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Chapter 165 :: Varicella and Herpes Zoster

25
:: Myron J. Levin, Kenneth E. Schmader,
& Michael N. Oxman

AT A GLANCE ÿ Antiviral therapy and analgesics reduce the acute

pain of herpes zoster. Lidocaine patch (5%), high
VARICELLA dose capsaicin patch, gabapentin, pregabalin,
ÿ Varicella (chickenpox) and herpes zoster (shingles) opioids, and tricyclic antidepressants may reduce

Zoster
Varice
Herpe
Chapt
and
165 :: are distinct clinical entities caused by a single
member of the herpesvirus family, varicella-zoster
virus (VZV).
ÿ Varicella, a highly contagious exanthem that occurs
most often in childhood, is the result of primary
VZV infection of a susceptible individual.
ÿ The rash of varicella usually begins on the face
and scalp and spreads rapidly to the trunk, with
relative sparing of the extremities. Lesions are
scattered, rather than clustered, reflecting viremic
spread to the skin, and they progress sequentially
from rose-colored macules to papules, vesicles,
the pain of PHN.
ÿ A live attenuated Oka/Merck strain VZV herpes
zoster vaccine (ZVL; Zostavax®) reduces the
incidence of herpes zoster by one-half and the
incidence of PHN by two-thirds. An adjuvanted
recombinant glycoprotein E subunit herpes zoster
vaccine (RZV; Shingrix®) has substantially greater
efficacy for herpes zoster and PHN, but it requires 2
doses and is more reactogenic.

pustules, and crusts. Lesions in all stages INTRODUCTION

are usually present at the same time.
ÿ In immunocompetent children, systemic symptoms
are usually mild and serious complications are
rare. In adults and immunocompromised persons
of any age, varicella is more likely to be severe
and can be associated with life-threatening
complications.
ÿ Varicella results in lifelong latent VZV infection of
sensory and autonomic neurons, and host
immunity to VZV.
ÿ Live attenuated Oka VZV varicella vaccines have
virtually eliminated varicella in countries where
they have been deployed.
HERPES ZOSTER
ÿ Herpes zoster is characterized by unilateral
dermatomal pain and rash that results from
reactivation and multiplication of latent
VZV that persisted within neurons following
varicella.
ÿ The erythematous maculopapular and vesicular
lesions of herpes zoster are clustered within a
single dermatome, because VZV reaches the skin
via the sensory nerve from the single ganglion in
which latent VZV reactivates, and not by viremia.
ÿ Herpes zoster is most common in older adults and
in immunocompromised individuals.
ÿ Pain is an important manifestation of herpes
zoster. The most common debilitating
complication is chronic neuropathic pain
that persists long after the rash resolves, a
complication known as postherpetic neuralgia
(PHN).
Varicella (chickenpox) and herpes zoster (shingles,
zoster) are distinct clinical entities caused by a single
member of the herpesvirus family, varicella-zoster
virus (VZV). The different clinical manifestations of
these 2 diseases are the result of differences in the host
immune response and in the pathogenesis of the
VZV infection, and not due to differences in the
etiologic agent. Varicella, a highly contagious
vesicular exan them that occurs most often in
childhood, is the result of exogenous primary
infection of a susceptible indi vidual. In contrast,
herpes zoster results from reactiva tion of endogenous
virus that persists in latent form within ganglionic
neurons following an earlier attack of varicella.
Herpes zoster is a localized dermatomal disease
characterized by unilateral radicular pain and a vesicular dermatomal eruptio
HISTORICAL PERSPECTIVE
There was a report in 1892 of 5 instances in which
varicella occurred in children exposed to adults with
herpes zoster, and in the ensuing half century, clinical
and histologic evidence lent support to the suggestion
that susceptible individuals could develop varicella
after exposure to someone with herpes zoster.1-5
This included the development of varicella by children
without a prior history of varicella who were inocu
lated with vesicle fluid from herpes zoster. In the
1950s, viruses isolated from varicella and herpes
zoster were shown to have similar properties in tissue
culture, and when compared by complement fixation
and immu nofluorescence techniques.6 Nucleic acid identification

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25 methods subsequently demonstrated that the viruses
isolated from a case of varicella and from a later case of
herpes zoster in the same patient were identical.7
EPIDEMIOLOGY
EPIDEMIOLOGY OF
VARICELLA
Varicella is distributed worldwide, but its age-specific
incidence differs in temperate versus tropical climates,
and in populations that have received varicella vaccine.
In temperate climates, in the absence of varicella vacci
nation, varicella is endemic, with a regularly recurring
seasonal prevalence in winter and spring, and periodic
epidemics that reflect the accumulation of susceptible
persons. In Europe and North America in the prevac
cination era, 90% of cases occurred in children younger
than 10 years of age and fewer than 5% in individu als
older than the age of 15.8 From 1988 to 1995, before
varicella vaccine was introduced, there were approxi
mately 11,000 hospitalizations and 100 deaths caused
by varicella each year in the United States.9,10 The risk
of hospitalization and death was much higher in infants
and adults than in children, and most varicella related
deaths occurred in previously healthy people.
In tropical and semitropical countries, the mean age of
varicella is higher, and susceptibility among adults is
significantly greater, than in temperate climates. High
levels of susceptibility to varicella among adult immi
grants from tropical climates are well documented in the
US military, for example, among recruits from Puerto
Rico.11 This geographical variation is important for
hospitals, where susceptible health care workers from
semitropical areas, such as the Philippines and Mexico,
may pose a significant risk of nosocomial varicella.
Widespread use of varicella vaccine has markedly
altered the epidemiology of varicella in the United
States. Two-dose varicella vaccine coverage now
exceeds 90% in young children.12 This has resulted in
a marked reduction in varicella-related morbidity. Vari
cella incidence and outpatient visits have declined by
>85%, and hospitalizations have declined by ÿ93%.13-18
The decline is greatest among children aged 1 to 4
years who were targeted for vaccination, but cases have
declined in all age groups, including unvacci nated
infants and adults, reflecting herd immunity.
Varicella-related mortality also declined substantially
after the introduction of the varicella vaccine, and is now
rare.19 Varicella vaccine effectiveness has been
demonstrated in a number of countries.20
Varicella is highly contagious. Attack rates of 87%
among susceptible siblings in households and nearly
70% among susceptible patients on hospital wards have
been reported.21 More than 95% of cases of vari cella
are clinically apparent, although occasionally the
exanthem may be so sparse and transient as to pass
3036 unnoticed. A typical patient is infectious for 1 to 2 days
before the exanthem appears, and for 4 or 5 days
Kang_CH165_p3035-3064.indd 3036
thereafter, until the last crop of vesicles has crusted.
Immunocompromised patients, who may experi ence
successive crops of lesions for a week or more, are
infectious longer. The mean incubation period of
varicella is 14 to 17 days, with a range of 10 to 23 days,
but it may be prolonged in patients who develop vari
cella after passive immunization with varicella-zoster
immune globulin, or after postexposure immunization
with varicella vaccine.22
The major route by which varicella is acquired and
transmitted is from the respiratory tract by airborne
droplets or aerosols, but infection also may be spread
by direct contact. Varicella crusts are not infectious, and
the duration of infectivity of droplets containing virus is
probably quite limited. Although the infectiousness of
patients with varicella is thought to depend largely on
virus shed from the mucous membranes of the
upper respiratory tract, VZV has rarely been cultured
from pharyngeal secretions. However, VZV DNA can be
detected in the oropharynx of most patients using
polymerase chain reaction (PCR)–based assays.23
Varicella generally confers lifelong immunity, although
subsequent exposure to VZV boosts humoral and cell-
mediated immune responses, indicating sub clinical
reinfection.24 Most reported second episodes of
varicella represent incorrect diagnoses. Second epi
sodes of varicella reported in immunocompromised
patients usually represent cutaneous dissemination of
herpes zoster.25 Even severely immunocompromised
patients very rarely develop second episodes of vari
cella after reexposure. Modified and breakthrough
varicella now account for a significant proportion of the
varicella occurring in the USA. Modified varicella occurs
in individuals who develop varicella early in infancy in
the presence of maternal antibody or fol lowing
postexposure prophylaxis with varicella-zoster immune
globulin or varicella vaccine. Breakthrough varicella
occurs when vaccinated individuals are rein fected
following exposure to wildtype VZV. Break through
varicella is frequently mild. However, both modified and
breakthrough varicella are infectious for susceptible
contacts.
EPIDEMIOLOGY OF
HERPES ZOSTER
Herpes zoster occurs sporadically throughout the year
without seasonal prevalence and independent of the
prevalence of varicella. There is no convincing evi
dence that herpes zoster can be acquired by contact
with persons with varicella or herpes zoster.1 Rather,
the incidence of herpes zoster is determined by factors
that influence the host–virus relationship and the pres
ence of immune responses necessary to prevent reacti
vation of latent VZV. The incidence of herpes zoster in
community-dwelling populations ranges from 2 to 5 per
1000 person-years.26,27
A major risk factor for herpes zoster is age (Fig.
165-1A). The incidence of herpes zoster increases
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Epidemiology of Herpes Zoster

25
14

12

Zoster
Varice
Herpe
Chapt
and
165 :: Incidence
persons
(cases
year)
1000
per
per
HZ
of
10

0
0-9 10-19 20-29 30-39 40-49 50-59 60-69 70+

A Age (y)

Epidemiology of Postherpetic Neuralgia

40

35

30

25

20

15

Percentage
cases
PHN
with
HZ
of

10

0
20-29 30-39 40-49 50-59 60-69 70+

B Age at rash onset (y)

Figure 165-1 Epidemiology of Herpes Zoster (HZ) and Postherpetic Neuralgia (PHN). A, Incidence of herpes zoster
(cases per 1000 persons per year) versus age. Dark red = data from Hope-Simpson RE. Proc R Soc Med. 1965;58:9.1
Bright red = data for persons ÿ60 years of age from the Shingles Prevention Study placebo recipients; Oxman MN et al. N
Engl J Med. 1995;352:2271.28 B, Percentage of cases of herpes zoster with postherpetic neuralgia. Postherpetic neuralgia
is defined as clinically significant pain or discomfort due to herpes zoster persisting for ÿ30 days after rash onset. Dark
red = data from Hope-Simpson RE. Postherpetic neuralgia. J R Coll Gen Pract. 1975;25:571-575. Bright red = data for
3037
persons ÿ60 years of age from the Shingles Prevention Study placebo recipients; Oxman MN et al: N Engl J Med. 1995;352:2271.28

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25 Duration of postherpetic neuralgia in persons ê60 years of age

