Herpes Zoster Pathogenesis

and Cell-Mediated Immunity

and Immunosenescence
Michael N. Oxman, MD

Herpes zoster, or shingles, is a localized disease characterized by unilateral radic-

ular pain and a vesicular rash limited to the area of skin innervated by a single dorsal
root or cranial sensory ganglion. Whereas varicella, or chickenpox, results from pri-
mary exogenous varicella-zoster virus (VZV) infection, herpes zoster is caused by
reactivation of endogenous VZV that has persisted in latent form within sensory
ganglia following an earlier episode of chickenpox. In contrast to recurrent herpes
simplex, herpes zoster is commonly associated with severe pain: prodromal pain
often precedes the rash by several days; pain usually accompanies the dermatomal
rash of herpes zoster; and clinically significant pain and allodynia may persist for
weeks, months, or even years after the herpes zoster rash has healed, a debilitating
complication known as postherpetic neuralgia (PHN). The incidence and severity
of herpes zoster and PHN increase with age in association with an age-related
decline in cell-mediated immunity to VZV. The Shingles Prevention Study—a ran-
domized double-blinded placebo-controlled trial—sought to evaluate the capacity
of a live attenuated VZV vaccine to protect older adults from herpes zoster and
PHN by boosting their waning cell-mediated immunity to VZV. The study demon-
strated that the zoster vaccine produced significant reductions in the incidence of
herpes zoster, in the burden of illness caused by herpes zoster, and in the incidence
of PHN.
J Am Osteopath Assoc. 2009;109(suppl 2):S13-S17

H erpes zoster results from reactiva-
tion of endogenous varicella-zoster
virus (VZV) that has persisted in latent
form within sensory ganglia following
varicella (chickenpox).1-3 More than 90%
of adults in the United States have sero-
This article was developed in part from an expert
panel discussion held October 29, 2008, during
the American Osteopathic Association 113th
Annual Convention and Scientific Seminar in Las
Vegas, Nev. A video of the discussion is accessible
at: http://www.cecity.com/ce-bin/owa/alnch?tid
=14415&ccd=MCK.
Dr Oxman discloses that he is the National
Chairman of The Shingles Prevention Study and its
substudies, which have been supported, in part, by
grants from Merck & Co, Inc, to the VA (Veterans
Affairs) Cooperative Studies Program, the VA San
Diego Medical Research Foundation, and the VA
Connecticut Research and Education Foundation.
Because Dr Oxman is an employee of the fed-
eral government, this article is in the public domain
and is not copyright protected.
Address correspondence to Michael N. Oxman,
MD, Professor of Medicine and Pathology, Uni-
versity of California, San Diego, Staff Physician
(Infectious Diseases), VA San Diego Healthcare
System, 3350 La Jolla Village Dr, San Diego, CA
92161-0001.
E-mail: mnoxman@ucsd.edu
logic evidence of prior VZV infection.3-6
Consequently, latent VZV is present in
the sensory ganglia of virtually every
older adult who was raised in the con-
tinental United States. Thus, almost
every older adult in the United States
is at risk of developing herpes zoster.1,3,7
Herpes zoster actually begins with
chickenpox, the clinical manifestation of
primary VZV infection. During chick-
enpox, infectious virus that is present in
large amounts in chickenpox vesicles
enters the endings of sensory nerves in
the skin, travels up the sensory nerves
to the dorsal root and cranial sensory
ganglia where the nerve cell bodies are
clustered, and establishes lifelong resi-
dence (ie, latent infection) in those sen-
sory neurons. Consequently, the dorsal
root and cranial sensory ganglia of
everyone who has had chickenpox are
latently infected with VZV—they con-
This supplement is supported by an independent educational grant from Merck & Co, Inc.
tain the genomic DNA of VZV, but not
infectious virus.
This latent VZV eventually reacti-
vates, presumably in a single sensory
neuron, to cause herpes zoster. The reac-
tivated virus multiplies and spreads
within the ganglion, infecting many addi-
tional neurons and supporting cells—a
process that causes intense inflamma-
tion and neuronal necrosis. The virus
then travels from the sensory ganglion
back down the nerve to the skin, where
it produces the characteristic dermatomal
rash of herpes zoster.1,3,8,9
The skin lesions of herpes zoster and
chickenpox are histopathologically iden-
tical: both contain multinucleated giant
cells with eosinophilic intranuclear inclu-
sion bodies. The rash of herpes zoster is
similar to chickenpox, except that it is
restricted to one area of the skin on one
side of the body—namely, the der-

