, or burning to severe, deep,
boring, or lancinating pain. The pain may be constant or intermittent and it is often
accompanied by tenderness and hyperesthesia of the skin in the involved dermatome. The
preeruptive pain of herpes zoster may simulate pleurisy, myocardial infarction, duodenal
ulcer, cholecystitis, biliary or renal colic, appendicitis, prolapsed intervertebral disk, or
early glaucoma, and this may lead to serious misdiagnosis and misdirected interventions.
Prodromal pain is uncommon in immunocompetent persons under 30 years of age, but it
occurs in the majority of persons with herpes zoster over the age of 60 years. A few
patients experience acute segmental neuralgia without ever developing a cutaneous
eruptiona condition known as zoster sine herpete.48

RASH OF HERPES ZOSTER.

The most distinctive feature of herpes zoster is the localization and distribution of
the rash, which is nearly always unilateral and is generally limited to the area of skin
innervated by a single sensory ganglion (Fig. 194-4A). The area supplied by the
trigeminal nerve, particularly the ophthalmic division, and the trunk from T3 to L2 are
most frequently affected; the thoracic region alone accounts for more than half of all
reported cases, and lesions rarely occur distal to the elbows or knees.14,18,39

Although the individual lesions of herpes zoster and varicella are


indistinguishable, those of herpes zoster tend to evolve more slowly and usually consist
of closely grouped vesicles on an erythematous base, rather than the more discrete,
randomly distributed vesicles of varicella. This difference reflects intraneural spread of
virus to the skin in herpes zoster, as opposed to viremic spread in varicella. Herpes zoster
lesions begin as erythematous macules and papules that often rst appear where super cial
branches of the affected sensory nerve are given off, for example, the posterior primary
division and the lateral and anterior branches of the anterior primary division of spinal
nerves.39 Vesicles form within 1224 hours and evolve into pustules by the third day.
These dry and crust in 710 days. The crusts generally persist for 23 weeks (Fig. 194-
4B). In normal individuals, new lesions continue to appear for 14 days (occasionally for
as long as 7 days). The rash is most severe and lasts longest in older people, and is least
severe and of shortest duration in children.

Between 10% and 15% of reported cases of herpes zoster involve the ophthalmic
division of the trigeminal nerve (Fig. 194-4C).49 The rash of ophthalmic zoster may
extend from the level of the eye to the vertex of the skull, but it terminates sharply at the
midline of the forehead. When only the supratrochlear and supraorbital branches are
involved, the eye is usually spared. Involvement of the nasociliary branch, which
innervates the eye as well as the tip and side of the nose, provides VZV with direct access
to intraocular structures. Thus, when ophthalmic zoster involves the tip and the side of
the nose, careful attention must be given to the condition of the eye. The eye is involved
in 20%70% of patients with ophthalmic zoster. Corneal sensation is generally impaired
and when impairment is severe, it may lead to neurotrophic keratitis and chronic
ulceration.

Herpes zoster affecting the second and third divisions of the trigeminal nerve as
well as other cranial nerves may produce symptoms and lesions in the mouth (Fig. 194-
5), ears, pharynx, or larynx. The so-called Ramsay Hunt syndrome (facial palsy in
combination with herpes zoster of the external ear or tympanic membrane, with or
without tinnitus, vertigo, and deafness), results from involvement of the facial and
auditory nerves.

PAIN OF HERPES ZOSTER.

Although the rash is important, pain is the cardinal problem posed by herpes
zoster, especially in the elderly. Most patients experience dermatomal pain or discomfort
during the acute phase (The first 30 days following rash onset) that ranges from mild to
severe. Patients describe their pain or discomfort as burning, deep aching, tingling,
itching, or stabbing. For some patients, the pain intensity is so great that words like
horrible or excruciating are used to describe the experience. Acute herpes zoster pain is
associated with decreased physical functioning, emotional distress, and decreased social
functioning.50,51

HERPES ZOSTER IN THE IMMUNOCOMPROMISED HOST.


Except for PHN, most serious complications of herpes zoster occur in
immunocompromised persons. These complications include necrosis of skin and scarring
(Fig. 194-6) and cutaneous dissemination (Fig. 194-7) with an incidence as high as 25%
50%. Patients with cutaneous dissemination also manifest widespread, often fatal,
visceral dissemination, particularly to the lungs, liver, and brain.

