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IMPROVING THEMANAGEMENTOF VARICELLA,
HERPES ZOSTER AND ZOSTER-
ASSOCIATED PAIN
Recommendations from the IHMF Management Strategies Workshop
Editors: Dr R JohnsonDr D Patrick
management s trategies in herpes
1
CONTENTS
Introduction 2
Recommendation Categories 3
Workshop Participants 4
Chapter 1Advances in the Pathogenesis, Molecular Biology and Immunology
of Varicella Zoster Virus 5
Chapter 2Introduction to Varicella 10
Chapter 3Varicella Vaccination 21
Chapter 4Management of Varicella in the Immunocompetent Host 33
Chapter 5Introduction to Herpes Zoster and Future Directions 46
Chapter 6Management of Herpes Zoster in the Immunocompetent Host 58
Chapter 7Varicella Zoster Infection of the Eye 69
Chapter 8Management of Varicella Zoster Virus Infections in the Immunocompromised Host 77
Chapter 9Managing Established Pain in Herpes Zoster 100
2
INTRODUCTION
The International Herpes Management Forum (IHMF) was established to improve the
awareness, understanding, counselling and management of infections caused by
herpesviruses. Steered by Professor Richard Whitley, Professor Lawrence Corey, Professor
Paul Griffiths, Dr Jean-Elie Malkin, Dr Antonio Volpi, Dr David Patrick, Dr Robert Johnson,
Dr Lawrence Stanberry and Dr Anders Strand, the IHMF involves international opinion
leaders in all aspects of the management of herpesvirus infections.
A Management Strategies workshop was held on 6–7 March 2001 to discuss the
management of varicella zoster virus (VZV) infections in immunocompetent and
immunocompromised individuals. At the workshop, draft recommendations were
formulated on:
J Pre-exposure varicella vaccination
J Management of varicella and herpes zoster in immunocompromised individuals
J Management of unusual manifestations of varicella and herpes zoster in
immunocompetent and immunocompromised individuals
J Management of herpes zoster-related eye disease
J Application of new technologies and models to understanding the pathogenesis of
VZV infection.
This monograph reviews the available information on these aspects of the management of
VZV infections.
The editors would like to thank all the participants in the Management Strategies
Workshop and those who contributed to the ratification of the guidelines on the IHMF
website (www.ihmf.org).
RECOMMENDATION CATEGORIES
Category 1 Consistent evidence from controlled clinical trials. For example, for an antiviral, this would
include results from at least one well-designed, randomized, controlled clinical trial, and,
in the case of laboratory studies, consistent evidence from comparative studies.
Category 2Evidence from at least one well-designed clinical trial without randomization, from cohort
or case-controlled analytical studies (preferably from more than one centre), or from
multiple time-series studies or dramatic results from uncontrolled experiments.
Category 3Evidence from opinions of respected authorities based on clinical experience, descriptive
studies or reports of expert committees.
Research NeedArea in which research is warranted.
3
4
WORKSHOP PARTICIPANTS
ChairsDr R Johnson Consultant Anaesthetist, Bristol Royal Infirmary, Department of
Anaesthesia, Level 7, Marlborough Street, Bristol, BS2 8HW, UK
Dr D Patrick Associate Professor, Epidemiology & Infectious Diseases,University of British Colombia, Centre for Disease Control, 655West 12 Avenue, Vancouver, British Colombia, V5Z 4R4, Canada
ParticipantsProfessor HH Balfour Professor of Laboratory Medicine & Pathology, Professor of
Pediatrics, University of Minnesota, 15-144 PWB, 516 DelawareStreet SE, Minneapolis, Minnesota 55455-0392, USA
Dr J Breuer Reader in Virology, Dept of Medical Microbiology, StBartholomew’s & the Royal London Hospitals Medical School,Queen Mary Westfield College, 37 Ashfield Street, London, E1 1BB, UK
Professor J Gnann Associate Professor of Medicine, Division of Infectious Diseases,The University of Alabama School at Birmingham, 220 BevilBiomedical Research Building, 845 19th Street South,Birmingham, Alabama 35294-2170, USA
Dr K Higa Professor of Anesthesiology, Department of Anesthesiology,Fukuoka University, School of Medicine, 18-19-1 Nanakuma,Jonan-ku, Fukuoka 814-0180, Japan
Dr M Rowbotham Associate Professor & Director, Pain Clinical Research Center,University of California, Mount Zion, 1701 Divisadero Street,Suite 480, San Francisco, California 94117, USA
Dr J Seward Chief, Varicella Activity, Acting Chief, Child Vaccine PreventableDisease Control Branch, National Immunization Program, CDC,1600 Clifton Road, MS E-61, Atlanta, Georgia 30333, USA
Professor RJ Whitley Director of the Division of Clinical Virology & Professor ofPediatrics, Microbiology & Medicine, The University of Alabamaat Birmingham, Suite 616 Children’s Hospital, 1600 7th AvenueSouth, Birmingham, Alabama 35233-0011, USA
Dr MJ Wood Consultant Physician, Department of Infection & TropicalMedicine, Birmingham Heartlands Hospital, Bordesley GreenEast, Birmingham, B9 5ST, UK
5
Management Recommendations and StatementsResearch needs J Improved and predictive animal models are needed for the study of acute disease and
of latent varicella zoster virus (VZV) infection and to assess the effect of potential new
drugs for the treatment of varicella and herpes zoster. It is recommended that the
development of suitable small animal models for studying VZV infection be continued.
J Although VZV reactivates in the dorsal root ganglia, it is unclear whether or not there
are other potential sites of reactivation. It is important to ascertain whether the virus
can reactivate in other sites and whether this reactivation can boost the immune
response. Further investigation of the hypothesis that reactivation occurs in peripheral
blood mononuclear cells is recommended, as this would offer the chance of regularly
monitoring reactivation and of predicting the onset of herpes zoster.
J Continued research is recommended to obtain a better understanding of VZV latency
and, in particular, knowledge of the viral antigens expressed during that period. This
may allow the development of approaches to prevent the reactivation of the virus and,
thus, the onset of herpes zoster.
IntroductionVZV (an alphaherpes virus) is the aetiological agent of two common diseases, varicella
(primary infection) and herpes zoster (reactivation of latent virus).1 Person-to-person
transmission of VZV is via the inhalation of aerosolized virus from
infected individuals, resulting in infection of the respiratory
mucosa.2 The pathogenesis of primary VZV infection resulting in
varicella is shown in Figure 1.
Varicella is a common disease, with a prevalence of approximately
95% in temperate countries. The majority of cases occur in children
aged <14 years.3-5 In addition to causing varicella, VZV establishes
latency during primary infection and may subsequently reactivate to
cause herpes zoster,6-8 with the attendant dermatomal rash and
associated pain.9 In tropical countries, the prevalence of VZV is
lower and varicella is usually contracted at a later age.10
The Need to Understand the MolecularMechanisms of VZV Replication and LatencyThe primary aim of treating VZV is to alleviate the acute and
chronic pain of herpes zoster and prevent the serious complications
of varicella. In addition, the current difficulty of managing both
ADVANCES IN THE PATHOGENESIS, MOLECULAR BIOLOGY
AND IMMUNOLOGY OF VARICELLA ZOSTER VIRUS1
FIGURE 1: Schematicrepresentation of thepathogenesis of varicella2
Incubation period
Acquisition by aerosol or direct contactInoculation of respiratory mucosa
Virus replication in regional nodesvirus-infected cells into capillaries
Primary viraemia replication inliver/spleen and other
reticuloendothelial sites
Secondary viraemia: mononuclear cellstransport virus to skin and mucous
membranes
Virus release into respiratory secretions
Replication in epidermal cellsVirus transported to dorsal root ganglia
Latency established
VZV-specific immunity cessationof virus replication
Acute Illness
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acute and chronic pain in herpes zoster11 together with the significant number of
hospitalizations caused by varicella and its attendant complications reinforce the need for
novel treatments of these conditions.
To assist in the development and testing of new agents for the prevention and treatment of
varicella and herpes zoster, improved understanding of the molecular mechanisms of VZV
pathogenesis, latency and reactivation, along with the development of suitable small
animal models of varicella and herpes zoster is required.
Animal and in vitro ModelsJ Improved and predictive animal models are needed for the study of acute disease and
of latent varicella zoster virus (VZV) infection and to assess the effect of potential new
drugs for the treatment of varicella and herpes zoster. It is recommended that the
development of suitable small animal models for studying VZV infection be continued
(research need recommendation).
The lack of suitable animal models of varicella and herpes zoster is a continuing
impediment to studying VZV infection. However, a number of new models may contribute
to our understanding of the pathogenesis of the virus. One such development is the use of
severe combined immunodeficiency disease (SCID) mice with implants of human fetal
lymphoid or skin tissue (SCID-hu), which can be infected with VZV to study virus
replication.12 Applying the technique of ‘knocking out’ individual virus genes by genetic
engineering allows the effect of those gene products to be investigated.13 However, a
problem with this is that as all these animals are immunocompromised, the role of the
immune system cannot be assessed.
A valuable contribution to the study of ocular VZV infection is the rabbit ocular VZV
infection model.14 An in vivo model of latent VZV infection in the rat was established by
Merville-Louis et al15 in 1989 using neurones from rat dorsal root ganglia and recently this
has been used to model the pain associated with herpes zoster.16
The further development of models such as these will provide greater insight into the
pathogenesis of VZV, and allow for the development of novel agents to treat varicella and
herpes zoster.
LatencyJ Although VZV reactivates in the dorsal root ganglia, it is unclear whether or not there
are other potential sites of VZV reactivation. It is important to ascertain whether virus
can reactivate in other sites and whether this reactivation can boost the immune
response. Further investigation of the hypothesis that reactivation also occurs in
peripheral blood mononuclear cells is recommended, as this would offer the chance
of regularly monitoring reactivation and of predicting the onset of herpes zoster
(research need recommendation).
J Continued research is recommended to obtain a better understanding of VZV latency
and, in particular, knowledge of the viral antigens expressed during that period. This
may allow the development of approaches to prevent the reactivation of the virus and,
thus, the onset of herpes zoster (research need recommendation).6
7
Although VZV latency and reactivation are only partly understood, emerging data suggest
that virus, cellular and immune factors determine whether VZV remains in a latent state or
reactivates. Greater knowledge of these determinants may lead to the development of
novel approaches to prevent VZV reactivation, thereby avoiding herpes zoster and post-
herpetic neuralgia (PHN).
Site of latent virusIncreased understanding of how VZV establishes and maintains latency may allow the
development of new approaches to minimize reactivation of VZV, thus reducing the risk of
herpes zoster. The identity of the cells where VZV latency occurs remains controversial
despite detection of the virus genome in human sensory ganglia at autopsy using in situ
hybridization and polymerase chain reaction amplification.17-21 Cohen22 documented that
latent VZV is located primarily within neurones (at a suggested frequency of 2–5 copies
per latently infected neurone). In addition to being found in neurones,17,18,21 VZV DNA has
also been detected in the satellite cells surrounding them.19-21 However, the extensive
distribution of VZV infection in both types of cell, and the fact that herpes zoster occurs in
a dermatomal distribution, indicate ganglionic reactivation and spread from satellite
cells.20 The disparity of these findings confirms the need for further investigation into the
cellular location of VZV latency.
VZV molecular mechanisms of infection, maintenance of latency and evasionof host immune systemsIncreased knowledge of the mechanisms by which VZV infects the host, establishes latency
and evades the immune system could lead to the development of new treatments and
vaccines for varicella and herpes zoster.
The VZV protein encoded by open reading frame (ORF) 47, which is essential for
replication, could be a target for antiviral agents. Mutant VZV deficient in the ORF47 gene
is unable to replicate in either fetal lymphocyte or skin implants in SCID-hu mice. In
comparison, wild-type VZV replicates in the same model.13 This suggests that the ORF47
gene product is required for VZV replication in lymphocytes and dermal tissue.13
Therefore, the potential exists to develop agents that target this gene product and prevent
virus replication in situations such as post-transplant prophylaxis.
VZV infection of fibroblasts downregulates major histocompatibility complex (MHC)
class I antigens on the cell surface, limiting presentation of virus peptides to cytotoxic T
cells.23 Furthermore, when VZV is reactivated, upregulation of MHC class II expression by
interferon (IFN)-γ is blocked by VZV gene products.24 By reducing the expression of MHC
class I and II proteins and limiting presentation of virus peptides to T cells, VZV-infected
cells may avoid destruction by the host’s immune system.25 Agents capable of boosting the
expression of these antigens, thereby increasing virus peptide presentation to cytotoxic
T cells, would have the potential to increase substantially the cell-mediated response to
VZV.
During latency, immunity to VZV persists; immune response may be regularly boosted by
exposure to exogenous virus6 or by low-level, asymptomatic reactivation of virus in nerve
cells and possibly leucocytes.26,27 With time, cell-mediated immunity (CMI) wanes and
8
may reach a critical threshold, allowing VZV to replicate and cause herpes zoster. CMI is
directed at two of the proteins expressed during latency (from the immediate early [IE]
genes IE62 and IE63).28,29 With increasing age, CMI to IE63 appears to decrease more than
CMI to IE62, indicating a possible role for IE63 in virus reactivation. Agents targeted
specifically at preventing expression of IE63 might prevent clinical reactivation of VZV,
and thus the development of herpes zoster.
VZV differs from herpes simplex virus (HSV) in that subsequent VZV reactivations following
an episode of herpes zoster are rare in immunocompetent individuals (available data suggest
only 5% experience a second herpes zoster outbreak).25 The molecular mechanisms that
maintain VZV latency differ from those controlling HSV, and analyses of these differences
could contribute to a greater understanding of latency in both viruses. Whereas latent HSV
is characterized by neuronal accumulation of latency-associated transcripts (LAT), which
appear to modulate reactivation,20 VZV has no DNA sequence homologous to LAT-coding
genes22,24 and, furthermore, VZV differs from other members of the alphaherpesvirus
subfamily in that five of its genes (ORF4, 21, 29, 62, 63) transcribed during lytic infection are
also expressed during the latent state.22 More recent experiments have shown that these
transcripts are also translated, e.g. IE63 in rats,30 and IE4, 21, 29, 62 and 63 in humans during
virus replication.31,32
The functions and interactions of the gene products expressed will need to be identified in
order to determine their role in latency. One hypothesis is that IE gene products
accumulate predominantly in the cytoplasm of latently infected cells instead of homing to
the nucleus, for example IE63,30 IE6233 and IE4.34 Finally, the observations by Lungu et al32
suggest that the intracellular localization of several IE proteins and two E proteins in
latently infected neurones is predominantly cytoplasmic and that this localization changes
during reactivation so that the proteins become detectable in the nuclei. This aberrant
localization may block or alter transcription.
Relationship between virus load and reactivation There is no clear relationship between the number of cells in which VZV establishes
latency and the risk that an individual will develop herpes zoster. In situ hybridization
studies have indicated that VZV remains latent in 0.01% to 0.03% of neurones,17,19
a significantly lower frequency than that reported for HSV (0.2% to 4.3% of the neuronal
population).17 The lower frequency of VZV latency in neurones as compared with HSV
may, however, explain the frequency of recurrences. Further research into the relationship
between the number of neurones infected, the number of copies of the VZV genome
present and the risk of reactivation is warranted. Potentially, this may allow physicians to
determine the patients most likely to develop herpes zoster within a short timeframe, and
thus allow them to implement suitable preventative measures if they become available.
SummaryIncreased knowledge of the mechanisms of VZV infection, latency and reactivation may
lead to new approaches to prevent varicella and herpes zoster. Some advances are being
made in the development of small animal models for VZV infection and reactivation,
which may provide useful insights into the pathogenesis and treatment of VZV. Continued
research in all these areas is recommended.
References1. Liesegang T. Varicella zoster viral disease. Mayo Clin Proc 1999;74:983-998.2. Arvin AM. Chickenpox (Varicella). In: Varicella-Zoster Virus. Molecular Biology, Pathogenesis and Clinical
Aspects. (Wolff MH, Schünemann S, Schmidt A, eds). Basel: Karger, 1999: 96-110.3. Muench R, Nassim C, Niku S et al. Seroepidemiology of varicella. J Infect Dis 1986;153(1):153-155.4. Schneweis KE, Krentler C, Wolff MH. Varicella-zoster virus infection and the serologic determination of first
infection immunity. Dtsch Med Woschenschr 1985;110:453-457.5. Finger R, Hughes JP, Meade BJ et al. Age-specific incidence of chickenpox. Public Health Rep
1994;109(6):750-755.6. Hope-Simpson RE. The nature of herpes zoster: a long-term study and a new hypothesis. Proc R Soc Med
1965;58:9-20.7. Ragozzino MW, Melton LJ, 3rd, Kurland LT et al. Population-based study of herpes zoster and its sequelae.
Medicine (Baltimore) 1982;61(5):310-316.8. McGregor RM. Herpes zoster, chicken pox and cancer in general practice. BMJ 1957;1:84-87.9. Lungu O, Annunziato PW. Varicella-zoster virus: latency and reactivation. In: Varicella-Zoster Virus.
Molecular Biology, Pathogenesis and Clinical Aspects. (Wolff MH, Schünemann S, Schmidt A, eds). Basel:Karger, 1999: 61-75.
10. Garnett GP, Cox MJ, Bundy DA et al. The age of infection with varicella-zoster virus in St Lucia, West Indies.Epidemiol Infect 1993;110(2):361-372.
11. Portenoy RK, Duma C, Foley KM. Acute herpetic and postherpetic neuralgia: clinical review and currentmanagement. Ann Neurol 1986;20(6):651-664.
12. Arvin AM, Moffat JF, Redman R. Varicella-zoster virus: aspects of pathogenesis and host response to naturalinfection and varicella vaccine. Adv Virus Res 1996;46:263-309.
13. Moffat JF, Zerboni L, Sommer MH et al. The ORF47 and ORF66 putative protein kinases of varicella-zostervirus determine tropism for human T cells and skin in the SCID-hu mouse. Proc Natl Acad Sci USA1998;95(20):11969-11974.
14. Dunkel EC, Geary PA, Pavan-Langston D et al. Varicella-zoster virus ocular infection in the rabbit: a modelof human zoster ophthalmicus. Neurology 1995;45(Suppl 8):S21-28.
15. Merville-Louis MP, Sadzot-Delvaux C, Delree P et al. Varicella-zoster virus infection of adult rat sensoryneurons in vitro. J Virol 1989;63(7):3155-3160.
16. Kress M, Fickenscher H. Infection by human varicella-zoster virus confers norepinephrine sensitivity tosensory neurons from rat dorsal root ganglia. FASEB J 2001;15(6):1037-1043.
17. Hyman RW, Ecker JR, Tenser RB. Varicella-zoster virus RNA in human trigeminal ganglia. Lancet1983;2(8354):814-816.
18. Gilden DH, Rozenman Y, Murray R et al. Detection of varicella-zoster virus nucleic acid in neurons ofnormal human thoracic ganglia. Ann Neurol 1987;22(3):377-380.
19. Croen KD, Ostrove JM, Dragovic LJ et al. Patterns of gene expression and sites of latency in human nerveganglia are different for varicella-zoster and herpes simplex viruses. Proc Natl Acad Sci USA1988;85(24):9773-9777.
20. Meier JL, Straus SE. Comparative biology of latent varicella-zoster virus and herpes simplex virus infections.J Infect Dis 1992;166(Suppl 1):S13-S23.
21. Lungu O, Annunziato PW, Gershon A et al. Reactivated and latent varicella-zoster virus in human dorsalroot ganglia. Proc Natl Acad Sci USA 1995;92(24):10980-10984.
22. Cohen JI, Straus SE. Varicella-zoster virus and its replication. In: Fields Virology. (Fields BN, Knipe DM,Howley P, eds). Philadelphia: Lippincott-Raven Publishers, 1996: 2525-2545.
23. Cohen JI. Infection of cells with varicella-zoster virus down-regulates surface expression of class I majorhistocompatibility complex antigens. J Infect Dis 1998;177(5):1390-1393.
24. Abendroth A, Arvin A. Varicella-zoster virus immune evasion. Immunol Rev 1999;168:143-156.25. Cohen JI, Brunell PA, Straus SE et al. Recent advances in varicella-zoster virus infection. Ann Intern Med
1999;130(11):922-932.26. Mahalingam R, Wellish M, Brucklier J et al. Persistence of varicella-zoster virus DNA in elderly patients with
postherpetic neuralgia. J Neurovirol 1995;1(1):130-133.27. Devlin ME, Gilden DH, Mahalingam R et al. Peripheral blood mononuclear cells of the elderly contain
varicella-zoster virus DNA. J Infect Dis 1992;165(4):619-622.28. Arvin AM, Sharp M, Smith S et al. Equivalent recognition of a varicella-zoster virus immediate early protein
(IE62) and glycoprotein I by cytotoxic T lymphocytes of either CD4+ or CD8+ phenotype. J Immunol1991;146(1):257-264.
29. Sadzot-Delvaux C, Kinchington PR, Debrus S et al. Recognition of the latency-associated immediate earlyprotein IE63 of varicella-zoster virus by human memory T lymphocytes. J Immunol 1997;159(6):2802-2806.
30. Debrus S, Sadzot-Delvaux C, Nikkels AF et al. Varicella-zoster virus gene 63 encodes an immediate-earlyprotein that is abundantly expressed during latency. J Virol 1995;69(5):3240-3245.
31. Mahalingam R, Wellish M, Cohrs R et al. Expression of protein encoded by varicella-zoster virus openreading frame 63 in latently infected human ganglionic neurons. Proc Natl Acad Sci USA 1996;93(5):2122-2124.
32. Lungu O, Panagiotidis CA, Annunziato PW et al. Aberrant intracellular localization of varicella-zoster virusregulatory proteins during latency. Proc Natl Acad Sci USA 1998;95(12):7080-7085.
33. Baudoux L, Defechereux P, Schoonbroodt S et al. Mutational analysis of varicella-zoster virus majorimmediate-early protein IE62. Nucleic Acids Res 1995;23(8):1341-1349.
34. Defechereux P, Debrus S, Baudoux L et al. Intracellular distribution of the ORF4 gene product of varicella-zoster virus is influenced by the IE62 protein. J Gen Virol 1996;77(Pt 7):1505-1513.
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Management Recommendations and StatementsCategory 3J Physicians should be aware of both complications and atypical manifestations of
varicella, including varicella zoster virus (VZV) encephalitis and associated cutaneous
bacterial complications. Intravenous aciclovir is warranted for severe, atypical and
complicated VZV infections, based on anecdotal evidence.
Research needJ It is recommended that further research be conducted to assess the impact of social,
economic and demographic factors on the epidemiology of varicella. Data from such
research would facilitate public health policy decisions on vaccine deployment and
treatment of varicella.
IntroductionThis chapter reviews the epidemiology of varicella and defines its clinical signs and
symptoms and associated complications. The use of vaccination and its impact upon the
epidemiology of varicella is reviewed in Chapter 3. The management of varicella in
immunocompetent and immunocompromised individuals is discussed in Chapters 4 and 8.
Epidemiology of VaricellaJ It is recommended that further research be conducted to assess the impact of social,
economic and demographic factors on the epidemiology of varicella. Data from such
research would facilitate public health policy decisions on vaccine deployment and
treatment of varicella (research need recommendation).
Knowledge of VZV prevalence in a population would identify those at risk of developing
varicella, thus helping to determine those at risk of complications, the likely
socioeconomic impact of the disease and assisting healthcare policy makers to formulate
decisions on the need for vaccination and likely demands for treatment.
