Varicella zoster virus infection
2017 Apr 5
Infection with varicella zoster virus (VZV)
causes varicella (chickenpox), which can be severe in immunocompromised
individuals, infants and adults. Primary infection is followed by latency in
ganglionic neurons. During this period, no virus particles are produced and no
obvious neuronal damage occurs. Reactivation of the virus leads to virus
replication, which causes zoster (shingles) in tissues innervated by the
involved neurons, inflammation and cell death — a process that can lead to
persistent radicular pain (postherpetic neuralgia). The pathogenesis of
postherpetic neuralgia is unknown and it is difficult to treat. Furthermore,
other zoster complications can develop, including myelitis, cranial nerve
palsies, meningitis, stroke (vasculopathy), retinitis, and gastroenterological
infections such as ulcers, pancreatitis and hepatitis. VZV is the only human
herpesvirus for which highly effective vaccines are available. After varicella
or vaccination, both wild-type and vaccine-type VZV establish latency, and
long-term immunity to varicella develops. However, immunity does not protect
against reactivation. Thus, two vaccines are used: one to prevent varicella and
one to prevent zoster. In this Primer we discuss the pathogenesis, diagnosis,
treatment, and prevention of VZV infections, with an emphasis on the molecular
events that regulate these diseases. For an illustrated summary of this Primer,
visit: http://go.nature.com/14×VI1
Varicella zoster virus (VZV, also known as human
herpesvirus 3) is a ubiquitous alphaherpesvirus with a double-stranded DNA
genome. VZV only naturally infects humans, with no animal reservoir; its main
targets are T lymphocytes, epithelial cells and ganglia. Primary infection
causes varicella (chickenpox), during which VZV becomes latent in ganglionic
neurons. As cellular immunity to VZV wanes with advancing age or in
immunocompromised individuals, VZV reactivates to cause zoster (shingles).
Zoster can be complicated by chronic pain (postherpetic neuralgia (PHN)) and
other serious neurological and ocular disorders (for example,
meningoencephalitis, myelitis, cranial nerve palsies, vasculopathy, keratitis
and retinopathy), as well as multiple visceral and gastrointestinal disorders,
including ulcers, hepatitis and pancreatitis1,2 (Fig. 1). Antiviral drugs
and vaccines against both varicella and zoster are available and are effective
in treating and preventing VZV-induced disease2.
1
VZV is
highly communicable and spreads by the airborne route, with an extraordinarily
high transmission rate3 in
temperate countries. Traditionally, the virus was thought to spread to others
from the respiratory tract, but such evidence is scant. Instead, most virus
comes from skin where it is highly concentrated in vesicles; skin cells and
cell-free VZV are frequently shed and are probably the major source of
infectious cell-free airborne virus4,5. Infected children without skin lesions are
not contagious to others4.
The highly efficient transmission of VZV assured that, before the
introduction of the varicella vaccine, most children would contract varicella
before 10 years of age. Varicella in children is usually self-limiting,
although complications can be unpredictable, and long-lasting immunity follows
once the patient recovers. Epidemics are also self-limiting because the high
rate of transmission and disease-induced immunity deplete the pool of
susceptible individuals6. Most older children and adults harbour
latent wild-type VZV or vaccinetype VZV (vOka)2. Sporadic reactivation of VZV causes zoster
and provides an evolutionary advantage for the pathogen by providing a source
of infection in new, susceptible birth cohorts.
VZV occurs worldwide, but
in some developed countries there is less concern for VZV than for other
infectious agents, such as influenza virus, Ebola virus and multidrug-resistant
staphylococci. However, even in countries where varicella vaccination is
routine there has not been an eradication of VZV disease. Import of varicella
from countries that do not vaccinate and zoster caused by reactivation of
latent wild-type VZV or vOka can occur. Given the increasing number of
immunocompromised individuals worldwide, it is important to maintain
substantial levels of herd immunity against varicella in developed countries
and to extend vaccination to developing countries. Recently, the WHO
recommended “routine immunization of children against varicella in countries
where varicella has an important public health impact”7. In addition, because of the current
anti-vaccine movement in some countries, it is also wise to maintain interest in
VZV research and to improve current methods to prevent and treat varicella and
zoster. In this Primer article, we summarize the diseases and complications of
VZV infection, how latency develops, how and when to vaccinate and treat
patients, and we highlight open research questions (BOX 1).