HIV-infected patients are fairly unique in their tendency to suffer multiple


recurrences of herpes zoster as their HIV infection progresses; herpes zoster may recur in
the same or different dermatomes or in several contiguous or noncontiguous dermatomes.
Herpes zoster in patients with AIDS may be severe, with cutaneous and visceral
dissemination. Patients with AIDS may also develop chronic verrucous, hyperkeratotic,
or ecthymatous cutaneous lesions caused by acyclovir-resistant VZV (Fig. 194-8) (see
also Chapter 198).

DIFFERENTIAL DIAGNOSIS

Most Likely

zosteriform herpes simplex


Contact dermatitis
Insect bites
Burns

Consider
Papular urticaria
Erythema multiforme
Drug eruptions
Scabies
Always Rule Out
Bullous pemphigoid
Pemphigus vulgaris
Dermatitis herpetiformis
Epidermolysis bullosa herpetiformis

CLINICAL DIAGNOSE
In the preeruptive stage, the prodromal pain of herpes zoster is often confused
with other causes of localized pain. Once the eruption appears, the character and
dermatomal location of the rash, coupled with dermatomal pain or other sensory
abnormalities, usually makes the diagnosis obvious (Figs. 194-4 and 194-5).
A cluster of vesicles, particularly near the mouth or genitals, may represent herpes
zoster, but it may also be recurrent HSV infection.27 Zosteriform herpes simplex is often
impossible to distinguish from herpes zoster on clinical grounds. A history of multiple
recurrences at the same site is common in herpes simplex but does not occur in herpes
zoster in the absence of profound and clinically obvious immune de ciency.
Box 194-1 lists other considerations in the differen- tial diagnosis of herpes
zoster.

LABORATORY DIAGNOSIS
The lesions of varicella and herpes zoster are indistinguishable by histopathology
(Fig. 194-9). The presence of multinucleated giant cells and epithelial cells containing
acidophilic intranuclear inclusion bodies (Fig. 194-9B) distinguishes the cutaneous
lesions produced by VZV from all other vesicular eruptions (e.g., those caused by variola
and other poxviruses, and by coxsackieviruses and echoviruses) except those produced by
HSV. These cells can be demonstrated in Tzanck smears prepared at the bedside; material
is scraped from the base of an early vesicle, spread on a glass slide, xed in acetone or
methanol, and stained with hematoxylin-eosin, Giemsa, Papanicolaou, or Paragon
multiple stain.
Punch biopsies provide more reliable material for histologic examination than
Tzanck smears and facilitate diagnosis in the prevesicular stage and in atypical lesions
such as the chronic verrucous lesions produced by acyclovir-resistant VZV in patients
with AIDS (Fig. 194-8).
The definitive diagnosis of VZV infection, as well as the differentiation of VZV
from HSV, is accomplished by the isolation of virus in cell cultures inoculated with
vesicle fluid, blood, cerebrospinal fluid or infected tissue, or by the direct identification
of VZV antigens or nucleic acids in these specimens. Virus isolation is the only technique
that yields infectious VZV for further analysis, such as determination of its sensitivity to
antiviral drugs; however, VZV is extremely labile, and only 30%60% of cultures from
proven cases are generally positive. To maximize virus recovery, specimens should be
inoculated into cell culture immediately. It is important to select new vesicles containing
clear fluid for aspiration, because the probability of isolating VZV diminishes rapidly as
lesions become pustular. VZV is almost never isolated from crusts.
VZV can be isolated and propagated in vitro in monolayer cultures of a variety of
human (and certain simian) cells. The cytopathic effects induced by the replicating virus
in such cell cultures are characterized by the formation of acidophilic intranuclear
inclusion bodies and multinucleated giant cells similar to those seen in the cutaneous
lesions of the disease. These changes are indistinguishable from those produced by HSV,
but whereas HSV rapidly spreads to infect the remaining cells in the culture, the
cytopathic effect of VZV remains focal. Cytopathic effects of VZV are generally not
apparent until several days after specimen inoculation. Modifications of the cell culture
assay in which vesicle fluid or lesion scrapings are centrifuged onto cells growing on
coverslips at the bottom of thin glass-walled shell vials followed 2472 hours later by
fixation and staining with fluorescein-or enzyme-labeled monoclonal antibodies to VZV
proteins, can confirm the presence of VZV relatively quickly, well before cytopathic
effects are evident in conventional cell cultures.52
Immunofluorescent or immunoperoxidase staining of cellular material from fresh
vesicles or prevesicular lesions has become the diagnostic method of choice in many
centers; it can detect VZV significantly more often and faster than virus culture, even
relatively late in the disease when cultures are no longer positive.52 Enzyme
immunoassays provide another rapid and sensitive method for antigen detection.
Detection of VZV DNA in clinical specimens following amplifications by PCR
provides the greatest assay sensitivity, very high specificity and rapid turnaround time. It
has revolutionized the diagnosis of VZV infections, and can distinguish among wild type
and Oka vaccine strains of VZV and HSV.52,53
Serologic tests permit the retrospective diagnosis of varicella and herpes zoster
when acute and convalescent sera are available for comparison.52 These assays can also
identify susceptible individuals who may be candidates for isolation or prophylaxis. The
technique most commonly used is a solid-phase enzyme-linked immunosorbent assay
(ELISA). However, this assay often lacks sensitivity and specificity, failing to detect
antibody in people who are immune and sometimes yielding false-positive results in
susceptible individuals. Several more sensitive techniques have been developed to
measure humoral responses to VZV. These include an immunofluorescence assay for
antibody to VZV-induced membrane antigens [fluorescent antibody to membrane antigen
(FAMA)] that reliably distinguishes immune from susceptible adults and a latex
agglutination test that is comparable in sensitivity and specificity to FAMA assays, but is
much simpler to perform.54