40

35

30

25

20

15

10

Percentage
significant
clinically
cases
pain
with
HZ
of

0
30 60 90 120 180

C Days after HZ rash onset

Figure 165-1 (Continued) C, Duration of postherpetic neuralgia in persons ÿ60 years of age. Bright red = duration of clinically
significant pain or discomfort due to herpes zoster among Shingles Prevention Study placebo recipients with confirmed herpes
zoster; calculated from data in Oxman MN et al. N Engl J Med. 1995;352:2271.28

with increasing age; in older adults, it ranges from 8 to 12 per
1000 person-years in population-based and health care records–
based studies on 4 continents.1,27-34
We estimate that there are at least 1.5 million new cases
of herpes zoster in the United States each year, more than half
of which occur in persons ÿ60 years of age; this number will
increase dramatically as the popula tion ages.1,27-29,33,35-38
Another major risk factor for herpes zoster is decreased VZV-
specific cell-mediated immunity.29,34,39
Immunocompromised patients have a significantly greater risk
of herpes zoster (depending on their underlying condition) than
immunocompetent indi viduals of the same age.40-43 Ten
percent of herpes zoster cases occur in immunocompromised
patients.33
Immunocompromising conditions associated with increased risk
of herpes zoster include bone marrow and solid organ
transplants, hematologic and solid tumor malignancies, and
immune-mediated diseases (eg, systemic lupus erythematous,
rheumatoid arthri tis). Many cases of herpes zoster that occur
in patients with immune-mediated diseases are the result of the
use of chemotherapy or therapy with immune modu lators or
corticosteroids.40-43 Herpes zoster is a promi nent and early
“opportunistic infection” in persons infected with HIV, in whom
3038 it is often the first sign of
immune deficiency.44,45 Thus, HIV infection should be
considered in young individuals who develop herpes
zoster.
Other factors reported to correlate with the risk of herpes
zoster include female sex,32 physical trauma in the affected
dermatome,46 IL-10 gene polymorphisms,47
family history of herpes zoster,48-50 and white race.31,32,51
The likelihood of recurrent herpes zoster is reported to range
from 1% to 6%.1,27,30,32 Much of this variation is dependent
on the observation interval after the first episode of herpes
zoster, as well as the accuracy of the diagnosis; not all of the
cases reported may have actually been herpes zoster. Among
the 19,276 placebo recipients in the Shingles Prevention Study
followed for a median of 3.12 years,28 the incidence of second
episodes of documented herpes zoster was less than 1/10th
the incidence of documented first episodes.
A large retrospective effectiveness study also indicated that the
recurrence rate of herpes zoster in immuno competent persons
is low.53 Recurrent herpes zoster is more common in patients
who are immunocompro mised, and they are more likely to
have multidermato mal or bilateral disease.52,54
Immunocompetent patients thought to be suffering multiple
episodes of herpes zoster, especially when they occur in the
same derma tome, are more likely to have recurrent zosteriform

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herpes simplex.55 Second episodes of herpes zoster in
immunocompetent persons almost always involve a
different dermatome than that involved in the first
episode.
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.1,56 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 immunocom
promised individuals. Patients with uncomplicated
herpes zoster appear to spread the infection by means
Zoster
Varice
Herpe
Chapt
and
165 :: of direct contact with their lesions, although airborne
transmission also has been documented.57,58 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 on the epidemiology of herpes zoster of
the marked reduction in endemic varicella, due to wide
spread varicella vaccination of children, is unclear. A
recent study showed that the age-specific incidence of
HZ has increased >4-fold over the last 6 decades.59
However, this temporal increase began before the
availability of varicella vaccine; has occurred in coun
tries without varicella vaccination programs60-62; was
not altered by the introduction of varicella vaccination
programs13,59,63,64; and has occurred in states that
had a relatively low inclusion of children in varicella
vacci nation programs. These observations indicate that
the reduction in exposure of adults to exogenous VZV
due to varicella vaccination does not explain the
temporal increase in the incidence of herpes
zoster.13,65,66 They also suggest that reactivations of
endogenous latent VZV, in which rapid mobilization of
host immune responses limits replication of the
reactivated virus and prevents progression to herpes
zoster (“neutral ized reversions”1,67), is the major factor stages of development (Fig. 165-2A and B). Careful
slowing the age-related decline in VZV-specific cell-
mediated immunity observed in immunocompetent persons. ber of lesions in healthy children is 250 to 500; second
CLINICAL FEATURES
VARICELLA
PRODROME
In young children, prodromal symptoms are uncom
mon. In older children and adults, the rash is often
preceded by 2 to 3 days of mild fever, chills, malaise,
headache, anorexia, backache and, in some patients,
sore throat and dry cough.
RASH
In unvaccinated persons, the rash usually begins on the
face and scalp and spreads rapidly to the trunk, with
relative sparing of the extremities.1,68,69 New
Kang_CH165_p3035-3064.indd 3039
lesions appear in successive crops, and are mainly dis 25
tributed centrally (Fig. 165-2A,B). The rash tends to be
denser on the back between the shoulder blades than
on the scapulae and buttocks, and more profuse on the
medial than on the lateral aspects of the limbs. It is not
uncommon to have a few lesions on the palms and
soles, and vesicles often appear earlier and in larger
numbers in areas of inflammation, such as diaper rash
or sunburn.
A characteristic feature of varicella lesions is their
rapid progression, over as little as 12 hours, from rose
colored macules to papules, and then to vesicles, pus
tules, and crusts (Fig. 165-2A-D). The typical vesicle is
2 to 3 mm in diameter and elliptical, with its long axis
parallel to the folds of the skin. The early vesicle is
superficial and thin-walled, and surrounded by an
irregular area of erythema (Fig. 165-2C), which gives
the lesions the appearance of a “dewdrop on a rose
petal.”70 The vesicular fluid soon becomes cloudy with
the influx of inflammatory cells that converts the vesicle
to a pustule, which then dries, beginning in the center,
producing an umbilicated pustule (Fig. 165-2E) and
then a crust. Crusts fall off spontaneously in 1 to 3
weeks, leaving shallow pink depressions that gradu
ally disappear. Scarring is rare unless the lesions were
traumatized by the patient or superinfected with bac
teria. Healing lesions may leave hypopigmented mac
ules that persist for weeks to months; if scars occur,
they are depressed and poxlike. In immunocompro
mised patients, lesions may lack surrounding ery
thema, and progression of vesicles to pustules may be
delayed or absent (Fig. 165-2F).
Vesicles also develop in the mucous membranes of
the mouth, nose, pharynx, larynx, trachea, esophagus,
GI tract, urinary tract, and vagina. These mucosal
vesicles rupture so rapidly that only shallow 2- to 3-mm
ulcers remain and the vesicular stage is typically missed.
A distinctive feature of varicella is the simultane ous
presence, in any one area of the skin, of lesions in all
prospective studies have shown that the average num
ary cases resulting from household exposure are more
severe than cases resulting from exposure at school,
presumably because more intense and prolonged
exposure at home results in a higher virus inoculum.21
FEVER
Fever usually persists as long as new lesions continue
to appear, and its height is generally proportional to the
severity of the rash. It may be absent in mild cases or
rise to 40.5°C (105°F) in severe cases with extensive
rash. Prolonged fever or recurrence of fever after defer
vescence may signify a secondary bacterial infection or
another complication.
PRURITUS
The most distressing symptom is pruritus, which is 3039
usually present until all lesions are crusted.
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25

A B

C D

AND F

Figure 165-2 Varicella. A and B, Typical cases of varicella in two 4-year-old children. Note the presence of lesions in all
stages of development and erosions at sites of excoriation. C, Early vesicles with surrounding erythema (“dewdrops on rose
petals”) in an immunocompetent child with varicella. D, Crusted lesions in the same child on rash day 3. E, Many large
pustules and umbilicated pustules in a 21-year-old woman who was febrile and “toxic” and had varicella pneumo nia. F,
Varicella in an immunocompromised bone marrow transplant recipient. There are large numbers of vesicles, many of which
have fused to form larger vesicles; none have progressed to pustules and none are surrounded by erythema.
3040 (Images A-D, Used with permission from Dr. M.G. Myers.)