Varicella occurs worldwide and is endemic in populations of
sufficient size to sustain year-round transmission, with epidemics occurring
every 2–3 years3.
Viral genomic studies have identified five viral clades and their geographical
distribution: clades 1, 3 and 5 are of European origin; clade 2 includes Asian
strains such as the parental Oka strain, from which varicella and zoster
vaccines were derived; and clade 4 contains African strains8. Varicella epidemiology and disease burden
have been studied primarily in developed countries. Although VZV seroprevalance
data are becoming more widely available, additional data are needed on severe
disease outcomes and deaths to better characterize the global health burden due
to varicella, particularly in regions with high HIV prevalence, such as Africa
and India7.
Varicella incidence ranges from 13 to 16 cases per 1,000 persons
per year, with substantial yearly variation3.
In temperate climates, age-specific varicella incidence is highest in preschool
aged children (1–4 years of age) or children in early elementary school (5–9
years of age) with an annual incidence of greater than 100 per 1,000 children;
as a result, >90% of people become infected before adolescence and only a
small proportion (<5–10%) of adults remain susceptible3,9. In tropical climates, acquisition of
varicella occurs at a higher overall mean age (for example, at 14.5 years in
Sri Lanka), with a higher proportion of cases in adults3,10. Differences in varicella epidemiology
between temperate and tropical climates might be related to the properties of VZV,
for example, inactivation by heat and/or humidity, or factors affecting the
risk of exposure3.
Varicella
shows a strong seasonal pattern, with peak incidence during winter and spring
or during the cool, dry season3,11. Outbreaks occur commonly in settings where
children congregate, such as childcare centres and schools, but can also occur
in other age groups and settings, including hospitals, facilities for
institutionalized people, refugee camps and military and correctional facilities12–14.
Although varicella is usually a self-limiting disease, it can
result in serious complications and death. In developed countries, ~5 out of
1,000 people with varicella are hospitalized and 2–3 per 100,000 patients die15,16. Serious varicella complications include bacterial
sepsis, pneumonia, encephalitis and haemorrhage3.
Adults, infants and individuals who are severely immunocompromised are at
higher risk of severe complications and death. Varicella acquired in the first
two trimesters of pregnancy causes severe congenital defects in the newborn in
~1% of affected pregnancies17.
VZV infection and replication
Primary infection
Following transmission to susceptible hosts, VZV proliferates in
the oral pharynx (tonsils), infects T cells that enter the circulation and
disseminate virus to the skin and possibly other organs; infection is at first
controlled by innate immunity32,33.
VZV can
remodel diverse T cell populations to facilitate skin trafficking34. VZV DNA can be detected in T cells
(viraemia) as early as 10 days prior to the occurrence of a rash and can
persist for a week afterwards35. Initially, innate immunity delays
viral multiplication in the skin, which provides time for adaptive immunity to
develop32. Eventually,
cutaneous innate immune responses are overcome by the virus, and there is
substantial viral replication in the skin (and sometimes the viscera),
resulting in the characteristic rash of varicella33 (FIG. 3). High titres of cell-free VZV develop
in skin vesicles and transmit VZV to others5. Important and unpredictable
complications of varicella in previously healthy children include encephalitis,
haemorrhagic manifestations, and bacterial superinfections involving skin,
blood, bones and lungs.
2
When VZV reactivates, ganglia become necrotic and
haemorrhagic48. VZV proteins are found in neurons and non-neuronal cells,
and ganglionitis is marked by the upregulation of MHC class I and II proteins
and the infiltration of CD4+ and CD8+ T cells49–51. Ganglionitis and CD8+ T cell infiltration can persist after
zoster51. Expression of late viral proteins, such as envelope
glycoprotein E, shows that lytic VZV infection has occurred2. However, the meaning of the immunocytochemi-cal detection
of immediate early and early proteins in neurons during latency is controversial2; these proteins have been detected in latently infected
neurons52–54. All latency-associated proteins are cytoplasmic, but become
nuclear during productive infection53–55. Immediate early and early proteins are also cytoplasmic in
latently infected guinea pig neurons and translocate to the nucleus when
reactivation is induced42,46,47,56.