COMPLICATION
Cutaneous Visceral Neurologic
Bacterial superinfection Pneumonitis Postherpetic neuralgia
Meningoencephalitis
Scarring Hepatitis
Transverse myelitis
Zoster gangrenosum Esophagitis Peripheral nerve palsies
Motor
Cutaneous dissemination Gastritis
Autonomic
Pericarditis Cranial nerve palsies
Sensory loss
Cystitis
Deafness
Arthritis Ocular complications
Granulomatous angiitis (causing
contralateral hemiparesis)

The sequelae of herpes zoster include cutaneous, ocular, neurologic, and visceral
complications.39 Most complications of herpes zoster are associated with the spread of
VZV from the initially involved sensory ganglion, nerve, or skin, either via the
bloodstream or by direct neural extension. The rash may disseminate after the initial
dermatomal eruption has become apparent. When immunocompetent patients are
carefully examined, it is not uncommon to have at least a few vesicles in areas distant
from the involved and immediately adjacent dermatomes. The disseminated lesions
usually appear within a week of the onset of the segmental eruption and, if few in
number, are easily overlooked. More extensive dissemination (with 2550 lesions or
more), producing a varicella-like eruption (generalized herpes zoster; Fig. 194-7), occurs
in 2%10% of unselected patients with localized herpes zoster, most of whom have
immunologic defects as a result of acquired immunodeficiency, as seen with HIV
infection, underlying malignancy (particularly lymphomas), or immunosuppressive
therapy. If the rash spreads widely from a small, painless area of herpes zoster, the initial
dermatomal presentation may go unnoticed, and the ensuing disseminated eruption may
be mistaken for varicella.
When the dermatomal rash is particularly extensive, as it often is in severely
immunocompromised patients,there may be superficial gangrene with delayed healing
and subsequent scarring (Fig. 194-6). Secondary bacterial infection may also delay
healing and cause scarring.
The eye is involved in 20%70% of patients with ophthalmic zoster, with a wide
range of possible complications.49 VZV is also the principal cause of acute retinal
necrosis (ARN), a fulminant sight-threatening disease observed primarily in otherwise
healthy individuals.46,63,64
Herpes zoster may be attended by a variety of neurologic complications (Table
65
191-1), of which PHN is the most common and important. PHN has been variably
defined as any pain after rash healing or any pain 1 month, 3 months, 4 months, or 6
months after rash onset.66,67 In clinic and community studies, the overall incidence of
PHN is 8%15% depending on the definition (Fig. 194-1A).21,68,69 Age is the most
significant risk factor for PHN (Fig. 194-1C). Clinically significant pain lasting 3 months
or more is rare in immunocompetent persons younger than 50 years of age, but
complicates 12%15% of cases of herpes zoster in persons 60 years of age and older.17
Other risk factors for PHN include the presence of prodromal pain, severe pain during the
acute phase of herpes zoster, greater rash severity, more extensive sensory abnormalities
in the affected dermatome and, possibly, ophthalmic (as opposed to thoracic or
abdominal) herpes zoster.70 Increasing age, greater acute pain severity, presence of
prodromal pain, and greater rash severity have each been reported to be independent
predictors of PHN.67 The positive predictive value of each factor alone was low, but,
together, the positive predictive value was almost 50%. PHN usually remits
spontaneously over several months but, as with PHN itself, the risk of long-lasting PHN
increases with increasing age.
Patients with PHN may suffer from constant pain (described as burning, aching,
throbbing), intermittent pain (stabbing, shooting), and/or stimulus-evoked pain,
including allodynia (tender, burning, stabbing). Allodynia (pain elicited by stimuli that
are normally not painful) is a particularly disabling component of the disease that is
present in approximately 90% of patients with PHN. Patients with allodynia may suffer
severe pain after even the lightest touch of the affected skin by things as trivial as a
breeze or a piece of clothing. These subtypes of pain may produce disordered sleep,
depression, anorexia, weight loss, chronic fatigue, and social isolation, and they often
interfere with dressing, bathing, general activity, traveling, shopping, cooking, and
housework.

