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Journal of Dermatology and Clinical Research

Mini Review

*Corresponding author

Herpes Zoster: New Preventive

Perspectives

Gabutti G, Department of Medical Sciences, University

of Ferrara,via Fossato di Mortara 64B, 4412, Ferrara,
ITALY, Tel: 390532455568; Fax:390532205066; E-mail:

Stefanati Armando, Valente Nicoletta, Previato Sara, Giordani Matilde,

Lupi Silvia and Gabutti Giovanni*

Published: 21 January 2015

Submitted: 01 December 2014

Accepted: 14 January 2015
Copyright
2015 Giovanni et al.

Department of Medical Sciences, University of Ferrara, Italy

OPEN ACCESS

Abstract
Herpes Zoster, due to reactivation of latent Varicella Zoster Virus in ganglia, is common in
adults 50 years of age and older. Aging and other conditions that involvea decline of VZVspecific cell-mediated immunity are related to the onset of the disease. The main complication is
Postherpetic Neuralgia, a debilitating long-lasting painful condition. Pharmacological treatment
may be sub-optimal and the impact on quality of life is significant, especially for older patients.
A preventive approach is strongly required. The currently available vaccine with a good profile
of immunogenicity, efficacy and safety represents an option to prevent Herpes Zoster and
Postherpetic Neuralgia.

ABBREVIATIONS
HZ: Herpes Zoster; VZV: Varicella Zoster Virus; CMI: Cell
Mediated Immunity; PHN: Postherpetic Neuralgia; VAS: Visual
Analogical Scale; PFU: Plaque-Forming Unit; FDA: Food and Drug
Administration; CI: Confidence Interval; SPS: Shingles Prevention
Study; STPS: Short Term Persistence Substudy; LTPS: Long Term
Persistence Substudy: ZEST: Zostavax Efficacy and Safety Trial.

INTRODUCTION

Herpes Zoster (HZ) is a well-known disease from ancient

times [1] caused by varicella zoster virus (VZV), a Herpesvirus,
airborne transmitted or/and by direct contact with skin lesions
of a patient. The reservoir of infectionisexclusively human and
the virus typically spreads with an endemic-epidemic trend
affecting mainly pediatric age [2]. The primary infection resultsin
varicella (chickenpox) that is highly contagious and results in
the development of VZV specific humoral and cell-mediated
immunity (CMI) [3]. During primary infection, VZV is transported
in a centripetal direction to the corresponding ganglionic neurons,
where it remains quiescentestablishing a lifetime immunecontrolled infection (latent infection). The onset of HZ is a multi
factorial process; evenits occurrence is closely related to a CMI
decrease. The decline of CMI is strictly age-dependent, greatly
increasing with age [4]. VZV, reactivated within sensory ganglia,
causes neuronal necrosis, intense inflammation and neuritis;
then the virus reaches the skin or mucosal surfaces innervated by
the affected neuronal segment, where it replicates, producing the
characteristic cluster of vesicles.In many patients, the rash with
typical dermatomeric distribution and radicular pain completely
disappears in 1-2 months [5]. The HZ associated pain reveals
VZV neurotropism and can assume a chronic course, named
postherpetic neuralgia (PHN) that can persist for at least 1-3
months after the eruption [6]. The estimated risk of developing

Keywords
Herpes Zoster
Shingles
Postherpetic Neuralgia
Rash
Vaccination

HZ during lifetime is 10-30%, with a marked rise with increasing

age, up to 50% in individuals over 85 years. A role in HZ onset
can also be played by gender, seasonality, race, psychological
stress, mechanical trauma, immune toxic chemicals and genetic
predisposition [7].
HZ incidence is worldwide comparable, withoutseasonal and
epidemic trend, and relatedto aging. Approximately two-thirds of
cases occur in people older than 50 years [8] and one person out
of four will develop HZ during life [9]. The international literature
describes 2-3 cases per, 000 person-years between 20 and 50
years of age, 5 cases per ,000 person-years in the sixth decade
and 6-7 cases per ,000 person-years in the seventh to eighth
decade of life. Over 50 years old subjects experiencing HZ may
suffer a significant decrease in quality of life [10]. The incidence
increases markedly with age, becoming four times higher among
older individuals aged over 70 years compared to those younger
than 60 years [11]. Therefore due the aging population, an
increasing incidence of HZ cases can be expected in the future
[12]. HZ usually occurs only once in life; anyway, recurrence rate
may be about 4-5% [13]. Complications occur in 13-40% of cases
[14]; the most frequent is PHN [15] whose incidence, affected by
different definitions and by the age of the patients observed, is
generally estimated between 10 and 20% of cases of HZ (up to
30% in the elderly) [16]. Generally 80% of all PHN cases occur in
individuals over 50 years of age [17].