Estimates of the incidence of varicella in the USA since 1970 have been obtained from the
National Health Interview Survey.1 In the UK, the incidence of varicella is defined by cases
reported to the Royal College of General Practitioners, by sentinel practices covering a
population of approximately 700 000 in England and Wales since 1967, and in Scotland
through statutory notifications since 1988.2 For many other countries the epidemiology of
varicella has been extrapolated from smaller seroprevalence studies. However, because of
the small sample sizes, differences in populations tested, and the varying techniques used
to store and analyse sera, comparisons between data sets are difficult.
INTRODUCTION TO VARICELLA2
11
Tropical and temperate countriesThe prevalence of VZV infection differs between tropical and temperate climates.2–13 In
temperate countries, the majority of primary infections occur in children.6-8 This is reflected
in its seroprevalence, which in the USA (prior to the introduction of varicella vaccine) and
Germany increases sharply in school-age children, reaching a peak prevalence of 90–95%
by adolescence (Figure 1). Only 5% of individuals remain susceptible to varicella after the
age of 15 years.6-8 An Italian study investigated the epidemiology of VZV through a sentinel
network of 39 paediatricians. Data from case reports of varicella among a monitored
population of 30 168 children were extrapolated to estimate a countrywide incidence of 5.1
cases per 100 population per year.9 However, as this study was conducted in a limited
population, the data are likely to be subject to larger error margins than the more complete
national monitoring data from France, UK and USA.
While most adults in temperate countries are VZV
seropositive, the incidence of varicella differs
between countries. For example, in France (1–
1.3 cases per 100 population per year) the incidence
is similar to that observed in the USA (1.5 cases per
100 population), but is notably higher than that
observed in the UK (0.5 cases per 100 population).11
The exact reasons for these differences between
temperate countries are not known.
In tropical countries, primary VZV infection tends to
occur much later in life than that in temperate regions.
Less than 10% of the population of St Lucia are
infected with VZV before the age of 15 years,10 there is then a gradual rise in seropositivity
until the age of 40 years, when VZV seroprevalence reaches around 70%. This figure is
considerably lower than the 95% seroprevalence observed in temperate countries over the
same age range. The mean age of infection in St Lucia is 38.3 years, compared with 10.6 years
in Germany. The high susceptibility in adults raised in tropical countries is demonstrated by
outbreaks of varicella when these individuals emigrate to countries with temperate climates.
For example, 42% of 810 US military personnel originally from Puerto Rico were found to be
seronegative, a much higher percentage than US-born recruits.12
In countries with intermediate climates, the seroprevalence of VZV falls between that
observed in tropical and temperate regions. A study in rural Nepal indicated that VZV
seroconversion rates were highest among the age groups 10–14 years and ≥15 years, with
an overall seroprevalence in adults of approximately 80%:13 a figure between that
observed in St Lucia (60%) and the USA or Europe (95%). However, the significance of
these data is difficult to assess owing to the variability observed between different
temperate countries and the different methods of data collection.
There are several possible explanations for the differences in VZV seroprevalence between
climates. The hypotheses include population size and density, exposure to the infectious agent
in confined spaces during the winter months in temperate climates, and higher ambient
temperatures and humidity in tropical climates. As such differences are not seen for measles –
also a highly contagious disease – and because VZV is heat-labile, the most likely explanation
FIGURE 1: VZVseroprevalence in St Lucia(tropical) compared withcombined data fromGermany, Spain, USA andJapan (temperate)10
1.0
0.8
0.6
0.4
0.2
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is that heat reduces the virus’ ability to survive and thus lowers the probability of transmission.
However, this hypothesis remains speculative.
Recent studies in urban populations of tropical countries demonstrate an epidemiological
picture similar to that observed in temperate countries, suggesting that other factors can
overcome the effect of climate on transmission of the virus. A study in Bengal, India found
that 96% of urban adults were VZV seropositive by the age of 25 years compared with
42% of rural adults, likely due to the differences in population density.14 The disparate
nature of the available data highlights the need for additional research to investigate the
impact of social, economic and demographic factors on the epidemiology of varicella and
consequent implications for healthcare policy.
Effect of societal changes on varicella epidemiologySentinel data from the UK indicate an increased incidence of varicella among children
younger than 5 years of age in the 1980s.15 This increase in incidence among the pre-
school population may be attributable to the larger number of children attending
organized pre-school daycare, increasing the likelihood of exposure to the virus. These
data from the UK are comparable, with a reported increase in the incidence of varicella
among pre-school children in some parts of the USA.8 These data highlight the need for
further research to assess the impact of social, economic and demographic factors on the
prevalence of varicella to guide future healthcare policy.
For a more complete review of the pre-varicella vaccine epidemiology of VZV in temperate
and tropical regions, refer to the IHMF Management Strategies in Herpes publication –
Management of Varicella.16
Clinical Signs and Symptoms of VaricellaVaricella has an incubation period of 10–21 days.17 The initial symptoms of varicella
include a prodrome consisting of fever, malaise, headache and abdominal pain. The
prodrome manifests approximately 24–48 hours prior to rash onset, and is usually more
pronounced in adolescents and adults than in children. Systemic symptoms that may
develop during the initial, viraemic phase include fever, fatigue and anorexia.
The exanthematous rash typical of varicella appears first on the face,
scalp or trunk, with a small number of isolated macropapular lesions
present. These lesions are often intensely pruritic, and change within
a few hours to the characteristic fluid-filled vesicles associated with
varicella (Figure 2). Crops of new lesions develop over the
subsequent 1–7 days and are usually located on the extremities.
Painful, ulcerative lesions of the mucous membranes frequently
accompany the evolution of the dermal rash. Varicella lesions often
involve the eyelids and bulbar conjunctivae, but serious ocular
complications are rare; unilateral anterior uveitis or corneal lesions
occasionally manifest, but usually resolve without further sequelae.17
Adolescents and adults typically develop more lesions than younger
children, as do secondary and tertiary household cases of
varicella.18,19
FIGURE 2: Typicalclinical manifestation of varicella
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ComplicationsJ Physicians should be aware of both complications and atypical manifestations of
varicella, including VZV encephalitis and cutaneous bacterial complications associated
with varicella. Intravenous aciclovir is warranted for severe, atypical and complicated
VZV infections, based on anecdotal evidence (category 3 recommendation).
Although varicella is generally a benign and self-limiting disease,17 complications may
develop following initial infection, and can involve the skin, lungs, liver and nervous
system. The complications of primary VZV infection are rare in immunocompetent
children but are more frequent in adolescents, adults and individuals with suppressed cell-
mediated immunity.18-20
The risk of dying from varicella mirrors the risk of its complications. Data from the USA
gathered over the last 30 years show a higher mortality among infants aged younger than
1 year and adults 20 years of age or older compared with children aged 1–4 and 5–9
years.21 In the 1980s, mortality from varicella amongst infants (case fatality rate [CFR]
6.7/100 000 cases) and adults (CFR 17.1/100 000) was 10- to 24-fold greater than that
observed in children aged 1–4 years (CFR 0.7/100 000).21 Similar data have been reported
for the UK.2 No population-based mortality data are available from countries with tropical
climates but case reports indicate serious disease among adults.21
The mortality associated with varicella is largely due to varicella-associated pneumonia;
up to 30% of adults with varicella have some evidence of pulmonary involvement, either
radiographic or clinical.22-26 In addition, immune-altered individuals such as pregnant
women, cancer patients and neonates are at greater risk from complications of varicella,
and mortality rates in immunocompromised children with varicella range from 15% to
20% in the absence of treatment, also largely due to pneumonia.26
Complications of varicella observed in immunocompetent individualsPulmonary complicationsWhile pulmonary complications are rare in immunocompetent children with varicella,
some 5–10% of adults will have respiratory symptoms, such as cough or shortness of
breath, and a further 15–20% of adults with varicella will show radiographic evidence of
pneumonitis (Figure 3).27-29 The risk of developing varicella-associated pneumonia is
increased in men and among smokers; an Australian study indicated
the risk to smokers was 15 times higher than that of non-smokers.30
Intravenous antiviral therapy is recommended for any adolescent or
adult presenting with varicella-associated pneumonia. Although there
are no controlled clinical trials to support this indication, clinical
experience and anecdotal reports suggest that intravenous aciclovir
(10 mg/kg every 8 hours) is effective in this setting.31-33
Cutaneous complicationsSeveral cutaneous complications of varicella have been recognized,
including bacterial cellulitis and necrotizing fasciitis. They occur
more often in children than adults and bacterial cellulitis is the most
common complication leading to hospitalization, accounting for13
FIGURE 3: Chest X-rayof an individual withvaricella and evidence ofpneumonitis
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30% of such cases.34 It is most often caused by Staphylococcus aureus or Streptococcus
pyogenes35 and the scarring commonly associated with varicella is frequently due to
bacterial cellulitis. Measures such as the use of antibacterial soaps and trimming of
fingernails can help prevent bacterial infection. Appropriate antibacterial therapy is
recommended, but regional differences in antibiotic resistance defy global
recommendations.
Streptococcal superinfection may be associated with the use of non-steroidal anti-
inflammatory drugs (NSAIDs) for the management of the minor pain and fever associated
with varicella.36,37 For this reason, many paediatricians avoid their use in children with
varicella, and opt for drugs such as paracetamol.
Necrotizing fasciitis is also usually caused by Staphylococcus aureus or Streptococcus
pyogenes,36,37 and is exemplified by deeper fascial plane trapping of bacteria.38
Necrotizing fasciitis is a rare complication, occurring in 0.08 cases per 100 000 population
per year.39 It constitutes an emergency requiring early surgical debridement, appropriate
antibiotic administration and intensive supportive care.40,41
Atypical presentations and complications of varicellaA range of atypical presentations and complications of varicella may occur in
immunocompetent individuals, including cerebellar ataxia, transverse myelitis,
encephalitis, Guillain-Barré syndrome and Reye’s syndrome (Table 1).42-50 In general, no
controlled trials of therapy have been conducted for any of these manifestations and the
treatment recommendations are based on anecdotal reports.
14
TABLE 1: Atypicalpresentations andcomplications of varicellain the immunocompetenthost42-50
Manifestation Cases:cases of varicella Signs and symptoms Diagnosis
Cerebellar ataxia 1:4000 Headache, vomiting, lethargy. Usually clinicalAtaxia accompanied by fever, nuchal rigidity and nystagmus
VZV encephalitis 1–2:10 000 Fever, headache, vomiting, altered mental status, Laboratory diagnosisfocal neurological abnormalities, seizures CSF: Increased opening
pressure, elevated protein,normal glucoseEEG: Non-specific slowwave activityMRI: cerebral oedema
Pulmonary 5–10% of adults, Cough, shortness of breath X-raycomplications rare in children
Guillain-Barré syndrome Acute idiopathic polyneuritis
Reye’s syndrome Very rare following Vomiting, listlessness, delirium, convulsions Clinical blood chemistry:advice not to administer and loss of consciousness hypoglycaemia liveraspirin during varicella function: elevated
transaminases liver biopsy:signs of degeneration CSF: <8 cells/mm3
CSF = cerebrospinal fluid; EEG = electroencephalograph; MRI = magnetic resonance imaging
Cerebellar ataxiaCerebellar ataxia occurs with an estimated incidence of 1 case per 4000 cases of varicella
in immunocompetent children.51 It is generally benign and self-limiting, with most
individuals recovering within 1–3 weeks without further sequelae.45 Neurological signs
(headache, vomiting and lethargy) usually occur concurrently with varicella rash onset,
15
but may also precede or follow the onset of dermatological symptoms.45 Fever, nuchal
rigidity and nystagmus occur in 25% of patients. In rare circumstances, seizures may also
occur.
The pathogenesis of cerebellar ataxia may involve virus replication in the cerebellum, as
indicated by the detection of VZV DNA by polymerase chain reaction (PCR) and increased
titres of VZV-specific antibodies in the CSF.52-54 However, a para-infectious, immune-
mediated mechanism may be responsible for its development.
The diagnosis of cerebellar ataxia is usually clinical, as laboratory test results are not
consistent. A low-grade pleocytosis (<100 white blood cells/mm3) in CSF is observed in
25% of patients. EEG recording detects diffuse slow-wave activity, consistent with ataxia,
in only 20% of patients with cerebellar ataxia. The role of computer tomography and MRI
scans in the diagnosis of the syndrome is uncertain, as most patients do not exhibit
abnormalities detectable by imaging.
The role of antiviral therapy in individuals presenting with varicella and cerebellar ataxia
has not been studied in a prospective or controlled fashion, but intravenous aciclovir
(10 mg/kg every 8 hours for adults, 500 mg/m2 body surface area every 8 hours for
children) is recommended.
VZV encephalitisVZV encephalitis usually has a worse prognosis than cerebral ataxia. It is characterized by
fever, headache, vomiting and an altered mental status indicative of increased intra-cranial
pressure.42,43 Other symptoms include focal neurological abnormalities, such as
hemiparesis and sensory changes. Seizures are a prominent feature of VZV encephalitis,
occurring in 29–52% of cases.55,56 The symptoms appear approximately 1 week after rash
onset, and may develop acutely or gradually.42,43 Estimates of reported mortality due to
VZV encephalitis range from 0% to 35%52,57 and neurological sequelae are observed in
10–20% of survivors.52,57
Although the absolute number of cases of varicella-associated encephalitis is highest in
children (due to the relative incidence of varicella itself in children and adults), the age-
specific incidence of encephalitis is higher in adults (1–2 cases per 10 000 cases of
varicella).55,56 In children, encephalitis following varicella (1 in 33 000 cases) is less
common than cerebellar ataxia.48,49
The role of VZV replication in the central nervous system (CNS) is not clearly defined in
the pathogenesis of VZV encephalitis. Numerous published pathology reports have
indicated a post-infectious demyelination process, whilst other findings are consistent with
direct virus cytopathology.58-60
Unlike cerebellar ataxia, laboratory diagnosis of encephalitis gives more consistent results
than clinical diagnosis. Examination of CSF indicates increased opening pressure,
pleocytosis and elevated protein with normal glucose levels. An EEG will show non-
specific slow-wave activity consistent with diffuse encephalitis.58 An MRI scan may
indicate cerebral oedema and areas of low attenuation consistent with
demyelination.58,61,62
16
Although there are no prospective or controlled trials to support the use of antivirals in
VZV encephalitis (due in part to the rarity of the condition), intravenous aciclovir is
recommended based upon anecdotal evidence.
Recommended doses of aciclovir are:
• UK: 10 mg/kg every 8 hours in adults and 500 mg/m2 body surface area every 8 hours
in children. The dosage in children aged under 3 months is calculated on the basis
of body weight.
• USA: 10 mg/kg every 8 hours for 7 days in adults and 20 mg/kg every 8 hours for 7 days
in children.
Varicella in the pregnant woman, fetus and neonatePregnant womenIn the USA, where more than 95% of adults are VZV seropositive, five in 10 000 pregnant
women are estimated to develop varicella.24,63,64 The probability of infection among
women of childbearing age is likely to be greater in tropical regions where a higher
percentage of adults remain susceptible to VZV infection.65
Pregnant women are recognized as being less able to mount effective cellular immune
responses to infection compared with otherwise healthy children and adults. Thus,
varicella in the pregnant woman and neonate is more likely to have a serious outcome
than in other immunocompetent individuals, although there are no reliable population-
based studies to confirm this. The anecdotal evidence available suggests pregnant women
are at greater risk of developing severe varicella and its complications than non-pregnant
women of the same age.66-68 Based on data reported to the UK Office of National Statistics,
the risk of fatal varicella appears to be about 5-fold higher in pregnant than in non-
pregnant immunocompetent adults.69 In a study of 43 pregnant women with varicella,
nine (20%) had varicella-associated morbidity (pneumonia, premature labour, premature
delivery) and one woman died.67 If varicella pneumonia occurs during pregnancy, the
maternal mortality rate in the absence of antiviral therapy may be as high as 40%.22,23,25
The larger risk of varicella complications observed during pregnancy, and the high
mortality in the pregnant woman with varicella-associated pneumonia, highlight the need
for its prevention and management. These are discussed in Chapters 3 and 4.
Congenital varicella syndromePrimary VZV infection during pregnancy can result in a range of congenital defects in the
fetus (congenital varicella syndrome [Table 2]). The main route for congenital infection is
haematogenous spread of virus across
the placenta and it occurs irrespective
of the severity of varicella in the mother.
Congenital varicella syndrome was
initially thought to occur during the first
trimester of pregnancy only. In one
study, approximately half of the recorded cases developed following second trimester
maternal varicella.69 This indicates that the risk of congenital varicella syndrome following
maternal infection extends throughout the first half of pregnancy.70
TABLE 2: Clinicalcharacteristics ofcongenital varicellasyndrome
Defect associated with VZV infection
Skin Scarring
Limb Hypoplasia of bone and muscle
CNS Microcephaly, mental retardation, sphincter dysfunction
Eye Cataract, chorioretinitis, microphthalmia
The risk of congenital varicella syndrome following maternal varicella is approximately
2–3%.71-73 In a prospective, case-controlled study,72 the pregnancy outcomes of 106
women with clinically diagnosed VZV infection in the first 20 weeks of pregnancy were
compared with 106 unexposed, age-matched controls. Only one in 86 live births (1.2%)
in the varicella group had features of congenital varicella syndrome (Table 2).
When these results were pooled with those of four previous studies, the estimated mean
risk was estimated to be 2.2%.72 In addition, this study found no difference between
infected and uninfected women in the proportion of live births (79% versus 85%),
miscarriages or elective terminations. There was a trend toward more pre-term deliveries
in the varicella-infected group (14.3% versus 5.6%; P=0.05) but gestational age at delivery
and birth weights were similar.72
These findings were corroborated by a larger, uncontrolled study of 1373 pregnant women
exposed to VZV in the first 36 weeks of pregnancy.71 In this study, the overall incidence of
congenital varicella syndrome was 0.7%, but the risk varied according to time of infection.
Congenital varicella syndrome occurred in seven out of 351 (2%) infants whose mothers
developed varicella infection between Weeks 13 and 20 of gestation, in two out of 472
(0.4%) whose mothers were infected during Weeks 8–13 and in none of 477 pregnancies
in which maternal infection was acquired after Week 20 (Table 3).71 A smaller study of 107
women who contracted varicella before 24 weeks of pregnancy recorded a risk of
congenital varicella syndrome of 2.8%.73
17
TABLE 3: Pooled resultsfrom prospective studiesmeasuring fetal riskfollowing maternal VZVinfection during pregnancy
Fetal risk* Reference
Maternal varicella in Maternal varicella in Maternal varicella infirst trimester, n (%) second trimester, n (%) third trimester, n (%)
2/27 (7.4) 0/32 (0) 2/76 (2.6) Siegel 197374
0/23 (0) 0/8 (0) 0/2 (0) Enders 198475✛
1/11 (9.0) 0/11 (0) 0/16 (0) Paryani & Arvin 198667
0/35 (0) Balducci et al. 199263
2/472 (0.4) 7/351 (2.0) 0/477 (0) Enders et al. 199471
1/86 (1.2)† 0/14 (0) Pastuszak et al. 199472
3/107 (2.8)‡ Mouly et al. 199773
*Ratio of the number of infants with congenital varicella syndrome compared with the total number of live-born infants†Estimated risk for mothers infected in the first 20 weeks of pregnancy‡Risk for mothers infected in the first 24 weeks of pregnancy✛ Figures also included in Enders et al. 199471
The potentially serious effects of congenital varicella syndrome highlight the need for
prevention and treatment of varicella during pregnancy in order to avoid congenital
varicella syndrome. These aspects are discussed in Chapters 3 and 4.
NeonatesNeonatal varicella can occur if the mother becomes infected with VZV between 4 days prior
to and 2 days after delivery. For these infections, transplacental virus transmission is the usual
route, while perinatal infection can result from contact with maternal lesions during or after
delivery.
The severity of neonatal varicella is largely dependent on the time of onset of maternal
illness in relation to delivery. The usual interval between maternal rash and onset in the
neonate is 9–15 days. Neonates are at highest risk of developing varicella when maternal
varicella begins between 3 days before and 2 days after delivery,76,77 leading to symptoms
in the neonate 5–10 days after birth. When maternal varicella develops during the perinatal
18
period, the incidence of neonatal varicella can be as much as 48%.76 Approximately 20%
of infants born in this high-risk period will develop symptomatic neonatal varicella, with
disseminated infection and visceral involvement.78 For the neonate infected outside the
immediate peripartum period, the disease is generally not life-threatening.22,23
The enhanced risk of visceral dissemination in neonatal varicella and the associated high
mortality emphasize the need for effective management, which is discussed in Chapter 4.
For a more complete review of maternal, congenital and neonatal varicella, the reader is
directed to the IHMF Management Strategies in Herpes publication – Herpesvirus
Infections in Pregnancy.79
Summary Information on the epidemiology of varicella (individuals within a population at risk of
developing varicella and its attendant complications, and the socioeconomic impact of the
disease) can help public health policy makers formulate decisions on its prevention and
treatment.
The incidence of varicella varies between countries; however, in most developed
countries, the majority of cases occur in children, with only 5% of individuals remaining
susceptible after the age of 15 years. Tropical countries have a lower incidence of
childhood varicella, with peak seroprevalence being reached in adults aged 40 years or
more. Factors such as population density, economic status and social conditions may play
an important role in determining the incidence of varicella in a given country.
Varicella, typified by an exanthematous rash, is generally self-limiting due to the
development of humoral and cellular immune responses in the host. Although it is
generally a benign disease, varicella may be followed by complications, which can
involve the skin, lungs, liver or nervous system, including pneumonitis, cerebellar ataxia,
VZV encephalitis, and cutaneous bacterial superinfection. These complications are more
frequent in newborns, adolescents and adults. In addition, varicella occurring in pregnant
women and the immunocompromised is more likely to be serious in nature than disease
occurring in immunocompetent individuals of the same age.
The potentially serious nature of these complications, coupled with the number of
hospitalizations due to the disease – 11 000 per year in the USA prior to initiation of the
vaccination programme – emphasize the importance of treating varicella, particularly in
high-risk individuals such as adolescents, adults, pregnant women and the
immunocompromised.
The prevention and management of varicella are discussed in more detail in Chapters 3, 4 and 8.
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Obstet Gynecol 1992;79:5-6.65. Weller TH. Varicella and herpes-zoster. Changing concepts of the natural history, control, and importance
of a not-so-benign virus (Part 1). N Engl J Med 1983;309:1362-1368.66. Gray F, Mohr M, Rozenberg F. Varicella-zoster virus encephalitis in acquired immunodeficiency syndrome:
a report of four cases. Neuropathol Appl Neurobiol 1992;18:502-514.67. Paryani SG, Arvin AM. Intrauterine infection with varicella-zoster virus after maternal varicella. N Engl J Med
1986;314(24):1542-1546.68. Cox SM, Cunningham FG, Luby J. Management of varicella pneumonia complicating pregnancy. Am J
Perinatol 1990;7:300-301.69. Enders G, Miller E. Varicella and herpes zoster in pregnancy and the newborn. In: Varicella-Zoster Virus:
Virology and Clinical Management. (Arvin A, Gershon A, eds). Cambridge: Cambridge University Press,2000.