Neurological complications of zoster
Zoster paresis
Manifestations of zoster paresis include arm or diaphragmatic
weakness after cervical zoster59, leg weakness after lumbar or sacral
zoster and urinary retention after sacral zoster60. MRI reveals involvement of both
dorsal and ventral roots of spinal nerves61. Rarely, cervical zoster paresis
extends to the brachial plexus62. The prognosis varies, but ~50% of
patients recover completely63.
Neuralgia
PHN, the most common complication of zoster, is defined as pain
that persists for at least 3 months after rash onset. Three non-mutually
exclusive theories have been proposed to explain the cause and pathogenesis of
PHN. One is that the excitability of ganglionic or spinal cord neurons is
altered during recovery64. The second is that persistent
productive VZV infection exists in ganglia, a notion that is supported by
possible chronic ganglionic inflammation in PHN65. A third theory is that PHN might be
due to gene expression and protein production without virus replication but
with disturbance of neuronal physiology.
Recently,
certain strains of VZV were postulated to produce PHN by altering voltage-gated
sodium channels, leading to altered excitability66,67. Isolated and then cultured VZV
strains from patients with PHN and those with zoster but without PHN were
applied to neuroblastoma cells that express fast and slow sodium channels.
Voltage-clamp recordings from infected neuroblastoma cells revealed that the
amplitude of the sodium current was greater in cells infected with VZV isolated
from those with PHN than in cells from those without PHN. Increased sodium
current is associated with neuropathic pain; thus, VZV-induced increases in
sodium currents could have a role in PHN. These experiments suggest that PHN
might be partly attributable to the particular strain causing zoster. This
intriguing possibility clearly needs confirmation and further research.
Virological
analyses of ganglia from patients with PHN are lacking. One study reported the
detection of VZV DNA in peripheral blood mononuclear cells (PBMCs) for up to 8
years after zoster in 11 out of 51 patients with PHN but not in controls68. A case report described a
correlation between pain and VZV DNA detection in PBMCs in an immunocompetent
elderly woman with PHN69. After treatment with famciclovir (a
guanosine analogue antiviral drug), pain resolved and the PBMCs no longer
contained VZV DNA.
If PHN is caused by persistent VZV replication in neurons,
antiviral treatment might decrease its severity. Treatment with oral antiviral
agents reduces pain associated with acute zoster; however, this acute treatment
has not reduced the incidence, severity or duration of chronic pain of
immunocompetent patients with PHN70–73. Acyclovir improved symptoms in 1 out
of 10 patients with PHN72, whereas valaciclovir improved
symptoms in 8 out of 15 patients73. Proof of a positive effect of
antivirals on PHN would require a randomized controlled study of patients with
PHN. Most studies, however, have not found antiviral therapy to be effective in
the treatment of PHN74 and regulatory authorities do
not recommend antivirals to treat this condition75.
VZV meningoencephalitis
Acute VZV infection may present as meningitis or meningoencephalitis
with or without rash. Detection of VZV DNA and antibodies in cerebrospinal
fluid has confirmed VZV as a cause of aseptic meningitis76, meningoradiculitis77 and cerebellitis78.
VZV vasculopathy
A serious complication of VZV reactivation is infection of the
cerebral arteries (VZV vasculopathy), which causes ischaemic and haemorrhagic
stroke. The incidence of VZV vasculopathy is unknown. In children, up to
one-third of ischaemic arteriopathies are associated with varicella79. In adults, the risk of stroke is
increased by 30% within 1 year of zoster80 and by 4.5-fold after zoster in
the ophthalmic branch of the trigeminal nerve81. One large population-based analysis
showed that the risk was even higher: stroke was observed within a 1-year of
follow-up in 8.1% of people with zoster ophthalmicus compared with only 1.7% in
a matched control group82. However, no cases of vasculopathy or
stroke were observed among 984 patients with documented zoster followed up for
>6 months after rash onset, although 86% received antiviral therapy22. Indeed, stroke following zoster
ophthalmicus is of high clinical importance83,84. VZV that reactivates in the
trigeminal nerve can travel via the ophthalmic sensory nerves to the face and
via afferent sensory fibres to the internal carotid artery and its intracranial
branches85,86. Thereafter, the virus establishes
infection in the arterial wall, which leads to inflammation, arterial
weakening, aneurysm formation, occlusion and stroke87. Infected cerebral arteries contain
multinucleated giant cells, Cowdry A inclusions (accumulations of viral DNA and
protein in the cell nucleus) and herpesvirus particles, as well as VZV DNA and
VZV antigens81,85.