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BREAKTHROUGH DISEASE
Approximately 10% to 15% of vaccinees immunized
with a single dose of varicella vaccine develop “break
through” varicella after exposure to active VZV infec
tions. Breakthrough varicella is usually atypical. The
rash is predominantly maculopapular, with fewer
lesions (less than 60) and fewer vesicles than the rash
of unmodified varicella. These patients shed VZV, but
are generally less contagious than patients who have
not been immunized. The incidence and severity of
fever is also less than that in natural varicella.71 The
routine administration of a second dose of varicella
vaccine has further reduced the incidence of varicella
Zoster
Varice
Herpe
Chapt
and
165 :: and greatly reduced the incidence of breakthrough
disease.18,66
COMPLICATIONS OF VARICELLA
In the normal child, varicella is rarely complicated.
The most common complication is secondary bacte
rial infection of skin lesions, usually by Staphylococci
or Streptococci, which may produce impetigo, celluli
tis, erysipelas, and, rarely, necrotizing fasciitis.72
These local infections often lead to scarring and, rarely,
to septicemia and metastatic infection. Bullous lesions
may develop when vesicles are superinfected by
Staphylococci that produce exfoliative toxins. Varicella
is frequently complicated by invasive group A strepto
coccal infections, which usually occur within 2 weeks
of the onset of the varicella rash and are particularly
virulent.73 In the prevaccine era, 15% to 30% of inva
sive group A streptococcal infections were associated
with varicella. Widespread varicella vaccination has
reduced the proportion of invasive group A strepto
coccal hospitalizations associated with varicella in the
United States to 2%.74
In adults, fever and constitutional symptoms are
more prominent and prolonged, the rash of varicella is
more profuse, and complications are more fre quent.
A small number of patients develop varicella pneumonia,
which is the major severe complication of varicella in
adults. Varicella pneumonia is char acterized by
cough, dyspnea, tachypnea, high fever, pleuritic chest
pain, cyanosis, and hemoptysis begin ning 1 to 6 days
after rash onset. The severity of the symptoms usually
exceeds the physical findings, but imaging typically
reveals diffuse, peribronchial nodular densities
throughout both lung fields with a tendency to
concentrate in the perihilar regions and at the bases.
The mortality in adults with frank vari cella pneumonia
is estimated to be between 10% and 30%, but it is less
than 10% if immunocompromised patients are excluded
and patients receive prompt antiviral therapy.75
Varicella during pregnancy is a threat to both mother
and fetus.76 Disseminated infection and vari
cella pneumonia may result in maternal death, but
neither the incidence nor the severity of varicella
pneumonia appear to be significantly increased by
pregnancy.77 The fetus may die as a consequence of
premature labor or maternal death caused by severe
Kang_CH165_p3035-3064.indd 3041
varicella pneumonia, but varicella during pregnancy 25
does not, otherwise, substantially increase fetal mor
tality. However, even in uncomplicated varicella,
maternal viremia can result in intrauterine (con genital)
VZV infection that results in a characteris tic
constellation of congenital abnormalities.76 The overall
risk of congenital varicella syndrome is about 1% when
maternal varicella occurs during the first 20 weeks of
gestation, with the highest risk (2%) when maternal
varicella occurs between 13 and 20 weeks.76
Perinatal varicella (occurring within 10 days of birth) is
much more serious than varicella in infants infected
even a few weeks later.78
The morbidity and mortality of varicella are mark
edly increased in immunocompromised patients. In
these patients, continued virus replication and dis
semination result in a prolonged high-level viremia,
more extensive rash, prolongation of new vesicle
formation, and clinically significant visceral involve
ment. Severe abdominal and back pain are common
prodromal symptoms of severe varicella with visceral
dissemination in immunocompromised patients.79
Immunocompromised patients may also develop
pneumonia, hepatitis, encephalitis, and hemorrhagic
complications of varicella, which range in severity from
mild febrile purpura to severe and often fatal purpura
fulminans with disseminated intravascular coagulation.
CNS complications of varicella include several dis
tinct syndromes. Formerly common, varicella-associated
Reye syndrome (acute encephalopathy with fatty
degeneration of the liver) is now very rare since the
etiologic role of salicylates was recognized and their
use in children with fever contraindicated.80 Acute cer
ebellar ataxia is more common than other neurologic
complications of varicella, occurring in 1 in 4000 cases,
but it has an excellent prognosis.81 Encephalitis is
much less common (1 per 33,000 cases), but frequently
causes death or permanent neurologic sequelae. The
patho genesis of cerebellar ataxia and encephalitis
remains obscure, but in many cases it is possible to
detect VZV antigens, VZV antibodies, and VZV DNA
in the cere brospinal fluid of patients, suggesting direct
infection of the CNS.
Although mildly elevated aminotransferase levels
are common during varicella, clinical hepatitis is rare,
except as a complication in immunocompromised
patients. Other rare complications of varicella include
myocarditis, glomerulonephritis, orchitis, pancreatitis,
gastritis and ulcerative lesions of the bowel, arthritis,
Henoch-Schönlein vasculitis, optic neuritis, keratitis,
and iritis. Most are likely due to parenchymal or endo
vascular VZV infection.
HERPES ZOSTER
PRODROME
Pain and paresthesia in the involved dermatome often 3041
precede the eruption by 1 to 3 days, but occasionally
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25 by a week or longer. Abnormal sensations 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 ten derness and hyperesthesia of
the skin in the involved dermatome. The prodromal pain of
herpes zoster may be confused with pain from disease in a
visceral organ (such as myocardial infarction, cholecystitis,
renal colic, prolapsed intervertebral disk), and this may lead to
misdiagnosis and misdirected investigations and interventions.68
Prodromal pain is uncommon in immunocompetent persons
younger than 30 years, but it occurs in the majority of persons
with herpes zos ter over the age of 60 years. A few patients
experience acute segmental neuralgia without ever developing
a cutaneous eruption—a condition known as zoster sine
herpete.
83
RASH
The most distinctive feature of herpes zoster is the localization
and distribution of the rash, which is uni lateral and is generally
limited to the area of skin inner vated by a single sensory
ganglion (Fig. 165-3A,B). The skin supplied by the trigeminal
nerve, particularly the ophthalmic division (10%-15%), and the
trunk from T3 to L2 (>50%), are most frequently affected;
herpes zoster lesions are uncommon distal to the elbows or
knees.1,30,68,69
Although the individual lesions of herpes zoster and varicella
are histologically 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 distrib uted vesicles of varicella (Fig.
165-3C,D). This differ ence reflects intraneural (axonal) 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 in a dermatomal distribution.
Vesicles form within 12 to 24 hours and evolve into pustules
by the third day (Fig. 165-3E). These dry and crust in 7 to 10
days. The crusts generally persist for 2 to 3 weeks. In normal
individuals, new lesions con tinue to appear for 1 to 4 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 dura tion in children.
Between 10% and 15% of cases of herpes zoster involve
the ophthalmic division of the trigeminal nerve (Fig. 165-4A,B).84
The rash of ophthalmic zos ter 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 (Hutchinson
sign), care ful attention must be given to the condition of the
eye.
3042
Involvement of the nasociliary branch is frequently
Kang_CH165_p3035-3064.indd 3042
accompanied by unilateral conjunctivitis and impaired corneal
sensation, which can lead to corneal ulceration and sight-
threatening bacterial infection. The eye is involved in 20% to
70% of patients with ophthalmic zoster.
Herpes zoster affecting the second and third divi sions of
the trigeminal nerve (Fig. 165-4C,D), as well as other cranial
nerves, may produce symptoms and lesions in the mouth (Fig.
165-4E,F), ears, pharynx, or larynx. The Ramsay Hunt
syndrome (facial palsy in combination with herpes zoster of
the external ear, ear canal, or tympanic membrane, with or
without tinnitus, vertigo, and deafness) results from involve
ment of the facial and auditory nerves. The ear and external
auditory canal are innervated by the 5th, 7th, 9th, and 10th
cranial nerves and by the upper cervical nerves, and the facial
nerve anastomoses with all of them. Thus, when herpes zoster
involves the ganglia of any of these nerves it may cause facial
paralysis and cutaneous lesions on or around the ear68
(Fig. 165-4G,H).
PAIN
Although the rash is important, pain is the cardinal symptom of
herpes zoster, especially in the elderly.
Some patients with herpes zoster do not experience pain, but
most (>85% over age 50) have 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,” or “stab bing.”
In some patients, itching may be the predomi nant symptom.
For some patients, the pain intensity is so great that words
like “horrible” or “excruciat ing” are used to describe the
experience. Acute her pes zoster pain is associated with
decreased physical functioning, emotional distress, and
decreased social functioning.85,86
PRURITUS
Itching is often a prominent and distressing symptom throughout
the acute phase of herpes zoster. It fre quently persists until
all crusts have fallen off.
COMPLICATIONS OF
HERPES ZOSTER
See Table 165-1.
The sequelae of herpes zoster include cutaneous, ocular,
neurologic, and visceral complications.68 Most are associated
with the spread of VZV from the ini tially involved sensory
ganglion, nerve, or skin, either via the bloodstream or by direct
neural extension, including involvement of the spinal cord. The
rash may disseminate after the initial dermatomal erup tion has
become apparent. When immunocompetent patients are
carefully examined, it is not uncommon to identify a few
vesicles in areas distant from the
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25

Zoster
Varice
Herpe
Chapt
and
165 :: A B

C D

AND

Figure 165-3 Herpes zoster. A, Classical herpes zoster in the left T4 dermatome. Note the concentration of lesions in
areas of the dermatome innervated by the posterior primary division and the lateral branch of the anterior primary division
of the left T4 spinal nerve. B, Right T10 herpes zoster with numerous pustular lesions. C, Early lesions of herpes zoster.
Note the closely grouped vesicles on a confluent erythematous base, in contrast to the discrete randomly distributed
vesicles of varicella (Fig. 165-2). D, Clustered vesicular lesions of herpes zoster. E, Left T8 herpes zoster with numerous
pustular lesions and early crusting.

3043

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25

A B

C D

AND F

Figure 165-4 Herpes zoster involving cranial nerves. A and B, Ophthalmic herpes zoster involving the first (ophthalmic)
divi sion of the fifth cranial nerve (V1). Involvement of the nasociliary branch, as evidenced by lesions on the tip and side
of the nose (Hutchinson sign), provides VZV with direct access to the eye. This is frequently accompanied by unilateral
conjuncti vitis and impaired corneal sensation, which can lead to corneal ulceration and sight-threatening bacterial infection.
A, Left ophthalmic herpes zoster with involvement of the nasociliary branch, as evidenced by lesions on the tip and side of
the nose (Hutchinson sign). B, Severe right ophthalmic herpes zoster with involvement of the nasociliary nerve and eye,
as well as superficial gangrene. C, Herpes zoster involving the second division of the right fifth cranial nerve (V2). D,
Herpes zoster involving the third division of the left fifth cranial nerve (V3). E and F, Cranial nerve herpes zoster in a 60-
3044 year-old woman with right-sided facial palsy (Hunt syndrome) and vesicles on her tongue (E) and palate (F). G & H, Ramsey
Hunt Syndrome: An 83-year-old woman developed left ear pain and fever followed by an erythematous vesicular rash involving her left ear

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25

Zoster
Varice
Herpe
Chapt
and
165 :: G H

Figure 165-4 (Continued) (G) with left-sided hearing loss and left facial paresis (H). She also had evidence of involvement
of the other cranial nerves as indicated by difficulty swallowing, leftward tongue protrusion, hoarse dysphonia and absent
palatal elevation on the left. Despite treatment with oral acyclovir, 800 mg 5 times daily for 10 days, she had no resolution of
her left-sided hearing loss and facial paresis 4 months later. (Images G and H, Reproduced with permission from Espay AJ,
Bull RL: Arch Neurol. 2005;62(11):1774-1775. Copyright © 2005 American Medical Association. All rights reserved.)

involved and immediately adjacent dermatomes, espe eruption (disseminated herpes zoster, Fig. 165-5), may
cially as age increases. The disseminated lesions usu ally occur in immunocompromised patients. If the rash spreads
appear within a week of the onset of the segmental eruption widely from a small, painless area of herpes zoster, the
and, if few in number, are easily overlooked and are not initial dermatomal presentation may go unnoticed, and the
problematic. More extensive dissemination (with 25-50 ensuing disseminated eruption may be mistaken for
lesions or more), producing a varicella-like varicella.25,68
When the dermatomal rash is particularly extensive, as it
often is in severely immunocompromised patients, there
may be superficial gangrene with delayed healing and
TABLE 165-1 subsequent scarring (Fig. 165-3B). Secondary bacte rial
Complications of Herpes Zoster infection (usually with Staphylococci or Streptococci) may
delay healing and cause scarring in both immuno competent
CUTANEOUS VISCERAL NEUROLOGIC and immunocompromised patients.
ÿ Bacterial ÿ
Bacterial ÿ Pneumonitis ÿ Postherpetic ÿ
Postherpetic Ophthalmic zoster may be accompanied by a wide range
superinfection ÿ Hepatitis neuralgia of complications.84 Corneal sensation is gener ally impaired
ÿ Scarring ÿ Esophagitis ÿ Meningoen ÿ
Meningoencephalitis and, when that impairment is severe, it may lead to
ÿ Zoster ÿ
Zoster ÿ Gastritis cephalitis
_ neurotrophic keratitis with chronic ulcer ation and bacterial
gangrenosum ÿ Pericarditis ÿ Transverse ÿ
Transverse infection.
ÿ Cutaneous ÿ
Cutaneous ÿ Cystitis myelitis
Herpes zoster may be attended by a variety of neu
dissemination ÿ Arthritis ÿ Peripheral
Peripheral nerve
nerve
palsies
ÿ
rologic complications, of which postherpetic neuralgia (PHN)
palsies
Motor
is the most common and important.87 PHN has been
Autonomic
variably defined as pain after rash healing, or any pain 1
ÿ Cranialnerve
Cranial nerve ÿ month, 3 months, 4 months, or 6 months after rash
palsies onset.88-91 The prevalence of PHN was reported to be 5%
ÿ Sensory loss to 30% in a systematic review of 49 studies pub lished
ÿ Deafness between 1945 and 2012 that encompassed a wide variety
ÿ Ocular ÿ
Ocular of PHN definitions and patient ages.27 Age is the most
complications significant risk factor for PHN (Fig. 165-1B). Clini cally
ÿ Granulomatous ÿ
Granulomatous
significant pain lasting 3 months or more is rare in
angiitis (causing
immunocompetent persons younger than 50 years of age.
contralateral
In a large UK general practice database study, PHN defined 3045
hemiparesis)
as any pain ÿ3 months from rash onset was 11%,