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 matome innervated by the ganglion in
which the latent virus reactivated. Also,
the lesions of herpes zoster consist of
closely grouped vesicles on an erythe-
matous base, whereas those of chick-
enpox are individual and randomly dis-
tributed. 8 These differences reflect
intraneural spread of virus to the skin in
herpes zoster, in contrast to viremic
spread in chickenpox.8
In temperate climates, chickenpox
occurs in epidemics in the late winter and
early spring, whereas herpes zoster occurs
sporadically throughout the year.1,3,4
Immunocompetent individuals usually
have herpes zoster only once, presum-
ably because an episode of herpes zoster
boosts immunity to VZV, essentially
“immunizing” against another episode.1,10
Course of Illness
Herpes zoster typically begins with severe
unilateral pain that persists for several
days before the rash appears.8 This pre-
sentation of herpes zoster reflects the
pathology caused by multiplication and
spread of the reactivated VZV in the
affected sensory ganglion. The prodromal
pain of herpes zoster can mimic the pain
of appendicitis, biliary or renal colic, chole-
cystitis, duodenal ulcer, glaucoma,
myocardial infarction, pleurisy, or pro-
lapsed intervertebral disk and, therefore,
can lead to serious misdiagnosis.8 Herpes
zoster is virtually impossible to diagnose
until the characteristic vesicular der-
matomal rash appears.
When the herpes zoster rash
develops, skin lesions appear in succes-
sive crops and quickly evolve from ery-
thematous macules to papules and then
to delicate intraepithelial vesicles (blis-
ters) filled with clear fluid. After poly-
morphonuclear leukocytes, macro -
phages, and lymphocytes infiltrate the
vesicles, the fluid becomes cloudy and
the vesicles become pustules. These pos-
tules subsequently dry to form flat
adherent crusts.8
Vesicles and pustules are usually
present for 7 to 10 days, while crusts per-
sist for 2 to 3 weeks. Healing (re-epithe-
lialization) is almost always complete
within 4 weeks of rash onset.8 However,
pain, which reaches maximum intensity
early in the second week, may persist
beyond rash healing, resulting in a debil-
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itating complication known as posther-
petic neuralgia (PHN).
Postherpetic Neuralgia
The incidence and severity of herpes
zoster increase with age, as does the risk
of developing PHN.1,11,12 Manifestations
of PHN vary from person to person.13
While it is rarely described identically
by two afflicted individuals, patients fre-
quently describe it as the worst pain that
they have ever experienced.
Clinically significant PHN was
described by R. Edgar Hope-Simpson in
197511 as long-lasting pain of sufficient
severity to interfere with activities of daily
living, decrease quality of life, and cause
patients to seek medical attention. Such
clinically significant PHN complicates
the more serious cases of herpes zoster,
which are characterized by severe pain
and extensive rash during the acute
phase of the disease.12-15
Patients with PHN often have a cen-
tral area of cutaneous scarring and sen-
sory loss surrounded by an area of hyper-
sensitivity and allodynia, 14,15 a
particularly distressing sensory abnor-
mality in which stimuli that are not nor-
mally painful (eg, light touch) elicit pain
and unpleasant sensations.
Allodynia is present in the majority
of patients with PHN and is responsible
for a large portion of their disability.14,15
Even the light touch of clothing may
cause severe pain and discomfort,
resulting in decreased quality of life and
reduced capacity to carry out activities of
daily living.14,15 For example, afflicted
individuals may find it impossible to
leave their home because it is too painful
to put on a shirt.
Individuals with prolonged PHN
have pathologic evidence of neuronal
loss and scarring in the portion of the
sensory ganglion and spinal dorsal horn
corresponding to the area of affected
skin.14 Thus, death of primary neurons
in the involved sensory ganglion and of
secondary neurons in the corresponding
dorsal horn of the spinal cord during the
acute phase of herpes zoster appear to
be responsible for many of the sensory
abnormalities that characterize PHN.14
Herpes Zoster vs Herpes Simplex
The pathogenesis of herpes zoster and
herpes simplex share a number of char-
acteristics that may cause the two dis-
eases to be confused clinically.3,8,9,12,16,17
Thus, it is important to differentiate them
(Figure 1).
Like VZV, herpes simplex virus
(HSV) is latent in sensory neurons. How-
ever, sensory neurons latently infected
with HSV are located primarily in the
first and second divisions of the trigem-
inal ganglion and in the sacral sensory
ganglia, reflecting the most common sites
of primary HSV infection. Most episodes
of recurrent herpes simplex involve these
same anatomic sites.16
In contrast, neurons latently infected
with VZV are present in essentially all
sensory ganglia. However, the frequency
of herpes zoster in individual der-
matomes corresponds to the density of
lesions in chickenpox. Thus, herpes zoster
most often involves the first division of
the trigeminal ganglion and dermatomes
on the trunk.1-3,8,9,17
When HSV reactivates, it does not
appear to multiply and spread within
the ganglion. Instead, it remains confined
to the neuron in which it reactivated.
Thus, when HSV travels back down the
sensory nerve to the skin, it usually pro-
duces lesions in the area innervated by
that individual neuron and thus involves
a very small portion of the dermatome.
Remarkably, the neuron in which latent
HSV reactivates does not appear to be
killed in the process but survives to
permit repeated reactivation. Thus, mul-
tiple recurrences of HSV (eg, herpes labi-
alis or cold sores) are common and usu-
ally involve the same anatomic
location.10,16
Conversely, recurrences of herpes
zoster are relatively uncommon in