VZV vasculopathy presents with headache, mental status changes and
focal neurological deficits. Large and small vessels are involved81. Brain MRI frequently reveals lesions
at grey-white matter junctions. In more than two-thirds of patients,
angiography reveals focal arterial stenosis and occlusion, aneurysm or
haemorrhage81.
VZV and giant cell arteritis
One of the most exciting recent developments is the detection of
VZV antigen, VZV DNA and virus particles in the temporal arteries of patients with
giant cell arteritis (inflammatory vasculopathy, most often involving the
temporal arteries)88. Analysis of temporal artery biopsies
from healthy individuals aged >50 years and from patients with arteritis
revealed VZV antigen in the temporal arteries of 61 out of 82 (74%) of patients
with arteritis compared with 1 out of13 (8%) in normal temporal arteries88. This discovery, if confirmed,
suggests that antiviral treatment might confer additional benefit to
corticosteroids in patients with giant cell arteritis.
VZV-induced diseases of the eye
VZV can cause stromal keratitis with corneal anaesthesia, acute
retinal necrosis and progressive outer retinal necrosis, particularly in
immunocompromised individuals. Patients complain of eye pain and loss of
vision. Retinal haemorrhages and whitening with bilateral macular involvement
may occur. Zoster, aseptic meningitis, vasculitis or myelitis can precede
retinal necrosis89. As with neurological disease,
VZV-associated ocular disorders can also occur without rash.
Diagnosis
Diagnosis of varicella and
zoster is most often made clinically on the basis of the characteristic
generalized or unilateral dermatomal vesicular rashes, respectively. Notable
exceptions include the following characteristics: atypical rashes, such as disseminated
zoster or a minimal or absent dermatomal rash; zosteriform herpes simplex;
modified (breakthrough) varicella in vaccinated individuals; and rashes caused
by enteroviruses, poxviruses, rickettsia, drug reactions or contact dermatitis;
and VZV infection in the absence of a rash. The latter includes, for example,
zoster without rash (known as zoster sine herpete, sometimes with or without
facial palsy90), meningitis1,91,92, stroke81,93–97, myelitis98 and enteric (gastrointestinal)
infections45,99–102. In these settings, rapid diagnosis is
necessary to plan appropriate therapy and public health measures. Diagnosis by
measurement of VZV-specific antibodies in serum samples is accurate but does
not yield results rapidly enough to be clinically useful because of the time it
takes for patients to develop antibodies. Serum antibodies are generally of no
help unless anti-VZV IgM is detected and even its presence can be nonspecific.
For laboratory diagnosis of VZV infection, the following
approaches are currently most useful: PCR on material from skin vesicles
(submitted as swabs, fluid or scabs102–104), saliva90,102,103,105–107 and cerebrospinal fluid if
neurological symptoms or signs are present91,92,108,109. Detection of VZV antigens by direct
immunofluorescence from vesicles is also rapid and specific, although less
sensitive than PCR110. During varicella and zoster, viral DNA can
be detected in saliva, and this method is diagnostically useful and specific in
symptomatic patients with or without rash102,104,106. PCR along with restriction enzyme digest
and sequencing of specific segments of the viral genome can be used to
determine whether VZV is resistant to acyclovir111.
When symptoms develop in vaccinated individuals that suggest VZV
infection, such as rash or meningitis (even without rash), it is important to
identify VZV by PCR, and it can be useful to determine whether the virus is
wild-type VZV or vOka104,112–114. In the United States, testing can be
performed free of charge at either the National Virus Laboratory at the Centers
for Disease Control and Prevention (CDC) or the Columbia University VZV
Identification Program of the Worldwide Adverse Experience System of Merck
& Co. The FDA is notified of these results if they are related to
complications of vaccination, and clinical information on these vaccinated
patients is often published2. Other countries have similar testing
facilities (for example, the VZV Reference Laboratory in the United Kingdom)115.