CLINICAL FEATURES AND THERAPY

HZ is characterized by a vesicular rash and pain with

dermatomal distribution [18]. The reactivation of latent VZV
includes a prodromal phase, which occurs 1-5 days before the
onset of the rash in 70%-80% of cases [19], characterized by an
immune response and a neuronal cell inflammation. Prodromal
symptoms are usually non-specific [20]. In the acute phase of the

Cite this article: Armando S, Nicoletta V, Sara P, Matilde G, Silvia L, et al. (2015) Herpes Zoster: New Preventive Perspectives. J Dermatolog Clin Res 3(1):
1042.

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disease, VZV infects cells of the dermis and epidermis, generating
a rash, which usually affects a single dermatome. The unilateral
dermatomal rash can be clinically divided into four stages:
erythematous, vesicular, pustular and ulcerative [21].

The HZ generally involves dermatomes from T1 to L2, and the

first branch of the trigeminal nerve, but it is not uncommon that
patients can develop lesions in adjacent dermatomes [22]. With
increasing age more cranial lesions, including ophthalmic, and
less involvement of the chest are observed. During non-vesicular
phases, the patient is not contagious. Along with eruption,
most patients have a dermatomal pain syndrome caused by
acute neuritis, described as a burning and deep pain, prickling,
lancinating itching or pain, mild to severe [23]. The HZ acute
pain is probably the result of a combination of nociceptive pain
caused by inflammation of the skin and neuropathic pain caused
by neuronal injury [24]. The chronic phase is represented by PHN
that arises when the pain continues even after the rash has healed.
In addition to old age, the increased severity of acute pain and the
gravity of the rash are risk factors for PHN [25]. PHN is the most
debilitating aspect of HZ and itsmost common complication. The
patient with PHN may experience pain as a constant (described as
burning or pulsating pain), intermittent (as lancinating or feeling
of tension), or arising from stimuli that are not normally painful
(all odynia). Moreover, PHN can compromise the functional
status of elderly patients by interfering with basic activities of
daily living.PHN is usually defined as a long-term chronic HZrelated pain that occurs or persists at least 3 months after the
onset of rash or acute pain caused by shingles, also taking into
account the intensity of the pain that is expected to reach a value
of at least 3 in a visual analogical scale (VAS) from 0 (no pain)
to 10 (maximum imaginable pain). Some recent perspective
studies have assessed the persistence of symptoms until 10 years
after the onset of HZ, recordingpainful episodes with functional
nervous alterations.Other major complications, although less
frequent, in elderly or immune compromised subjects, are:
disseminated zoster, ocular inflammation with visual disabilities
[26-27], stroke [28], focal motor paralysis. Another complication
is the Ramsay-Hunt syndrome that occurs when VZV affects
the geniculate ganglion of the facial nerve presenting itself as
a unilateral facial paralysis accompanied by a vesicular rash in
the external ear canal, in the ear flap or tympanic membrane, or
involving hard palate or tongues [29]. The first goal of treatment
aims to accelerate the recovery of the eruption, to relieve the pain
and to reduce complications [30]. Although several progresses
in HZ and PHN treatment has been made, available therapeutic
options, using anti-viral, anti-inflammatory and analgesic drugs,
are only partially effective. Antiviral therapy is more effective if
started within 72 hours after the appearance of the rash [31], but
the early diagnosis of HZ is often difficult because of the delay in
seeking doctors advice.

Guidelines recommend oral antiviral agents for 7 days in

patients with HZ who are at risk of developing PHN (patients over
50 years old with serious acute pain, severe rash, or significant
prodromal symptoms) [31]. Despite the combined use of tricyclic
antidepressants, anticonvulsants (gabapentin and pregabalin)
and analgesics, PHN is often refractory to pharmacological
treatments and to prevention strategies [32,33].
J Dermatolog Clin Res 3(1): 1042 (2015)