70. Gershon AA. Varicella-zoster virus: prospects for control. Adv Pediatr Infect Dis 1995;10:93-124.71. Enders G, Miller E, Cradock-Watson J et al. Consequences of varicella and herpes zoster in pregnancy:
prospective study of 1739 cases. Lancet 1994;343(8912):1548-1551.72. Pastuszak AL, Levy M, Schiek B et al. Outcome after maternal varicella infection in the first 20 weeks of
pregnancy. N Engl J Med 1994;330:901-905.73. Mouly M, Mirlesse V, Meritet JF. Prenatal diagnosis of fetal varicella-zoster virus infection with polymerase
chain reaction of amniotic fluid in 107 cases. Am J Obstet Gynecol 1997;177:894-898.74. Siegel M. Congenital malformations following chickenpox, measles, mumps and hepatitis: results of a
cohort study. JAMA 1973;226:1521-1524.75. Enders G. Varicella-zoster virus infection in pregnancy. Prog Med Virol 1984;29:166-196.76. Miller E, Cradock-Watson JE, Ridehalgh MK. Outcome in newborn babies given anti-varicella-zoster
immunoglobulin after perinatal maternal infection with varicella-zoster virus. Lancet 1989;2(8659):371-373.
77. Gershon A. Infections in the fetus and newborn infant. New York: Alan R Liss, 1975.78. Meyers JD. Congenital varicella in term infants: risk reconsidered. J Infect Dis 1974;129(2):215-217.79. Pass R, Weber T, Whitley RJ. Management Strategies in Herpes: Herpesvirus Infections in Pregnancy.
Worthing: PAREXEL MMS Europe Ltd, 2000.
20
21
VARICELLA VACCINATION3
Management RecommendationsCategory 2J If there is a policy of routine childhood vaccination, all children and adolescents
should be immunized. Immunizing only a subset of the paediatric population is likely
to increase the risk of creating a population of adults vulnerable to varicella and its
attendant morbidity.
J Considerations as to whom to vaccinate may differ between temperate regions (where
varicella is almost exclusively a disease of young children) and tropical regions (where
a larger proportion of the population contracts varicella at an older age).
J To facilitate the uptake of universal vaccination in the USA and other countries, it is
recommended that proof of varicella vaccination or positive varicella zoster virus
(VZV) serostatus should be considered a requirement for school entry.
J Targeted vaccination of at-risk groups is recommended in countries not considering
universal vaccination programmes. Such programmes should include teachers,
healthcare workers, identified seronegative adults, seronegative women of
childbearing age who are not pregnant and patients undergoing haematopoietic stem
cell transplantation.
J Programmes should be established to screen for VZV-seropositivity in healthcare
workers, teachers and other adults likely to come into sustained contact with VZV-
infected children, and to vaccinate susceptible individuals. This would serve to protect
healthcare workers from VZV-infected patients, protect susceptible patients from
healthcare workers with varicella, and protect seronegative teachers from VZV-
infected children.
J Clinicians caring for women of childbearing age should be encouraged to determine
the VZV serological status of their patients. Women with no history of varicella should
undergo serological testing and susceptible women should be vaccinated. Vaccination
of susceptible women will reduce the risk of severe maternal morbidity caused by the
varicella-related complications that can occur during pregnancy and obviate the need
for varicella zoster immune globulin (VZIG) prophylaxis during pregnancy. Pregnant
women with no history of varicella should not be vaccinated while pregnant but
should undergo serological testing to determine susceptibility.
22
Research needsJ More data are required on the long-term outcomes (prevalence, frequency of
complications, economic factors) following a varicella vaccination programme. As the
USA moves toward universal varicella vaccination, the effect of this programme on the
epidemiology of varicella and herpes zoster must be monitored. In addition, the
economic impact of the programme should be assessed. Analysis of data from
immunocompromised individuals will provide valuable information but should not
replace monitoring of the general vaccinated population in the USA.
J Comparative analyses of health-outcome benefits should be conducted comparing the
USA with countries that do not have universal varicella vaccination programmes. To
facilitate policy decisions on the implementation of varicella vaccination programmes,
health policy decision-makers will require the maximum amount of data possible on
the medical and economic impact of varicella and varicella vaccination.
IntroductionVaricella has generally been regarded as a mild, self-limiting disease in otherwise healthy
children. However, in the USA, before the licensing of the varicella vaccine in 1995, there
were approximately 4 million cases per year, resulting in nearly 9300 hospitalizations1 and
100 deaths each year.2 The impact was greatest on children, who accounted for more than
90% of cases, 66% of hospitalizations and 45% of deaths.1 However, the risk of severe
complications and death was highest among infants and adults2 (see Chapter 2). Maternal
infection and infection of the newborn can also have severe sequelae. A further group at
risk from varicella is immunocompromised patients with impaired cell-mediated
immunity.3,4
A live attenuated varicella vaccine (VZVoka vaccine) was developed and clinically tested
in Japan in 1974.5 The VZVoka strain is the basis for all currently available varicella vaccines
(produced by Biken; Merck & Co Inc; SmithKline Beecham [now GlaxoSmithKline];
Aventis Pasteur). Experience with the live attenuated VZVoka vaccine for prevention of
varicella has accumulated over the last 25 years in Japan and the USA. The vaccine is well
tolerated and effective in healthy children and adults. Thus, this highly infectious disease
and its complications are preventable by vaccination.
Efficacy and Safety of Varicella VaccineVaccination in immunocompetent individualsEfficacy of varicella vaccineA number of retrospective and prospective clinical studies have demonstrated that
varicella vaccination is effective in immunocompetent individuals.6-11 However, of all
these trials, only two have been placebo-controlled. One trial, using the Merck vaccine,
was conducted in children (1–14 years of age), 468 of whom were immunized with a dose
of 17430 plaque-forming units (pfu) of virus and 446 were administered placebo.9 During
the initial 9 months following vaccination, 39 of the placebo recipients developed
varicella, compared with no cases in the varicella vaccine group. Thus, the vaccine
efficacy was 100%. During the second year of the study, one vaccinated child developed
varicella, giving an efficacy rate of 98%.9 Over a 7-year follow-up period, the efficacy of
the vaccine was estimated at 95% in immunocompetent children. The vaccine was well
tolerated, although it had a much higher titre than those commercially produced.9
23
In the second placebo-controlled trial,12 performed with the SmithKline Beecham vaccine,
513 healthy children (10–30 months old) were randomized to receive either:
• High-titre vaccine dose (10 000 or 15 850 pfu/dose)
• Low-titre vaccine dose (630 or 1260 pfu/dose)
• Placebo.
Between 94% and 100% of previously seronegative children developed varicella-specific
antibodies. The attack rate during an average of 29 months follow-up was 3% (5 cases) in
the high-titre group and 11.4% (5 cases) in the low-titre group. Both these attack rates were
significantly lower than the 26% observed with placebo (41 cases; P≤0.005).
Placebo-controlled trials of the varicella vaccine in two groups at high risk of varicella
complications, adults and immunocompromised children, have not yet been conducted.
Trials conducted in healthy young adults and leukaemic children indicate that the vaccine
is less effective in these two groups.13,14 This may be due to both groups having impaired
responses to VZV, as humoral and cell-mediated immunity was lower in these vaccinees
than in individuals who had experienced natural varicella infection. In general, two doses
of the vaccine are required to achieve a seroconversion rate of 95–98%. In adults, the
efficacy of the vaccine was estimated to be 65–70% following household exposure.15
The two placebo-controlled trials indicate that dose is important in defining efficacy.
Currently, the VZVoka-Merck vaccine (Varivax; Merck & Co Inc) used in the USA provides a
dose of approximately 2500 pfu but high levels of protection are still observed. Data from
the American trials of the VZVoka-Merck vaccine, in which vaccinated individuals of all ages
were followed up for up to 9 years, demonstrated seroconversion rates of 95.6–99% per
year depending on vaccine batch and time since vaccination.16 A prospective follow-up
study in the USA demonstrated that protection lasted at least 10 years following
vaccination;17 similar studies in Japan have shown protection persisting for 20 years.18
In the USA, trials with no placebo control have demonstrated that vaccination of adults
and children significantly lowers the attack rate among household exposures.10,11 The
incidence of varicella following household exposure in vaccinees was approximately
12%; household contact historically results in 87% infection. Nearly all of the vaccinees
who had varicella after vaccination had a clinically modified disease. Varicella infections
were milder than wild-type infections in the unvaccinated (Table 1).10
TABLE 1:Seroconversion andduration of protectionobserved in clinical trialswith varicella vaccine10
Study group Follow-up (years) Rash or fever (%) Seroconversion (%) Protection 1–3 years (%) Protection >3 years (%)
Children 2–16 5 95 89–94 88 Adults na 10 >90 (two doses) 70 86
na=not applicable
A potential weakness of the available data on the persistence of protection in the US
populations is that these studies were conducted prior to the adoption of universal
vaccination. High levels of vaccine coverage may reduce the chance of exposure to wild-
type VZV, thereby lowering the opportunities for immunological boosting from subclinical
infection with exogenous VZV. Periodic boosting of cellular immunity by such exposure
may be a factor in maintaining protection against varicella. Further studies will establish
whether vaccination provides protection which is as durable as that of natural infection or
whether booster doses will be required to maintain lifelong protection.
Safety of vaccination Varicella vaccination is generally well tolerated in healthy adults and children. In healthy
children, the frequency of rash after immunization is approximately 5% and there are very
few skin lesions observed.8,19 Other common adverse events include fever (15%),
temporary discomfort at the injection site (19–24%) and rash at the injection site
(3–4%).8,19 Similar adverse event rates are seen in healthy adolescents and adults, in
whom two doses of vaccine are required. However, the rate of vaccine-associated rash in
adults (10%) is twice that seen in healthy children.8,19
Vaccination for women of childbearing ageJ Clinicians caring for women of childbearing age should determine the VZV
serological status of their patients. Women with no history of varicella should undergo
serological testing and susceptible women should be vaccinated. Vaccination will
reduce the risk of severe maternal morbidity caused by the varicella-related
complications that can occur during pregnancy and obviate the need for VZIG
prophylaxis during pregnancy. Pregnant women with no history of varicella should not
be vaccinated while pregnant but should undergo serological testing to determine
susceptibility (category 2 recommendation).
Vaccination of susceptible women of childbearing age may potentially also prevent
congenital varicella syndrome or neonatal varicella. Seronegative women are at risk of
exposure to varicella from children in their household as most cases occur in those under
5 years of age. In addition, the attack rate of varicella is extremely high following
household contact. Thus, vaccination should be considered for non-pregnant seronegative
women of childbearing age. The US Advisory Committee on Immunization Practices
(ACIP) has recently strengthened its recommendations for varicella so that vaccination is
recommended for susceptible, non-pregnant women of childbearing age.20
Pregnancy is a contraindication for varicella vaccination. No epidemiological data are
available on exposure to the vaccine during pregnancy and the effects on the fetus are
unknown. A theoretical risk is that a vaccinated woman may develop varicella infection
from the attenuated virus with the consequence of fetal varicella infection. Therefore, in
the USA, the Varivax manufacturer (Merck & Co Inc) advises a 3-month interval between
vaccination and conception, although the ACIP and Centers for Disease Control suggest
that vaccinated non-pregnant women should avoid becoming pregnant for 1 month
following each injection of vaccine.16 However, inadvertent vaccination immediately
prior to or early in pregnancy is not a justification for termination of pregnancy. In the
USA, a Varivax Pregnancy Registry (telephone: ++1 800 986 8999) has been established
to monitor the maternal and fetal outcomes of pregnant women who receive varicella
vaccine up to 3 months before, or at any time during, pregnancy.
Potential of Vaccine to Prevent Herpes ZosterThe availability of a safe and effective varicella vaccine presents the opportunity to
determine whether it may also be effective for preventing herpes zoster in the elderly. The
initial suggestion that vaccination may reduce the likelihood of herpes zoster was
prompted by a study in children with leukaemia who received the VZVoka vaccine. Among
these, the incidence of herpes zoster was lower than in children who had experienced
natural VZV infection.2124
25
Based on the results of the study described above, investigators have hypothesized that
administration of live attenuated VZV vaccine to older adults (who are likely to be already
latently infected with VZV) may stimulate their waning cellular immune responses, thereby
preventing herpes zoster during the last decades of life when individuals are at highest
risk.22,23 Administration of a VZVoka vaccine (at a higher dose than that routinely used to
immunize children) boosts the number of circulating T-lymphocytes that are responsive to
VZV antigens; the duration of this booster effect is at least 6 years.22 A large-scale
serological study has provided evidence that VZVoka can reactivate in vaccinees who have
declining anti-VZV antibody titres.24 Reactivation of VZVoka may result in a mild varicella-
like illness and also in a substantial boost in anti-VZV antibody titres, thus extending the
duration of protection against clinically significant varicella. Such boosting of the VZV
immune responses in older adults has the potential to reduce the incidence of herpes
zoster or at least attenuate the severity of the disease.
To determine the clinical value of vaccination in older adults, a double-blind, placebo-
controlled trial of varicella vaccine investigating its effects on the severity and
complications of a first occurrence of herpes zoster is underway in the USA (the Shingles
Prevention Trial). Its target population was 37 200 volunteers over the age of 60 years. With
a 3-year follow-up period, the study will last approximately 5 years.
Prophylactic administration of the inactivated varicella vaccine has also reduced the risk
of zoster in patients undergoing haematopoietic stem cell transplantation (see Chapter 8
for further details).25
Vaccination StrategiesJ Comparative analyses of health-outcome benefits should be conducted comparing the
USA with countries that do not have universal varicella vaccination programmes. To
facilitate policy decisions on the implementation of varicella vaccination programmes,
health policy decision-makers will require the maximum amount of data possible on
the medical and economic impact of varicella and varicella vaccination (research
need recommendation).
J More data are required on the long-term outcomes following varicella vaccination
with the aim of optimizing the target population. As the USA moves toward universal
varicella vaccination, the effect of this programme on the epidemiology of varicella
and herpes zoster must be monitored. In addition, the economic impact of the
programme should be investigated. Analysis of data from immunocompromised
individuals will provide valuable information but should not replace monitoring of the
general vaccinated population in the USA (research need recommendation).
J Considerations as to whom to vaccinate may differ between temperate regions (where
varicella is almost exclusively a disease of young children) and tropical regions (where
a larger proportion of the population contracts varicella at an older age) (category 2
recommendation).
Varicella vaccination strategies may be either universal for all children or targeted at those
susceptible individuals who are considered to be at high risk of exposure. The choice of
which strategy to adopt is influenced by many factors including cost effectiveness and
perceptions of the seriousness of varicella. The USA is the first country in which routine
varicella vaccination for all children has been recommended.20,26 The vaccine has been
licensed in other countries, where it is mainly used for high-risk individuals and their
contacts. Gathering data on the long-term medical, epidemiological and socioeconomic
outcomes following the introduction of universal childhood vaccination in the USA will allow
critical analysis of the benefits of this strategy. Should similar data become available for targeted
vaccination, a comparison of the benefits of the two different strategies will be possible.
The choice of strategy employed may also be influenced by the differences in the
epidemiology of varicella between temperate and tropical regions. There may be a greater
need for universal vaccination in tropical countries, where a greater proportion of adults
remain susceptible to varicella, and a relatively high complication rate is expected in this
group. However, the implementation of such a strategy should be viewed in the context of
other, more serious, childhood diseases preventable by vaccinations. For example, in
Africa, vaccine coverage for measles (a far more life-threatening illness) falls below the
World Health Organization global goals; thus, varicella vaccination may be considered
neither feasible nor a priority.
Universal vaccinationThe objective of a universal varicella vaccination programme in children is to achieve an
overall reduction in varicella cases and complications among both children and adults. In
theory, a universal programme has the potential to eradicate clinical varicella and reduce
the severity of herpes zoster, should it develop.
A major argument for the routine varicella programme in the USA comes from a series of
detailed cost-effectiveness analyses conducted since 1985.27-29 The first of the analyses,
performed, found that universal vaccination was cost-effective if parents’ loss of income
from time taken off work to care for their sick children was taken into account along with
the medical costs.27 The second analysis, in 1994, compared universal vaccination with no
intervention.28 Direct medical costs of US$2.00 per case of varicella prevented were
calculated. In terms of overall cost to society (including direct medical costs and the cost of
pay-loss by parents), for every US$1.00 spent on vaccination, US$5.00 was saved. Another
study conducted at the same time also had similar conclusions for universal vaccination.30
Epidemiology of varicella in the USA following vaccine introductionSince the introduction of the varicella vaccine in the USA in 1995, active varicella
surveillance has been conducted in the states of California, Pennsylvania and Texas.
Reporting sources include schools, childcare centres, pre-school groups, private
physicians, public-health clinics, hospitals, large companies and the general public.
Vaccine used in these geographical areas has been monitored in private healthcare
providers’ offices, immunization registries, and through the Vaccines for Children Program.
In children aged 12–23 months, vaccine coverage in the three US states increased from
30–50% in 1997 to 60–80% in 1999. The surveillance has highlighted a declining trend
in the number of varicella cases and hospitalizations due to varicella-related illness. In
these three areas, there was a 77–84% reduction in the number of cases of varicella or
associated complications and a 79% reduction in hospitalizations due to varicella in all
age groups (including infants and adults) in 1999 compared with 1995. 26
27
Strategies to improve vaccination rates in the USA J To facilitate the uptake of universal vaccination, it is recommended that proof of
varicella vaccination or positive VZV serostatus should be considered a requirement
for school entry (category 2 recommendation).
Despite the availability of varicella vaccine in the USA, significant numbers of preventable
deaths from varicella continue to occur among both children and adults.31-33 The US
Department of Health and Human Services has set an objective to achieve >90% vaccine
coverage of children 19–35 months of age, and >95% at school entry by the year 2010.34
To increase vaccine uptake, it is proposed that proof of varicella vaccination or positive VZV
serostatus should be considered a requirement for school entry.
Mathematical models of varicella incidence following universal childhoodvaccinationJ If a policy of routine childhood vaccination is pursued, it is recommended that all
children should be immunized, with countries following the model used in the USA.
Immunizing only a subset of the paediatric population is likely to increase the risk of
creating a population of adults vulnerable to varicella and its attendant morbidity
(category 2 recommendation).
The initial evidence suggests that the introduction of universal childhood vaccination in
the USA is reducing the overall morbidity of varicella. However, the data are from the first
5 years of the programme and it remains to be seen what levels of coverage will be
achieved in the longer term. Mathematical modelling suggests that the success of universal
vaccination is heavily dependent on the level of vaccination coverage achieved. It predicts
that if the coverage were too low, there would be an ongoing circulation of wild-type virus,
albeit at a reduced level. This would probably lead to a gradual increase in the age of
varicella disease onset and move it into older, more susceptible age groups who are at
greater risk of varicella disease complications.35,36 However, higher levels of coverage
would reduce the overall incidence of varicella and its complications.
Halloran and colleagues (1994)37 used an age-structured transmission model to investigate
the effects of routine varicella immunization of pre-school children over a period of
10–50 years. It compared the age distribution and overall morbidity of varicella in a
number of scenarios, which differed according to:
• Level of vaccine coverage (50%, 70%, 97%); the target coverage in each case being
attained 6 years after introduction of the immunization programme, and vaccination
at this level continued for 70 years37
• Whether a catch-up programme was instituted; 12-year-old children who had neither
a history of varicella, nor prior varicella vaccination, were vaccinated. The catch-up
programme was initiated 11 years after the introduction of the vaccine to pre-school
children and continued for an 11-year period.
28
The model predicted that 30 years after initiation of the vaccine programme, the average
number of varicella cases and hospitalizations per year would decrease irrespective of the
level of vaccine coverage and the utilization of a catch-up programme. However, the
greatest reduction was seen with the 97% vaccine coverage which was larger than if a
catch-up programme accompanied the 70% or 50% coverage scenarios (Table 2).37
Despite these results, varicella is occurring in targeted cities, suggesting that the model
may have flaws. It does, however, highlight the importance of attaining a high level of
coverage when implementing a routine vaccination programme. Currently, varicella
vaccine coverage is only 50% in the USA, although a higher percentage is likely when a
combined varicella-measles-mumps-rubella vaccine becomes available.26
The model demonstrated that a varicella vaccine programme would shift the age
distribution of varicella cases upwards for those who were not vaccinated. Although older
individuals are at high risk of the complications of varicella, the overall reduction in cases,
especially with high vaccine coverage, resulted in decreased overall morbidity as
measured by the number of primary cases and hospitalizations.37 The model is limited by
the unknown relationship between incidence of herpes zoster and varicella; exposure to
varicella may boost immune response and provide some protection against the former.
The Halloran model is being used by many countries to evaluate the cost-effectiveness of
varicella vaccination. However, there are limitations of the model, one being that the
vaccination efficacy parameters were optimistic.38 Brisson and colleagues39 revisited the
Halloran model to quantify key parameters describing varicella vaccine efficacy. These were
identified by finding the best fit of the predicted number of annual breakthrough infections
(defined as that occurring in seroconverted individuals, which is clinically modified and less
severe than natural varicella) that was observed in three trials conducted in the USA on
different batches of the varicella vaccine. Their model used the assumption that immunity
wanes over time, although this has not been observed to date. The findings suggest that
vaccination appears to result in a high proportion (97%) of individuals who are initially
protected, but that they lose this protective immunity at a rate of 3% per year. Consequently,
these individuals would be likely to develop breakthrough varicella if exposed to VZV later
in life. Brisson and colleagues39 concluded that studies conducted using Halloran et al’s
data might overestimate the effectiveness of varicella immunization.
Other limitations of the Halloran model include the fact that its age structure did not
accurately reflect the epidemiology of varicella, no sensitivity analysis was performed on
patterns of mixing, and it did not explore the possible effects of immunization on herpes
zoster occurrences. Addressing these aspects, Brisson et al,38 therefore, developed a model
to simulate the incidence of varicella and herpes zoster before and after universal
vaccination, using Canada as an example.
TABLE 2: Predictedannual average number of varicella cases andnumber of hospitalizationsby vaccine coverage andpre-vaccineimplementation37
Without catch-up programme With catch-up programme
Coverage (%) Number of cases (mean per year) Hospitalizations Number of cases (mean per year) Hospitalizations
Pre-vaccine 3960000 9870 3960000 987050 2125000 6268 1698000 471770 1190000 3958 786000 247997 240000 610 202000 504
The modelling by Brisson et al38 demonstrated that varicella incidence and morbidity
(measured by in-patient days) would be reduced by mass vaccination of 12-month-old
children. This reduction in overall morbidity occurred despite a shift in the average age of
infection and an increase in morbidity with age. In agreement with the earlier work by
Halloran et al,37 the authors concluded that the overall effectiveness of immunization is
highly dependent upon the level of vaccine coverage achieved. Varicella morbidity was
predicted to decrease if coverage was more than 70%, with >80% having the greatest
impact. However, even at such high levels, epidemics are likely to occur because not all
would have been vaccinated. The model showed that use of catch-up campaigns could
reduce epidemics as well as minimize the overall number of varicella cases. The successful
catch-up strategies vaccinated children aged 1–11 years in the first year of a vaccination
programme or implemented an annual catch up of 11-year-olds for the first 11 years of the
programme. Which of these choices is preferable depends on the decision-makers’ attitudes
to current versus future health benefits.