TREATMENT
ANTIVIRAL AGENTS
The nucleoside analogues acyclovir, famciclovir, valacyclovir, and brivudin and
the pyrophosphate analog foscarnet show efficacy in treating VZV infections. Acyclovir
is a guanosine analogue that is selectively phosphorylated by VZV thymidine kinases (it
is a poor substrate for cellular thymidine kinase) and thus is concentrated in infected
cells. Cellular enzymes then convert acyclovir monophosphate to acyclovir triphosphate,
which interferes with viral DNA synthesis by inhibiting viral DNA polymerase. VZV is
approximately tenfold less sensitive to acyclovir than herpes simplex virus.
Two prodrugs, valacyclovir and famciclovir, are better and more reliably absorbed
than acyclovir following oral administration. Thus, they produce much higher blood
levels of antiviral activity and permit less frequent dosing than acyclovir. Valacyclovir is
a valine ester of acyclovir that is converted enzymatically to acyclovir after absorption.
Famciclovir is a prodrug of penciclovir, a nucleoside analogue similar to acyclovir in
mechanism of action and antiviral activity against VZV and HSV. Famciclovir is
converted enzymatically to penciclovir after absorption.
Brivudin is a uracil analogue with very high activity against VZV. Although
effective in the treatment of herpes zoster, and licensed for such use outside the United
States, it is not licensed in the United States, in part because of a potentially lethal
interaction with 5-fluorouracil.
Foscarnet is an analogue of inorganic pyrophosphate that inhibits the replication
of all known herpesviruses in vitro. It exerts its antiviral activity by selective inhibition at
the pyrophosphate-binding site of virus-specific DNA polymerases and reverse
transcriptases at concentrations that do not affect cellular DNA polymerases. Foscarnet
does not require phosphorylation by thymidine kinase to be activated and is therefore
active against acyclovir-resistant VZV mutants that have reduced or altered thymidine
kinase activity.
Topical antiviral therapy lacks efficacy in patients with varicella and herpes zoster
and is not recommended. Systemic therapy, either oral or parenteral, is required. Because
of their superior pharmacokinetics, the lower sensitivity of VZV compared to HSV, and
the existence of barriers to the entry of antiviral agents into tissues that are sites of VZV
replication, famciclovir or valacyclovir are preferred to acyclovir for oral therapy of VZV
infections. Acyclovir-resistant VZV has been documented in varicella and herpes zoster
in patients with advanced AIDS (Fig. 194-8). Because of the mechanism of acyclovir
resis- tance (mutations in the viral thymidine kinase gene),these acyclovir-resistant
mutants are cross-resistant to ganciclovir, valacyclovir, famciclovir, and penciclovir.
They usually respond to foscarnet, 40 mg IV every 8 hours; however, the infections
commonly recur after treatment has ended.

TOPICAL THERAPY
During the acute phase of herpes zoster, the application of cool compresses,
calamine lotion, cornstarch, or baking soda may help to alleviate local symptoms and
hasten the drying of vesicular lesions. Occlusive ointments should be avoided, and
creams or lotions containing glucocorticoids should not be used. Bacterial superinfection
of local lesions is uncommon and should be treated with warm soaks; bacterial cellulitis
requires systemic antibiotic therapy. Topical treatment with antiviral agents is not
effective.