immunocompetent persons.1,3,9,17 When
they do occur, they rarely involve the
same dermatome. When VZV reacti-
vates, it does not remain confined to a
single neuron, as does HSV, but multi-
plies and spreads in the ganglion to infect
many neurons. Consequently, it reaches
the skin via the axons of many neurons,
and the resulting rash involves a large
portion of the dermatome. Reactivation
of latent VZV also results in extensive
damage to the ganglion, which is
believed to explain the frequent devel-
opment of PHN.12,14,15,17
Oxman • Herpes Zoster Pathogenesis
 vation replication and spread of VZV by
Characteristic Herpes Zoster Recurrent Herpes Simplex host immune defenses,1 as described in
the following section.
Sites of latent infections Sensory neurons Sensory neurons in
in all sensory ganglia trigeminal and sacral
sensory ganglia
Cell-Mediated Immunity
In 1965, Hope-Simpson published a land-
Viral gene expression Several “immediate early” No HSV proteins are
during latency and “early” VZV proteins synthesized; only
mark study1 on all cases of herpes zoster
are synthesized “latency-associated and chickenpox that occurred in his med-
transcripts” ical practice during the previous 16 years.
Symptomatic reactivation Infrequent (rarely involves Frequent (usually involves He recorded the sporadic nature of
of latent virus the same dermatome) the same dermatome) herpes zoster and the absence of any tem-
poral relationship between its onset and
Asymptomatic reactivation None Frequent
with asymptomatic virus exogenous exposure to VZV. He also
shedding documented the increased frequency and
severity of herpes zoster with increasing
Proportion of the affected Large (sensory fields Small (often the sensory age, as well as the relative rarity of second
dermatome involved by rash of many neurons) field of a single neuron)
episodes of herpes zoster.1
Consequences of reactivation Extensive ganglionic No obvious ganglionic To explain these observations, Hope-
of latent virus pathology and neuronal pathology or neuronal Simpson1 proposed that in addition to
death death
establishing latent VZV infections in sen-
Postherpetic neuralgia Common Extremely rare sory neurons, chickenpox elicits an
immune response that limits the ability of
Frequency of symptomatic Increases with increasing Decreases over time the latent virus to reactivate and cause
reactivation age (and time after after primary infection
primary infection)
herpes zoster. The level of this immu-
nity to VZV gradually declines over time
but is periodically boosted by subclin-
Figure 1. Comparison of herpes zoster and recurrent herpes simplex. ical infections resulting from exogenous
exposure to VZV (eg, when caring for a
child with chickenpox) and by episodes
Recurrent herpes simplex is almost The mechanisms of HSV and VZV of reactivation limited by rapidly mobi-
never associated with sensory loss or latency are also different, and this dif- lized immune responses so that no rash
PHN.16 Many individuals have experi- ference may have significant clinical develops (Figure 2). Hope-Simpson1
enced hundreds of cold sores in a life- implications.9,10,12,16,17 Neurons latently called such abortive cases of herpes zoster
time without developing sensory loss or infected with HSV express a unique class “contained reversions” and noted that
PHN. of viral RNA molecules (“latency-asso- they could sometimes result in pain in
Herpes simplex and varicella- zoster ciated transcripts”) but do not express the corresponding dermatome without
viruses also differ in their epidemiology, any HSV proteins.16 Thus, in theory, the the development of a rash, a syndrome
particularly in the role of asymptomatic immune system has no means of recog- called zoster sine herpete.8,9,17
infection and asymptomatic virus shed- nizing neurons latently infected with As described by Gelb19 in this sup-
ding.4,9,16,17 A large proportion of primary HSV.10,16 In contrast, neurons latently plement to JAOA—The Journal of the
and recurrent HSV infections are asymp- infected with VZV express several American Osteopathic Association, these
tomatic. Consequently, transmission of “immediate early” and “early” VZV pro- boosts in VZV-specific immune response
HSV, whether oral or genital, is usually teins.9,10,12 Therefore, in theory, the host help slow the age-related decline in host
the result of asymptomatic virus shed- immune system may be able to recog- resistance to herpes zoster. However,
ding. nize neurons latently infected with VZV VZV-specific immunity eventually falls
In contrast, most primary and recur- and limit reactivation.10 below some critical threshold, which
rent VZV infections are symptomatic, In addition, the important role of allows the latent virus to reactivate and
and asymptomatic virus shedding does postreactivation multiplication and spread cause herpes zoster (Figure 2). The large
not appear to occur with VZV.4,9,17 Sus- of VZV within the ganglion provides amount of VZV produced during an
ceptible individuals acquire chickenpox another target for host immune responses, episode of herpes zoster elicits a sub-
from someone with symptomatic chick- which may limit VZV replication and stantial boost in immunity, essentially
enpox or herpes zoster, though respira- spread and, thereby, prevent the devel- “immunizing” the host against another
tory transmission makes chickenpox con- opment of herpes zoster even when latent episode and explaining the rarity of
tagious for a day or more before the VZV has reactivated. The well-recognized second cases of herpes zoster in immuno-
appearance of skin lesions. Only about syndrome of herpes zoster without rash— competent individuals (Figure 2).1
4% of chickenpox cases are so clinically zoster sine herpete—may represent an Every aspect of Hope-Simpson’s
mild as to be undiagnosed.18 example of such limitation of postreacti- remarkable theory has been validated,10