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25
A infected dermatome. Thus, herpes zoster lesions in the
B
Figure 165-5 Disseminated herpes zoster. A and B, An
immunocompromised adult with leukemia on treatment
with disseminated herpes zoster and varicella-zoster
virus pneumonia.
13%, 15%, 18%, and 21% in patients ages 60-64, 65-69,
70-74, 75-79, and 80-84 years, respectively.92 A meta
analysis of 18 cohort studies found that the incidence of
PHN increased by 1.22% to 3.11% for each 10-year
increase in age.93 Other risk factors for PHN include the
presence of prodromal pain, severe pain during the acute
phase of herpes zoster, extensive rash, and signifi cant
sensory abnormalities in the affected dermatome.
PHN usually remits gradually over several months (Figs.
165-1C) but, as with the incidence of PHN, its duration
3046 increases with increasing age.
Kang_CH165_p3035-3064.indd 3046
Patients with PHN may suffer from constant pain
(described as “burning,” “aching,” or “throbbing”),
intermittent lancinating pain (“stabbing,” “shooting”), and/
or stimulus-evoked pain, including allodynia (“tender,”
“burning,” “stabbing”). Allodynia, which is pain elicited by
stimuli that are normally not pain ful, is a particularly
disabling component of the dis ease that is present in
approximately 90% of patients with PHN.94 Patients with
allodynia may suffer severe pain after even the lightest
touch to the affected skin, such as by a breeze or by
contact with clothing. PHN often results in disordered
sleep, depression, anorexia, weight loss, chronic fatigue,
and social isolation, and it may interfere with dressing,
bathing, general activity, traveling, shopping, cooking,
and housework.93
Dorsal root ganglia contain visceral, as well as cuta
neous, afferent neurons, which likely explains the
occurrence of visceral as well as cutaneous lesions in
patients with herpes zoster. The affected viscera usu
ally have afferent innervation corresponding to the
gastric mucosa are observed in patients with thoracic
herpes zoster, hemicystitis is observed in patients with
sacral herpes zoster, and herpes zoster in other derma
tomes can result in mucosal lesions causing esopha
gitis, pleuritis, and peritonitis. Infection via visceral
afferents originating in mechanoreceptors involved with
GI and bladder motility and sphincter function can result
in ileus, symptoms of GI obstruction, and dysfunction of
the bladder and anus. Transmission of ganglionic
infection via proprioceptive afferents can also result in
myositis.68 Latent VZV in enteric neurons provides
another potential source of virus causing vis ceral
complications, which may explain episodes of visceral
herpes zoster in the absence of skin lesions.95
Innervation of cerebral blood vessels by neurons in cra
nial and dorsal root ganglia accounts for a syndrome of
ophthalmic herpes zoster and delayed contralat eral
hemiplegia.96-98 VZV from infected neurons in the
involved ganglion infects these cerebral arteries, caus
ing segmental granulomatous angiitis that results in a
contralateral stroke, which may occur weeks to months
after the episode of ophthalmic herpes zoster (average
interval = 7-8 weeks); the delayed onset of the contralat
eral stroke may obscure its relationship to the episode of
ophthalmic herpes zoster.96-98 Although most cases
have followed ophthalmic herpes zoster and involved the
ipsilateral middle and anterior cerebral arteries, some
have followed herpes zoster in other cranial and cervi
cal dermatomes. Evidence also has been presented
asso ciating temporal arteritis, myocardial infarction, and
aortic aneurysms due to granulomatous angiitis with
reactivation of latent VZV.99,100 Other studies of this
rela tionship have not always been confirmatory, and
these associations remain controversial.101-104
Most serious complications of herpes zoster are more
common in immunocompromised persons. These include
necrosis of skin and scarring, and cutaneous dis
semination (Fig. 165-5). Patients with cutaneous dissemi
nation may also have widespread, often fatal, visceral
dissemination, particularly to the lungs, liver, and brain.
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Zoster
Varice
Herpe
Chapt
and
165 ::
Figure 165-6 Chronic disseminated herpes zoster caused
by acyclovir-resistant varicella-zoster virus in an immu
nocompromised patient. Chronic verrucous lesions dis
seminated herpes zoster caused by acyclovir-resistant
varicella-zoster virus in an immunocompromised patient
with AIDS. (Used with permission from Dr. V. Asensi.)
HIV-infected patients who are not treated with
combination antiretroviral therapy often suffer multiple
recurrences of herpes zoster as their HIV infection
progresses. Recurrences may be in the same or different
dermatomes or in several contigu ous or noncontiguous
dermatomes. Cutaneous and visceral dissemination may
also occur in patients with untreated HIV infection. In
addition, patients with AIDS may develop chronic
verrucous, hyper keratotic, or ecthymatous cutaneous
lesions caused by acyclovir-resistant VZV (Fig. 165-6)
(see also Chap. 168). These manifestations of severe
HIV infec tion are rare in the current era of effective
antiretrovi
ral therapy for HIV infection.
ETIOLOGY AND
PATHOGENESIS
VZV is a member of the herpesvirus family. All her
pesviruses are morphologically indistinguishable and
share a number of properties, including the capacity to
establish latent infections that persist for life. VZV and
herpes simplex virus (Types I and II) are further classi
fied as ÿ-herpesviruses because they become latent in
sensory neurons after primary infection.
Kang_CH165_p3035-3064.indd 3047
The VZV genome contains at least 71 genes, most of 25
which have functional and DNA- sequence homol ogy
to genes of other herpesviruses.105 Immediate early
gene products regulate VZV replication. Early gene
products, such as VZV thymidine kinase and VZV DNA
polymerase, support virus replication, whereas late
genes encode virus structural proteins. There is only 1
VZV serotype. However, there are 7 or 8 VZV genotypes
(clades) that display geographic segrega tion and
recombination.106,107 Variations in nucleotide sequences
allow one to distinguish wildtype from vac cine virus
strains, and to “fingerprint” viruses isolated from individual
patients.105,108-110
PATHOGENESIS
OF VARICELLA
Entry of VZV is through the mucosa of the upper respi
ratory tract and oropharynx, where VZV infects ton sillar
T cells that disseminate virus via the blood and
lymphatics (the primary viremia). Infected T cells carry
virus to the reticuloendothelial system, the major site of
virus replication during the remainder of the incu bation
period, and to the skin. Viremia occurs early in the
incubation period, but VZV replication and rash formation
are delayed by innate immune responses, for example,
by interferon and natural killer cells, and by developing
VZV-specific immune responses.105,111,112
Virus replication eventually overcomes these host
defenses, so that some 10 to 14 days after infection a
much larger (secondary) viremia occurs, resulting in
systemic symptoms and skin lesions. In addition, immu
nopathology contributes to rash development. Skin
lesions appear in successive crops, reflecting a cyclic
viremia that in the normal host is terminated after about
3 to 5 days by VZV-specific immune responses, primar
ily VZV-specific T cell–mediated immune responses.
Virus circulates in mononuclear leukocytes, primarily
lymphocytes. Even in uncomplicated varicella, viremia
results in subclinical infection of many organs in addi
tion to the skin. T cell–mediated immunity to VZV is
required for recovery from varicella. The immunologic
memory that develops during varicella persists for life
and is essential to protect against second episodes of
varicella and against herpes zoster.1,29,111,112
PATHOGENESIS OF
HERPES ZOSTER
During varicella, VZV passes from lesions in the skin and
mucosal surfaces into contiguous endings of sen sory
nerves and is transported up the sensory fibers to the
sensory ganglia. In the ganglia, the virus estab lishes
latent infections in neurons that persist for life. The
density of latent VZV is greatest in ganglia innervating
areas of skin with the greatest density of 3047
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25 varicella lesions. Consequently, herpes zoster occurs most
often in dermatomes where the rash of varicella
is most dense-skin innervated by the first (ophthalmic) division
of the trigeminal ganglion and by spinal sen sory ganglia from
T1 to L2.1,68,69 The viremia that occurs during varicella may
provide VZV with another means to access sensory neurons.
Latent VZV in ganglia produces a latency-associated
transcript (LAT) homologous to that produced by latent HSV,
but no infectious virus.113 However, latent VZV may reactivate
sporadically, producing infec tious virus. The frequency and
mechanism of these reactivations are unknown, but VZV
reactivation and replication resulting in HZ has been associated
most clearly with immunosuppression. VZV may also reactivate
without producing overt disease; pre sumably, because
replication and spread of the reac tivated virus is terminated
by preexisting or rapidly mobilized VZV-specific immunity. The
small quantity of viral antigen released during such “contained
reac tivations” is postulated to stimulate and sustain host
immunity to VZV.1,67,114
When VZV-specific T cell–mediated immunity falls below
some critical level, reactivated virus can no longer be
contained.1,29 Virus multiplies and spreads within the ganglion,
causing neuronal necro sis and intense inflammation,
processes that are often accompanied by severe neuropathic
pain.115,116
VZV then spreads antidromically down the sensory nerve, and
is released from the sensory nerve end ings 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 spinal cord may result in local
leptomeningitis, cerebrospinal fluid pleocytosis, and segmental
myelitis. Infection and destruction of neurons in the dorsal horn
may play a role in persis tent neuropathic pain (see section
“Pathogenesis of Pain in Herpes Zoster and Postherpetic
Neuralgia” below); 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.115
Extension of infection within the CNS may result in rare
complications of herpes zoster, such as meningoencephalitis
or transverse myelitis. Viremia also occurs during herpes
zoster.23
PATHOGENESIS OF PAIN
IN HERPES ZOSTER AND
POSTHERPETIC NEURALGIA
A number of different but overlapping mechanisms, which vary
from patient to patient and over time in any individual patient,
appear to be involved in the pathogenesis of pain in herpes
zoster and in PHN.91,117-119 Injury to the peripheral nerve
and to neurons in the ganglion trigger afferent pain signals
(neuropathic pain). Inflammation in the skin trig gers nociceptive
3048 pain signals that further amplify
Kang_CH165_p3035-3064.indd 3048
this pain. Damage to neurons in the spinal cord and ganglion,
and to the peripheral nerve, is important in the pathogenesis of
PHN. Postmortem examination of patients with herpes zoster
and severe PHN com pared with patients with herpes zoster
and no persis tent pain demonstrated dorsal horn atrophy and
cell, axon, and myelin loss with fibrosis in sensory gan glia only
in patients with persistent pain.115 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.91,118-121 Clinically, these mechanisms result in
allodynia.
DIAGNOSIS
CLINICAL DIAGNOSIS
VARICELLA
Varicella can usually be diagnosed by the appearance and
evolution of the rash (see Fig. 165-2), particularly when there is
a history of exposure within the preced ing 2 to 3 weeks. The
rapid evolution of lesions from macules to papules, to vesicles,
to pustules and crusts, and the simultaneous presence of
lesions at all stages of development, distinguish varicella from
most other generalized rashes.
Disseminated herpes zoster may be mistaken for varicella,
especially when there is widespread dis semination of VZV
from a small, painless area of her pes zoster or from the
affected sensory ganglion in the absence of an obvious
dermatomal eruption. Although disseminated HSV infections
may resemble varicella, this is a rare disease that is limited to
severely immu nocompromised patients. There is usually an
obvious concentration of lesions at and surrounding the site of
the primary or recurrent infection, for example, the mouth or
external genitalia, and there is often marked toxicity and visceral
involvement.
The remaining differential diagnoses of varicelli form rashes
are listed in Table 165-2. The character, dis tribution, and
evolution of the lesions, together with a careful epidemiologic
history, usually differentiate these diseases from varicella.
When any doubt exists, the clinical impression should be
confirmed by labora tory testing.
HERPES ZOSTER
In the preeruptive stage, the prodromal pain of her pes zoster
is often confused with other causes of local ized pain. Once
the eruption appears, the character and dermatomal location of
the rash, coupled with dermatomal pain and localized sensory
abnormali ties, usually makes the diagnosis obvious (Figs.
165-3
and 165-4).68
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TABLE 165-2
distinguishes zosteriform herpes simplex from herpes
zoster. Table 165-2 lists other considerations in the dif
25
Differential Diagnosis of Varicella and ferential diagnosis of herpes zoster.
Herpes Zoster

VARICELLA HERPES ZOSTER

Most Likely Most Likely LABORATORY DIAGNOSIS

ÿ Vesicular exanthems of Coxsackie viruses ÿ Zosteriform herpes simplex
and echoviruses ÿ Contact dermatitis The lesions of varicella and herpes zoster are indistin
ÿ Eczema herpeticum ÿ Insect bites guishable by histopathology (Fig. 165-8). VZV infec tion
ÿ Burnsÿÿÿ
ÿ Disseminated herpes zoster of the skin is initiated by infection of epithelial cells in the
ÿ Impetigo basal layer (stratum germinativum) and the stratum
ÿ Insect bites
spinosum. The resulting papular lesions evolve into
ÿ Contact dermatitis
intraepithelial vesicles within 12 to 24 hours as a result of