ANTIVIRAL THERAPY
The major goals of therapy in patients with herpes zoster are to (1) limit the
extent, duration, and severity of pain and rash in the primary dermatome; (2) prevent
disease elsewhere; and (3) prevent PHN.
Patient Group Regimen
Normal Symptomatic treatment alone, or
Age <50 years Famciclovir 500 mg PO every 8 h for 7 days or
Valacyclovir 1 g PO every 8 h for 7 days or
Acyclovir 800 mg PO 5 times a day for 7 daysa
Famciclovir 500 mg PO every 8 h for 7 days or
Age 50 years, and patients of any age with cranial
Valacyclovir 1 g PO every 8 h for 7 days of
nerve
Acyclovir 800 mg PO 5 times a day for 7 daysa
involvement (e.g., ophthalmic zoster)
Immunocompromised Famciclovir 500 mg PO every 8 h for 710 days or
Mild compromise, including HIV-1 infection Valacyclovir 1 g PO every 8 h for 710 days or
Acyclovir 800 mg PO 5 times a day for 710 daysa

Severe compromise Acyclovir 10 mg/kg IV every 8 h for 710 days


Acyclovir resistant (e.g., advanced AIDS) Foscarnet
40 mg/kg IV every 8 h until healed

Normal Patients
Lists the current recommendations for treatment of herpes zoster. Randomized
controlled trials indicate that oral acyclovir (800 mg ve times a day for 7 days),
famciclovir (500 mg q 8 hours for 7 days), and valacyclovir (1 g three times a day for 7
days) reduce time to rash healing, and the duration and severity of acute pain in older
adults with herpes zoster who are treated within 72 hours of rash onset.77 In some studies,
the duration of chronic pain was also reduced, but the FDA has not approved these agents
for the prevention of PHN.78,79 Randomized controlled trials comparing acyclovir to
valacyclovir, acyclovir to famciclovir, and valacyclovir to famciclovir demonstrated
equivalent results in rash healing, acute pain, and the duration of chronic pain.8082 All
three drugs are acceptable agents for older adults, with cost and dosing schedule
determining the choice of agent. However, the reduced sensitivity of VZV compared with
HSV, the existence of barriers to the entry of antiviral agents into tissues that are sites of
VZV replication, and the higher and more reliable blood levels of antiviral activity
achieved, make famciclovir or valacyclovir preferable to acyclovir for oral treatment of
herpes zoster.
Because of the lower risk of PHN, antiviral therapy is less valuable or necessary
for treatment of uncomplicated herpes zoster in healthy people younger than 50 years of
age. The utility of antiviral agents is unproven if treatment is initiated more than 72 hours
after rash onset. Nevertheless, we believe that it is prudent to initiate antiviral therapy
even if more than 72 hours have elapsed after rash onset in patients who have herpes
zoster involving cranial nerves (e.g., ophthalmic zoster) or who continue to have new
vesicle formation.77,79
Ophthalmic zoster represents a special therapeutic challenge because of the risk of ocular
complications. Examination by an ophthalmologist should be sought in most cases. Oral
acyclovir has been shown in a randomized, controlled trial to be effective in preventing
ocular complications of ophthalmic zoster.83 Famciclovir and valacyclovir appear to have
efficacy comparable to that of acyclovir in the treatment of ophthalmic zoster, and are
preferred for the reasons cited above.84,85

Immunocompromised Patients
A randomized, double-blind, placebo-controlled trial in immunocompromised
patients with herpes zoster showed that IV acyclovir (500 mg/m2 q8h for 7 days) halted
progression of the disease, both in patients with localized herpes zoster and in patients
with cutaneous dissemination prior to treatment.86 Acyclovir accelerated the rate of
clearance of virus from vesicles and markedly reduced the incidence of visceral and
progressive cutaneous dissemination. Pain subsided faster in acyclovir recipients, and
fewer reported PHN, but these differences were not statistically significant. Clinical trials
comparing IV acyclovir to IV vidarabine for the treatment of herpes zoster in
immunocompromised patients showed that acyclovir was significantly more effective and
less toxic.86,87 In patients with mild immunocompromise and localized herpes zoster, oral
acyclovir, valacyclovir, or famciclovir will usually suffice.88,89 A randomized, controlled
trial of oral famciclovir versus oral acyclovir in patients with localized herpes zoster
following bone marrow or organ transplantation or cancer chemotherapy showed that the
two treatments were equivalent in rash healing and loss of acute pain, and that both were
well tolerated.89