VACCINATION
Considering the epidemiological impact, the complications,
and the costs of drug treatment (that is often suboptimal), a
preventive approach was urgently needed. Some investigators
have suggested a specific intervention to decrease the frequency
and the severity of HZ: during the years, it has been confirmed
that the vaccines for chickenpox, mainly those with high antigenic
content, elicit a significant increase in cell-mediated immunity.
Currently a vaccine against HZ has been licensed. It is a live,
attenuated cell-free preparation of the Oka strain of VZV used
for paediatric varicella immunization, but with a greater average
power, equalto 24,600 PFU (antigen content at least 14 times
higher than the chickenpox vaccine used in childhood) [34]. In
2006, the United States Food and Drug Administration (FDA) first
approved the vaccine for over 60 years of age subjects and in 201,
also for adults aged between 50 and 59 years on the basis of an
extensive safety and efficacy study in this age group (ZEST) [3536]. In Europe the authorization was granted in May 2006.The
vaccine, available as a powder and a solvent to be reconstituted
in suspension for injection, is indicated for the immunization
of individuals 50 years of age or older and is administered
subcutaneously as a single dose of 0.65 ml in the deltoid region
of the arm [37].
The clinical efficacy of the vaccine has been demonstrated in
two large phase III studies in over 60 years old subjects (SPS) and
in 50-59 years old individuals (ZEST). HZ vaccine significantly
reduces the risk of developing the disease and PHN and it also has
an effect on the burden od illness associated with HZ. The study
SPS [33] showed that the use of the vaccine led to a significant
reduction in the incidence of shingles of 51.3% (95% CI= 44.257.6) and decreased PHN incidence by 66.5% (95% CI=47.579.2). In the group aged between 60 and 69 years, the incidence
was decreased by 63.9%, compared to 37.6% of the population
of 70 years old and 18% in those over 80 years, proving to be
less effective in older people. During the SPS study, it was also
demonstrated that the HZ vaccine was safe and well tolerated
[33].

The ZEST study included 22,439 subjects aged 50-59

years, showing an efficacy of 69.8% (95% CI= 54.1-80.6) in the
prevention of HZ during follow-up (mean 1.3 years) [38]. A study
of persistence in the short term (STPS), started in 2004 as a
secondary study of the SPS with the aim to continue to monitor
the effectiveness of the HZ vaccine, was conducted on a subset of
14,270 subjects from 4 to 7 years after vaccination and showed
an efficacy of 39.6% (95% CI= 18.2-55.5) for the prevention of
HZ and 60.1% (95% CI= 9.8-86.7) for the prevention of PHN [39].
The LTPS, extending the follow-up to 12 years after
vaccination, assessed the duration of protection against HZ and
PHN in about a third of the subjects previously vaccinated in SPS
and STPS studies (6,867 subjects). The estimated vaccine efficacy
(in over 70 years old subjects) was 21% for the incidence of HZ
and 35% for the incidence of PHN.
The profile of effectiveness has been confirmed by other
studies indicating anadequate level of protection against HZ and
PHN [40,41].

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DISCUSSION AND CONCLUSION

HZ is a very common disease that can be associated with
severe complications with a negative impacton quality of life.
Despite the widespread of the disease, rapid and early diagnosis
and treatment are sometimes missed. The most common
complication is PHN, a severe chronic pain that can persist for
months or even years. Since effective treatment, with tolerable
side effects, is a major clinical challenge and the proportion of
frail and elderly population is increasing, preventive strategies
are essential.
In conclusion, the currently available vaccine has a good
profile in terms of immunogenicity and efficacy, also supported
by effectiveness studies, while the data of follow-up (STPS
and LTPS) showed persistent efficacy, even if the protection
progressively decreases over time and with increasing age of the
patient. It seems evident therefore the favorable profile of HZ
vaccine, whose use could have a positive impact on the health of
vulnerable elderly, helping to provide to the target population an
healthy aging, free from pain and complications by HZ, first of all
PHN.

CONFLICT OF INTEREST

GG received grants from GlaxoSmithKline Biologicals SA,

Sanofi Pasteur MSD, Novartis, Crucell/Janssen, and Pfizer for
taking part in advisory board, expert meetings, being a speaker
or an organizer of congresses/conferences, and acting as
investigator in clinical trials; SA, VN, PS, GM, LS have no conflicts
to disclose.

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Cite this article

Armando S, Nicoletta V, Sara P, Matilde G, Silvia L, et al. (2015) Herpes Zoster: New Preventive Perspectives. J Dermatolog Clin Res 3(1): 1042.

J Dermatolog Clin Res 3(1): 1042 (2015)

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