Notably, VZV DNA can be detected transiently in the saliva of
severely stressed adults116 and children117 in the absence of specific symptoms,
indicating subclinical reactivation of the virus. Nevertheless, testing of
saliva is remarkably specific because VZV DNA is rarely detected in
asymptomatic human volunteers aged <60 years40,102,118. The presence of VZV DNA does not
necessarily equate to the presence of infectious virus. During zoster, a single
infected cell can contain thousands of copies of VZV DNA and that DNA can
persist long after infectious VZV has been cleared. ‘Contained reversions’
(silent reactivation of latent VZV) (FIG. 5) may also be a source of VZV DNA, which makes
it problematic to demonstrate that vasculopathy without rash is a complication
of zoster or that PHN is associated with continuing VZV replication.
Furthermore, despite evidence of asymptomatic shedding of VZV DNA, there is
little epidemiological evidence to indicate that asymptomatic individuals
transmit VZV infection3,4. By contrast, most infections with herpes
simplex virus result from asymptomatic shedding. Nevertheless, detection of VZV
DNA in saliva or blood in immunocompetent individuals with minimal symptoms may
permit diagnostic suspicion of early zoster before rash onset and the
initiation of antiviral therapy sufficiently early to halt ganglionic infection
before the damage responsible for PHN has occurred.
Prevention
Varicella vaccine
A live attenuated varicella vaccine was developed in Japan by
Takahashi and colleagues in 1974 (REF 119). VZV was isolated from a boy with
varicella, and the virus was attenuated by cultivation for 33 serial passages
in human and guinea pig fibroblasts, with some passages at low temperature
(34°C)119. Live,
attenuated vOka consists of a mixture of distinct VZV genotypes, with 42 single
nucleotide polymorphisms distinguishing vOka from the wild-type Oka parent
strain120,121. The exact mechanisms for the
attenuation of VZV in live vaccines remain unknown; mutations in ORF62 were identified
in vOka122 and
mutations at positions 106262, 107252 and 108111 in ORF62 are important112, as is a stop codon mutation at
position 560 in ORF0 (REF 123). These mutations, particularly the
unique mutations at positions 106262 and 108111 in ORF62, can be used to
differentiate parental Oka and other wild-type strains of VZV from vOka104,112.
Initially,
the vaccine was highly controversial because of the fear of latent vOka, the
possibility that the virus might be oncogenic and the possibility that immunity
from vaccination would not be long-lasting. The vaccine was tested in Japan for
~5 years before reaching the rest of the world124,125. By 1979, there was much interest in
the vaccine in the United States because many young children who had been cured
of leukaemia died of varicella infection. In a large collaborative trial,
>500 children with leukaemia in remission who were still receiving
maintenance chemotherapy were vaccinated with vOka. The vaccine was
considerably safer than infection with wild-type VZV and protected ~85% of
recipients from varicella126. Studies in healthy children also
demonstrated a high degree of safety and protection against varicella127–129. In 1995, this live attenuated
varicella vaccine was licensed in the United States and routine immunization
recommended for healthy American children at 1 year of age9. In 2007, when a second dose was shown
to offer even greater protection than one dose130, a two-dose schedule, with the
second dose given at aged 4–6 years or at least 3 months after the first dose,
was recommended by the CDC9. Two doses of the varicella vaccine
are also recommended for older children, adolescents and adults without
evidence of varicella immunity, including health-care workers. Currently, the
varicella vaccine, using one or two doses, is also licensed in Australia,
Brazil, Canada, China, Germany, Greece, Israel, Italy, Japan, Qatar, South
Korea, Spain, Taiwan and Uruguay.
In countries without varicella vaccination, prevention by passive
immunization (injection of VZV-specific antibodies) might be available, which
provides temporary protection for several weeks131. Antiviral therapy has been used for
the prevention of varicella132,133 and zoster134,135 in immunocompromised patients,
but is not uniformly accepted as useful. Acyclovir-resistant VZV rarely
develops in a small number of treated immunocompromised patients136–138.
Immunity after vaccination
The varicella vaccine is highly effective in preventing varicella,
with little decline in immunity over time139,140. Between 1995 and 2003 the incidence
of varicella decreased by 80% in some areas of the United States141, and the number of hospitalizations
and deaths decreased19. In a study of >7,000 vaccine
recipients, long-lasting (15 years) immunity was demonstrated, with 90%
efficacy in preventing varicella despite 70% of children having received only
one dose of the vaccine139. At present, there seems to be no
need for booster doses of the varicella vaccine because significant waning immunity
has not been observed139,140.