ANTI-INFLAMMATORY THERAPY
The possibility that PHN might be caused by inflammation of the sensory
ganglion and contiguous neural strutures provided the rationale for the use of
glucocorticoids during the acute phase of herpes zoster in an attempt to further reduce
acute pain and prevent PHN. Randomized controlled trials, however, showed that the
addition of glucocorticoids to acyclovir did not change the incidence of chronic pain.9092
However, glucocorticoids did reduce acute pain in most trials, and in one trial of
acyclovir and prednisone, the time to uninterrupted sleep, return to baseline daily activity,
and cessation of analgesic therapy was reduced in patients who received
glucocorticoids.91 Consequently, some experts advocate oral glucocorticoids for
otherwise healthy older adults whose rash is complicated by moderate-to-severe pain and
who have no contraindications to glucocorticoids.77 Others believe that the common
adverse effects of glucocorticoids argue against their routine use in older patients with
herpes zoster. We agree and do not recommend the use of glucocorticoids in this setting.
Glucocorticoids, in combination with effective antiviral therapy, may improve motor
outcomes and acute pain in VZV-induced facial paralysis and cranial polyneuritis, where
compression of affected nerves may contribute to disability.

ANALGESICS
Greater severity of acute pain is a risk factor for PHN, and acute pain may
contribute to central sensitization and the genesis of chronic pain. Therefore, aggressive
pain control is both reasonable and humane.77 The severity of acute herpes zoster pain
should be determined using simple standardized pain scales. Clinicians should prescribe
nonopiate or opiate analgesics with the goal of limiting the severity of pain to less than 3
or 4 on a 0-to-10 scale, and to a level that does not interfere with sleep. The choice,
dosage, and schedule of drugs are governed by the patients pain severity, underlying
conditions, and response to specific drugs. A randomized controlled trial of oxycodone,
gabapentin, or placebo in older adults with herpes zoster showed that oxycodone, but not
gabapentin, provided significantly greater pain relief than placebo in patients with
moderate-to-severe pain.93 This trial was not powered to analyze PHN, and there are no
other controlled trials of the effect of treatment with opioids or gabapentin during the
acute phase of herpes zoster on the subsequent development of PHN. A crossover study
of a single dose of 900 mg of gabapentin during the acute phase of herpes zoster showed
greater pain relief than placebo.94 If pain control remains inadequate, regional or local
anesthetic nerve blocks should be considered for acute pain control.77,95 A randomized
controlled trial demonstrated that a single epidural injection of corticosteroids and local
anesthetics in the acute phase of herpes zoster did not prevent the subsequent

development of PHN.95

POST HERPETIC NEURALGIA TREATMENT


Once established, PHN is difficult to treat. Fortunately, it resolves spontaneously in
most patients, although this often requires several months (Fig. 194-1B). Clinicians have
advocated a wide range of treatments, including many oral and topical medications,
epidural injection of local anesthetic and glucocorticoids, acupuncture, biofeedback,
subcutaneous injections of triamcinolone, trans-epidermal electric nerve stimulation
(TENS), spinal cord stimulators, and systemic administration of a variety of compounds,
but most have not been validated by controlled trials. The results of randomized
controlled trials demonstrated efficacy for pain relief in PHN for the following drugs:
gabapentin, pregabalin, tricyclic antidepressants (TCAs), opioid analgesics, tramadol,
lidocaine patch 5%, and highconcentration capsaicin patch.96101 The choice of these
medications should be guided by the adverse event profiles, potential for drug
interactions, and patient comorbidities and treatment preferences. On average, these
agents provide adequate pain relief (defined as reduction of pain to below 4 on a 010
point scale or by 50% on a visual analog or Likert scale) in 30%60% of patients. These
modalities are now recommended as evidence-based pharmacotherapy for PHN in
practice management guidelines.9698

TOPICAL THERAPY
Topical anesthesia delivered by means of a 5% lidocaine patch has been shown in
controlled clinical trials to produce significant pain relief in patients with PHN. The
10x14-cm lidocaine patch contains 5% lidocaine base, adhesive, and other ingredients on
a polyester backing. It is easy to use and is not associated with systemic lidocaine
toxicity.102 Up to three patches are applied over the affected area for 12 hours a day. The
disadvantages of the patch are application site reactions, such as skin redness or rash, and
substantial cost. Eutectic mixture of local anesthetics (EMLA) cream applied once a day
over the affected area under an occlusive dressing is an alternative method of delivering
topical anesthesia.
A single 1-hour application of a high-concentration capsaicin patch (8%)
compared with a low-concentration control patch significantly reduced pain from PHN
from the second week after the capsaicin application throughout a subsequent 12-week
period.99 The high-concentration patch was generally well tolerated. Adverse events
include increases in pain associated with patch application (usually transient) and
application-site reactions (e.g., erythema). The role of the high-concentration capsaicin
patch in the treatment of PHN is yet to be clearly established, partly because its long-term
benefits are not yet known. However, this intervention has promise because a single 1-
hour application may yield several weeks of pain reduction.