The Brisson model also predicted that an effective vaccination strategy would lead to a
short- to medium-term increase in the incidence of herpes zoster. The assumption used in
the model was that exposure to wild-type varicella prevents, or delays, the development
of herpes zoster.39 However, vaccination may itself prevent herpes zoster, a possibility that
was not modelled in the simulations. Data from a study of 192 children with leukaemia,
where half received vaccine and half did not, support this theory.40,41 The incidence of
herpes zoster was significantly lower in the vaccinated children than in those who had
experienced natural infection. Continued, long-term follow-up in the USA, and the results
of the ongoing trial of the effect of vaccination on herpes zoster, will determine exactly
how varicella vaccination will influence the epidemiology of varicella and herpes
zoster.1,42-44
Targeted Vaccination J Programmes should be established to screen for VZV-seropositivity in healthcare
workers, teachers and other adults likely to come into sustained contact with VZV-
infected children and to vaccinate susceptible individuals. This would serve to protect
healthcare workers from VZV-infected patients, protect susceptible patients from
healthcare workers with varicella and protect seronegative teachers from VZV-infected
children (category 2 recommendation).
J Targeted vaccination of at-risk groups is recommended in countries not considering
universal vaccination programmes. Such programmes should include teachers,
healthcare workers, identified seronegative adults, and seronegative women of
childbearing age who are not pregnant (category 2 recommendation).
In addition to recommending universal vaccination of children, the ACIP strongly
recommends vaccination of all susceptible individuals aged ≥13 years at high risk of
exposure to VZV20 (see text box page 30). In Germany, varicella vaccination has been
recommended for susceptible individuals at risk of varicella and their contacts.45 In the UK,
it has been proposed that immunocompromised patients and susceptible healthcare workers
be immunized, but such an approach has not, as yet, gained widespread acceptance.46
Targeted vaccination has the advantage that it is less costly than universal and protects high-
risk individuals, and also that immunological boosting from circulating wild-type VZV in the
29
community is not forfeited, as would happen with a universal vaccination programme. The
major difficulty encountered with targeted vaccination is in its implementation, as it depends
largely on the vigilance and commitment of each medical practitioner. In addition, many of
the at-risk populations require two doses of vaccine, adding to the logistical problems. There
may also be people who have severe immunosuppressive disorders, making them unsuitable
for vaccination, but who are still at risk from naturally acquired varicella. Finally, as with
universal vaccination, there is the issue of potential waning immunity over time.
Just as universal vaccination has been shown to be cost-effective, so targeted vaccination
of at-risk groups has been shown to yield economic benefits. For example, in a study of
472 leukaemic children, vaccination was calculated to be 11–13 times cheaper than
treatment of varicella.29
The targeted vaccination of women of childbearing age has been estimated to cost
US$7000 per case of varicella prevented.47 In the model used, it was assumed that 95%
of women were seropositive, the incidence of varicella in pregnancy was three women per
1000 and that all women were screened regardless of disease history. The intervention
might have been cost-saving if the costs of diagnosis and treatment of varicella, and those
relating to congenital varicella, were taken into account. A similar analysis using data from
a clinical population in the UK found that vaccination of women was cost-saving. In the
population considered, 80% of women were VZV-seropositive and the incidence of
varicella in pregnancy was 7.7 cases per 1000 women.48 Thus, vaccination of women may
be cost-effective if the seroprevalence in that element of the population is low.
A strategy of serological screening of healthcare workers with no history of varicella (or
herpes zoster), followed by vaccination of non-immune workers, is a cost-effective
strategy.49 Savings accrue from reduced absenteeism by employees with varicella and
reduced medical expenses for patients who contract varicella from healthcare workers.49,50
The American Medical Association has recommended that all susceptible healthcare
workers receive the varicella vaccine.51
SummaryVaricella is generally regarded as a benign, self-limiting disease in otherwise healthy children;
however, infants, adults, adolescents, pregnant women and the immunocompromised are at
risk of more severe disease with serious outcomes and are more likely to experience
complications.
A live, attenuated varicella vaccine (VZVoka vaccine) was developed in Japan in 1974. All
currently available varicella vaccines are based on the VZVoka strain, and experience of their use
for the prevention of varicella has accumulated over the past 25 years in Japan and the USA.
30
High-risk groups appropriate for varicella vaccination (susceptible individuals)20
• VZV-seronegative persons living or working in environments where transmission of VZV is likely (e.g. healthcare workers, teachers ofyoung children, child daycare employees)
• VZV-seronegative persons living and working in environments where transmission can occur (e.g. college students, inmates and staffmembers of correctional institutions, military personnel)
• VZV-seronegative non-pregnant women of childbearing age
• VZV-seronegative adolescents and adults living in households with children
• VZV-seronegative international travellers
Varicella vaccination is effective in children, susceptible adolescents and adults, including
selected groups of immunocompromised children, such as those with leukaemia in
remission and selected transplant recipients. Whilst vaccination of certain
immunocompromised children is beneficial, there is a lack of data regarding the use of
varicella vaccine in immunocompromised adults.
The effectiveness in a country of a universal vaccination programme in reducing the
overall morbidity due to varicella is largely dependent upon the actual coverage achieved.
If it is low, there will be an ongoing circulation of wild-type virus which, in the presence
of some vaccinated individuals, may lead to an increase in the age of onset of varicella.
This will shift the disease burden into older, more susceptible age groups who are at
greater risk of complications.
Targeted vaccination of at-risk individuals, such as healthcare workers, teachers and non-
pregnant women of childbearing age, is less costly than universal vaccination whilst still
providing protection for those individuals at greatest risk of complications. The main
disadvantages of targeted vaccination are that it relies upon the vigilance of individual
medical practitioners and that there may be those, such as immunocompromised adults,
who are unsuitable for vaccination but who are at risk from naturally acquired varicella.
Routine vaccination of children is recommended as are screening programmes to identify
susceptible adolescents and adults. Healthcare workers, teachers and non-pregnant
women of childbearing age should be considered priority groups for screening and
vaccination as necessary. Continuing surveillance of the vaccinated is required to assess
long-term efficacy, safety and effect on the occurrence of herpes zoster.
References1. Meyer PA, Seward JF, Jumaan AO et al. Varicella mortality: trends before vaccine licensure in the United
States, 1970-1994. J Infect Dis 2000;182(2):383-390.2. Preblud SR. Age-specific risks of varicella complications. Pediatrics 1981;68:14-17.3. Feldman S, Hughes WT, Daniel CB. Varicella in children with cancer: Seventy-seven cases. Pediatrics
1975;56(3):388-397.4. Perronne C, Lazanas M, Leport C et al. Varicella in patients infected with the human immunodeficiency
virus. Arch Dermatol 1990;126(8):1033-1036.5. Asano Y. Varicella vaccine: the Japanese experience. J Infect Dis 1996;174 (Suppl 3):S310-S313.6. Asano Y, Nagai T, Miyata T. Long-term protective immunity of recipients of Oka strain of live varicella
vaccine. Pediatrics 1985;75:667-671.7. Gershon A, Steinberg S, Gelb L. A multicentre trial of live attenuated varicella vaccine in children with
leukaemia in remission. Postgr Med J 1985;61(Suppl):S73-S78.8. Weibel RE, Neff BJ, Kuter BJ. Live attenuated varicella virus vaccine. Efficacy trial in healthy children. N Engl
J Med 1984;310:1409-1415.9. Kuter BJ, Weibel RE, Guess HA. Oka/Merck varicella vaccine in healthy children: final report of a 2-year
efficacy study and 7-year follow-up studies. Vaccine 1991;9:643-647.10. Gershon A, LaRussa P, Hardy I. Varicella vaccine: the American experience. J Infect Dis 1992;166
(Suppl 1):S63-S68.11. White CJ, Kuter BJ, Hildebrand CS. Varicella vaccine (VARIVAX) in healthy children and adolescents: results
from clinical trials 1987–1989. Pediatrics 1991;87:604-610.12. Varis T, Vesikari T. Efficacy of high-titer live attenuated varicella vaccine in healthy young children. J Infect
Dis 1996;174 (Suppl 3):S330-S334.13. Kuter BJ, Ngai A, Patterson CM et al. Safety, tolerability, and immunogenicity of two regimens of Oka/Merck
varicella vaccine (Varivax) in healthy adolescents and adults. Oka/Merck Varicella Vaccine Study Group.Vaccine 1995;13(11):967-972.
14. Gershon AA, Steinberg SP, National Institute of Allergy and Infectious Diseases Varicella VaccineCollaborative Study Group. Live attenuated varicella vaccine: Protection in healthy adults compared withleukemic children. J Infect Dis 1990;161:661-666.
15. Gershon AA, Steinberg SP, LaRussa P et al. Immunization of healthy adults with live attenuated varicellavaccine. J Infect Dis 1988;158(1):132-137.
16. Prevention of varicella: Recommendations of the Advisory Committee on Immunization Practices (ACIP).Centers for Disease Control and Prevention. MMWR Morb Mortal Wkly Rep 1996;45(RR-11):1-36.
17. Johnson CE, Stancin T, Fattlar D et al. A long-term prospective study of varicella vaccine in healthy children.Pediatrics 1997;100(5):761-766.
31
18. Asano Y, Suga S, Yoshikawa T et al. Experience and reason: twenty-year follow-up of protective immunity ofthe Oka strain live varicella vaccine. Pediatrics 1994;94(4 Pt 1):524-526.
19. Gershon AA. Varicella-zoster virus: prospects for control. Adv Pediatr Infect Dis 1995;10:93-124.20. Prevention of varicella. Update recommendations of the Advisory Committee on Immunization Practices
(ACIP). MMWR Morb Mortal Wkly Rep 1999;48(RR-6):1-5.21. Takahashi M. Current status and prospects of live varicella vaccine. Vaccine 1992;10(14):1007-1014.22. Levin MJ, Barber D, Goldblatt E et al. Use of a live attenuated varicella vaccine to boost varicella-specific
immune responses in seropositive people 55 years of age and older: duration of booster effect. J Infect Dis1998;178 Suppl 1:S109-112.
23. Raeder CK, Hayney MS. Immunology of varicella immunization in the elderly. Ann Pharmacother2000;34(2):228-234.
24. Krause PR, Klinman DM. Varicella vaccination: evidence for frequent reactivation of the vaccine strain inhealthy children. Nat Med 2000;6(4):451-454.
25. Hata A, Asanuma H, Rinki M et al. Use of an inactivated varicella vaccine in recipients of hematopoietic-cell transplants. N Engl J Med 2002;347:26-34.
26. American Academy of Pediatrics. Committee on Infectious Diseases. Varicella vaccine update. Pediatrics2000;105(1 Pt 1):136-141.
27. Preblud SR, Orenstein WA, Koplan JP et al. A benefit-cost analysis of a childhood varicella vaccinationprogramme. Postgrad Med J 1985;61(Suppl 4):S17-S22.
28. Lieu TA, Cochi SL, Black SB et al. Cost-effectiveness of a routine varicella vaccination program for USchildren. JAMA 1994;271(5):375-381.
29. Lieu TA, Finkler LJ, Sorel ME et al. Cost-effectiveness of varicella serotesting versus presumptive vaccinationof school-age children and adolescents. Pediatrics 1995;95(5):632-638.
30. Huse DM, Meissner HC, Lacey MJ et al. Childhood vaccination against chickenpox: an analysis of benefitsand costs. J Pediatr 1994;124(6):869-874.
31. Spingarn RW, Benjamin JA. Universal vaccination against varicella [letter]. N Engl J Med 1998;338(10):683;discussion 684.
32. From the Centers for Disease Control and Prevention. Varicella-related deaths among children–UnitedStates, 1997. JAMA 1998;279(22):1773-1774.
33. Varicella-related deaths among children—United States, 1997. Can Commun Dis Rep 1998;24(13):108-111.
34. Healthy People 2010 Objectives: Draft for Public Comment. Immunizations and infectious diseases.1998:22-36.
35. Halloran ME. Epidemiologic effects of varicella vaccination. Infect Dis Clin North Am 1996;10(3):631-655.36. Ferguson NM, Anderson RM, Garnett GP. Mass vaccination to control chickenpox: the influence of zoster.
Proc Natl Acad Sci USA 1996;93(14):7231-7235.37. Halloran ME, Cochi SL, Lieu TA et al. Theoretical epidemiologic and morbidity effects of routine varicella
immunization of preschool children in the United States. Am J Epidemiol 1994;140(2):81-104.38. Brisson M, Edmunds WJ, Gay NJ et al. Modelling the impact of immunization on the epidemiology of
varicella zoster virus. Epidemiol Infect 2000;125(3):651-669.39. Brisson M, Edmunds WJ, Gay NJ et al. Analysis of varicella vaccine breakthrough rates: implications for the
effectiveness of immunisation programmes. Vaccine 2000;18(25):2775-2778.40. Hardy I, Gershon AA, Steinberg SP et al. The incidence of zoster after immunization with live attenuated
varicella vaccine. A study in children with leukemia. Varicella Vaccine Collaborative Study Group. N Engl JMed 1991;325(22):1545-1550.
41. Lawrence R, Gershon AA, Holzman R et al. The risk of zoster after varicella vaccination in children withleukemia. N Engl J Med 1988;318(9):543-548.
42. Nowgesic E, Skowronski D, King A et al. Direct costs attributed to chickenpox and herpes zoster in BritishColumbia–1992 to 1996. Can Commun Dis Rep 1999;25(11):100-104.
43. Deguen S, Chau NP, Flahault A. Epidemiology of chickenpox in France (1991–1995). J EpidemiolCommunity Health 1998;52 (Suppl 1):46S-49S.
44. Fairley CK, Miller E. Varicella-zoster virus epidemiology–a changing scene? J Infect Dis 1996;174 (Suppl3):S314-S319.
45. Impfempfehlungen der Ständigen Impfkomission (STIKO) am Robert-Koch-Institut. EpidemiologischesBulletin 15/97 1997.
46. Jones EM, Reeves DS. Controlling chickenpox in hospitals. BMJ 1997;314(7073):4-5.47. Seidman DS, Stevenson DK, Arvin AM. Varicella vaccine in pregnancy. BMJ 1996;313(7059):701-702.48. Griffiths PD, Volpi A. Management Strategies in Herpes: Progress with Diagnostic Tests and Vaccines for
Alphaherpesviruses. Worthing, PAREXEL MMS Ltd, 1998.49. Gray AM, Fenn P, Weinberg J et al. An economic analysis of varicella vaccination for health care workers.
Epidemiol Infect 1997;119(2):209-220.50. Weinstock DM, Rogers M, Lim S et al. Seroconversion rates in healthcare workers using a latex agglutination
assay after varicella virus vaccination. Infect Control Hosp Epidemiol 1999;20(7):504-507.51. Lyznicki JM, Bezman RJ, Genel M. Report of the Council on Scientific Affairs, American Medical
Association: immunization of healthcare workers with varicella vaccine. Infect Control Hosp Epidemiol1998;19(5):348-353.
32
33
MANAGEMENT OF VARICELLA IN THE
IMMUNOCOMPETENT HOST4
Management RecommendationsCategory 2Antiviral treatmentJ Oral aciclovir (20 mg/kg up to 800 mg four times daily for 5 days) is recommended as
the treatment of choice for otherwise healthy children up to the age of 12 years with
varicella. Valaciclovir and famciclovir are likely to be as effective as aciclovir, but have
not been studied in controlled clinical trials and no paediatric formulation of
valaciclovir or famciclovir exists.
J Complications are more likely and frequently more serious in nature in adults and
adolescents than in children. They are also more likely and often more severe in
secondary cases in a household than in the index case. Therefore, treatment with oral
aciclovir (800 mg four to five times daily for 5–7 days) should be offered to all adults
and adolescents with varicella presenting within 48 hours of rash onset.
Category 3Antiviral treatmentJ Valaciclovir (1000 mg three times daily) and famciclovir (250 mg or 500 mg three
times daily) are likely to be as effective as aciclovir; although they have not been
studied in controlled clinical trials, pharmacokinetic data support their use.
J It is recommended that all patients presenting with varicella-associated pneumonia,
whether pregnant or not, should receive intravenous aciclovir (10 mg/kg every
8 hours).
J It is recommended that post-exposure prophylaxis of pregnant women and neonates
be provided with varicella zoster immune globulin (VZIG). Prophylactic aciclovir
(800 mg five times daily) and varicella vaccine could play a role in these settings but
have not been the subject of controlled studies.
J It is recommended that treatment of more severe cases of varicella in children, and
varicella in adults, adolescents and other at-risk individuals, is maintained as a priority
even in the presence of a varicella vaccination programme. For example, post-
exposure prophylaxis with aciclovir in pregnant women should theoretically be
effective but this strategy is currently not advocated, at least during the first
20 weeks of pregnancy.
Varicella vaccineJ Varicella vaccine may be considered for post-exposure prophylaxis in
immunocompetent hosts as it will effectively prevent or ameliorate varicella when
34
given to a susceptible individual within 3–5 days after exposure to varicella zoster
virus (VZV). Although post-exposure vaccination and post-exposure aciclovir (800 mg
fives times daily) administration have not been compared directly, they are likely to
have similar efficacy, while the former is probably less expensive.
J Post-exposure prophylaxis with aciclovir (800 mg five times daily) may remain a
viable option when the VZV exposure is not recognized until more than 5 days later.
J The use of oral aciclovir (800 mg five times daily), valaciclovir or famciclovir for
pregnant women who contract varicella in their second or third trimester is
recommended. However, it is important to note that this recommendation is based on
anecdotal evidence, and that patients should be advised that these drugs are not
licensed for use during pregnancy.
J Physicians should be aware of rare but serious complications and atypical
manifestations of varicella, such as cerebellar ataxia, varicella-associated pneumonia,
VZV encephalitis and cutaneous bacterial complications. The use of intravenous
aciclovir (10 mg/kg every 8 hours) is warranted in these cases, based on anecdotal
evidence.
J Pre-pregnancy serological screening of non-pregnant women of childbearing age and
varicella vaccination are recommended. This approach has the potential to prevent
maternal varicella, congenital varicella syndrome and neonatal varicella where the
infant acquires their infection from the mother.
J Neonates (<28 days old) who are exposed to varicella post-natally should be
administered prophylactic VZIG.
Research needsJ It is recommended that further investigation be conducted to assess whether pregnant
women who contract varicella during the first trimester of pregnancy should be
administered intravenous aciclovir (10 mg/kg every 8 hours). There is currently no
evidence that this treatment results in fetal malformations or that it prevents congenital
varicella.
J It is recommended that the efficacy of valaciclovir and famciclovir be assessed in
adults with varicella. It may be applicable for such studies to be conducted in tropical
countries due to the larger potential adult study population.
Although varicella is a generally benign and self-limiting disease, as discussed in
Chapter 2, there are potentially serious complications associated with it. These are more
likely to manifest in neonates, pregnant women, adolescents and adults, but can, in rare
instances, occur in otherwise healthy children. The potentially serious nature of these
complications highlights the need for effective prevention and management of varicella in
high-risk individuals.
35
Pre-Exposure Varicella VaccinationAs discussed in Chapter 3, experience with the live attenuated VZVoka vaccine for
prevention of varicella has accumulated over the last 25 years in Japan and the USA. The
vaccine is well tolerated and effective in healthy children and strongly indicated in VZV-
seronegative adolescents and adults.1,2 The vaccine offers long-term protection against
clinically severe varicella.3 For a detailed discussion, see Chapter 3.
Post-Exposure ProphylaxisJ Varicella vaccine may be considered for post-exposure prophylaxis in
immunocompetent hosts as it will effectively prevent or ameliorate varicella when
given to a susceptible individual within 3–5 days after exposure to VZV (category 3
recommendation). Although post-exposure vaccination and post-exposure aciclovir
(800 mg fives times daily) administration have not been compared directly, they are
likely to have similar efficacy, while the former is probably less expensive.
J Post-exposure prophylaxis with aciclovir (800 mg five times daily) may remain a viable
option when the VZV exposure is not recognized until more than 5 days later (category 3
recommendation).
Due to the potentially serious nature of the complications of varicella, and the costs
associated with treating and managing patients presenting with severe disease, prevention
of varicella in susceptible individuals following exposure to VZV is likely to be both
beneficial to the patient and cost-effective.
Post-exposure prophylaxis with varicella vaccine A small, controlled study of 40 immunocompetent children indicates that the varicella
vaccine is likely to be effective for post-exposure prophylaxis of varicella in children,
provided it is administered sufficiently soon after exposure to VZV.4 In the study,
experimental VZVoka vaccines of varying doses administered within 72 hours of initial
exposure to VZV prevented the development of varicella symptoms; all of the
unvaccinated controls developed clinical varicella.4 Case studies also support the concept
of post-exposure immunization to prevent varicella. In a study of 10 susceptible siblings
given varicella vaccine within 72 hours of lesion onset in the index case, five did not
develop varicella and five developed only mild disease (four of five exhibited <20
lesions).5 In a recent study, post-exposure administration of varicella vaccine limited
spread of varicella among children and adults in a women’s refuge.6 In the study, residents
of the refuge with no history of varicella were offered vaccination when one of the
residents and her child developed varicella. This was administered within 3 days of the
rash onset. None of 25 adults and only two of 42 children developed illness. However, the
two children with varicella were siblings of the index case, and were housed in the same
room. The illness that developed in the children was brief, afebrile and was characterized
by fewer than 20 lesions (Table 1). The mildness of the illness in the secondary cases
suggests that the vaccine ameliorated the disease as, untreated, varicella is usually more
severe in secondary and tertiary household contacts compared with the index case.7
However, as there was no control group, the actual effect of vaccination cannot be
determined.
36
Despite issues with some of these studies, including the small numbers of subjects, the
different vaccine formulations used, and the inadequate assessment of susceptibility, the
US Advisory Committee on Immunization Practices (ACIP) now recommends varicella
vaccine for susceptible persons following exposure to varicella. Vaccine should be
administered within 3–4 days of exposure.2 In terms of cost, post-exposure vaccination is
less expensive than post-exposure prophylaxis with aciclovir; both of these options are less
expensive than VZIG administration.8
Post-exposure prophylaxis with antiviralsA small number of studies have investigated post-exposure prophylaxis with aciclovir for
susceptible immunocompetent children following VZV exposure. Aciclovir may be
effective in preventing the development of varicella.
In 50 exposed infants and children, oral aciclovir (40–80 mg/kg/day) initiated 7–9 days
after exposure to VZV and administered for 7 days prevented the development of clinical
varicella in 21 out of 25 treated children; all of the 25 untreated children in the control
group developed varicella.9 In another study, in which children were given oral aciclovir
(40 mg/kg/day) 1–3 days after exposure to VZV, 10 out of 13 children developed varicella
within 28–42 days.10 These studies were performed in different populations, some of
whom received different doses of aciclovir and were followed up for different lengths of
time, making it difficult to draw direct comparisons. Despite this, the data suggest that
post-exposure prophylaxis with aciclovir is less effective if administered too soon
following VZV exposure. Up to 20% of individuals receiving aciclovir for post-exposure
prophylaxis may not seroconvert; this may be due to lack of actual exposure to VZV, or
there may be blunting of the immune response following the termination of VZV
replication by aciclovir.9,11,12
If susceptible patients can be identified within 5 days of varicella exposure, post-exposure
vaccination would be a more efficient approach than aciclovir administration.13 However,
there is minimal and conflicting evidence regarding protection when vaccine is received
4 to 5 days after exposure.4
Antiviral TreatmentJ Oral aciclovir (20 mg/kg up to 800 mg four times daily for 5 days) is recommended as
the treatment of choice for otherwise healthy children up to the age of 12 years with
varicella (category 2 recommendation). Valaciclovir and famciclovir are likely to be as
effective as aciclovir, but have not been studied in controlled clinical trials and no
paediatric formulation exists.