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 and it has been demonstrated that the crit- trast, patients with X-linked agamma- (aged 60-69 years and aged 70 years or
ical element of the host immune response globulinemia whose VZV-CMI responses older) to receive a single dose of zoster
is cell-mediated immunity (CMI) to VZV are relatively intact are not at increased vaccine or placebo.
(Figure 2).6,7,10 Antibody to VZV, which risk of herpes zoster.6,7,10,20 Therefore, it is As noted by Gelb19 zoster vaccine
can protect against primary exogenous clear that the level of CMI to VZV deter- stimulated VZV-CMI and reduced the
VZV infection (ie, chickenpox), appears mines the risk and severity of herpes burden of illness caused by herpes
to play no role in host resistance to herpes zoster and PHN, whereas antibody to zoster—a severity-by-duration measure
zoster. Instead, it is VZV-CMI that limits VZV plays no clinically significant role.6,20 of the total pain and discomfort caused
the ability of latent VZV to reactivate and by herpes zoster—by 61.1% (P⬍.001).7
cause herpes zoster.20 Shingles Prevention Study Zoster vaccine also reduced the incidence
Levels of VZV-CMI decline with age As described by Gelb,19 Hope-Simpson’s of clinically significant PHN by 66.5%
in immunocompetent individuals in hypothesis suggested that herpes zoster (P⬍.001) and the incidence of herpes
association with the age-related increase might be prevented or attenuated in zoster by 51.3% (P⬍.001).7 The zoster
in the incidence and severity of herpes elderly patients if their waning CMI to vaccine was well tolerated and did not
zoster, whereas levels of antibody to VZV VZV could be boosted with a VZV vac- induce or cause herpes zoster in this pop-
do not decline substantially with cine.1,7,10 This hypothesis was the basis ulation.7
increasing age.6,7,20 Moreover, the inci- of the Shingles Prevention Study,7 a ran- An Immunology Substudy6,20 of the
dence of herpes zoster markedly domized double-blinded placebo-con- Shingles Prevention Study involved a
increases after hematopoietic stem cell trolled trial conducted by the US Depart- subset of participants who had immuno-
transplantation, a circumstance in which ment of Veterans Affairs to evaluate the logic assessments before and after vacci-
VZV-CMI is depressed while VZV anti- efficacy and safety of a high potency live nation. Blood samples were collected from
body levels are maintained with intra- attenuated VZV vaccine (zoster vaccine) 1396 subjects at two study sites before
venous ␥-globulin. for the prevention of herpes zoster and vaccination and at 6 weeks and 1, 2, and
The age-specific incidence of herpes PHN. 3 years thereafter. The samples were tested
zoster is also markedly increased in The study7 enrolled 38,546 immuno- for VZV-CMI by interferon-␥ enzyme-
patients with human immunodeficiency competent adults aged 60 years or older linked immunospot assay (ELISPOT) and
virus infection or Hodgkin disease, in who had a history of chickenpox or had responder cell frequency (RCF) assays,
organ transplant recipients, and in resided in the continental United States and for antibody to VZV by glycoprotein
patients receiving immunosuppressive for more than 30 years. Study partici- enzyme-linked immunosorbent assay.
therapy in whom VZV-CMI is sup- pants had no history of herpes zoster. Six weeks after vaccination, the
pressed but levels of antibody to VZV Subjects at each of the 22 study sites were immune responses in the vaccine recip-
are relatively well maintained. In con- separately randomized by age strata ients as measured by all three assays
Herpes Zoster (“successful” reversion)
Primary Varicella-Zoster Virus Infection