Zoster
Varice
Herpe
Chapt
and
165 :: ÿ Rickettsialpox
ÿ Disseminated herpes simplexa

Consider

ÿ Papular urticaria
ÿ Erythema multiforme
ÿ Drug eruptions
ÿ Disseminated herpes simplex
ÿ Molluscum contagiosum
ÿ PLEVAab
ÿ Scabies

ÿ Secondary syphilis
ÿ Dermatitis herpetiformis
ÿ Bullous pemphigoid
Consider

ÿ Papular urticaria
ÿ Erythema multiformea
ÿ Drug eruptionsa
ÿ Scabies

ÿ Molluscum contagiosum
ÿ Bullous
Bullous pemphigoid
pemphigoid
response)ÿÿ
(isotopic
(isotopic
ÿ
response)ÿÿ
infection of increasing numbers of epithelial cells, which
show acanthosis, “ballooning degeneration,” eosinophilic
(acidophilic) intranuclear inclusion bodies, and
multinucleated giant cell forma tion. An influx of edema
fluid elevates the uninvolved stratum corneum to form a
delicate clear vesicle con
taining large amounts of cell-free infectious virus and
multinucleated giant cells with eosinophilic intranu clear
inclusion bodies (Fig. 165-8A,B). The multinucle ated giant
cells form by fusion of infected epithelial cells with adjacent
infected and uninfected cells at the base and periphery of
the vesicle. The underlying der mis shows edema and
ÿ Pemphigus vulgaris mononuclear cell infiltration.

a May resemble disseminated herpes zoster.

b
Acute lichenoid pityriasis and varioliformis.
A cluster of vesicles, particularly near the mouth or
genitals, may represent herpes zoster, but it also may be
recurrent HSV infection (Fig. 165-7).55 Zosteriform herpes
simplex is often impossible to distinguish from herpes
zoster on clinical grounds. In the absence of profound and
clinically obvious immune deficiency, a history of multiple
recurrences in the same dermatome
The presence of multinucleated giant cells and epithe lial
cells containing acidophilic intranuclear inclusion bodies
distinguishes the cutaneous lesions produced by VZV from
all other vesicular eruptions, such as those caused by
poxviruses, Coxsackieviruses, and echoviruses, except for
those produced by HSV. These cells can be demonstrated
in Tzanck smears prepared at the bedside from material
scraped from the base of vesicular lesions and stained with
hematoxylin and eosin, Giemsa, or similar stains (Fig.
165-8C). When virus-containing vesicle fluid is inoculated
into human fibroblast tissue cultures, similar multinucleated
giant cells containing acidophilic intranuclear inclusion
bodies form by fusion of infected cells with adjacent infected
and uninfected cells (Fig. 165-8D).

The best diagnostic test for detection of VZV is poly

Figure 165-7 Zosteriform herpes simplex. This immuno
competent adult with no history of genital herpes or prior
herpetic lesions presented with a 1-day history of mild
tenderness of her left buttock, followed by the onset of the
clustered vesicular lesions in her left S2/S3 dermatomes.
They were mildly tender and pruritic. PCR assay and viral
culture both revealed HSV-2.
merase chain reaction (PCR) because of its very high
sensitivity and specificity, ready availability, and rela tively
quick (1 day or less) turnaround time.110,122,123
Vesicle fluid is the best specimen for PCR analysis, but
lesion scrapings, crusts, tissue biopsy, or cerebro spinal
fluid are equally useful. PCR can distinguish VZV from
HSV, and wildtype VZV from Oka vaccine strains of
VZV.110 Isolation of virus is less sensitive and
may take a week or more, but it is the only technique that
yields infectious VZV for further analysis, such as
determination of sensitivity to antiviral drugs. VZV is
extremely labile, and only 30% to 60% of cultures from
proven cases are generally positive. To maximize virus
recovery, specimens should be inoculated into cell cul
ture immediately. It is important to select new vesicles
containing clear fluid for aspiration, because the prob
ability of isolating VZV diminishes rapidly as lesions
become pustular. VZV is almost never isolated from crusts. 3049

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25

NOT B

C D

Figure 165-8. Varicella zoster histopathology. A and B, Papular lesions of varicella evolve into intraepithelial vesicles
within 12 to 24 hours. An influx of edema fluid elevates the uninvolved stratum corneum to form a delicate clear vesicle
containing large amounts of cell-free infectious virus and multinucleated giant cells, containing eosinophilic intranuclear
inclusion bodies, formed by fusion of infected epithelial cells with adjacent infected and uninfected cells. The underlying
dermis shows edema and mononuclear cell infiltration (A, H&E ×100; B, H&E ×400). C, The multinucleated giant cells
are readily identified in Tzanck smears prepared from material scraped from the base of vesicular lesions and stained
with H&E, Giemsa, or similar stains. Giemsa ×1000. D, Infected human fibroblast tissue cultures show similar
multinucleated giant cells containing eosinophilic intranuclear inclusion bodies that are formed by fusion of infected cells
with adjacent infected and uninfected cells. H&E ×1000. (Images A and B, Used with permission from Dr. R. J. Barr.)

Immunofluorescent or immunoperoxidase staining of
cellular material from fresh vesicles or prevesicular lesions
can detect VZV significantly more often and faster than
virus culture.124 Enzyme immunoassays provide another
rapid and sensitive method for anti gen detection. These
3050 techniques have a somewhat faster turnaround time than
PCR, but lack the excellent
sensitivity and specificity of PCR, which remains the
diagnostic method of choice.122,123
Serologic tests permit the retrospective diagnosis of
varicella and herpes zoster when acute and con valescent
sera are available for comparison, but this is rarely
done.122,123 Serologic tests are more impor tant to
identify susceptible individuals who may be

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candidates for isolation or prophylaxis. The technique most
commonly used is a solid-phase enzyme-linked immunosorbent
assay (ELISA). However, these assays (there are many
commercial sources) often lack sensi tivity, failing to detect
antibody in a significant num ber of persons who are immune,
especially those who received varicella vaccine. False-positive
results in sus ceptible individuals are less common, but
problematic, especially in health care workers in whom
susceptibil ity to VZV is a risk for nosocomial varicella.
DIFFERENTIAL DIAGNOSIS
See Table 165-2.
Zoster
Varice
Herpe
Chapt
and
165 :: MANAGEMENT
ANTIVIRAL AGENTS
Chapter 191 provides a detailed description of the treatment of
varicella and herpes zoster. The nucleo side analogs acyclovir,
famciclovir, valacyclovir, and brivudin, and the pyrophosphate
analog foscarnet, are efficacious in treating VZV infections.
Acyclovir and penciclovir are guanosine analogs that are selec
tively phosphorylated by VZV thymidine kinase; they are poor
substrates for cellular thymidine kinase and thus are not
activated in, and are not toxic for, uninfected cells. Cellular
enzymes then convert acy clovir monophosphate and
penciclovir monophos phate to the corresponding triphosphates,
which interfere with viral DNA synthesis by inhibiting viral DNA
polymerase. VZV is approximately tenfold less sensitive than
HSV to acyclovir and penciclovir.
Two prodrugs, valacyclovir (for acyclovir) and famciclovir
(for penciclovir), are better and more reliably absorbed than
acyclovir following oral administration.125 Thus, they produce
much higher blood levels of antiviral activity and permit less fre
quent 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
analog 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 thymi
dine analog, also activated by viral thymidine kinase, with very
high activity against VZV. Although effec tive in the treatment
of herpes zoster, it is not licensed in the United States, in part
because of a potentially lethal interaction with 5-fluorouracil.126
Foscarnet, a second-line drug that is an analog of inorganic
pyrophosphate, 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 at concentrations that do not greatly inhibit cellular
DNA polymerases. Foscarnet does not require phos phorylation
by thymidine kinase to be activated and is therefore active
against nucleoside-resistant VZV
Kang_CH165_p3035-3064.indd 3051
mutants that have reduced or altered thymidine kinase activity, 25
but it is more toxic than the nucleoside ana logs. Cidofovir is
another drug that directly inhibits viral DNA polymerase but,
because of its toxicity, is considered a third-line drug. A new
antiviral agent, amenamevir, is a potent helicase-primase
inhibitor that is active against acyclovir-resistant VZV and HSV.
A single dose of 400 mg daily was as effective and as well
tolerated as valacyclovir 1 g 3 times daily in Japanese patients
with proven herpes zoster.127
Topical antiviral therapy has no role in the treatment of
varicella. It has limited efficacy against herpes zoster and is
not recommended. Systemic therapy, either oral or parenteral,
is the standard of care. Because of their superior
pharmacokinetics and the reduced sensitivity of VZV compared
to HSV to acyclovir and penciclovir, famciclovir, or valacyclovir
are preferred over acyclovir for oral therapy of VZV infections.
Acyclovir-resistant VZV has been documented in varicella and
herpes zoster in severely immunosuppressed patients, such
as patients with advanced AIDS. Because of the usual
mechanism of acyclovir resistance (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 and are sensitive
to amenamevir, an investi gational helicase-primase inhibitor.
TREATMENT OF VARICELLA
TOPICAL THERAPY
In healthy children, varicella is generally benign and self-limited.
Cool compresses, calamine lotion or Caladryl Clear (zinc
acetate 0.1% + pramoxine 1%) locally, tepid baths with baking
soda or colloidal oatmeal (3 cups per tub of water), and oral
antihis tamines may relieve itching. Creams and lotions
containing glucocorticoids and occlusive ointments should not
be used. Antipyretics may be needed, but salicylates must be
avoided because of their association with Reye syndrome.
Minor bacterial infections are treated with warm soaks. Bacterial
cel
lulitis requires systemic antimicrobial therapy that is effective
against Staphylococcus aureus and group A ÿ-hemolytic
streptococcus.
ANTIVIRAL THERAPY
Immunocompetent Children: See Table 165-3.
A large randomized, controlled trial of acyclovir treat ment of
otherwise healthy children 2 to 12 years of age found that
treatment with oral acyclovir (20 mg/kg 4 times per day for 5
days) initiated within 24 hours of rash onset modestly reduced
the maximum number of lesions, the time to cessation of new
lesion formation, and the duration of the rash, fever, and
constitutional symptoms when compared to placebo.128
Treatment initiated more than 24 hours after rash onset was
not effective. Because varicella is a relatively benign
3051
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25 TABLE 165-3
age, persons with chronic cutaneous or pulmonary dis
orders or other debilitating diseases, persons receiving
Antiviral Treatment of Varicella in the Normal long-term salicylate therapy, and persons receiving
and Immunocompromised Host short, intermittent, or aerosolized courses of cortico
steroids because these individuals are at increased
PATIENT GROUP REGIMEN
risk for moderate-to-severe varicella.130
Normal