Silent reactivation (contained reversions) of latent VZV (FIG. 5) can boost immunity endogenously2 and is likely to contribute to
long-lasting immunity to varicella and zoster20. Exogenous boosting due to exposure
to individuals with VZV infections also occurs27,142 (FIG. 5). Not appreciating the potentially
important role of asymptomatic reactivation in maintaining immunity to VZV,
epidemiologists predicted that widespread vaccination and the resulting lack of
exogenous immune stimulation would result in increased incidence of zoster143,144. This has been the justification for
not using the varicella vaccine universally in children in several countries in
Europe. The incidence of zoster has been increasing in the United States since
the 1950s, long before the varicella vaccine was available, and increases are
also reported in other countries without vaccination programmes145. Thus, it seems that the varicella
vaccine is unlikely to contribute substantially to an increase in the incidence
of zoster. The role of subclinical (or mild) endogenous reactivation of latent
VZV in maintaining immunity is evidenced by a study performed in France: the
rate of zoster (15–16%) in isolated populations over ~30 years was no higher
than it was in the general public146. Accordingly, latency (with the
possibility of silent or minimal viral reactivation) might be an asset rather
than a liability for the varicella vaccine146.
Vaccine safety
The varicella vaccine is safe and well tolerated. Serious adverse
events after vaccination are unusual; ~100 million children and adults have
been vaccinated and vaccine-related serious adverse event reactions have been very
rarely reported and have occurred almost exclusively in recipients who were
immunocompromised but not recognized to be so3,138. The development of varicella in
vaccine recipients (breakthrough varicella) is unusual, and when it occurs it
is almost invariably mild3.
Vaccinated children who develop a rash in the first month after
immunization rarely transmit vOka to close contacts; those who develop
varicella due to wild-type VZV are more likely to transmit the virus to others3.
Transmission is positively correlated with the number of skin lesions4,147. Rash caused by vOka is unusual
following vaccination in children and even if it occurs, vaccinated children
usually develop few skin lesions. When wild-type VZV infects vaccinated
children, they rarely develop an extensive rash. Transmission of vaccine-type
type VZV from vaccinated individuals is rare. The risk of developing zoster
after vaccination is lower than after varicella caused by wild-type VZV; at
present, 30–50% of cases of zoster in vaccinated children are attributable to
wild-type VZV148,149.
Zoster vaccine
Development of the varicella vaccine paved the way for the
development of a vaccine to prevent zoster and its complications119. Clinical observations by
Hope-Simpson, reported in a landmark publication in 1965 (REF 20), provided the rationale for the
development of a therapeutic zoster vaccine. Hope-Simpson postulated that
primary VZV infection establishes lifelong latency of VZV in sensory ganglia
and induces immunity to VZV that prevents the reactivation, replication and
spread of latent VZV and, therefore, zoster. He proposed that this immunity
gradually decreases, eventually permitting latent VZV to reactivate, multiply
and re-emerge as zoster. He further proposed that both exogenous and endogenous
exposure to VZV stimulate the host’s immunity (FIG. 5). Noting that second episodes of zoster
were uncommon, he proposed that an episode of zoster also stimulates immunity
to VZV, essentially immunizing the host against another episode of zoster.
Subsequent investigations have validated every component of Hope-Simpson’s
prescient hypothesis3,150.
In the
Shingles Prevention Study (SPS), a doubleblind, placebo-controlled trial,
38,546 healthy adults aged ≥60 years (median 69 years) were randomly assigned
to receive a single dose of high-potency vOka (14 times greater potency than
the varicella vaccine) or placebo22,151,152. Two co-primary end points were
investigated: the burden of illness owing to zoster (a severity-by-duration
measure representing the total pain and discomfort) and the incidence of
clinically significant PHN. The incidence of zoster was also determined. The
higher-potency vaccine was required to increase VZV-specific cell-mediated
immunity in latently infected older adults22,151.
A total
of 19,270 people who received the zoster vaccine and 19,276 who received
placebo were followed up on average for 3.13 years22,152. There were 957 confirmed evaluable
cases of zoster (315 in vaccine recipients and 642 in placebo recipients). In
both groups, >93% of the subjects with zoster were positive for wild-type
VZV DNA by PCR and none had vOka DNA22,104.