TABLE 1: Summary ofstudies of varicellavaccine used for post-exposure prophylaxis
Population Study Vaccine administered Results Reference
40 children Vaccination versus Within 72 hours of No cases of varicella in the Asano Y et al. 19774
no vaccination initial exposure to VZV vaccinated group; all developed varicella in the group that was not vaccinated
10 children Susceptible siblings Within 72 hours of lesion 5 had no disease; 5 developed mildwere given varicella vaccine onset in the index case disease (4 of these had <20 lesions) Salzman M, et al. 19985
42 children and Individuals with no Within 3 days of rash onset None of the adults developed Watson B et al. 20006
25 adults history of varicella were in mother and her child illness; 2 children developed offered vaccination mild illness
37
J Complications are more likely, and frequently more serious, in adults and adolescents
than in children. They are also more likely and often more severe in secondary
household cases than the index case. Therefore, treatment with oral aciclovir (800 mg
four to five times daily for 5–7 days) should be offered to all adults and adolescents
with varicella presenting within 48 hours of rash onset (category 3 recommendation).
J Valaciclovir (1000 mg three times daily) and famciclovir (250 or 500 mg three times
daily) are likely to be as effective as aciclovir, but have not been studied in controlled
clinical trials (category 3 recommendation).
J It is recommended that all patients presenting with varicella-associated pneumonia (or
symptoms or signs of respiratory involvement), whether pregnant or not, should
receive intravenous aciclovir (10 mg/kg every 8 hours) (category 3 recommendation).
J Physicians should be aware of rare but serious complications and atypical
manifestations of varicella, such as cerebellar ataxia, VZV encephalitis and cutaneous
bacterial complications. The use of intravenous aciclovir (10 mg/kg every 8 hours) is
warranted in these cases, based on anecdotal evidence (category 3 recommendation).
J It is recommended that studies of valaciclovir and famciclovir be conducted in adults
with varicella to assess efficacy. It may be applicable for such studies to be conducted
in tropical countries due to the larger potential adult study population (research need
recommendation).
Treatment options available are summarized in Table 2.
Prospective, controlled, large-scale
clinical trials document the efficacy of
oral aciclovir for the treatment of
varicella in immunocompetent
children, adolescents and adults.14-17
It increases the rate of rash resolution,
decreases the duration of febrile illness
and reduces the systemic symptoms of
varicella. The limited scale of these benefits means that the case for aciclovir treatment of
varicella, at least in otherwise healthy children, has not been universally accepted.
In immunocompetent children aged 2–12 years of age, oral aciclovir (20 mg/kg four times
daily for 5 days) initiated within 24 hours of rash onset resulted in a shorter duration of
febrile illness, fewer skin lesions (294 versus 347), and accelerated lesion healing (2.7 days
versus 3.2 days) compared with placebo (Table 3).16 Similarly, in adolescents, oral
aciclovir (800 mg four times daily for 5 days) initiated within 24 hours of rash onset was
more effective than placebo in reducing the duration of febrile illness and resulted in more
rapid cessation of lesion formation (by 0.5 days).15 Because the treatment provides a
relatively modest reduction in duration and severity of illness, the decision to treat children
should be individualized.
TABLE 2: Treatmentoptions for immuno-competent individualswith varicella8
Patient group Treatment options
Neonates Intravenous aciclovir for 10 days Children <12 years of age Symptomatic care only; oral aciclovir may
be considered
Adolescents/adults Oral valaciclovir, famciclovir or aciclovir for 5–7 days
Women in last trimester of pregnancy Oral aciclovir for 5–7 days
Patients with pneumonitis or other Intravenous aciclovir for 7–10 dayssevere infection
38
TABLE 3: Cutaneousevents in children withvaricella treated withaciclovir or placebo16
Aciclovir group Placebo group P-value
Median number of lesions 294 (277) 347 (386) <0.001 Number with >500 lesions (%) 78 (21.3) 137 (38.4) <0.001 Median number of residual lesions on D28 13 (6) 33 (13) <0.001
In adults, oral aciclovir (800 mg five times daily for 7 days) administered within 24 hours
of rash onset was beneficial compared with placebo. Aciclovir accelerated the time to
cutaneous healing, decreased the duration of fever (by 1.8 days), and lessened systemic
symptoms (Figure 1).17 However, if therapy was administered after 24 hours following rash
onset, there was no appreciable benefit.
The results of these trials have been confirmed by data from a recent study of aciclovir
versus placebo in 177 children, adolescents and adults with varicella.18 In this study,
maximum clinical benefit was achieved when aciclovir therapy was initiated within 24
hours of rash onset, although children and adolescents (but not adults) showed significant
improvement in clinical end-points when aciclovir therapy was initiated 48 hours after
rash onset.18 The populations studied in these trials
were not sufficiently large, or the incidence of
complications was too low, to assess the impact of
aciclovir therapy on the incidence of varicella
complications.
Valaciclovir and famciclovir are likely to be as
effective as aciclovir for treatment of varicella, as
pharmacokinetic data show that they achieve serum
levels of aciclovir or penciclovir at least as high as
the parent compounds.19,20 No data from
controlled, prospective trials have yet been
published to support this indication. However, a
family case study indicates that valaciclovir has potential as a therapy for adult varicella.21
As a consequence of the limited clinical benefit of antiviral therapy, many clinicians view
it as an optional treatment for otherwise healthy children with varicella. For example, the
Committee on Infectious Disease of the American Academy of Pediatrics (AAP) does not
consider the prescribing of aciclovir to healthy children to be of sufficient benefit to justify
routine administration.22 However, it acknowledges that aciclovir use is justified in some
cases, as complications and severe varicella may occur in adolescents and adults, or in
secondary-case patients who live in the households of infected children.1
The role of antiviral therapy in individuals presenting with rarer complications of varicella,
such as cerebellar ataxia and encephalitis, has not been studied in a prospective or
controlled fashion. Despite this, administration of intravenous aciclovir (10 mg/kg every
8 hours) to such patients is likely to be appropriate, based upon anecdotal evidence.
(J Gnann, RJ Whitley, personal communication.)
As there are no published data from randomized, controlled trials available on the efficacy
of valaciclovir or famciclovir for the treatment of varicella in the immunocompetent host,
specific recommendations regarding their use, especially in high-risk populations, cannot
be made. However, following valaciclovir administration, significantly higher plasma
FIGURE 1: Dailyconstitutional illnessscores of adults withvaricella treated withaciclovir or placebowithin 24 hours of rashonset17
1 2Day of study3 4 5
2.0
1.6
1.2
0.8
0.4
0
Illne
ss s
core
s
0.2
0.6
1.0
1.4
1.8
6 7
AciclovirPlacebo
P=0.141
P=0.049
P=0.002
P=0.087
P=0.082P >0.2
P >0.2
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39
levels of aciclovir are achieved than are possible following administration of oral
aciclovir.19 Similarly, famciclovir delivers high levels of penciclovir.20 Both valaciclovir
and famciclovir are likely to be effective for the treatment of varicella, and at least as
effective as aciclovir at preventing complications.
Prevention and Management of Varicella in the Pregnant Womanand NeonateJ It is recommended that post-exposure prophylaxis of pregnant women and neonates is
based on passive immunization with VZIG. Prophylactic aciclovir (800 mg five times
daily) and varicella vaccine could play a role in these settings but have not been the
subject of controlled studies (category 3 recommendation).
J The use of oral aciclovir (800 mg five times daily) for pregnant women who contract
varicella in their second or third trimester is recommended. It is important to note that
this recommendation is based on anecdotal evidence, and that patients should be
advised that antiviral drugs are not licensed for use during pregnancy (category 3
recommendation). The roles of valaciclovir and famciclovir for the treatment of
varicella infection in the pregnant woman remain to be evaluated in clinical trials.
J Pre-pregnancy serological screening of non-pregnant women of childbearing age and
varicella vaccination are recommended. This approach has the potential to prevent
maternal varicella, congenital varicella syndrome and neonatal varicella where the
infant acquires infection from the mother (category 3 recommendation).
J Neonates (<28 days old) who are exposed to varicella post-natally should be
administered prophylactic VZIG (category 3 recommendation).
J It is recommended that further investigation be conducted to assess whether pregnant
women who contract varicella during the first trimester of pregnancy should be
administered intravenous aciclovir (10 mg/kg every 8 hours). There is currently no evidence
that this treatment results in fetal malformations (research need recommendation).
The high risk of complications in the pregnant woman with varicella, coupled with the
potentially devastating fetal abnormalities caused by congenital varicella syndrome and
the risks to neonates if maternal varicella occurs immediately before or after birth,
emphasize the need for effective prevention and management.
Varicella vaccination in the pregnant womanAs discussed in Chapter 3, vaccination of pregnant women is not recommended because
of the theoretical risk to both the fetus and the mother.
Prevention of maternal varicella may be achieved by pre-pregnancy serological screening
of women of childbearing age and subsequent varicella vaccination as appropriate. This
approach would also help minimize the risk of congenital varicella syndrome and
neonatal varicella. The US ACIP recommends varicella vaccination for susceptible, non-
pregnant women of childbearing age.2
40
For a detailed discussion on the use of varicella vaccination in pregnant women, see
Chapter 3.
Post-exposure prophylaxis in the pregnant womanThe aim of post-exposure prophylaxis in the pregnant woman is to prevent or modify
illness, and to reduce the risk of intrauterine VZV infection. It should be offered to
susceptible pregnant women with significant virus exposure (e.g. from their own family)
during the first 20 weeks of gestation, because secondary household cases may be more
severe and there is a 1–2% risk of congenital varicella.23 Before administering post-
exposure prophylaxis, it is important to ascertain the type of VZV exposure and the
previous varicella history of the pregnant woman. If there is any uncertainty regarding
infection history, VZV antibody status should be determined rapidly.
Unfortunately, in this time-critical scenario, the true VZV serological status of pregnant
women without a history of varicella is often not known. The clinician may be faced with
a decision as to whether to initiate prophylactic treatment empirically or wait for
serological test results. The ideal time to determine VZV serological status would be before
pregnancy, when vaccination can be offered to women confirmed to be VZV seronegative.
Antiviral prophylaxisJ Post-exposure prophylaxis with aciclovir in pregnant women should theoretically be
effective but this strategy is currently not advocated, at least not during the first 20
weeks of pregnancy (category 3 recommendation).
VZIG prophylaxis in pregnancyAs maternal varicella can result in fetal and neonatal morbidity, susceptible pregnant
women who have a close exposure to VZV should receive passive immunotherapy with
VZIG. In the UK, recommendations are that VZIG is effective in the pregnant woman if
given up to 10 days after initial exposure and to neonates up to 28 days post-partum.23
The American Academy of Pediatrics
(AAP) recommendations are shown in
Table 4; differences in UK and US
recommendations arose because the
findings did not agree. This may have
been due to differences in the VZIG
preparations used. Similarly, as antibody
content varies between countries, a
particular dose of VZIG cannot be
recommended.1
Although the purpose of VZIG administration in early pregnancy is principally the prevention
of maternal VZV infection, the possible attenuation of the disease with VZIG is also valuable.
In a study of 212 seronegative pregnant women, VZIG was administered either
intramuscularly (for a 70 kg woman: 2100 IU) or intravenously (for a 70 kg woman: 1750 IU)
and within 1–3 days of significant exposure to VZV. Forty-one per cent of the women
developed clinical varicella, and a further 5% developed subclinical infection (Table 5).22
TABLE 4: AAPrecommendations forimmunocompetentcandidates benefitingfrom VZIG administrationfollowing varicellaexposure22
AAP recommendations
• Susceptible pregnant women
• Newborn infants whose mothers have varicella within 5 days before or48 hours after delivery
• Hospitalized premature infants (>28 weeks gestation) whose mothers have nohistory of varicella
• Hospitalized premature infants (<28 weeks gestation or <1000 g) irrespective ofmaternal history
41
TABLE 5: Outcome ofvaricella exposure in 212seronegative pregnantwomen followingadministration of VZIG23
Outcome
VZIG administration Number treated No infection Subclinical infection Modified/normal varicella (Days after exposure) n (%) n (%) n (%)
1–3 153 83 (54) 7 (5) 63 (41) 4–5 46 27 (59) 1 (2) 18 (39) 6–10 13 4 (31) 3 (23) 6 (46) Total 212 114 (54) 11 (5) 87 (41)
In summary, VZIG should be administered as soon as possible to susceptible (seronegative)
women following exposure to VZV in the first 20 weeks of gestation. VZIG prophylaxis for
women exposed later in pregnancy is a lower priority.23-29
There is limited evidence that VZIG benefits the fetus and reduces the risk of intrauterine
varicella infection.23,30 In a prospective study of 97 pregnant women who contracted
varicella despite receiving VZIG, there were no cases of congenital varicella syndrome,
and VZV-specific IgM antibodies were detectable at birth in only one infant (maternal
varicella in Week 36 of gestation).23 However, this study did not demonstrate a statistically
significant protective effect of VZIG to the fetus because the numbers were too small.31 In
another prospective study, 6 (5%) of 106 varicella-infected women received VZIG after
exposure in early pregnancy.32 The only infant with congenital varicella syndrome was
born to a woman who received VZIG. The VZV-susceptible mother received VZIG 4 days
after her exposure to varicella at Week 11 of pregnancy; she developed varicella 2 weeks
later. These two studies demonstrate the need for a large prospective trial to clarify whether
passive prophylaxis can prevent congenital varicella syndrome.
Post-exposure vaccination in pregnancyAs discussed above and in Chapter 3, post-exposure prophylaxis with vaccine is not advocated
for pregnant women, but is recommended for non-pregnant women of childbearing age.
Management of the pregnant woman with varicellaAntiviral treatment of varicella in pregnancyTreatment of varicella with oral aciclovir in adults, including pregnant women with a
normal course of illness, differs from country to country. In the UK and Australia, oral
aciclovir for 7 days (800 mg five times daily) is offered to individuals, including pregnant
women past 20 weeks of gestation, presenting within 24 hours of rash onset. This
procedure reduces the severity of disease in non-pregnant adults,1,15,17,33 but no studies
have prospectively assessed the efficacy of antiviral therapy in pregnant women. A
retrospective analysis of aciclovir in pregnant women with varicella pneumonia noted
reduced morbidity and mortality when varicella infection occurred during the last two
trimesters; aciclovir reduced mortality rates to 14% compared with 41% in untreated
historic controls.34
In pregnant women, the potential benefits of treatment and post-exposure prophylaxis
should be balanced against potential adverse outcomes in the fetus. Although aciclovir is
not licensed for use in pregnancy, the prospective follow-up of 1205 women treated during
the first (n=739), second (n=188) and third (n=278) trimester of pregnancy did not
demonstrate an increase in the number of birth defects when compared with that expected
in the general population.35,36 In addition, there is no consistent pattern of defects among
42
prospective or retrospective reports of aciclovir use. Although the data from the Pregnancy
Registry are not strong enough to exclude a teratogenic effect of aciclovir, this treatment
should not be withheld in early pregnancy if clinically indicated.
As the complications of varicella are more common in adults, and given the limited
Pregnancy Registry data available, there is no apparent reason to withhold aciclovir at any
time during pregnancy. The dosage and route of administration are determined by the
severity of disease. If a woman has severe or complicated disease (e.g. pneumonitis),
intravenous aciclovir should be given (10 mg/kg every 8 hours for 7 days or longer).
Pregnant women with less severe disease should be treated with oral aciclovir (800 mg five
times per day for 7 days or longer). More data are required on long-term follow-up of
children exposed to aciclovir in utero. The roles of valaciclovir and famciclovir for the
treatment of varicella infection in pregnancy remain to be evaluated in clinical trials.
The pregnant woman with varicella should avoid contact with all other pregnant women
and neonates until her lesions are crusted.
Pregnant women exposed to herpes zosterFollowing exposure to herpes zoster, passive prophylaxis with VZIG is recommended only
for VZV-seronegative pregnant women up to 21 weeks of gestation intimately exposed to
patients with extensive herpes zoster lesions. Local guidelines for treating herpes zoster in
adults should be followed. Women who develop localized herpes zoster in pregnancy
should be reassured that the risk to the fetus is negligible. In addition, passive
immunization of neonates whose mothers develop perinatal herpes zoster is not indicated.
Post-exposure prophylaxis in the neonateVZIG prophylaxis in neonatesAdministration of VZIG to the infant is advised if the mother develops varicella within
7 days before or after delivery. The neonate of a mother with active varicella should be
isolated while in hospital, from birth to Day 21 (or Day 28 if the infant has been given
VZIG). Early discharge of the mother should be considered where feasible.
Despite VZIG prophylaxis, approximately one-half to two-thirds of infants exposed to
maternal varicella around the time of delivery will become infected.24 In the UK, VZIG is
also recommended for infants with non-maternal post-natal exposure during the first
7 days of life who test negative for VZV antibodies.
VZIG does not appear to reduce the infection rate for varicella in neonates although it may
reduce the risk of serious infection. In a study in which VZIG was administered to 41
neonates born to women whose varicella lesions began 4 days before to 2 days after
delivery, the neonatal attack rate was 51% despite VZIG therapy.37 There were no fatalities
and only two cases of severe disseminated varicella. In a larger UK study of 280 infants who
received VZIG after being born to mothers with varicella or herpes zoster in the perinatal
period, the attack rate was 48%, with the infection being severe in 19 infants (6.8%).38
Management of the neonate with varicellaAlthough in most cases neonatal VZV infection is mild, fatal outcomes in VZIG-treated
infants have occured in those whose mothers developed varicella rash in a narrow window
43
of time (4 days before to 2 days after delivery).39-41 See also Table 4, the AAP
recommendations for VZIG administration to newborn infants whose mothers develop
varicella within 5 days before to 48 hours after delivery.
Neonates exposed to varicella should be observed closely. If they develop vesicles, they
should be treated as early as possible with intravenous aciclovir (10 mg/kg every 8 hours).
Therapy with aciclovir should be considered in neonates developing varicella despite
receiving VZIG prophylaxis.
For a more detailed discussion of varicella and its management in pregnant women and
neonates, the reader is directed to the previous IHMF Management Strategies in Herpes
publication – Herpesvirus Infections in Pregnancy.
SummaryAlthough generally benign and self-limiting, varicella can have serious complications
associated with it. These complications are more common and serious in neonates,
pregnant women, adolescents and adults; however, complications can occur, albeit rarely,
in otherwise healthy children. The potentially serious nature of these complications
highlights the need for effective treatment of varicella especially in high-risk individuals.
Varicella vaccine may be effective as post-exposure prophylaxis in immunocompetent hosts
when administered to a susceptible individual within 3–5 days of exposure to VZV.
Additionally, post-exposure prophylaxis with oral aciclovir (800 mg five times daily) may
remain a viable option when the VZV exposure is not recognized until more than 5 days later.
Oral aciclovir (20 mg/kg up to 800 mg four times daily for 5 days) is the treatment of
choice when antiviral therapy is indicated in otherwise healthy children less than 12 years
of age with varicella. Valaciclovir and famciclovir are likely to be as effective as aciclovir,
but have not been studied in controlled clinical trials.
Due to the increased severity of varicella and increased likelihood of complications in
adolescents and adults compared with children, oral aciclovir (800 mg four or five times
daily for 5–7 days) should be offered to all adults and adolescents with varicella presenting
within 48 hours of rash onset. Valaciclovir (1000 mg three times daily) and famciclovir
(250 mg or 500 mg three times daily) are likely to be as effective as aciclovir, but have not
been studied in controlled clinical trials.
Patients presenting with varicella-associated pneumonia or complications of varicella,
such as cerebellar ataxia and VZV encephalitis, should receive intravenous aciclovir
(10 mg/kg every 8 hours).
Post-exposure prophylaxis of pregnant women and neonates should be based on passive
immunization with VZIG. Prophylactic aciclovir and varicella vaccine are not advocated
for either population.
The use of oral aciclovir (800 mg five times daily for 7 days) for the treatment of pregnant
women who contract varicella in their second or third trimester is recommended.
However, it is important to note that this recommendation is based on anecdotal evidence,
44
and that patients should be advised that aciclovir is not licensed for use during pregnancy.
The roles of valaciclovir and famciclovir for the treatment of varicella infection in the
pregnant woman remain to be evaluated in clinical trials.
Neonates exposed to varicella should be observed closely; if vesicle formation is apparent,
treatment with intravenous aciclovir (10 mg/kg every 8 hours) should be initiated as early
as possible.
References1. Prevention of varicella: Recommendations of the Advisory Committee on Immunization Practices (ACIP).
Centers for Disease Control and Prevention. MMWR Morb Mortal Wkly Rep 1996;45(RR-11):1-36.2. Prevention of varicella. Update recommendations of the Advisory Committee on Immunization Practices
(ACIP). MMWR Morb Mortal Wkly Rep 1999;48(RR-6):1-5.3. White CJ. Varicella-zoster virus vaccine. Clin Infect Dis 1997;24(5):753-761.4. Asano Y, Nakayama H, Yazaki T. Protection against varicella in family contacts by immediate inoculation
with live varicella vaccine. Pediatrics 1977;59:3-7.5. Salzman MB, Garcia C. Postexposure varicella vaccination in siblings of children with active varicella.
Pediatr Infect Dis J 1998;17(3):256-257.6. Watson B, Seward J, Yang A et al. Postexposure effectiveness of varicella vaccine. Pediatrics 2000;105
(1 Pt 1):84-88.7. Arvin AM. Chickenpox (Varicella). In: Varicella-Zoster Virus. Molecular Biology, Pathogenesis and Clinical
Aspects (Wolff MH, Schünemann S, Schmidt A, eds). Basel: Karger, 1999: 96-110.8. Cohen JI, Brunell PA, Straus SE et al. Recent advances in varicella-zoster virus infection. Ann Intern Med
1999;130(11):922-932.9. Asano Y, Yoshikawa T, Suga S et al. Postexposure prophylaxis of varicella in family contact by oral acyclovir.
Pediatrics 1993;92(2):219-222.10. Suga S, Yoshikawa T, Ozaki T et al. Effect of oral acyclovir against primary and secondary viraemia in
incubation period of varicella. Arch Dis Child 1993;69(6):639-642; discussion 642-633.11. Kumagai T, Kamada M, Igarashi C et al. Varicella-zoster virus-specific cellular immunity in subjects given
acyclovir after household chickenpox exposure. J Infect Dis 1999;180(3):834-837.12. Yoshikawa T, Suga S, Kozawa T et al. Persistence of protective immunity after postexposure prophylaxis of
varicella with oral aciclovir in the family setting. Arch Dis Child 1998;78(1):61-63.13. Ogilvie MM. Antiviral prophylaxis and treatment in chickenpox. A review prepared for the UK Advisory Group
on Chickenpox on behalf of the British Society for the Study of Infection. J Infect 1998;36 (Suppl 1):S31-S38.14. Balfour HH, Jr., Kelly JM, Suarez CS et al. Acyclovir treatment of varicella in otherwise healthy children.
J Pediatr 1990;116(4):633-639.15. Balfour HH, Jr., Rotbart HA, Feldman S et al. Acyclovir treatment of varicella in otherwise healthy
adolescents. The Collaborative Acyclovir Varicella Study Group. J Pediatr 1992;120(4 Pt 1):627-633.16. Dunkle LM, Arvin AM, Whitley RJ et al. A controlled trial of acyclovir for chickenpox in normal children.