Neonate Acyclovir 10 mg/kg or 500 mg/m2 every 8 h for Immunocompetent Adolescents and Adults: A
10 d randomized, controlled trial of acyclo vir treatment of
Child (2 to <18 y of age) Symptomatic treatment alone, or
healthy adolescents 13 to 18 years of age found that
Valacyclovir 20 mg/kg every 8 h for 5 db early treatment with oral acyclovir (800 mg 5 times a
(not to exceed 3 g/d) or day for 5 days) reduced the maxi mum number of
Acyclovir 20 mg/kg orally 4 times a day × lesions and time to cessation of new lesion formation
5 d (not to exceed 3200 mg/d) compared to placebo.131 A random ized, placebo-
Adolescent (ÿ40 kg) or Valacyclovir 1 g orally every 8 h for 7 d or controlled trial of oral acyclovir in healthy young adults
adult, especially with Famciclovir 500 mg orally every 8 h for with varicella showed that early treat ment (within 24
mild immu 7 d or hours of rash onset) with oral acyclovir (800 mg 5
nocompromise Acyclovir 800 mg orally 5 times a day times a day for 7 days) significantly reduced the time
(eg, use of inhaled for 7 d
to crusting of lesions, the extent of disease, and
glucocorticoids)
duration of symptoms and fever.75 Thus, routine treat
Pneumonia Acyclovir 10 mg/kg IV every 8 h × 7-10 db ment of varicella in adults seems reasonable, especially
Pregnancy Routine use of acyclovir is not because varicella complications are more frequent in
recommended. adults. Although not tested, famciclovir 500 mg orally
If there are complications (eg, pneumonia) treat every 8 hours or valacyclovir 1000 mg orally every 8
pneumonia as per recommenda tion above. hours would be more convenient and appropriate
substitutes for acyclovir in normal adolescents and
Immunocompromised adults. Many physicians do not prescribe oral acy
Mild varicella or mild Valacyclovir 1 g orally every 8 h for 7-10 d or clovir in uncomplicated varicella during pregnancy
immunocompromise Famciclovir 500 mg orally every 8 h for 7-10 d because the risk of treatment to the fetus is unknown.
or Other physicians recommend oral antiviral therapy for
Acyclovir 800 mg orally 5 times a day for infections in the third trimester when organogen esis
7-10 d
is complete, because of the risk of varicella pneu
Severe varicella or severe Acyclovir 10 mg/kg IV every 8 h for 7–10 d monia, and of spread of the infection to the newborn.
immunocompromise Intravenous acyclovir is often considered for pregnant
Acyclovir resistant Foscarnet 40 mg/kg IV every 8 h until healed
women with varicella who have extensive cutaneous
(advanced AIDS) healed and/or systemic disease. Though limited in size, reg
a Oral acyclovir or preferably, famciclovir or valacyclovir, should be con sidered for
istries of pregnant women treated with acyclovir did
otherwise healthy persons at increased risk for moderate-to severe varicella (eg, persons
not reveal any toxicity for pregnant women or their
aged >12 y, persons with chronic cutaneous or pulmonary disorders, persons receiving fetuses,132-134 and extensive, though unrecorded,
long-term salicylate therapy, and persons receiving short, intermittent, or aerosolized clinical experience also confirms its safety in pregnant women.
courses of cor ticosteroids). (From Marin M et al. Prevention of varicella: Recommen Consequently, we recommend treatment for pregnant
dations of the Advisory Committee on Immunization Practices [ACIP]. women with varicella who have extensive rash, toxic
ity, any signs of systemic infection, or any risk factors
MMWR Recomm Rep. 2007;56:1-40.)
such as the use of immunosuppressive medications.
b Must prepare suspension by grinding 500-mg valacyclovir caplets and suspending in
Uncontrolled trials in immunocompetent adults with
cherry-flavored Suspension Structural Vehicle USP-NF (SSV) at 25 mg/mL or 50 mg/mL
varicella pneumonia suggest that early treatment
in lots of 100 mL at time of dispensing.
(within 36 hours of hospitalization) with IV acyclovir (10
mg/kg every 8 hours) reduces fever and tachypnea
infection in children and the clinical benefits of treat and improves oxygenation.135 Other serious compli
ment are modest, routine antiviral treatment is not cations of varicella in the immunocompetent host, such
recommended in immunocompetent children.66,129,130 as encephalitis, meningoencephalitis, myelitis, and
Some experts favor its use where cost is not a concern; ocular complications, should be treated with IV
when it can be begun in time to benefit the patient acyclovir.
(within 24 hours of rash onset); and where there is a
perceived need to speed resolution of the infection. Immunocompromised Patients: Controlled trials in
Because secondary cases among susceptible children immunocompromised patients with vari cella
in the household are generally more severe than the demonstrated that treatment with IV acyclovir decreased
index cases,21 and because early initiation of treatment the incidence of life-threatening visceral complications
is more readily accomplished in that setting, treatment when treatment was initiated within 72 hours of rash
with acyclovir is an option for such secondary cases. onset.136 Intravenous acyclovir has been the standard
3052 We recommend oral antiviral therapy, preferably of care for varicella in patients with substantial
valacyclovir or famciclovir, for persons >12 years of immunodeficiency. Although oral therapy