The
vaccine reduced burden of disease by 61.1% (65.5% in people aged 60–69 years
and 55.4% in people aged ≥70 years). The duration of pain and discomfort among
subjects with zoster was shorter in vaccinated candidates compared with placebo
recipients22,152. The vaccine reduced the incidence
of zoster by 51.3% (63.9% in people aged 60–69 years but only 37.6% in people
aged ≥70 years). The incidence of clinically significant PHN was reduced by
more than 65% for both age groups. Furthermore, the zoster vaccine reduced the
percentage of people with zoster who developed PHN by >31%, with most
benefit in the group aged ≥70 years, which had the highest risk of developing
this complication22,152. The SPS also demonstrated that the
vaccine reduced the adverse impact of zoster on patients’ capacity to perform
activities of daily living and health-related quality of life153.
The zoster
vaccine is safe. Rates of serious adverse events, systemic adverse events,
hospitalizations and deaths in the SPS were low in vaccine recipients and
comparable with those in placebo recipients22,151,154. During the first 42 days after
vaccination, 24 cases of zoster in placebo recipients were reported and 7 cases
in the vaccination group, none of which were caused by vOka104. In contrast to prophylactic
vaccines, such as those against varicella and measles, the zoster vaccine is a
therapeutic vaccine intended to prevent reactivation and replication of latent
VZV with which the recipient is already infected before vaccination and to
which the recipient already has substantial immunity.
The
zoster vaccine was licensed by the FDA in 2006 and recommended by the CDC in
2008 for the routine immunization of healthy adults aged ≥60 years for
prevention of zoster and its complications, primarily PHN155. Post-licensure studies have
confirmed the vaccine’s safety and efficacy151,156,157. Unfortunately, uptake of the zoster
vaccine has been low, which is probably due to the high cost and general lack
of appreciation of the importance of preventing infectious diseases in older
adults121. The
vaccine has now been shown to be safe and effective in healthy individuals aged
50–59 years158. At present, the zoster vaccine can
be used in this age group but it is not yet officially recommended.
The SPS demonstrated persistent efficacy 4 years after
vaccination. In additional substudies159,160, efficacy for burden of disease persisted
for 10 years after vaccination but efficacy for the incidence of zoster
persisted only for 8 years160. The CDC currently does not
recommend booster doses of the zoster vaccine, but it might do in the future.
New subunit vaccine
The development by GlaxoSmithKline of a liposome-based subunit
vaccine (HZ/su), which contains the VZV glycoprotein E and the adjuvant ASO1B,
promises to change prospects for immunization against zoster and its
complications. Phase I and II studies established that two doses of HZ/su
containing 50 μg of recombinant VZV glycoprotein E administered 1 or 2 months
apart were well tolerated and induced much more robust VZV-specific and VZV
glycoprotein E-specific CD4+T cell and antibody responses than vOka161,162. Two large Phase III placebocontrolled
efficacy trials have been recently completed in individuals aged ≥50 years and
in individuals aged ≥70 years163,164. The efficacy against zoster in the
younger study group was ~97%. HZ/su has not been tested for its efficacy in
preventing varicella, partly because vOka is extremely effective for this
purpose. The adjuvanted glycoprotein E vaccine is non-replicating, and can,
therefore, be used in immunosuppressed patients who are currently precluded
from receiving the live attenuated vOka zoster vaccine155.
Severe varicella is characterized by extensive
and prolonged viral replication, often associated with fever, continued
development of new skin vesicles for >5 days, and/ or involvement of the
lungs, liver and/or brain (FIG. 3 illustrates a
dense vesicular rash in a febrile infant on day 5). Severe varicella is a
feared complication that was a major impetus towards vaccine development.
Severe varicella has caused many deaths in individuals with congenital or
acquired impairment of cellular immunity, even after the development of
antiviral therapy169. Children with impaired innate immunity, for example, those
with natural killer cell abnormalities, are also at risk for severe varicella,
including that caused by vOka170. Thus, strenuous
measures should be taken to prevent VZV infection in this group, including
post-exposure prophylaxis9,171. Since the 1980s, the main treatment has been antiviral
therapy with high-dose intravenous acyclovir172 together with
supportive intensive care. Acyclovir is a guanosine analogue that inhibits the
synthesis of viral DNA (FIG. 7) and treatment
with acyclovir reduces visceral dissemination of the virus. It is typically
given for 7–10 days and can be switched to oral therapy 48 h after the last
lesions appear or continued until all lesions are crusted. Oral acyclovir has
poor bioavailability; thus, the related drugs valaciclovir and famciclovir,
which have excellent absorption from the intestinal tract, produce high blood
antiviral activity and have a long half-life, should be used for oral therapy
instead. Valaciclovir and famciclovir are prodrugs, which are converted to
active guanosine analogues in vivo. As both prodrugs
need less frequent administration than acyclovir, patient compliance is
improved and they are frequently used in children aged >2 years and in
adults. Immunocompromised patients with severe VZV infections still receive
intravenous acyclovir, which results in higher blood levels than oral therapy.