ORAL AGENTS
Gabapentin has been shown to produce moderate or greater pain relief in 41%
43% of patients with PHN compared to 12%23% in patients receiving placebo.103,104
Frequent adverse effects of gabapentin include somnolence, dizziness, and peripheral
edema. Pregabalin has been shown to produce 50% or greater pain relief in 50% of
patients with PHN compared to 20% in placebo recipients.105,106 Dizziness, somnolence,
and peripheral edema were also the most common adverse effects reported for
pregabalin.105107 Pregabalin has a less complicated dose titration schedule and a faster
onset of action than gabapentin.
TCAs have been shown to produce moderate-to-good pain relief in 44%67% of
elderly patients with PHN in several randomized, controlled trials.96,97,100,108 Nortriptyline
and desipramine are preferred alternatives to amitriptyline because they cause fewer
cardiac adverse effects, sedation, cognitive impairment, orthostatic hypotension, and
constipation in the elderly.109
Treatment with scheduled opioids may also reduce PHN. In a randomized,
placebo-controlled crossover trial of sustained-release oxycodone in patients with PHN,
patients reported significant pain relief when treated with opioid compared to placebo.110
In a cross-over study in patients with PHN, both controlled- release morphine and TCAs
provided significant pain relief compared to placebo.111 In this trial, patients preferred
treatment with opioid analgesics to either TCAs or placebo, despite a greater incidence of
adverse effects and more dropouts during opioid treatment.
The use of combinations of these drugs for PHN is common in clinical practice
and undergoing increasing investigation. In a crossover trial, patients with diabetic
polyneuropathy or PHN were randomized to daily active placebo (lorazepam), sustained-
release morphine, gabapentin, and a combination of gabapentin and morphine.112
Combination therapy with morphine and gabapentin produced greater pain relief than
either agent alone or placebo, but with an increase in adverse effects (constipation,
sedation, and dry mouth). In a crossover trial, patients with diabetic polyneuropathy or
PHN were randomized to receive one of three sequences of daily oral gabapentin, nortrip-
tyline, and a combination of the two.113 Combination therapy with gabapentin and
nortriptyline produced greater pain relief than either agent alone. The most common
adverse event was dry mouth secondary to nortriptyline. These results suggest that
combination therapy may benefit some individuals with PHN who have responded to one
of the agents chosen, but at the risk of increased adverse effects than with either drug
alone.