N Engl J Med 1991;325(22):1539-1544.17. Wallace MR, Bowler WA, Murray NB et al. Treatment of adult varicella with oral acyclovir. A randomized,
placebo-controlled trial. Ann Intern Med 1992;117(5):358-363.18. Balfour HH, Jr., Edelman CK, Anderson RS et al. Controlled trial of acyclovir for chickenpox evaluating time
of initiation and duration of therapy and viral resistance. Pediatr Infect Dis J 2001;20:919-926.19. Weller S, Blum MR, Doucette M et al. Pharmacokinetics of the acyclovir pro-drug valaciclovir after escalating
single- and multiple-dose administration to normal volunteers. Clin Pharmacol Ther 1993;54:595-605.20. Filer CW, Allen GD, Brown TA et al. Metabolic and pharmacokinetic studies following oral administration
of 14C-famciclovir to healthy subjects. Xenobiotica 1994;24(4):357-368.21. Walsh JB, Geaney M. Valaciclovir in secondary and tertiary cases of adult chickenpox. J Eur Acad Dermatol
Venereol 1996;6(3):290-291.22. American Academy of Pediatrics: Committee on infectious diseases. Pediatrics 1994:510-517.23. Enders G, Miller E, Cradock-Watson J et al. Consequences of varicella and herpes zoster in pregnancy:
prospective study of 1739 cases. Lancet 1994;343(8912):1548-1551.24. Miller AE, Marshall R, Vardien J. Epidemiology, outcome and control of varicella-zoster infection. Rev Med
Microbiol 1993;4:222-230.25. Enders G. Varicella-zoster virus infection in pregnancy. Prog Med Virol 1984;29:166-196.26. Prober CG, Gershon AA, Grose C. Consensus: varicella-zoster infections in pregnancy and the perinatal
period. Pediatr Infect Dis 1990;9:865-869.27. Enders G. Management of varicella-zoster contact and infection in pregnancy using a standardized varicella-
zoster ELISA test. Postgrad Med 1985;61:23-30.28. Gilbert GL. Chickenpox during pregnancy. BMJ 1993;306:1079-1080.29. Greenspoon JS, Masaki DI. Fetal varicella syndrome. J Pediatr 1988;112:505-506.30. Brunell PA. Varicella in pregnancy, the fetus and the newborn: problems of management. J Infect Dis
1992;166 (Suppl 1):S42-S47.31. Grose C. Varicella infection during pregnancy. Herpes 1999;6:633-637.32. Pastuszak AL, Levy M, Schiek B et al. Outcome after maternal varicella infection in the first 20 weeks of
pregnancy. N Engl J Med 1994;330:901-905.33. Al-Nakib W, Al-Kandari S, El-Khalik DM et al. A randomised controlled study of intravenous acyclovir
(Zovirax) against placebo in adults with chickenpox. J Infect 1983;6(1 Suppl):49-56.
45
34. Smego RA, Asperilla MO. Use of acyclovir for varicella pneumonia during pregnancy. Obstet Gynecol1991;78:1112–1116.
35. From the Centers for Disease Control and Prevention. Varicella-related deaths among children – UnitedStates, 1997. JAMA 1998;279(22):1773-1774.
36. Chung CS, Myrianthopoulos NC. Factors affecting risks of congenital malformations. I. Epidemiologicalanaylsis. New York: Stratton Intercontinental, 1975.
37. Hanngren K, Grandier M, Grandstrom C. Effect of zoster immunoglobulin for varicella prophylaxis in thenewborn. Scand J Infect Dis 1985;17:343-347.
38. Miller E, Cradock-Watson JE, Ridehalgh MK. Outcome in newborn babies given anti-varicella-zosterimmunoglobulin after perinatal maternal infection with varicella-zoster virus. Lancet 1989;2(8659):371-373.
39. Bakshi SS, Miller TC, Kaplan M. Failure of varicella-zoster immunoglobulin in modification of severecongenital varicella. Pediatr Infect Dis 1986;5:699-702.
40. King SM, Gorensek M, Ford-Jones EL. Fatal varicella-zoster infection in a newborn treated with varicella-zoster immunoglobulin. Pediatr Infect Dis 1986;5:588-589.
41. Holland P, Isaacs D, Moxon ER. Fatal neonatal varicella infection. Lancet 1986;2:1156.42. Pass R, Weber T, Whitley RJ. Management Strategies in Herpes. Herpesvirus Infections in Pregnanacy:
PAREXEL MMS Europe Ltd, 2002.
46
Management RecommendationsCategory 3J It is important that clinicians recognize that acute and chronic pain and different
chronic pain subtypes are engendered by different mechanisms.
J Physicians should be aware of the existence of rare but serious complications and
atypical manifestations of herpes zoster, such as delayed contralateral hemiparesis,
and neurological complications. The use of intravenous aciclovir (10 mg/kg every
8 hours for adults, 500 mg/m2 or 20 mg/kg every 8 hours for children) is warranted in
the majority of these cases, based on anecdotal evidence.
Research needsJ A trial is recommended using polymerase chain reaction (PCR) techniques to estimate the
peak concentration of virus in serum during the course of herpes zoster (encompassing
prodrome, acute rash and post-herpetic neuralgia [PHN] where possible).
J The further application of statistical models to understanding pain in herpes zoster is
encouraged, particularly in the assessment of new treatment modalities.
IntroductionHerpes zoster is known to be the cause of considerable morbidity, especially among
elderly patients.1 Over a lifetime, estimates of the proportions of individuals experiencing
herpes zoster vary from 10% to 20%1 and up to 23%,2 with the incidence increasing with
age. The most debilitating symptom of herpes zoster is the associated pain, which may be
both acute and chronic in nature and can persist for months or even years.3-5 This has a
major impact on patients’ quality of life and, once established, can be difficult to manage
effectively,6 making this the most compelling reason for early treatment of herpes zoster.7
Analysis of several studies indicates that antiviral treatment initiated within 72 hours of
rash onset increases the rate of rash healing and also speeds the resolution of zoster-
associated pain in some patients.8
Clinical FeaturesHerpes zoster is a manifestation of the reactivation of varicella zoster virus (VZV).
Following initial infection, the virus remains latent in dorsal sensory ganglia until it
reactivates and replicates. Virus replication and transmission in nerves and ganglia,
together with the subsequent development of skin rash, contribute to the prodromal and
acute-phase pain of herpes zoster. Subsequent to this, there can be chronic pain. Thus,
pain associated with herpes zoster is typically compartmentalized into three phases –
prodromal, eruptive or rash, and PHN.
INTRODUCTION TO HERPES ZOSTER AND FUTURE
DIRECTIONS5
47
Prodromal phaseThe prodrome may precede rash onset by 48–72 hours, but can occasionally occur a week
or more prior to the rash becoming visible. During this phase, the patient may experience
acute neuritis characterized by pain and paraesthesia. The type of pain during the
prodromal phase, often accompanied by malaise, can vary widely but the most common
description is throbbing. It can be intermittent or constant.
Eruptive or rash phaseClinical diagnosis of herpes zoster is
usually achieved during the eruptive or
rash phase, when the typical
papulovesicular rash appears. The
vesicles are typically clustered in a
unilateral dermatomal distribution. In the
immunocompetent host, new lesions appear for
3–5 days, and healing usually occurs over a period
of 2–4 weeks (see Table 1 and Figure 1). Extensive
cutaneous dissemination is unusual and visceral
dissemination rare in the immunocompetent host.
In immunocompromised individuals and the elderly,
the healing process is likely to be slower with new
vesicle formation continuing for a week or more.9
Pain accompanies the rash in 60–90% of
immunocompetent individuals. Pain occurs in
fewer than 20% of individuals aged less than
20 years, but in more than 80% of individuals over
50 years old.3 The pain, which can be constant or
intermittent, has been variously described as
shooting, stabbing, tender, itching or hot.
PHN and zoster-associated painAlthough the pain experienced during the acute phase usually resolves as the rash heals,
chronic pain can persist for prolonged periods (e.g. months or even years). The term PHN
has been variously used to describe:
• Pain that persists or occurs after resolution of the cutaneous rash10
• Pain persisting more than 30 days after rash onset
• Pain at 3–6 months after the acute episode.10
Thus, there is a continuum of pain – from the pain of the prodrome through to the
persisting pain. This continuum is referred to as zoster-associated pain.
Pathogenesis of chronic painIn normal pain perception, noxious stimuli activate nerve endings in the skin and generate
signals which pass to the dorsal root ganglia and then to the dorsal horn (see Figure 2).
Spinal cord neurones are inhibited by powerful descending signals from the brain,
mediated by biogenic amines such as serotonin. Drugs which potentiate such chemicals
may act by enhancing these descending inhibitory pathways. The net result of peripheral
afferent input and descending inhibitory input is perceived pain.
TABLE 1: Stages ofhealing of acute herpeszoster in theimmunocompetent
Time Stage of healing
3–5 days Cessation of new vesicle formation 4–6 days Total pustulation 7–10 days Total scabbing 2–4 weeks Complete healing
Primary infection withVZV
(varicella)
Latency
Reactivation Zoster sineherpete
Herpes zoster
Myelitis Large-vesselgranulomatous
arteritis
PHN Myelitis Small-vesselencephalitis
Immunocompromisedpatients
Immunocompetentpatients
FIGURE 1: Naturalhistory of herpes zoster
48
In the case of herpes zoster,
damage to peripheral nerves by
virus reactivation and
inflammation in the skin, and
altered signal processing in the
central nervous system (CNS),
can lead to the development of
chronic neuropathic pain.12
Injured neurones have lower
activation thresholds and may
discharge spontaneously and
frequently in response to weak,
non-noxious stimuli. Noxious
stimuli cause more pain than
normal (primary hyperalgesia).
In addition to peripheral sensitization, central sensitization may also occur, in which
abnormal signal amplification in the CNS causes hyperalgesia. As the damaged axons
repair, the growth cone and nerve sprout are also sensitive and may be the source of
abnormal discharges, particularly when their growth becomes interrupted or blocked by
scarring. The discharges give rise to pain sensations and maintain a state of
hyperexcitability in the dorsal horn, and this in turn causes exaggerated responses in the
CNS to all stimuli.
Epidemiology of Herpes ZosterThere have been few recent reports on the incidence of herpes zoster in general
populations; the figures that are most often quoted are based on surveys conducted
between 1949 and 1959 in the USA by Ragozzino et al4 and in the UK from 1947 to 1962
by Hope-Simpson.13 More recent studies have explored the incidence of herpes zoster in
large cohorts in the USA and Iceland. The overall incidence of herpes zoster in these
studies is 120–350 per 10 0000 person-years (Table 2).
FIGURE 2: Normalpain perception11
Skin or mucousmembrane
Descending noradrenergic andserotoninergic inhibitory fibres
Ascendingspinothalamic fibres
Dorsal-rootganglion
TABLE 2: Incidence ofherpes zoster in largecohort studies4,13-18
Age range (years) Location (date of study) Incidence (per 100 000 patient-years)
0–99 Cirencester, UK (1947–1962)13 340
0–75+ Rochester, Minnesota, USA (1949–1959)4 131 < 14 40 25–30 100 ≥75 400
0–19 Rochester, Minnesota, USA (1960–1981)14 42
0–75+ Boston, USA (1990–1992)15 215 (unadjusted)287 (age adjusted to represent the same age
distribution as in Ragozzino et al4 study)
65–104 North Carolina, USA (1987–1990)16 710
0–80+ Iceland (1990–1995)17 460
≥ 15 Italy (1995)18 410
Comparison of these studies reveals marked differences in the incidence of herpes zoster
in the USA4 and UK.13 The incidence of herpes zoster in the Ragozzino et al4 study has
been adjusted to the 1970 population structure in the USA to give a rate of 131/100 000
person-years. This incidence rate is lower than that reported in England by Hope-Simpson3
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49
in 1965 (340/100 000 person-years) during a similar time period. The reason for this is
uncertain but may be due partly to differences in study methodology as well as true
population differences.
Studies conducted in the USA suggest that the incidence of herpes zoster is increasing.
In the study by Ragozzino et al,4 the rate increased from 112 to 150/100 000 person-years
over the 10-year period of the survey (1949–1959). A later study by Donahue et al (1995)15
surveyed the population of a health maintenance organization in the USA from 1990 to
1992. It found a higher incidence (287 per 100 000 patient-years) after age adjustment to
the same standard population as described in the earlier study by Ragozzino et al
(Table 1). The rise reported over the period of the Ragozzino et al study, if it continued,
may explain the higher incidence in the Donahue et al study. The difference in rates may,
however, be explained by differences in the ascertainment of herpes zoster between the
two studies.
Relationship between risk of herpes zoster and age A striking feature of herpes zoster is its increase in incidence with ageing. It is relatively
uncommon in the immunocompetent individual less than 40 years old, but has a marked
rise in the over 50-year-olds and an even higher
incidence in those over 75 years (Figure 3).4 This
relationship between age and risk of herpes zoster is
illustrated by the fact that although the overall
lifetime probability of developing herpes zoster in
the USA and UK is 10–20%, the risk for those living
to ≥80 years increases to 50%. However, the age
structure of most populations means that even
though the incidence is highest among those over
75 years, the prevalence is greatest in the 55–
75-year age group. Changing population
demographics and increasing longevity are likely to
lead to an increase in the number of individuals who will experience herpes zoster.
Prodromal symptoms are more frequent in the elderly, and are likely to be of greater
duration than in younger individuals (Figure 4).3 In a UK study of herpes zoster in
individuals aged over 60 years (n=205), 40% of the study participants experienced
prodromal pain for more than 4 days.19,20 The rash
phase is also frequently extended in elderly patients
compared with younger patients, with new lesions
continuing to develop for a number of days. The
median time to loss of vesicles is 7 days in the
elderly, with full crusting occurring more than 10 days
after rash onset.9 This compares with a median time
to loss of vesicles of 48 hours in younger
individuals.8 Studies have indicated that elderly
patients experience prolonged pain more often than
younger patients.3 PHN is one of the most severe
chronic pain syndromes experienced, and one of the
worst seen at a pain clinic.9
FIGURE 3: Theincidence of herpeszoster increases with age4
Age (years)
500
400
300
200
100
0
Inci
denc
e/10
0 00
0 pe
rson
– y
ears
≤14 15–24 25–34 35–44 45–54 55–64 65–74 ≥75
FemalesMales
FIGURE 4: Duration ofzoster-associated pain indifferent age groups3
≥70
60–69
50–59
40–49
30–39
20–29
0–19
Age
(yea
rs)
Percentage with pain0 10 20 30 40 50 60 70 80 90 100
<1 month 1–6 months 6–12 months >1 year
© R
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as JM
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d R
R. T
heou
tcom
e of
pat
ient
s w
ith h
erpe
s zo
ster
. Arc
h D
erm
atol
1957
;75:
193-
196.
Cam
brid
ge M
edic
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ublic
atio
ns.
© R
epro
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ith p
erm
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on R
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MW
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ton
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3rd,
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land
LT
et a
l.Po
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tion-
base
d st
udy
of h
erpe
szo
ster
and
its
sequ
elae
. Med
icin
e (B
altim
ore)
1982
;61(
5):3
10-3
16.
50
The vulnerability of elderly individuals to herpes zoster is most likely due to the
senescence of their cellular immune system.21 Rates of positive skin tests for VZV antigens
and in vitro measurements of the lymphoproliferative response to VZV reduce with
increasing age. This reduction in immune response to the virus is inversely correlated with
the frequency of reactivation of latent VZV.22
Although rare in children, herpes zoster has been reported in some aged less than 2 years
whose mothers contracted varicella during pregnancy and also in children who contracted
varicella during their first year.23 The incidence of herpes zoster is less where contact with
varicella is greater. Hope-Simpson13 originally observed that herpes zoster was less likely
to occur during epidemic years for varicella, leading him to postulate that each time a
person who has had varicella (i.e. is VZV seropositive) comes into contact with the virus,
their immunity is boosted. This may reverse the decline in antibodies that normally occur
with age, and therefore delay the chance of an episode of herpes zoster.
Rare Complications in the ImmunocompetentHostJ Physicians should be aware of the existence of rare but serious
complications and atypical manifestations of herpes zoster, such
as delayed contralateral hemiparesis, and neurological
complications. The use of intravenous aciclovir (10 mg/kg every
8 hours for adults, 500 mg/m2 or 20 mg/kg every 8 hours for
children) is warranted in the majority of these cases, based on
anecdotal evidence (category 3 recommendation).
PHN is the most commonly observed complication of herpes zoster.
However, a number of other rare but distinct neurological syndromes
are also associated with it, including encephalitis (both large and
small vessel) (Figure 5), ophthalmic zoster (with delayed contralateral
hemiparesis, myelitis, polyradiculitis), and numerous cranial and
peripheral nerve palsies (including Bell’s palsy and Ramsay Hunt
syndrome).24 Ophthalmic zoster is discussed in Chapter 7.
Delayed contralateral hemiparesisDelayed contralateral hemiparesis, involving the first division of the trigeminal nerve, is a
rare but serious complication of herpes zoster that can occur weeks to months (average
7 weeks) after an episode of herpes zoster.25-27 Hemiparesis has been reported in both
immunocompetent and immunocompromised individuals. The mortality rate associated
with the condition is 20–25% and there is a high probability of permanent neurological
sequelae among survivors.25,28
The pathogenesis of hemiparesis is thought to be direct VZV invasion of cerebral arteries
along intracranial branches of the trigeminal nerve, resulting in inflammation of the
internal carotid artery or one of its branches on the same side as the rash.29
The typical presentation of delayed contralateral hemiparesis is headache and hemiplegia
occurring in a patient with a recent history of herpes zoster ophthalmicus. Examination of
cerebrospinal fluid (CSF) reveals mononuclear cell pleocytosis (usually <100 cells per cm3)
FIGURE 5: Encephalitisassociated with thereactivation of VZV24
© 2
002.
Rep
rodu
ced
with
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sion
, Gild
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Neu
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N E
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2000
;342
(9):6
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645.
Mas
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51
and increased protein.28 Arteriography is usually diagnostic and demonstrates
inflammation, narrowing and thrombosis of the proximal branches of the anterior or
middle cerebral artery.30,31
Management of delayed contralateral hemiparesisBoth aciclovir and corticosteroids have been used to treat this syndrome, although neither
therapy has been evaluated in controlled trials.32,33 Antiviral therapy is warranted because
of the demonstrated presence of VZV in the inflamed arteries. However, the benefit of
therapy is difficult to assess, since irreversible cerebral infarction has often occurred by the
time the diagnosis is made.
Zoster sine herpeteClinicians have frequently noted patients who present with herpes zoster-like neuropathic pain,
but do not develop the characteristic dermatomal rash. This presentation is known as zoster sine
herpete, and is characterized by radicular neuropathic pain in a dermatomal distribution
without cutaneous eruption. Recent studies of patients presenting with dermatomal pain
without rash have established that some of these cases are due to VZV reactivation.34
Patients with zoster sine herpete have raised titres of VZV-specific antibody (up to 4-fold
increase) compared with other immunocompetent individuals, and raised levels of VZV
DNA in the CSF and peripheral blood mononuclear cells.34,35 The lack of a simple and
accurate diagnostic method for zoster sine herpete means that its prevalence remains
unknown. Some anecdotal reports indicate that it responds to intravenous aciclovir, but
these reports are not consistent.
Prolonged Zoster-Associated PainThe incidence of PHN is unclear because of the lack of good prospective population-based
studies and the absence of a standardized definition. Information on the incidence of
prolonged zoster-associated pain comes from retrospective population surveys and the
placebo arms of clinical trials.
Retrospective population-based studies have reported that, in the absence of therapy,
8–14% of patients with herpes zoster develop pain persisting for longer than
4 weeks.4,13,17,36 The pain generally improves and, overall, these studies suggest that 3–7%
of patients with herpes zoster have pain that persists for more than 3 months and only
2–5% have pain after 1 year. The data from prospective trials is more robust than that from
retrospective studies; prospective data on the incidence of PHN have been supplied by
clinical trials of aciclovir. They suggest an incidence of 50–60% at 1 month, which
decreases with time. For example, in a placebo-controlled trial of aciclovir in patients aged
over 60 years, the incidence of PHN in the placebo recipients fell from 61% at 1 month
after the onset of rash to 13% at 6 months.20 Although this is a low estimate for the over-
60s age group, this trend is also observed in other placebo-controlled studies; in one
aciclovir study of acute herpes zoster in patients >16 years of age, the incidence of PHN
in the placebo recipients fell from 40% at 1 month after rash onset to 20% at
6 months.37 Overall, these placebo-controlled trials give higher incidence figures than the
population-based studies. This may be due to differences in study design and because
patients in clinical trials may differ from those in the general population.
52
Predicting patients at greater risk of PHNEstablished PHN remains difficult to treat. Antiviral therapy (and possibly tricyclic antidepressants
or sympathetic nerve blocks) can accelerate the resolution of zoster-associated pain. However,
optimal use of antiviral therapy requires accurate prediction of herpes zoster patients at risk of
developing PHN, and prompt initiation of therapy in the acute phase.
Age has a major influence on the incidence and duration of PHN, for example, the study by
Hope-Simpson13 demonstrated an incidence of 74 cases per 100 000 for children aged
0–9 years, rising to 292 per 100 000 for those aged 40–49 years. The reliability of age as a
predictor of PHN was confirmed in three recent analyses.38-40 One of these studies was a large,
observational study.38 The second study analysed baseline data of 1778 patients with herpes
zoster collected prior to randomization into antiviral drug studies.39 In the third, Cox’s
proportional hazard modelling was used to identify a range of factors influencing pain outcome
in controlled trials of antiviral therapies in herpes zoster (total number of subjects = 2367).40
The severity of the acute pain during herpes zoster is predictive of prolonged pain,40,41 and
is illustrated by a study comparing aciclovir with prednisolone; patients who presented with
severe or incapacitating pain and a large number of lesions were less likely to achieve
resolution of both acute neuritis and zoster-associated pain (risk ratio [RR], 18.0; 95%
confidence interval [CI], 6.6–48.6, and RR, 5.3; 95% CI, 4.2–17.2, respectively).40 Similarly,
in an analysis of data from six randomized, controlled double-blind studies, severe pain at
presentation was a highly significant prognostic factor for prolonged zoster-associated
pain.41 The same analysis reported that the presence of a prodrome is also a significant risk
factor for the prolonged pain in patients 50 years of age or older (hazard ratio [HR], 1.30;
CI, 1.06–1.56; P=0.008) and approached significance in those younger than 50 years
(HR, 1.32; CI, 0.99–1.72; P=0.06). The importance of both presence of a prodrome and
intensity of acute pain was confirmed further in a large observational study (Figure 6).38
Thus, the three main risk factors that predict PHN following herpes zoster are:41,42
• Advancing age
• Presence of a prodrome
• Acute pain severity.
Other hypothetical factors predictive for PHN
include viraemia, rash severity, and adverse
psychosocial factors.
As well as being related to the incidence of PHN,
there is a strong association between age and the
duration of pain following herpes zoster. This is
shown by a study in the USA conducted during the
1950s in which 20% of those aged 50–59 had short-
lived PHN (defined as any subjective, painful
sensation that persisted after the acute phase of
infection), whereas in the over-60s, more than 30%
had PHN that persisted for many months.42 Another
study in the USA, also conducted in the 1950s,
showed that individuals under the age of 40 years
FIGURE 6: Time tocessation of painfollowing herpes zoster ina) subjects aged 18–50 years and >50 years;b) subjects with no/mild,moderate and severeprodromal pain.38 Allsubjects receivedvalaciclovir treatment.