Alternatively, intravenous foscarnet and cidofovir can be used. However,
because of toxicity, these drugs should be only used in immunocompromised
individuals with acyclovir-resistant VZV. Notably, intravenous antivirals,
including acyclovir, can be nephrotoxic; both acyclovir and foscarnet require
dose adjustment in patients with renal impairment.
VZV
infection in individuals aged >13 years is associated with an increased risk
of severe or fatal outcome, and oral antiviral therapy is recommended, even in
otherwise healthy adolescents and adults3 (FIG. 6). In immunocompetent patients, oral acyclovir,
or preferably famciclovir, or valaciclovir need to be started within 24 h of
the first skin lesions to shorten the duration of fever and rash173; 5 days and 7 days of treatment have
comparable efficacy174.
Varicella in pregnant women is also problematic: pregnancy
increases the risk of severe disease in the mother and VZV can harm the unborn
child and lead to congenital abnormalities (congenital varicella syndrome)17,175. Thus, pregnant women with varicella are
usually treated with intravenous acyclovir, even though this is a category B
drug (that is, animal studies have failed to demonstrate a risk to the fetus
but no wellcontrolled studies have been conducted in pregnant women) and not
licensed in pregnancy. The effect of treatment on the development of congenital
varicella syndrome is unknown. Maternal onset of varicella between 5 days
before and 2 days after delivery is associated with a high risk of severe
varicella in the newborn, who should receive prophylaxis with VZV-specific
immunoglobulin175. Newborns with congenital varicella
syndrome should receive high-dose intravenous acyclovir every 8 h owing to
increased clearance of the drug in this age group. Oral acyclovir is poorly
absorbed and should be used cautiously, if at all.
Bacterial superinfection
is the most common severe complication of varicella; varicella is a major risk
factor for invasive group A streptococcal disease176. Superinfection presents with recurrence of
fever with or without localized signs of cellulitis (infection of the skin and
subcutaneous fat tissue), bone and joint infection or pneumonia. Cellulitic
features accompanied by disproportionate pain, fatigue and systemic signs and
symptoms can indicate necrotizing fasciitis, even in the absence of fever, and
should prompt immediate antibacterial therapy together with resuscitative
measures, analgesia and urgent consideration of surgical debridement. Other
possible complications of varicella are cerebellar ataxia, ischaemic stroke and
acquired protein S deficiency with purpura fulminans and venous thrombosis3,177,178. The effect of antiviral therapy on
individual complications is unclear but a pragmatic approach is to treat if
there is evidence of ongoing viral replication (such as continuing new vesicle
formation and/or persistent PCR positivity in blood or cerebrospinal fluid in a
symptomatic patient).
Latency and reactivation
How VZV latency is
achieved and maintained is a challenging question. It remains unclear whether
VZV latency is a period of relative viral quiescence due to a transient block
in complete gene expression or whether the virus is often or constantly in a
state of abortive reactivation. Studies of surgical removal of enteric ganglia
suggest a block in gene expression43,44, although recent autopsy studies support the
hypothesis of abortive reactivation, but further research is needed42. Asymptomatic VZV reactivation is also of
great interest. For example, whether some viral genes are translated with or
without synthesis of virus particles, and whether these are delivered to skin
by axonal transport with or without spread to satellite cells surrounding the
neuron, remain unclear. Delivery of virions to skin may not necessarily cause
lesions if replication is controlled rapidly by innate immunity and by adaptive
immune responses. Further research in this area is important.
The recognition that VZV
is a pathogen in the human gut was an unanticipated finding because VZV
infections were long associated with cutaneous manifestations, which may not
occur when VZV reactivates in enteric neurons. The nature of enteric zoster is,
therefore, another issue that requires further study.
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