Contained
Reversions
Contact With a Case of Varicella

Exogenous
established in sensory ganglia)

exposure to VZV
Contained
Varicella (viral latency
Increasing Levels of VZV-CMI

Reversions
Clinically apparent
disease
Contained
Reversions

Critical Level
of VZV-CMI

3 6 9 12 15 18

Days Months Years

Figure 2. The pathogenesis of herpes zoster according to Hope-Simpson, 1965. Source: Modified from Hope-Simpson R. Proc
R Soc Med. 1965;58:9-20.1

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 were significantly increased compared
with those of the placebo recipients. The
vaccine-induced increases in VZV-CMI
persisted during the 3-year follow-up
period, although they decreased in mag-
nitude over time.6
The immune responses among dif-
ferent age groups were also measured
to determine the effect of increasing age
on immune responses to VZV. When
baseline (preimmunization) values of
VZV-CMI and VZV antibody among
subjects in various age groups were com-
pared, the age-related decline in VZV-
CMI levels known to occur beginning
early in adulthood was found to con-
tinue among older adults in the Shingles
Prevention Study.6 The estimated annual
decline in the level of VZV-CMI per year
of increase in age was 2.7% for RCF and
3.9% for ELISPOT. In contrast, levels of
antibody to VZV did not decline with
increasing age.6
The VZV-CMI responses to zoster
vaccine, measured 6 weeks after vaccina-
tion by both RCF and ELISPOT assays,
also decreased with age, and average
levels were significantly lower in subjects
aged 70 years or older than in subjects
aged 60 to 69 years. RCF and ELISPOT
responses at week 6 decreased by 3.5%
and 3.8%, respectively, per year of age. In
contrast, the effect of age on the antibody
response to zoster vaccine was negligible.6
At baseline, VZV-specific immune
responses were lower, on average, in
subjects in whom herpes zoster devel-
oped than in those in whom it did not,
regardless of group assignment (ie,
placebo or vaccine). Cox regression anal-
yses also revealed a significant inverse
relationship between the immune
responses 6 weeks after vaccination and
the risk of herpes zoster.6
Severity of illness among subjects
in whom herpes zoster developed was
inversely correlated with the level of
VZV-CMI measured at the first clinic
visit following rash onset.20 Subjects with
higher levels of VZV-CMI at this early
time point had lower herpes zoster
severity of illness scores. The average
levels of VZV-CMI were also significantly
lower in subjects in whom PHN devel-
oped than those in whom it did not.20
A similar correlation was not
observed between levels of antibody to
Oxman • Herpes Zoster Pathogenesis
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VZV and severity of herpes zoster. In
fact, VZV antibody levels were highest in
the group of individuals with the most
severe disease and in those who devel-
oped PHN.20 The increased level of anti-
body most likely reflected the more
extensive replication of VZV in subjects
with more severe disease. Thus, higher
levels of VZV-CMI at the onset of herpes
zoster correlated with reduced severity of
disease and with a lower incidence of
PHN, whereas higher levels of antibody
to VZV did not.20
Comment
The Shingles Prevention Study7 and its
Immunology Substudy6,20 demonstrated
that administration of zoster vaccine to
subjects aged 60 years or older reduced the
incidence and severity of herpes zoster
and the incidence of PHN. This clinical
response was correlated with a vaccine-
induced increase in VZV-CMI. In the
placebo recipients, the age-related increase
in the incidence and severity of herpes
zoster and in the incidence of PHN was
shown to be correlated with an age-related
decline in VZV-CMI, but a comparable
age-related decline in levels of antibody to
VZV was not observed.
Finally, the study7 demonstrated
that increased levels of VZV-CMI at rash
onset were correlated with a reduction in
the severity of herpes zoster and in the
incidence of PHN, whereas increased
levels of antibody to VZV were not.
These results strongly support the
hypothesis that the increase in the fre-
quency and severity of herpes zoster that
accompanies increasing age is caused by
an age-related decline in VZV-CMI.
These results also indicate that the clinical
efficacy of zoster vaccine is the result of
its capacity to increase the waning levels
of VZV-CMI observed in older adults.7
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