1.00.90.80.70.60.50.40.30.20.1
00 20 40 60 80 100 120 140 160 180
Prop
ortio
n of
cas
esw
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soci
ated
pai
n
Time (days)
Median duration (days)Pain at 6 months (%)HR (95% CI)
18–50 years
921.91 (1.71, 2.12)
>50 years
2311P < 0.0001
1.00.90.80.70.60.50.40.30.20.1
00 20 40 60 80 100 120 140 160 180
Prop
ortio
n of
cas
esw
ith z
oste
r-as
soci
ated
pai
n
Time (days)
Age (years)18–50>50
Maximum intensity of prodromal painNon/noticeable/mildModerateSevere/very severe
a)
b)
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oste
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):23-
33. B
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Ltd
.
53
rarely had pain lasting beyond 1 month but that 47% of patients aged over 70 years of age
still had pain at 1 year.3 These early studies have been confirmed by a recent, large,
observational study in which pain resolved almost twice as rapidly in patients aged
between 18 and 49 years compared with those older than 50 years (P<0.0001; Figure 6).38
Application of PCR to Understanding Pathogenesis and RiskFactors for Prolonged Zoster-Associated PainJ A trial is recommended using PCR techniques to estimate the peak level of virus in
blood during the course of herpes zoster (encompassing prodrome, acute rash and
PHN where possible) (research need recommendation).
The importance of detectable VZV in peripheral blood cells on the development of PHN is
uncertain. It has been reported that the occurrence of PHN was not correlated with the
presence of VZV DNA in lymphocytes. However, the existence of VZV DNA was correlated
significantly with increasing age (P<0.05).43 More recent data have suggested that there is
a link between detectable viraemia at presentation and development of PHN.44
A 52-week prospective study determined whether VZV DNA in lymphocytes at
presentation predicted the likelihood of PHN development.45 One hundred and sixty five
patients with herpes zoster were asked to quantify the severity of their pain at presentation
using the Visual Analogue Scale (VAS), the McGill Pain Questionnaire and Active Daily
Living Scores. Blood samples were collected from 119 of the patients and the presence of
VZV DNA in lymphocytes from these was assessed by nested PCR directed at open reading
frame 29.45 Forty per cent of patients received antiviral medication. Amitriptyline was
prescribed for any patient who experienced pain persisting for more than 6 weeks.45
The presence of PCR-detectable VZV viraemia at presentation was significantly associated
with prolonged pain of >6 months’ duration (P<0.05). This association was more significant
in those patients aged >50 years (P<0.01).
Age and pain severity are independent predictors of the development of PHN. In keeping with
the findings of the studies discussed on page 52, a significantly larger proportion of patients
aged >50 years reported experiencing prolonged pain compared with those aged <50 years.
Moreover, patients with more severe pain at presentation (VAS score >6) were more likely to
experience prolonged pain than patients with less severe pain (VAS score <6).45
These data suggest that patients at greatest risk of developing prolonged zoster-associated
pain are likely to be over 50 years old, have high pain scores at presentation and have
detectable viraemia at presentation. This may offer a virological explanation for previously
identified risk factors for pain persisting after herpes zoster and may in turn lead to the
development of laboratory tests for the clinical evaluation of patients at highest risk of
prolonged pain.
Mathematical Modelling of Zoster-Associated PainJ It is important that clinicians recognize that acute and chronic pain and different chronic
pain subtypes are engendered by different mechanisms (category 3 recommendation).
54
J The further application of statistical models to understanding pain in herpes zoster is
encouraged, particularly in the assessment of new treatment modalities (research need
recommendation).
Background to model Existing methods to analyse the clinical trials of antiviral therapy can lead to bias. In an
effort to increase the understanding of the mechanisms of zoster-associated pain and
improve the design of future herpes zoster studies, a mathematical model of the
progression and resolution of pain associated with herpes zoster has been developed.44
Currently, considering the effect of treatments on PHN means that only a subset of patients
who actually develop persistent pain will be included in any given analysis. Because this
subset is chosen after randomization, early treatment effects cannot be assessed and
baseline characteristics may be unbalanced among the different groups. Similarly,
considering pain over a follow-up period of 1 year may be rigorous, as it accounts for the
early effects of lesion healing and termination of acute pain. However, this approach has
the major disadvantage that it looks at all pain (both acute and chronic pain together).
Therefore, treatment effects specific to PHN cannot be evaluated.
To overcome these limitations, the model assumes that zoster-associated pain manifests,
and resolves, in three distinct phases:
• Acute pain, observed in most patients, caused by inflammation of nerve tissue and
damage to skin, occurring at the time of acute zoster VZV reactivation and relating to
ongoing viral replication
• Subacute pain, observed in a proportion of patients, caused by mixed aetiology
• Chronic pain observed in a smaller subset of patients, brought about by pathological
changes in the CNS and peripheral nervous system (PNS).
In considering pain as three phases, the model allows the change points of the phases
(i.e. the change from acute to subacute; change from subacute to chronic pain) and the
rates of pain resolution of each phase to be determined. It also permits examination of the
effect on each phase of any proposed treatment regimen to alleviate zoster-associated
pain, while controlling for its effect on the other phases.
Findings from the model of zoster-associated painThe model provides insight into the natural history of zoster-associated pain. Based on data
from trials of aciclovir, the change points in zoster-associated pain (time of transition from
acute to subacute pain; time of change from subacute to chronic pain) had previously
been proposed to be 30 and 120 days, respectively, but this hypothesis had not been
tested. The model yielded estimates of change points that were similar to those estimated
from historical data (Table 3).44,46
TABLE 3: Zoster-associated pain changepoints in immuno-competent and immuno-compromised individuals44
Trial Acute to subacute pain Standard error Subacute to chronic Standard error change point (days) pain change point (days)
Aciclovir and steroids in 46.2 9.8 138.3 21.4immunocompetent hosts ≥50 years
Aciclovir versus sorivudine in cancer 36.9 13.5 136.4 19.9patients
Aciclovir versus sorivudine in 26.9 8.4 124.3 23.6individuals with HIV
55
In addition, by understanding the rate of resolution of the different phases of zoster-
associated pain, the model can further contribute to an understanding of its natural history.
The model demonstrated that for each patient group, there were differences in the rates of
pain resolution between the different phases, but that these differences were not consistent.
For example, the rates of resolution of subacute and chronic phases were not significantly
different for either the immunocompetent adults or the cancer patients but were different for
the HIV-infected cohort. This difference can be important when translating or evaluating
treatment regimens when herpes zoster occurs in patients with different underlying diseases.
Barriers to the Treatment of Herpes ZosterDespite available evidence as to the benefits of treating patients who have herpes zoster (see
Chapters 6, 7 and 9), a number of barriers to treatment persist (see Table 4). One such barrier
is the perception among some physicians that treating herpes zoster is expensive. However,
an analysis of valaciclovir and famciclovir, using a Markov decision model, indicated that
treatment of severe acute herpes zoster
was cost-effective from a third-party
payer perspective.47 In addition,
treatment of mildly symptomatic acute
herpes zoster was cost-effective in
situations where there was an increased
risk of PHN, e.g. in the elderly and
immunocompromised.47
SummaryHerpes zoster is caused by the reactivation of latent VZV infection. It is characterized by
the presence of dermatomal pain, and usually a papulovesicular rash also in a dermatomal
distribution, although the rash is not always accompanied by pain and vice versa. The rash
associated with herpes zoster typically resolves within 2–4 weeks, although this can take
significantly longer in immunocompromised individuals. Some 9–15% of patients will
experience prolonged pain that may continue for months or even years.
Complications of herpes zoster may include delayed contralateral hemiparesis, myelitis,
polyradiculitis and nerve palsies.
Prevention and management of PHN are the main objectives of therapy. In addition,
treatment of herpes zoster aims to prevent complications and increase the rate of rash
healing. The treatment and management of patients with herpes zoster and PHN are
discussed in Chapters 6, 7 and 9.
The continued application of mathematical modelling and detection techniques, such as
PCR, will increase understanding of the pathogenesis and risk factors involved and provide
the potential to develop new treatment methodologies to manage the pain associated with
herpes zoster.
TABLE 4: Barriers to thetreatment of herpes zoster
• Lack of clear initial symptoms due to the variable nature of prodromal pain
• Time taken to obtain a consultation once rash appears due to waiting lists andappointment systems, and patients’ fear of illness – especially in the elderly
• Time between consultation and dispensing of prescription
• Lack of awareness by some physicians of the suffering experienced by patients withherpes zoster
• Perception among some physicians that treatments are expensive
56
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193-196.4. Ragozzino MW, Melton LJ, 3rd, Kurland LT et al. Population-based study of herpes zoster and its sequelae.
Medicine (Baltimore) 1982;61(5):310-316.5. Rogers RS, Tindall JP. Geriatric herpes zoster. J Am Geriatr Soc 1971;19(6):495-504.6. Tyring SK, Beutner KR, Tucker BA et al. Antiviral therapy for herpes zoster: randomized, controlled clinical
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41. Whitley RJ, Shukla S, Crooks RJ. The identification of risk factors associated with persistent pain followingherpes zoster. J Infect Dis 1998;178 (Suppl 1):S71-S75.
42. Burgoon CFJ, Burgoon JS, Bladridge GD. The natural history of herpes zoster. JAMA 1957;164:265-269.43. Devlin ME, Gilden DH, Mahalingam R et al. Peripheral blood mononuclear cells of the elderly contain
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Management RecommendationsCategory 1J Antiviral therapy for immunocompetent adults over 50 years of age with herpes zoster
is recommended, particularly if therapy can be instituted within 72 hours of lesion
onset. As a result of their improved pharmacokinetic profiles and simpler dosing
regimens, valaciclovir (1000 mg three times a day for 7 days) or famciclovir (250 mg
or 500 mg three times a day) have replaced aciclovir (800 mg five times a day) as the
preferred treatment.
J It is recommended that physicians consider the use of steroids to reduce the
inflammation that may be contributing to acute pain, provided there are no contra-
indications and the potential risk of excess side-effects is explained. Although they do
not prevent post-herpetic neuralgia (PHN), steroids reduce acute symptoms and may
facilitate return to normal quality of life.
J There is no indication for the use of topical antiviral agents in the treatment of
cutaneous herpes zoster.
Category 2J Early use of tricyclic antidepressants should be considered as they may prevent or
reduce PHN in elderly patients who present with acute herpes zoster.
J Intravenous aciclovir (10 mg/kg every 8 hours) remains the drug of choice for those
rare immunocompetent patients with herpes zoster who develop evidence of
pneumonitis or disseminated infection (e.g. varicella zoster virus [VZV] encephalitis).
Category 3J It is important that patients with herpes zoster are encouraged to present to physicians
as early as possible for prompt medical care. Both public and medical education
efforts may be beneficial.
J The presence of risk factors for the development of PHN should be assessed and
documented for each patient.
J If the patient has severe acute pain, the following treatments may be beneficial:
sympathetic nerve blocks, corticosteroids, antidepressants, gabapentin and opioids.
J There is no published evidence for the use of famciclovir 750 mg once daily for the
treatment of herpes zoster, and no follow-up data on its use beyond 1 month.
MANAGEMENT OF HERPES ZOSTER IN THE
IMMUNOCOMPETENT HOST
58
6
59
Research needsJ Studies are required to establish the role of gabapentin and other treatment modalities
in the prevention of PHN.
J Severity of acute pain may be predictive of long-term persistence of pain. Severity of pain
may, therefore, be an appropriate decision factor in initiating antiviral treatment. Further
research is recommended to evaluate the benefit and applicability of this approach.
J Although every effort should be made to encourage early treatment, research is needed
to assess the effectiveness of initiating antiviral treatment in patients presenting more
than 72 hours after rash onset.
IntroductionJ It is important that patients with herpes zoster are encouraged to present to physicians
as early as possible for prompt medical care. Both public and medical education
efforts may be beneficial (category 3 recommendation).
For the majority of immunocompetent individuals, herpes zoster manifests as a rash with
pain of relatively short duration. In others there is the risk of complications (e.g. herpes
zoster ophthalmicus) and, particularly in the elderly, of prolonged pain. The goals of
therapy in immunocompetent individuals with herpes zoster include accelerating
cutaneous healing, reducing acute pain
and, more importantly, preventing
complications such as persistent pain
and herpes zoster ophthalmicus. A
number of therapeutic options have
been assessed, including antiviral
therapy, corticosteroids and anti-
depressants, each of which has a
different rationale for its use (Table 1).
Antiviral Therapy in Herpes ZosterJ Antiviral therapy for immunocompetent adults >50 years of age with herpes zoster is
recommended, particularly if therapy can be instituted within 72 hours of lesion onset.
As a result of their improved pharmacokinetic profiles and simpler dosing regimens,
valaciclovir (1000 mg three times a day for 7 days) or famciclovir (250 mg or 500 mg
three times a day) have replaced aciclovir (800 mg five times a day) as the preferred
treatment (category 1 recommendation).
J There is no published evidence for the use of famciclovir 750 mg once daily for the
treatment of herpes zoster, and no follow-up data on its use beyond 1 month (category
3 recommendation).
J There is no indication for the use of topical antiviral agents in the treatment of
cutaneous herpes zoster (category 1 recommendation).
J Intravenous aciclovir (10 mg/kg every 8 hours) remains the drug of choice for those
rare immunocompetent patients with herpes zoster who develop evidence of
pneumonitis or disseminated infection (e.g. varicella zoster virus [VZV] encephalitis)
(category 2 recommendation).
TABLE 1: Summary oftreatment options forimmunocompetentindividuals with herpeszoster1
Patient group Treatment options
Age <50 years with mild pain Symptomatic care only
Ophthalmic rash Oral valaciclovir, famciclovir oraciclovir for 7 daysOphthalmological examination
Age ≥50 years or moderate-to-severe pain Oral valaciclovir, famciclovir oraciclovir for 7 daysConsider corticosteroidsConsider tricyclic antidepressants
60
The clinical manifestations of herpes zoster result from reactivation of VZV and, therefore,
to reduce disease severity, it is logical to inhibit such replication. Three antiviral drugs –
aciclovir (800 mg five times a day for 7 days), valaciclovir (1000 mg three times a day) and
famciclovir (250 mg or 500 mg three times a day) – are widely available for treatment of
VZV infection. All three are effective, have excellent safety profiles, and are approved for
the treatment of herpes zoster in many countries.
AciclovirAciclovir was the first antiviral therapy investigated in herpes zoster patients. Intravenous
aciclovir (5–10 mg/kg three times daily for 5 days) was effective in several randomized,
placebo-controlled trials.2 All the trials demonstrated that aciclovir reduced acute pain,
providing therapy was initiated within 72 hours of rash onset. The impracticalities of
intravenous therapy led to the investigation of oral aciclovir. A series of randomized,
placebo-controlled studies were conducted with an aciclovir dose of 800 mg five times
daily for 7–10 days administered within 72 hours of rash onset. Oral aciclovir reduced the
duration of virus shedding and new lesion formation, and significantly accelerated healing
of the rash. A meta-analysis of four trials demonstrated that aciclovir treatment significantly
shortened the duration of zoster-associated pain.3 Benefit was particularly evident in
patients aged 50 years and older, in whom pain relief was on average twice as fast as those
receiving placebo.
A further meta-analysis of the placebo-controlled trials of aciclovir compared the efficacy
of early therapy (started within 48 hours of rash onset) with late therapy (not started until
48–72 hours after rash onset).4 Irrespective of when aciclovir therapy was initiated, within
72 hours of rash onset, there was a statistically significant reduction in median time to
resolution of acute pain versus placebo. These data have been discussed fully in the
previous IHMF Management Strategies in Herpes publication – Reducing the Burden of
Zoster-Associated Pain – Update.5
Aciclovir, therefore, is effective in the treatment of herpes zoster and has been the
benchmark for the assessment of valaciclovir and famciclovir.
ValaciclovirValaciclovir (1000 mg three times daily for 7 or 14 days) was compared with aciclovir
(800 mg five times daily for 7 days) for the treatment of herpes zoster in 1141 patients aged
over 50 years (mean age 68 years).6 In an intent-to-treat analysis, all regimens had similar
effects on rash healing but both valaciclovir regimens alleviated pain significantly faster
than aciclovir.
The 7-day valaciclovir regimen accelerated the resolution of zoster-associated pain 34%
faster than aciclovir (hazard ratio [HR] 1.34, 95% confidence interval [CI] 1.12, 1.60;
TABLE 2: Relative risksfor the duration of pain inpatients with herpeszoster treated withvalaciclovir 1000 mgthree times daily for 7 or 14 days or aciclovir800 mg five times dailyfor 7 days6
Intent-to-treat analysis (n=1141) P-value Ophthalmic zoster subset (n=119) P-value
Valaciclovir 7 day 1.34 (1.12, 1.60) 0.001 1.27 (0.72, 2.22) ns versus aciclovir
Valaciclovir 14 day 1.22 (1.03, 1.46) 0.03 1.15 (0.66, 2.00) nsversus aciclovir
Valaciclovir 7 day 1.10, (0.92, 1.30) ns 1.10 (0.63, 1.93) nsversus valaciclovir 14 day
ns=not significant
61
P=0.001) (Table 2, Figure 1).6 The median time to cessation of pain was shorter in the 7- and
14-day valaciclovir groups (38 and 44 days, respectively) than in the aciclovir group
(51 days). However, 14-day administration did not have additional clinical benefit over the
7-day regimen. Treatment with valaciclovir (pooled
7- and 14-day treatment data) resulted in a lower
incidence of prolonged pain greater than 6 months’
duration than aciclovir treatment (19.3% versus
25.7%; P=0.02).7,8
A subsequent analysis of these data has shown that
the benefit of valaciclovir over aciclovir was
maintained whether treatment was started within
48 hours of rash onset or 48–72 hours after rash
onset.4
A Japanese study compared valaciclovir (1000 mg
three times daily for 7 days) with aciclovir (800 mg five times daily for 7 days) for the
treatment of herpes zoster in 200 patients.9,10 There were no significant differences
between valaciclovir and aciclovir with respect to time to 50% vesicle crusting or time to
complete healing. However, valaciclovir showed a significant improvement over aciclovir
in terms of time to cessation of new lesion formation (P=0.0039). PHN – defined by the
authors as pain persisting for more than 2 weeks following initiation of therapy – was
observed in 28% and 35% of valaciclovir-treated and aciclovir-treated patients,
respectively. The median times to resolution of PHN were 58 days and 86 days for
valaciclovir-treated and aciclovir-treated patients, respectively.10 Formal statistical analysis
was not possible as only those patients experiencing PHN were followed.
FamciclovirFamciclovir (500 mg and 750 mg three times daily for 7 days) has undergone evaluation
in a placebo-controlled study in patients with herpes zoster, aged 18 years or over,
presenting within 72 hours of rash onset. Analysis of patients (44%) who developed PHN
(pain persisting after rash healing) showed a significant reduction in its duration in the
famciclovir arm compared with placebo.11 In terms of acute pain, neither famciclovir dose
showed benefit compared with placebo.11 An analysis of prolonged zoster-associated pain
was not presented by Tyring et al.11 Importantly, the study evaluated a famciclovir dose of
500 mg three times daily, the dose that is approved in the USA; however, no connection
can be inferred between this and the 250 mg three times daily dose approved for use in
many other countries.12
An international study of 545 patients with herpes zoster, presenting within 72 hours of
rash onset, evaluated famciclovir 250 mg, 500 mg or 750 mg three times daily for 7 days
compared with aciclovir 800 mg three times daily for 7 days.13 This study showed no
difference between any of the three doses of famciclovir and aciclovir with respect to
cutaneous healing parameters. In a subset analysis of all patients treated within 48 hours
of rash onset, famciclovir 500 mg three times daily reduced the duration of zoster-
associated pain significantly faster than aciclovir; however, no significant difference was
observed between either the 250 mg or 750 mg famciclovir dose and aciclovir.13 A further
subset analysis – patients treated within 48 hours of rash onset, who did not have crusts at
enrolment (39% of the original sample size) – demonstrated faster resolution of zoster-
FIGURE 1: Time tocessation of pain in herpeszoster patients treatedwith valaciclovir or oralaciclovir6
Time from first dose (days)
1.0
0.8
0.6
0.4
0.2
0
Prop
ortio
n of
pat
ient
sex
peri
enci
ng p
ain
Cox regression P≤0.03
Aciclovir (7 day)
Valaciclovir (7 day)
0 20 40 60 80 100 120 140 160 180
© 2
002
Rep
rodu
ced
with
per
mis
sion
from
Els
evie
r Sc
ienc
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R, F
ried
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DJ,
Fors
zpan
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Cet
al.
Val
acic
lovi
r co
mpa
red
with
acy
clov
ir fo
r im
prov
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rpes
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imm
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95;3
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6-15
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62
associated pain for all three doses of famciclovir compared with aciclovir 800 mg five
times daily.13 However, when these data were age-adjusted, only the famciclovir 250 mg
three times daily dosage was statistically significant.13
Valaciclovir compared with famciclovir Valaciclovir (1000 mg three times daily for 7 days)
was compared with famciclovir (500 mg three times
daily for 7 days) for the treatment of herpes zoster in
597 patients.12 No differences (either statistical or
clinical) were observed between famciclovir
(n=300) and valaciclovir (n=297) with respect to
either rash healing, acute pain resolution or
resolution of PHN (Figure 2).12 At treatment
initiation, prodromal pain was absent in more
patients in the famciclovir group than in the
valaciclovir group (30 versus 22, P=0.03). Of those
patients experiencing prodromal pain, a higher
proportion in the valaciclovir group experienced
severe or very severe prodromal pain compared with the famciclovir group (34/78 versus
24/70 respectively, P=0.03).12 More intense or prolonged prodromal pain and more severe
acute pain are important risk factors for prolonged zoster-associated pain, so it is possible
that the baseline disease characteristics were biased.
With their superior pharmacokinetics and convenience of administration, valaciclovir7
and famciclovir11 are preferable to aciclovir for cases of uncomplicated herpes zoster in
otherwise healthy adults.
Effect of time of initiation of antiviral therapyJ Although every effort should be made to encourage early treatment, research is needed
to assess the effectiveness of initiating antiviral treatment in patients presenting more
than 72 hours after rash onset (research need recommendation).
Valaciclovir and aciclovir are equally effective for
herpes zoster when treatment initiation is 48–72 hours
after rash onset or within 48 hours of rash onset
(Figure 3).4,14,8
An observational, non-comparative study enrolled
1897 patients treated with valaciclovir (1000 mg
three times daily for 7 days) from the day of
presentation.15 As the impact of valaciclovir on pain
outcome may not be limited to patients whose
treatment is initiated within 72 hours of rash onset,
patients who presented after this were included in
the study. All patients were assessed for time to
cessation of zoster-associated pain, time to
complete cessation of abnormal sensations, and
time to complete rash healing on Days 1, 8 and 29,
and then every 28 days up to 24 weeks. Resolution
FIGURE 2: Resolutionof pain in patients withherpes zoster treated withvalaciclovir (1000 mgthree times daily) orfamciclovir (500 mg threetimes daily)12
1.00.90.80.70.60.50.40.30.20.1
00 50 75
Prop
ortio
n of
pat
ient
s w
ith p
ain
17515012510025
ValaciclovirFamciclovir
l f h h l l
Duration of zoster-associated pain (days)
FIGURE 3: Effect of timeto treatment initiation onduration of zoster-associated pain in patientstreated with valaciclovir oraciclovir for 7 days.8
<72 <48
Time to treatment after rash onset (hours)
48–72
50
40
30
20
10
0Med
ian
dura
tion
of z
oste
r-as
soci
ated
pai
n (d
ays)
Valaciclovir (1000 mg 3x/day) n=384
Aciclovir (800 mg 5x/day) n=376
***
*
**
*P=0.03, **P=0.02, ***P=0.001 versus aciclovir
At least 60% of patients in each group began treatment within 48 hours of rash onset.