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Machine Translated by Google
with famciclovir or valacyclovir should suffice for
patients with mild degrees of immunologic impair
ment, there are no controlled clinical trials to guide the
decision. Patients who are started on IV therapy may
be switched to oral therapy when new lesions cease
to appear and the patient is stable.
TREATMENT OF
HERPES ZOSTER
TOPICAL THERAPY
Zoster
Varice
Herpe
Chapt
and
165 :: During the acute phase of herpes zoster, the applica
tion of cool compresses, calamine lotion or Caladryl
Clear, cornstarch, or baking soda may lessen local
symptoms and hasten the drying of vesicular lesions.
Occlusive ointments and creams or lotions containing
glucocorticoids should not be used. Topical treatment
with antiviral agents is not effective. Bacterial super
infection of herpes zoster lesions is uncommon and
should be treated with warm soaks; bacterial cellulitis
requires systemic antibiotic therapy.
ANTIVIRAL THERAPY
The major goals of antiviral therapy in patients with
herpes zoster are to limit the extent, duration, and
severity of pain and rash in the primary dermatome
and to prevent disease elsewhere.
Except for PHN, most complications of herpes zos
ter, including vasculopathy, result from continuing
replication and spread of VZV from the affected gan
glion, and may thus be prevented by early initiation of
effective antiviral therapy.
Immunocompetent Adolescents and Adults: Table
165-4 lists current evidence-based rec ommendations
for treatment of herpes zoster based on the results of
randomized controlled trials. Recom mended antivirals
reduce the 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.137 In
some studies, the duration of chronic pain was also
reduced, but the FDA has not approved these agents
for the prevention of PHN.138 Random ized controlled
trials comparing antivirals demon strated equivalent
results in rash healing, acute pain, and the duration of
chronic pain.139-141 Oral acyclovir, famciclovir, and
valacyclovir are all acceptable anti virals for older
adults. However, famciclovir or vala cyclovir are
preferred because of their thrice-daily dosing schedule,
their greater oral bioavailability, and the higher and
more reliable blood levels of antiviral activity achieved.
This is important because of the reduced sensitivity to
acyclovir of VZV compared with HSV, and the potential
existence of barriers to the entry of antiviral agents into
tissues that are sites of VZV replication.
The utility of antiviral agents is unproven if treat
ment is initiated more than 72 hours after rash onset.
Kang_CH165_p3035-3064.indd 3053
TABLE 165-4
25
Antiviral Treatment of Herpes Zoster in the
Normal and Immunocompromised Host
PATIENT GROUP REGIMEN
Normal
Age <50 y Symptomatic treatment alone, or
Famciclovir 500 mg orally every 8 h for
7 d or
Valacyclovir 1 g orally every 8 h for 7 d or
Acyclovir 800 mg orally 5 times a day for 7 da
Age ÿ50 y, and patients of Famciclovir 500 mg orally every 8 h for
any age with cranial nerve
involvement (eg, ophthalmic
zoster)
Immunocompromised
Mild immunocompro
mise, including HIV-1
infection
Severe
7 d or
Valacyclovir 1 g orally every 8 h for 7 d or
Acyclovir 800 mg orally 5 times a day for 7 da
Famciclovir 500 mg orally every 8 h for
7-10 d or
Valacyclovir 1 g orally every 8 h for 7-10 d
or
Acyclovir 800 mg orally 5 times a day
for 7-10 then
Acyclovir 10 mg/kg IV every 8 h for
immunocompromise 7-10 d
Acyclovir resistant (eg, Foscarnet 40 mg/kg IV every 8 h until
advanced AIDS) healed
a Famciclovir or valacyclovir are preferred because their greater and more reliable oral
bioavailability result in higher blood levels of antiviral activity, the lower susceptibility of
VZV (compared to HSV) to acyclovir and pen ciclovir, and the existence of barriers to the
entry of antiviral agents into tissues that are sites of VZV replication.
Nevertheless, we believe that it is prudent to initiate
antiviral therapy even if more than 72 hours have
elapsed after rash onset in patients with herpes zos
ter involving cranial nerves (eg, ophthalmic zoster), in
patients who continue to have new vesicle forma tion,
or in patients who are of advanced age and may thus
have a delay in development of effective immune
responses.135
Ophthalmic zoster represents a special therapeutic
challenge because of the risk of ocular complications.
Examination by an ophthalmologist should be sought
in most cases, for example, when there is any evidence
of involvement of the eye and when the nasociliary
nerve is involved. Oral acyclovir was effective in pre
venting ocular complications of ophthalmic zoster in a
randomized, controlled trial.142 Famciclovir and vala
cyclovir appear to have efficacy comparable to that of
acyclovir in the treatment of ophthalmic zoster, and
are preferred for the reasons cited above.143,144
Immunocompromised Patients: A random ized,
double-blind, placebo-controlled trial in immu
nocompromised patients with herpes zoster showed
that IV acyclovir (500 mg/m2 every 8 hours for 7 days)
halted progression of the disease, both in patients with
localized herpes zoster and in patients with cutane 3053
ous dissemination.145 Acyclovir accelerated the rate of
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Machine Translated by Google
25 clearance of virus from vesicles and markedly reduced
the incidence of subsequent visceral and progres sive
cutaneous dissemination. Pain subsided faster in
acyclovir recipients, and fewer reported PHN, but these
differences were not statistically significant. In patients
with mild immunocompromise and localized herpes
zoster, oral famciclovir or valacyclovir will usu ally
suffice.146,147 A randomized, controlled trial of oral
famciclovir versus oral acyclovir in patients with local
ized herpes zoster following bone marrow or organ
transplantation or cancer chemotherapy showed that
both treatments were equivalent in rash healing and
loss of acute pain, and were well tolerated.147 However,
oral famciclovir or valacyclovir are preferable to oral
acyclovir.
ANTIINFLAMMATORY THERAPY
The possibility that inflammation within the sensory
ganglion and contiguous neural structures contributes
to PHN provided the rationale for the use of glucocor
ticoids during the acute phase of herpes zoster. Ran
domized controlled trials, however, showed that the
addition of glucocorticoids to acyclovir did not change
the incidence of chronic pain.148-150 However,
glucocor ticoids did reduce acute pain in most trials,
and in one trial of acyclovir and prednisone, the time
to uninter rupted sleep, return to baseline daily activity,
and ces sation of analgesic therapy was reduced in
patients who received glucocorticoids.149 Consequently,
some experts advocate oral glucocorticoids for otherwise
healthy older adults whose rash is complicated by
moderate-to-severe pain and who have no contrain
dications to glucocorticoids.137 Others believe that the
common adverse effects of glucocorticoids outweigh
their benefits, and argue against their routine use in
older patients with herpes zoster. We agree and do not
recommend the use of glucocorticoids in this setting.
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, aggres
sive pain control is both reasonable and humane.137
The severity of acute herpes zoster pain should be
determined using standardized pain scales. Clinicians
should prescribe analgesics with the goal of limiting the
severity of pain to less than 3 on a 0-to-10 scale, and to
a level of pain that does not interfere with sleep. The
choice, dosage, and schedule of drugs are governed
by the patient’s pain severity, underlying conditions,
and response to and side effects of specific drugs. A
randomized controlled trial of oxycodone, gabapentin,
or placebo in older adults during the early phase of
herpes zoster showed that oxycodone, but not gaba
pentin, provided significantly greater pain relief than
placebo in patients with moderate-to-severe pain.151
This trial was not powered to analyze PHN, and there
are no other controlled trials of the effect of treatment
3054
with opioids or gabapentin during the acute phase of
Kang_CH165_p3035-3064.indd 3054
herpes zoster on the subsequent development of PHN.
A crossover study of a single dose of 900 mg of gaba
pentin during the acute phase of herpes zoster showed
greater pain relief than placebo.152 If pain control
remains inadequate, regional or local anesthetic nerve
blocks should be considered for acute pain control.137,153
A randomized controlled trial demonstrated that a
single epidural injection of corticosteroids and local
anesthetics in the acute phase of herpes zoster reduced
acute pain but did not prevent the subsequent devel
opment of PHN.153
TREATMENT OF
POSTHERPETIC NEURALGIA
PHN is difficult to treat. Fortunately, it resolves spon
taneously in most patients, although this often requires
several months (Fig. 165-1C). Severity and duration of
PHN are a function of age. Clinicians have advocated
a wide range of treatments, including many oral and
topical medications, epidural injection of local anes
thetic and glucocorticoids, acupuncture, biofeedback,
subcutaneous injections of triamcinolone, transepi
dermal electrical nerve stimulation, spinal cord stim
ulators, and systemic administration of a variety of
compounds, but most have not been validated by con
trolled trials. The results of randomized controlled tri
als demonstrated efficacy for pain relief in PHN for the
following drugs: gabapentin, pregabalin, tricyclic anti
depressants, opioid analgesics, tramadol, 5% lidocaine
patch, and high-concentration capsaicin patch.154-157
The choice among these medications should be guided
by the adverse event profiles, potential for drug inter
actions, patient comorbidities, and treatment prefer
ences. On average, these agents provide adequate
pain relief (defined as reduction of pain to below 3 on a
0- to 10-point scale or by 50% on a visual analog scale)
in 30% to 60% of patients. These modalities are now
rec ommended as evidence-based pharmacotherapy
for PHN as described in more detail in practice manage
ment guidelines.154,155,158-160
PREVENTION
PREVENTION OF VARICELLA
VARICELLA VACCINE
Live attenuated Oka VZV varicella vaccines are immu
nogenic and efficacious in protecting susceptible chil
dren against varicella. Similar results were obtained in
susceptible adults when 2 doses were given 4 to 8
weeks apart. Vaccinated children and adults devel
oped breakthrough varicella caused by wildtype VZV at
a rate of 1% to 3% per year (cumulative ÿ15%) com
pared to an attack rate of 8% to 13% per year in unvac
cinated children.161 Breakthrough varicella is relatively
mild, with fewer lesions and milder constitutional
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Machine Translated by Google
symptoms. The FDA licensed the Oka/Merck varicella
vaccine in the United States in 1995. In 2005, the FDA
approved a combined measles, mumps, rubella, and
varicella (MMRV) vaccine for routine immunization of
children 12 months to 12 years of age.
Because of the frequency of breakthrough varicella,
the CDC Advisory Committee on Immunization Prac
tices (ACIP) now recommends two 0.5-mL doses of
varicella vaccine for healthy children aged ÿ12 months,
and for all adolescents and adults without evidence of
immunity.162 Because of the increased severity of
varicella in adults, all susceptible adults should be
identified and vaccinated. Particular effort should be
devoted to identifying and vaccinating susceptible
Zoster
Varice
Herpe
Chapt
and
165 :: adults who may be at increased risk for exposure or
transmission, including (1) health care providers, (2)
household contacts who might infect immunocom
promised persons, or susceptible pregnant women, (3)
persons who live or work in environments in which
transmission of VZV is likely (eg, teachers, day care
employees, residents, and staff in institutional set
tings), (4) persons who live or work in environments in
which transmission has been reported (eg, college
students, inmates and staff members of correctional
institutions, and military personnel), (5) nonpregnant
women of childbearing age, (6) adolescents and adults
living in households with children, and (7) interna tional in preventing illness or modifying varicella severity in
travelers. Second-dose catch-up varicella vacci nation
is recommended for children, adolescents, and adults
who previously received only 1 dose.66,163
The immunity to varicella induced by varicella vaccine alternative for these patients is VARIZIG, a purified
is not as solid as that induced by wildtype VZV infection, human immune globulin prepared from plasma
and the duration of vaccine-induced immunity is not yet
known. However, a high percent age of children
followed long-term have remained seropositive.164
Recent experience in clinical prac tice indicates that
vaccine effectiveness in children is
modestly lower than vaccine efficacy in clinical trials,
and outbreaks of breakthrough varicella in schools and
day care centers still occur.163,165-167 Several stud
ies have indicated that vaccine effectiveness declines
over 10 years.168 A CDC analysis of 10 years of
surveil lance data for varicella (1995-2004) showed that
the annual rate of breakthrough varicella increased with
time since vaccination, from 1.6 cases per 1000 person
years within 1 year after vaccination to 9.0 cases per
1000 person-years at 5 years and 58.2 cases per 1000
person-years at 9 years.168 Although most break
through varicella in children is characterized by mild
disease, more recent reports indicate that 25% to 30%
of breakthrough cases are not mild, are clinically similar posure treatment with acyclovir had either no vari cella
to varicella in unvaccinated children,169 and are often
as contagious as cases in unvaccinated persons.
Varicella vaccine is remarkably safe and well toler
ated, causing mainly minor rashes and injection site
reactions.169 Serious adverse events have been rare
(2.6/100,000 doses distributed) and, in the majority of
cases, a causal relationship between the serious
adverse event and varicella vaccine could not be established.
Herpes zoster occurs in vaccinees, but at a lower
rate than herpes zoster following varicella caused by
wild type VZV. Cases of laboratory-confirmed herpes zoster varies with the age and immune status of the
Kang_CH165_p3035-3064.indd 3055
in vaccinees include cases caused by reactivation of 25
vaccine virus and many cases caused by reactivation
of wildtype VZV that established latent infection dur
ing unrecognized varicella acquired prior to or after
vaccination.82
Among children <18 years of age in a managed care
plan, the incidence of herpes zoster was 79% lower
among recipients of varicella vaccine than among
unvaccinated children. Half of the cases of herpes zos
ter in vaccinated children were caused by Oka vaccine
VZV and half were caused by wildtype VZV, whereas
all cases of herpes zoster in unvaccinated children
were caused by wildtype VZV.82
POSTEXPOSURE PROPHYLAXIS AND
INFECTION CONTROL
Patients with varicella and herpes zoster often transmit
VZV to susceptible individuals. When exposure is rec
ognized (risk period of 1-2 days before rash until crust
ing is well under way), preventive measures include
varicella vaccine, high-titer varicella-zoster immune
globulin (VARIZIG), and postexposure chemoprophy
laxis with acyclovir.
Active immunization with varicella vaccine is effective
immunocompetent children if adminis tered within 3
days after exposure.170 Comparable information is not
available for immunocompromised patients. An
containing high levels of immunoglobulin G antibody to
VZV. This product may be considered for patients who
have been exposed to varicella and are at increased
risk for severe disease and complications.171
It is dosed on a weight basis and should be given as
soon as possible, preferably with 96 hours of exposure,
although current recommendations permit an interval
of up to 10 days.172
Whereas protection afforded by VARIZIG is tran
sient, varicella vaccine induces long-lasting VZV
immunity and protection against subsequent expo
sures. Therefore, the ACIP recommends varicella vac
cine for postexposure prophylaxis in unvaccinated
susceptible immunocompetent persons.162 Varicella
vaccine is also much less expensive than VARIZIG.
Chemoprophylaxis with acyclovir also has been
studied in susceptible children following household
exposure to varicella. Children who received postex
or experienced fewer and less severe cases of varicella
than children in the control group.173 How ever,