PREVENTION
ZOSTER VACCINE
Until universal varicella vaccination greatly reduces the number of people latently
infected with wild-type VZV, prevention of herpes zoster must be aimed at preventing
reactivation and spread of the latent wild-type VZV. Long-term suppressive acyclovir
treatment is only practical in immnocompromised patients at proven risk of developing
herpes zoster within a defined time period, for example, in the year following bone
marrow or solid organ transplantation. Other strategies must be devised for the general
population.
One approach to the prevention of herpes zoster is the stimulation of immunity to
VZV, which wanes in the elderly and in other high-risk individuals.40,127 Studies of
healthy adults over 55 years of age with a history of varicella have demonstrated an
increase in VZV-specific T lymphocytes and humoral immunity after vaccination with
live attenuated VZV vaccine that is similar to the increase observed after an episode of
herpes zoster.128 These findings suggested that vaccination of older persons may be
useful in preventing herpes zoster and its complications.33,127 A recent VA Cooperative
Study (the Shingles Prevention Study) tested the hypothesis that vaccination against
VZV would decrease the incidence and/or severity of herpes zoster and PHN among
older adults.17 The study enrolled 38,546 adults 60 years of age or older in a randomized,
double-blind, placebo-controlled trial of a live attenuated Oka/Merck VZV vaccine of
much greater potency than the currently licensed varicella vaccine. A total of 957
confirmed cases of herpes zoster (315 among vaccine recipients and 642 among
placebo recipients) and 107 cases of PHN (27 among vaccine recipients and 80 among
placebo recipients) were included in the efficacy analysis. The zoster vaccine reduced the
burden of illness due to herpes zoster by 61.1% (P<0.001), reduced the incidence of PHN
by 66.5% (P<0.001), and reduced the incidence of herpes zoster by 51.3% (P<0.001).
Reactions at the injection site were more frequent among vaccine recipients but were
generally mild. The proportion of subjects reporting serious adverse events, and rates of
hospitalization and death were comparable in vaccine and placebo recipients.129
Furthermore, the zoster vaccine neither caused nor induced herpes zoster in recipients.
This landmark study showed that the zoster vaccine markedly reduced morbidity from
herpes zoster and PHN among older adults. The FDA licensed the zoster vaccine for the
prevention of herpes zoster in adults 60 years of age and older in 2006. The ACIP of the
CDC unanimously recommended the vaccine for the prevention of herpes zoster and its
complications, including PHN, in immunocompetent adults 60 years of age and older,
irrespective of a history of herpes zoster.23 Zoster vaccine has now been added to the US
schedule of routinely recommended adult immunizations.23
The zoster vaccine may be administered without screening for a history of
varicella or herpes zoster, nor should one conduct serologic testing for varicella immunity
before vaccination.23 Persons known to be VZV seronegative should be vaccinated
against varicella according to current recommendations.30 Older adults who have PHN or
who have a current episode of herpes zoster may ask to be vaccinated, but zoster
vaccination is not indicated to treat acute herpes zoster or PHN. Some patients may want
to receive zoster vaccine after a recent episode of herpes zoster has resolved. The optimal
time to immunize an individual after a recent episode of herpes zoster is unknown, and
the clinical diagnosis of herpes zoster is not always correct. The authors believe that an
interval of 35 years after the onset of a well-documented case of herpes zoster is
reasonable.
A history of anaphylactic reaction to any of the vaccine components is a
contraindication to the vaccine.23 Neomycin is a vaccine component but contact
dermatitis due to neomycin does not represent anaphylaxis and therefore is not a
contraindication to zoster vaccination. The zoster vaccine should not be given to persons
who have severe acute illness, including active untreated tuberculosis, until the illness has
subsided. Persons with leukemia, lymphomas, or other malignant neoplasm affecting the
bone marrow or lymphatic system, or with AIDS or other clinical manifestations of HIV

infection, including those with CD4+ T-lymphocyte counts < 200 per mm3 and/or <15%
of total lymphocytes should not receive zoster vaccine.23 Persons on immunosuppressive
therapy, including high-dose corticosteroid therapy, should not receive the vaccine. The
ACIP defines high-dose corticosteroids as 20 mg or more per day of oral prednisone or
equivalent for 14 days or more.130 Low doses of methotrexate (<0.4 mg/kg/week),
azathioprine (<3.0 mg/kg/day), or 6-mercaptopurine (<1.5 mg/kg/day) are not considered
to have significant immunosuppression.23
When considering the zoster vaccine, older adults may express concerns about
transmission of vaccine virus to other individuals. Transmission of VZV requires the
development of a vesicular rash containing vaccine virus after vaccination. If there is no
rash, there is no transmission. Zoster vaccine-associated vesicular rashes are very
unusual. In the Shingles Prevention Study, vesicular lesions at the injection site were
observed in 20 of 19,270 vaccine recipients a median of 34 days after vaccination and in
7 out of 19,276 placebo recipients. Neither vaccine virus nor wild-type VZV were
detected by DNA PCR testing in the few specimens that were available for testing.
Transmission of vaccine virus from recipients of zoster vaccine to susceptible household
contacts has not been documented. Thus, immunocompetent older adults in contact with
immunosuppressed patients should receive zoster vaccine to reduce the risk that they will
develop herpes zoster and transmit wild-type VZV to their susceptible
immunosuppressed contacts.23,33 For the same reasons, adult contacts of susceptible
pregnant women and infants should receive zoster vaccine. Zoster vaccine recipients with
susceptible pregnant or immune compromised contacts need not take any special
precautions following vaccination, except in the rare situation that a vesicular rash
develops, in which case standard contact precautions are adequate. Eligible residents and
personnel in nursing homes and other facilities housing older adults should also be
vaccinated against herpes zoster. However, VZV-seronegative persons (e.g., health care
workers from tropical countries who have not had varicella) should be vaccinated against
varicella. These recommendations are consistent with those of the ACIP.23 In the unlikely
event that an immunocompromised contact develops a significant illness caused by
vaccine virus, he/she may be treated with standard anti-VZV agents (acyclovir,
valacyclovir, or famciclovir).
With the development of the varicella and zoster vaccines, antiviral therapy, and
neuropathic pain treatments, clinicians now have multiple effective tools to reduce human
suffering from varicella and herpes zoster.

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