appropriate timing is critical, and immunity to varicella
may not be achieved, especially with early postexposure
treatment. Reported experience with postexposure
treatment with acyclovir is lacking in immunocompromised
patients. Oral famciclovir or valacyclovir are preferable
to oral acyclovir for postex posure chemoprophylaxis.
The importance of infection control practices for VZV 3055
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25 exposed susceptible individual. It is not imperative to
prevent exposure of susceptible normal children to
VZV, but exposure of immunocompromised patients,
newborn infants, and adults, particularly women of
childbearing age, should be avoided. Exposure of sus
ceptible immunocompromised patients to VZV war
rants reduction in the dosage of glucocorticoids and
other immunosuppressive drugs, and administration
of VariZIG. Hospital and long-term care facility per
sonnel without a clear history of varicella or herpes
zoster should be tested for antibody to VZV prior to
employment, and susceptible personnel vaccinated
against varicella. Appropriate leave from work should
be instituted following VZV exposure of any suscep
tible personnel who are not vaccinated. In hospitals,
airborne and contact precautions are recommended
for patients with varicella, immunocompromised
patients with localized herpes zoster, and any patient
with dis seminated herpes zoster until all lesions are crusted.174
Contact precautions are recommended for immuno
competent patients with localized herpes zoster.
PREVENTION OF
HERPES ZOSTER
Until universal varicella vaccination greatly reduces
the number of people latently infected with wildtype
VZV, prevention of herpes zoster must be aimed at
preventing reactivation of latent VZV that results in
clinical disease. Long-term suppressive acyclo vir
treatment is only practical in immunocompro mised
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.
LIVE ATTENUATED ZOSTER VACCINE
Live attenuated Oka VZV zoster vaccines (ZVL) boost
VZV-specific cellular immunity in older adults suf
ficiently to prevent or attenuate herpes zoster.108 The
clinical rationale for zoster vaccine is the substantial
morbidity of herpes zoster in older adults and the need
to initiate antiviral therapy within 72 hours of rash
onset for maximum benefit; even then, antiviral therapy
does not prevent PHN. In addition, treatment of PHN
is often ineffective and poorly tolerated by older adults.
In 2006, the ACIP recommended routine administra
tion of live attenuated Oka/Merck strain VZV zoster
vaccine (ZVL; Zostavax®) to adults 60 years of age
and older for the prevention of herpes zoster and its
com plications, particularly PHN.37 This
recommendation is based on the results of the Shingles recommendation to administer ZVL at ÿ60 years of
Prevention Study, a randomized, double-blind, placebo
controlled VA Cooperative Study conducted in 38,546
community dwelling adults ÿ60 years of age at 22
study sites across the continental United States.28
3056
ZVL reduced the bur den of illness due to herpes zoster (a clinically relevant of ZVL even when herpes zoster is not prevented.28,181
Kang_CH165_p3035-3064.indd 3056
measure of the adverse impact of herpes zoster) by
61.1%; reduced the incidence of clinically significant
PHN by 66.5%; and reduced the incidence of herpes
zoster by 51.3%. Clinically significant PHN is defined
as pain and discomfort (eg, allodynia, severe pruritus)
due to herpes zoster scored as ÿ3 on a 0-10 scale that
persists for more than 90 days after rash onset. ZVL
also decreased the adverse impact of herpes zoster
on capacity to perform activities of daily living and
health-related quality of life.175 Reactions at the injec
tion site were more frequent among vaccine recipients
but were generally mild. The proportion of subjects
reporting serious adverse events, and rates of hospi
talization and death were comparable in vaccine and
placebo recipients.28,176
Long-term followup studies of Shingles Prevention
Study participants demonstrated that ZVL efficacy for
herpes zoster burden of illness and incidence of her
pes zoster declined over time, but persisted through 5
to 7 years postvaccination, declining markedly
thereafter.177,178 ZVL efficacy for herpes zoster
burden of illness was 61.1% from 0.0 to 4.9 years
postvaccina tion, 50.1% from 3.3 to 7.8 years
postvaccination, and 58.6% from 0.0 to 7.8 years
postvaccination. Compa rable figures for incidence of
herpes zoster were 51.3%, 39.6%, and 48.7%, and for
incidence of PHN were 66.5%, 60.1%, and 64.9%.
A number of retrospective reviews of the use of ZVL
in “real world” practice settings using electronic records
from large integrated health care organiza tions and
administrative medical claims databases showed very
similar results for vaccine effectiveness for the
incidence of herpes zoster.179-185 These studies
confirmed declines in effectiveness of ZVL for inci
dence of herpes zoster similar to those demonstrated
in the Shingles Prevention Study and its Persistence
Substudies.28,177,178 However, ZVL effectiveness
in per sons vaccinated when they were ÿ70 years of
age was similar to vaccine effectiveness in younger
vaccinees; furthermore, ZVL effectiveness for PHN
was higher and better preserved over time than for
incidence of herpes zoster.181-184 In addition, ZVL
reduced the dura tion and severity of pain in vaccinees
who developed herpes zoster, reduced the incidence
of ophthalmic zoster, and reduced the incidence and
severity of pro dromal pain.179,185 Although these
data suggest that a second dose of ZVL may be
needed, and a second dose of ZVL administered ÿ10
years after the initial dose did significantly boost VZV-
specific immune responses,186 there is currently no
recommendation for revaccination from the ACIP.187
In a large, randomized, placebo-controlled trial, the
efficacy of ZVL for inci dence of herpes zoster in 50-
to 59-year-old individuals was 69.8%, which led to
expansion of FDA licensure to include this age
group.188 However, the ACIP did not modify the
age. Neither the FDA nor the ACIP have set an upper
age limit for the use of ZVL. Older individu als are at
highest risk for herpes zoster and PHN, and reduction
in herpes zoster pain, severity, and duration occurs in
very old recipients
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Although highly attenuated, ZVL is contraindicated
in immunocompromised persons.
Nevertheless, it has been administered to a number
of immunocompromised patients, with very rare adverse
events.180,189-199 With more than 30 million doses
admin istered to persons ÿ60 years of age in the United
States since 2006, more than 10 million doses
administered to persons ÿ70 years of age in the United
Kingdom since 2010, and additional doses in Japan and
other countries, ZVL has proven to have a remarkable
safety profile.184,200
ZVL may be administered without screening for a
history of varicella or herpes zoster, or serologic test ing
for varicella immunity.37 Persons known to be VZV
Zoster
Varice
Herpe
Chapt
and
165 :: seronegative should be vaccinated against varicella
according to current recommendations.162 Older adults
who have PHN or who have a current episode of her
pes zoster may ask to be vaccinated, but ZVL is not
indicated to treat acute herpes zoster or PHN. Some
patients may want to receive ZVL after a recent epi
sode 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 2 to 3 years after onset of a well-documented
case of herpes zoster is reasonable.
Administration of ZVL to Shingles Prevention Study
placebo recipients 5 to 85 months after documented
herpes zoster was safe and well tolerated.201
When considering ZVL, older adults may express
concerns about transmission of vaccine virus to other
individuals, but transmission of vaccine virus from
recipients of ZVL to susceptible household contacts has
not been documented. Thus, immunocompetent older
adults in contact with immunocompromised patients
should receive ZVL to reduce the risk that they will
develop herpes zoster and transmit wild type VZV to
their susceptible immunocompromised contacts.37,108
For the same reasons, older adult con tacts of
susceptible pregnant women and infants should receive
zoster vaccine. ZVL recipients with susceptible pregnant
or immunocompromised con tacts need not take any
special precautions following vaccination, except in the
rare situation that a vesic ular rash develops, in which
case standard contact precautions are adequate.37 In
the very unlikely event that an immunocompromised
contact develops a sig nificant illness caused by vaccine
virus, he or she can be treated with antiviral agents.
ADJUVANTED GLYCOPROTEIN E
SUBUNIT ZOSTER VACCINE
A new adjuvanted recombinant VZV subunit zoster
vaccine (RZV; Shingrix®) consisting of recombinant VZV
glycoprotein E (gE) and a powerful AS01B adju vant
system was approved in October 2017 by the US FDA
for the prevention of herpes zoster in adults ÿ50 years of
age. RZV is administered intramuscularly on a 2-dose
schedule with a 2- to 6-month interval.202
The ACIP has recommended RZV for prevention of
Kang_CH165_p3035-3064.indd 3057
herpes zoster in immunocompetent adults ÿ50 years of 25
age, with preference for RZV over ZVL for initial
immunization and for administration to older adults who
have already received ZVL.203 VZV gE is a major
component of the virus envelope that is essential for
virus replication and cell-to-cell spread and is a major
target for VZV-specific CD4+ T-cell responses. AS01B is
a liposome-based adjuvant system that contains mono
phosphoryl lipid A (a Toll-like receptor 4 agonist) and the
saponin QS21 (a purified extract from the Quillaja
saponaria tree). QS21 stimulates strong humoral and
CD4+ T-cell responses to gE.204 A number of Phase I,
I/II, and II studies established that 2 doses of RZV for
mulated with 50 µg of gE and AS01B containing 50 µg
monophosphoryl lipid A and 50 µg QS21 administered 2
months apart induced strong immune responses to gE
that, on the basis of a small followup study, appear to
decline significantly over the first 3 years postvac
cination and then persist above baseline levels for at
least 9 years.205,206 The VZV/gE-specific CD4+ T-cell
and humoral responses induced by RZV were much
more robust and long-lasting than those induced by ZVL,
and addition of an Oka varicella vaccine did not increase
the magnitude or durability of the immune responses to
RZV.204
Two large blinded randomized placebo-controlled
Phase III trials conducted concurrently at the same sites
in 18 countries assessed the safety and efficacy of 2
doses of RZV administered intramuscularly 2 months
apart in adults ÿ50 years of age (ZOE-50; 15,411
participants) and ÿ70 years of age (ZOE-70; 13,900 participants).207,208
In ZOE-50 and ZOE-70, subjects were stratified into
decades (50-59, 60-69, and ÿ70 years) and (70-79 and
ÿ80 years), respectively; the study design was similar to
that of the Shingles Prevention Study, except that T cell–
mediated immune responses were measured by
enumerating T cells expressing ÿ2 of 4 activation mark
ers: interferon-ÿ, interleukin-2, tumor necrosis factor-ÿ,
and CD40 ligand207,208 rather than by responder cell
fre quency and ELISPOT.28,209,210 In ZOE-50, during
a mean followup of 3.2 years, RZV had an overall
efficacy for incidence of herpes zoster of 97.2%, with no
decrement in the ÿ70-year age group.207 Solicited and
unsolicited adverse events were reported in 84.4% of
RZV recipi ents and 37.8% of placebo recipients. Most
were mild to moderate intensity, but 17.0% in RZV
recipients and 3.2% in placebo recipients prevented
normal everyday activities (grade 3). These were mostly
injection-site reactions (pain, redness, swelling) in 81.5%
of RZV recipients (9.5% grade 3) and 11.9% of placebo
recipi ents (0.4% grade 3), and systemic reactions
(myalgia, fatigue, headache, shivering, fever, and GI
symptoms) in 66.1% of RZV recipients (11.4% grade 3)
and 29.5% of placebo recipients (2.4% grade 3).207
In ZOE-70, during a mean followup of 3.7 years, RZV
efficacy for incidence of herpes zoster was 89.8%; 90.0%
in 70- to 79-year-olds and 89.1% in those ÿ80 years of
age.208 In a pooled analysis of data from subjects ÿ70
years of age in ZOE-50 and ZOE-70 (15,596 subjects),
RZV efficacy for incidence of herpes zoster was 91.3%
and for PHN was 88.8%. Adverse reactions were similar
3057
to those reported in ZOE-50, but tended
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25 to be less frequent among subjects ÿ80 years of age than
among younger subjects. Incidence of serious adverse events
and potential immune-mediated diseases were similar in the
RZV and placebo recipients.208 Most were mild to moderate
intensity, but 11.9% in RZV recipi ents and 2.0% in placebo
recipients prevented nor mal everyday activities (grade 3).
These were mostly injection-site reactions (pain, redness,
swelling) in 74.1% of RZV recipients (8.5% grade 3) and 9.9%
of placebo recipients (0.2% grade 3), and systemic reac tions
(myalgia, fatigue, headache, shivering, fever, and GI
symptoms) in 53.0% of RZV recipients (6.0% grade 3) and
25.1% of placebo recipients (2.0% grade 3).208
Because RZV contains only the gE subunit of VZV, it is
incapable of replication, and there is no danger of vaccine
virus replication causing disease. A num ber of Phase I, I/II,
and small Phase III studies have demonstrated that RZV is
safe and immunogenic in persons with various
immunosuppressive condi tions, including HIV infection and
hematopoietic cell transplant recipients.211,212 RZV can be
safely coadmin istered with other vaccines,213 to persons
previously vaccinated with ZVL,214 and to persons with
previous herpes zoster.215 Although no results are available
from head-to-head studies, RZV appears to be substantially
more immunogenic in persons previously immunized with ZVL
than a booster dose of ZVL.186,214 Table 165-5
summarizes the current ACIP recommendations.
The development and clinical evaluation of RZV are
summarized in an excellent review by Cunningham and
Heineman,217 in which pooled data from ZOE-50 and ZOE-70
indicate that overall RZV efficacy for inci dence of herpes
zoster declines from 97.6% in year 1 to 87.9% in year 4
postvaccination. If that rate of decline continues, persons
vaccinated with RZV at 50 years of age, as recommended by
the ACIP may require addi tional immunization to ensure an
adequate level of protection later in life when the incidence
and severity of herpes zoster and PHN are markedly increased.
Although the absence of recognized autoimmune diseases
in RZV recipients followed for approximately 4 years
postvaccination is encouraging, it does not elimi nate the
theoretical concern that the powerful AS01B
TABLE 165-5
Recommendations for the Use of Herpes Zoster
Vaccines (2018 ACIP Recommendations)203
1. Recombinant zoster vaccine (RZV) is recommended for the preven
tion of herpes zoster and related complications for immunocompe
tent adults aged ÿ50 y. RZV is administered in 2 doses 2-6 mo apart.
2. RZV is recommended for the prevention of herpes zoster and
related complications for immunocompetent adults who previ
ously received live attenuated zoster vaccine (ZVL). RZV should not
be administered <2 mo after receipt of ZVL.
3. RZV is preferred over ZVL for the prevention of herpes zoster and
related complications.
Note: These recommendations serve as a supplement to the existing
recommendations for the use of ZVL in immunocompetent adults aged ÿ60
3058 y. RZV can be administered concomitantly, at different anatomic sites, with
other adult vaccines.216
Kang_CH165_p3035-3064.indd 3058
adjuvant system might induce or aggravate autoim mune
diseases, especially because the interval between their
initiation and clinical recognition may be many years. At this
point, it is incumbent on the US FDA, to ensure that large, well-
designed, and relevant Phase IV postmarketing studies are
expeditiously completed.218,219
ACKNOWLEDGMENTS
Dedicated to the memory of Stephen E. Straus, a coau thor
of this chapter in previous editions and to Mich iaki Takahashi
who developed the attenuated Oka strain of VZV used in all
live attenuated zoster and varicella vaccines.
MNO is grateful to M. Ashbaugh and W. Buchanan for
assistance with the figures, to R. Harbecke and D.
Mussatto for useful discussion and invaluable assis tance
with manuscript preparation, and for the sup port of the
Veterans Medical Research Foundation and the James R. and
Jesse V. Scott Fund for Shingles Research.
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