© R
epro
duce
d w
ith p
erm
issi
on, T
yrin
g SK
, Beu
tner
KR
, Tuc
ker
BAet
al.
Ant
ivir
al th
erap
y fo
r he
rpes
zos
ter:
ran
dom
ized
, con
trol
led
clin
ical
tria
lof
val
acyc
lovi
r an
d fa
mci
clov
ir th
erap
y in
imm
unoc
ompe
tent
pat
ient
s50
yea
rs a
nd o
lder
. Arc
h Fa
m M
ed20
00;9
(9):8
63-8
69. A
mer
ican
Med
ical
Ass
ocia
tion.
© R
epro
duce
d w
ith p
erm
issi
on, O
rmro
d D
, Goa
K. V
alac
iclo
vir:
a r
evie
w o
f its
use
in th
em
anag
emen
t of h
erpe
s zo
ster
. Dru
gs20
00;5
9(6)
:131
7-13
40.
63
of zoster-associated pain and abnormal sensations was similarly rapid in patients whose
treatment was initiated more than 72 hours after rash onset compared with patients whose
treatment was initiated earlier (Table 3).
This finding is important as it indicates that valaciclovir may have a benefit even when
treatment is commenced outside what is
considered to be the ‘normal’
therapeutic window. It also shows that
the duration of rash is not a predictor of
the outcome of zoster-associated pain.
As the study demonstrated that patients
with moderate-to-severe prodromal pain or acute pain during the rash phase were at
greater risk of zoster-associated pain, it showed that prior duration or severity of pain
should be used to select or stratify cases in future studies.15 There are no published data
available on the efficacy of famciclovir when treatment is initiated more than 72 hours
after rash onset.
Corticosteroid Therapy in Herpes ZosterJ It is recommended that physicians consider the use of steroids to reduce the
inflammation that may be contributing to acute pain, provided there are no
contraindications and the potential risk of excess side-effects is explained. Although
they do not prevent PHN, steroids reduce acute symptoms and may facilitate return to
normal quality of life (category 1 recommendation).
The premise that the pain experienced by people with herpes zoster is primarily due to
inflammation and necrosis of neurones led to the suggestion that, by reducing
inflammation, corticosteroids would reduce pain. Small studies provided conflicting data
on the efficacy of corticosteroids. However, the debate on the role of corticosteroid therapy
in herpes zoster has largely been resolved by two large prospective clinical trials.16,17 While
both larger studies demonstrated their benefit in reducing the duration of acute pain, neither
study showed any reduction in the incidence or duration of PHN among corticosteroid
recipients.
In one of the studies, which was placebo-controlled, 349 patients received aciclovir (800 mg
five times daily) for 7 or 21 days with either prednisolone (40 mg daily tapering to
5 mg daily) or placebo for 21 days.17 Steroid treatment had a significant effect on rash healing
at Days 7 and 14 (P=0.02), and significantly reduced the proportion of patients experiencing
pain on Days 7 and 14 (P<0.01). However, there was no significant benefit in the time to
complete cessation of pain with steroid administration compared with placebo.17
In the second study, 208 immunocompetent herpes zoster patients aged over 50 years
were randomized to one of four treatment groups: either aciclovir (800 mg five times daily)
alone, prednisolone (60 mg per day on Days 1–7, 30 mg per day on Days 8–14, 15 mg
per day on Days 15 to 21) alone, aciclovir in combination with prednisolone, or placebo
alone.16 Patients receiving aciclovir plus prednisolone had significant improvements
compared with placebo recipients with respect to time to:
TABLE 3: Time to loss of abnormal sensationsand zoster-associatedpain in patients treatedwith valaciclovir ≤72 hours and >72 hoursafter rash onset15
Treatment initiation in relation to rash onset
Parameter ≤72 hours >72 hours
Time to cessation of abnormal 24 days 22 dayssensations
Time to loss of zoster-associated pain 16 days 15 days
64
• Total crusting
• Lesion healing
• Cessation of acute neuritis
• Return to normal activities (i.e. uninterrupted sleep, usual daily activity)
• Cessation of analgesic therapy (P<0.05 for all) (Table 4).16
TABLE 4: Diseaseresolution based uponCox regression model foraciclovir withprednisolone andaciclovir alone in thetreatment of herpeszoster16
Dependent variable risk ratio (95% CI)
Aciclovir plus prednisolone Aciclovir aloneversus placebo n (range) versus placebo n (range)
1-month evaluation of cutaneous healingTime to total crusting 2.27 (1.46–3.55)* 1.51 (0.98–2.33) Time to total healing 2.07 (1.26–3.38)* 1.57 (0.97–2.53)
1-month evaluation of quality of life Time to cessation of acute neuritis 3.02 (1.42– 6.41)* 1.47 (0.67–3.21) Time to uninterrupted sleep 2.12 (1.25–3.58)* 1.16 (0.58–2.05) Time to return to 100% usual activity 3.22 (1.92–5.40)* 1.63 (0.96–2.76) Time to no use of analgesic agents 3.15 (1.69–5.39)* 1.27 (0.66–2.49)
6-month evaluation of pain Time to cessation of zoster-associated pain 1.56 (0.92–2.66) 1.39 (0.84–2.32)
* P<0.05
Although benefits were shown for resolution of acute pain, there was no significant
difference in zoster-associated pain at 6 months between patients receiving prednisolone
plus aciclovir and those receiving placebo.16
In a third, large study of aciclovir with and without prednisolone,17 treatment with
aciclovir for 21 days or the addition of prednisolone to aciclovir therapy conferred only
slight benefits over standard 7-day treatment with aciclovir. Additional treatment with
prednisolone did not reduce the frequency of PHN, and the steroid recipients reported
more adverse events.
The data support the use of corticosteroids plus an antiviral compound in older individuals
(≥50 years of age) with significant pain at presentation. Corticosteroid therapy without co-
administration of an antiviral compound to limit viral replication is not recommended.
Since corticosteroid therapy has a range of adverse effects, its potential short-term benefit
on acute herpes zoster needs to be weighed against possible risks. Published studies have
examined only the combination of aciclovir and corticosteroids, although there are no
theoretical reasons why similar benefits would not be seen with corticosteroids used in
combination with valaciclovir or famciclovir.
Antidepressant Treatment for Herpes ZosterJ It is recommended that early use of tricyclic antidepressants in elderly patients with
acute herpes zoster should be considered as it may prevent or reduce PHN (category 2
recommendation).
Tricyclic antidepressant treatment initiated early in the clinical course of herpes zoster has
the potential to reduce the number of patients with prolonged pain, and shorten the
duration of pain in patients experiencing prolonged zoster-associated pain.18 In addition
to their effect of alleviating depression, these agents also have analgesic properties. This is
most likely due to their action of blocking re-uptake of monoamine neurotransmitters
released by descending axons from the brainstem.
65
In elderly patients (>60 years of age), amitriptyline (25 mg once daily for 90 days) alone and
in combination with aciclovir (800 mg five times daily for 7 days) given within 48 hours of
rash onset was compared with placebo for the treatment of herpes zoster.18 Patients entering
the study were randomized to either amitriptyline or placebo; they received aciclovir
(800 mg five times daily for 7 days) according to their physician’s discretion.
When data from all patients receiving amitriptyline (amitriptyline alone and amitriptyline plus
aciclovir groups) were compared with those receiving placebo only, a significantly higher
proportion of the amitriptyline recipients were pain-free at 6 months (84.2% versus 64.7%;
P=0.05) .18 This controlled trial suggests that treatment of herpes zoster with aciclovir (or another
effective antiviral) and low-dose amitriptyline reduces the duration of PHN. As the efficacy of
amitriptyline may be dose-dependent, further studies are needed to confirm this finding,
evaluate other doses of the antidepressant and assess the benefit of other antiviral therapies.
Sympathetic Nerve Blocks and Other Agents to Treat Acute Painin Herpes Zoster and for Prevention of PHNJ The presence of risk factors for the development of PHN should be assessed and
documented for each patient (category 3 recommendation).
J If the patient has severe acute pain, the following treatments may be beneficial:
sympathetic nerve blocks, antidepressants, gabapentin and opioids (category 3
recommendation).
J Studies are required to establish the role of gabapentin and other treatment modalities
in the prevention of PHN (research need recommendation).
J Severity of acute pain may be predictive of long-term persistence of pain. Severity of pain
may, therefore, be an appropriate decision factor in initiating antiviral treatment. Further
research is recommended to evaluate the benefit and applicability of this approach
(research need recommendation).
Numerous authors have reported the utility of sympathetic nerve blockade to reduce acute
pain in herpes zoster. Because greater acute pain severity increases the risk of PHN, any
intervention that reduces the duration or intensity of this pain has the potential to reduce
the severity or incidence of PHN. Thus, many of the studies of the efficacy of sympathetic
nerve blockade in acute zoster pain also examined the effect of this procedure on the
development of PHN.
In a retrospective analysis, Colding19 examined the effects of sympathetic nerve blocks
administered every second day in 243 patients with acute zoster-associated pain. The
patients were aged from 10 to 92 years, with 60% over 60 years. In all cases, the nerve
blocks were performed with a 1% solution of lidocaine and norepinephrine, and on
average, patients each received two doses. Improvement or complete relief from the acute
pain was observed in 206 patients, with the remaining 37 individuals reporting no change
in pain level. Seventy-one patients were followed up for 6 months, including 14 who had
reported no change in pain level following the nerve block. Five of the 71 patients
developed PHN but as the ages of the patients in the follow-up group were not specified,
it is not possible to determine how this observed rate compares with the expected rate.19
66
A second retrospective analysis by Colding20 of 483 patients with acute herpes zoster,
using the same treatment regimen as described above, demonstrated improvement or
complete pain relief in 430 patients, with 53 not responding to treatment. Twelve-month
follow-up was obtained for 155 patients, of whom 5% developed PHN. The author
concluded that, based on a comparison with previously published data, nerve blocks
prevented PHN.20 However, given that different rates of PHN have been observed both in
clinical trials and in retrospective studies, this conclusion is questionable.21
A randomized, double-blind, placebo-controlled trial was conducted in 20 patients aged
over 50 years with herpes zoster of less than 6 weeks’ duration.22 The patients were
randomized to receive four daily injections of either bupivacaine or placebo.
A significantly higher proportion of the bupivacaine group were pain-free following the
four injections, compared with the placebo group (9/10 bupivacaine versus 2/10 placebo;
P<0.01).22 The remaining patient in the bupivacaine group and seven patients from the
placebo group who were still experiencing pain received a second series of four daily
injections of bupivacaine, irrespective of the group to which they were initially
randomized. The patient from the original bupivacaine group continued to experience
pain following the second series of injections. Four of the seven patients from the original
placebo group experienced complete pain relief following the second series of injections,
two reported persistent pain, but at approximately 20% of its original intensity, and one
continued to experience unmitigated persistent pain (Table 5).22 Over a 12-month follow-
up period, all subjects continued to report the same degree of pain relief that was noted
immediately following the treatment course. Based on these findings, the authors suggest
that nerve blocks may prevent the
development of PHN, although there
was no comparison with other studies.
A retrospective study of the effectiveness
of sympathetic nerve blocks in
preventing PHN when administered at
numerous intervals following the onset
of herpes zoster documented that nerve blocks initiated within 2 months were more
effective than treatment initiated after 2 months (n=122).23 Approximately 90% of patients
treated within 2 months of herpes zoster onset had complete pain resolution by 1 year,
compared with only 14% of patients whose treatment was initiated between 2 months and
1 year following onset of herpes zoster. This suggests, as expected, that earlier treatment,
before the establishment of chronic pain, is more effective. No relevant baseline data were
provided to allow comparison with expected outcome had no treatment been given.
Epidural administration of local anaesthetics with or without steroids was investigated in a
randomized, controlled study of 485 adults aged over 55 years with acute pain associated
with herpes zoster.24 Patients with rash of less than 7 days’ duration and severe pain were
randomized to receive either:
• Intravenous aciclovir 10 mg/kg three times daily for 9 days plus prednisolone (60 mg
daily with progressive reduction) for 21 days
or
• 6–12 ml bupivacaine (0.25%) every 6–8 or 12 hours plus methylprednisolone 40 mg
every 3–4 days by epidural catheter during a period ranging from 7 to 21 days.
TABLE 5: Number ofpatients experiencingpain due to herpes zosterfollowing treatment withsympathetic nerve block22
No pain Pain n (%) n
First series Bupivacaine 9 (90) 1 Electrolyte solution 2 (20) 8
Second series Bupivacaine-Bupivacaine 0 1 Electrolyte-Bupivacaine 4 3
67
In this study, the incidence of pain at 12 months was 22.2% in patients receiving aciclovir
plus steroids, but only 1.6% after epidural analgesia plus steroids, supporting the suggestion
that earlier treatment, before the establishment of chronic pain, is more effective.
However, another study found that PHN developed in 14% (10/72) of patients given
sympathetic nerve blocks within 30 days of the onset of herpes zoster.25 The place of nerve
blocks in the management of acute pain is clearer than their use in prevention of PHN.
Sympathetic nerve blocks are not without hazard and would place a major demand on
healthcare resources if widely used. Further work may identify a group of patients where
benefit may justify increased risk and cost.
Whether or not the administration of sympathetic nerve blocks has the potential to prevent
PHN or reduce the likelihood of its development remains controversial.21 This is partly
because of methodological issues associated with the trials of this intervention (e.g.
patients selected for follow-up), but also due to the lack of proper comparison groups,
which makes it difficult to determine whether treatment resulted in fewer patients with
PHN than would be expected from natural history studies.
Gabapentin and opioids may also be beneficial for the treatment of acute pain in herpes
zoster. These agents should be titrated at similar doses as those given for the treatment of
chronic pain (see Chapter 9).
SummaryIn many individuals, herpes zoster comprises rash and pain of relatively short duration.
However in some individuals, especially the elderly, herpes zoster is associated with
complications and prolonged pain. The aims of treating herpes zoster are to minimize the
duration and severity of pain and prevent the associated complications.
Antiviral therapy for immunocompetent adults over 50 years of age with herpes zoster is
routinely recommended, particularly if it can be instituted within 72 hours of lesion onset.
Because of their improved pharmacokinetic profiles and simpler dosing regimens,
valaciclovir (1000 mg three times a day) or famciclovir (250 mg or 500 mg three times a
day) have replaced aciclovir (800 mg five times a day) as the preferred treatment. In
addition, it is recommended that physicians consider the use of steroids to reduce the
inflammation that may be contributing to zoster associated-pain.
There is some evidence that antiviral therapy should be considered for patients whose rash
has been present longer than 72 hours and in whom clinical examination reveals new
vesicle formation (indicative of ongoing virus replication). Similarly, if risk factors for
severe or protracted pain are evident at presentation, antiviral therapy should be initiated
irrespective of time since rash onset.
Tricyclic antidepressants, such as amitriptyline (25 mg once daily; 10 mg in the frail and
elderly, elevated every few days to a dose that is effective without severe side-effects),
particularly if initiated early in the clinical course of herpes zoster, can relieve the acute
pain associated with the disease and have the potential to prevent the development
of PHN.
68
Sympathetic nerve blocks have been studied in several trials, most of which were
uncontrolled and lacked comparison groups. Thus, it is difficult to draw any conclusions
about the efficacy of this intervention in herpes zoster.
In general, patients with herpes zoster should receive antiviral therapy to limit viral
replication and, thereby, minimize the acute pain associated with herpes zoster, help
prevent PHN, prevent complications and speed the resolution of rash.
References
1. Cohen JI, Brunell PA, Straus SE et al. Recent advances in varicella-zoster virus infection. Ann Intern Med1999;130(11):922-932.
2. Wood MJ. Treatment of zoster. Rev Med Microbiol 1995;6:165-174.3. Wood MJ, Kay R, Dworkin RH et al. Oral acyclovir therapy accelerates pain resolution in patients with
herpes zoster: a meta-analysis of placebo-controlled trials. Clin Infect Dis 1996;22(2):341-347.4. Wood MJ, Shukla S, Fiddian AP et al. Treatment of acute herpes zoster: effect of early (< 48 h) versus late
(48-72 h) therapy with acyclovir and valaciclovir on prolonged pain. J Infect Dis 1998;178 Suppl 1:S81-84.5. Wood MJ, Kroon S. Management Strategies in Herpes: Reducing the burden of zoster-associated pain—
update. 2nd ed. Worthing: PPS Europe Ltd, 1995.6. Beutner KR, Friedman DJ, Forszpaniak C et al. Valaciclovir compared with acyclovir for improved therapy
for herpes zoster in immunocompetent adults. Antimicrob Agents Chemother 1995;39(7):1546-1553.7. Beutner KR. Valacyclovir: a review of its antiviral activity, pharmacokinetic properties, and clinical efficacy.
Antiviral Res 1995;28(4):281-290.8. Ormrod D, Goa K. Valaciclovir: a review of its use in the management of herpes zoster. Drugs
2000;59(6):1317-1340.9. Taylor-Wiedeman J, Yamashita K, Miyamura K et al. Varicella-zoster virus prevalence in Japan: no significant
change in a decade. Jpn J Med Sci Biol 1989;42(1):1-11.10. Niimura M, Honda M, Nishikawa T. Phase III study of valaciclovir hydrochloride tablets in patients with
herpes zoster: double-blind comparative study with aciclovir tablets [in Japanese]. Rinsho Iyaku1998;14(16):2867-2902.
11. Tyring S, Barbarash RA, Nahlik JE et al. Famciclovir for the treatment of acute herpes zoster: effects on acutedisease and postherpetic neuralgia. A randomized, double-blind, placebo-controlled trial. CollaborativeFamciclovir Herpes Zoster Study Group. Ann Intern Med 1995;123(2):89-96.
12. Tyring SK, Beutner KR, Tucker BA et al. Antiviral therapy for herpes zoster: randomized, controlled clinicaltrial of valacyclovir and famciclovir therapy in immunocompetent patients 50 years and older. Arch FamMed 2000;9(9):863-869.
13. Degreef H, Group FHZCS. Famciclovir, a new oral antiherpes drug: results of the first controlled clincialstudy demonstrating its efficacy and safety in the treatment of uncomplicated herpes zoster inimmunocompetent patients. Int J Antimicrob Agents 1994;4:241-246.
14. Wood MJ. Treatment of herpes zoster in the elderly. Herpes 1998;5:60-63.15. Decroix J, Partsch H, Gonzalez R et al. Factors influencing pain outcome in herpes zoster: an observational
study with valaciclovir. Valaciclovir International Zoster Assessment Group (VIZA). J Eur Acad DermatolVenereol 2000;14(1):23-33.
16. Whitley RJ, Weiss H, Gnann JW, Jr. et al. Acyclovir with and without prednisone for the treatment of herpeszoster. A randomized, placebo-controlled trial. The National Institute of Allergy and Infectious DiseasesCollaborative Antiviral Study Group. Ann Intern Med 1996;125(5):376-383.
17. Wood MJ, Johnson RW, McKendrick MW et al. A randomized trial of acyclovir for 7 days or 21 days withand without prednisolone for treatment of acute herpes zoster. N Engl J Med 1994;330(13):896-900.
18. Bowsher D. The effects of pre-emptive treatment of postherpetic neuralgia with amitriptyline: a randomized,double-blind, placebo-controlled trial. J Pain Symptom Manage 1997;13(6):327-331.
19. Colding A. The effect of regional sympathetic blocks in the treatment of herpes zoster. Acta AnaesthesiolScand 1969;13:133-141.
20. Colding A. Treatment of pain: organization of a pain clinic: treatment of acute herpes zoster. Proc R Soc Med1973;66(6):541-543.
21. Wu CL, Marsh A, Dworkin RH. The role of sympathetic nerve blocks in herpes zoster and postherpeticneuralgia. Pain 2000;87(2):121-129.
22. Tenicela R, Lovasik D, Eaglestein W. Treatment of herpes zoster with sympathetic blocks. Clin J Pain1985;1:63-67.
23. Winnie AP, Hartwell PW. Relationship between time of treatment of acute herpes zoster with sympatheticblockade and prevention of post-herpetic neuralgia: clinical support for a new theory of the mechanism bywhich sympathetic blockade provides therapeutic benefit. Reg Anesth 1993;18(5):277-282.
24. Pasqualucci A, Pasqualucci V, Galla F et al. Prevention of post-herpetic neuralgia: acyclovir andprednisolone versus epidural local anesthetic and methylprednisolone. Acta Anaesthesiol Scand2000;44(8):910-918.
25. Riopelle JM, Naraghi M, Grush KP. Chronic neuralgia incidence following local anesthetic therapy forherpes zoster. Arch Dermatol 1984;120(6):747-750.
Management RecommendationsCategory 2J To prevent ocular complications, antiviral therapy is recommended for all patients
with herpes zoster ophthalmicus who present within 1 week of onset of lesions.
Aciclovir (800 mg five times a day for 7 days), valaciclovir (1000 mg three times daily)
and famciclovir (500 mg three times daily) have been proven to reduce the ocular
complications of herpes zoster ophthalmicus. Valaciclovir and famciclovir have the
advantage of a simpler dosing schedule.
J Intravenous aciclovir (10 mg/kg every 8 hours for adults, 500 mg/m2 every 8 hours for
children) followed by the oral formulation is the treatment of choice for acute retinal
necrosis caused by varicella zoster virus (VZV). Valaciclovir (1000 mg three times
daily) and famciclovir (500 mg three times daily) should also be considered for use in
this situation.
Category 3J It is recommended that patients with herpes zoster ophthalmicus are treated with
systemic antiviral therapy, and that topical antivirals should only be administered in
addition to systemic medication during the acute phase of herpes zoster ophthalmicus.
J It is strongly recommended that patients with obvious ocular involvement should be
referred to an ophthalmologist.
J It is not recommended that corticosteroid therapy (either topical or systemic) be
prescribed except upon the advice of an ophthalmologist.
J It is recommended that antiviral treatment of herpes zoster ophthalmicus is initiated up
to 7 days following rash onset.
Research needJ It is recommended that a study is initiated to research the benefit of long-term antiviral
treatment on the outcome of herpes zoster ophthalmicus.
Herpes Zoster OphthalmicusHerpes zoster ophthalmicus occurs in 10–25% of patients with herpes zoster; this
dermatomal presentation is second in frequency only to thoracic herpes zoster.1-3 The scale
of the problem is demonstrated by the statistic that of the 1 million physician visits for
herpes zoster in the USA, one quarter involve the eye.4 Ocular complications occur in
50–90% of herpes zoster ophthalmicus patients and can lead to substantial visual
disability;5-8 10–15% of patients with herpes zoster ophthalmicus experience anatomical
or functional sequelae.9 69
VARICELLA ZOSTER VIRUS INFECTION OF THE EYE7
Herpes zoster ophthalmicus is due to reactivation of latent VZV in the first division of the
trigeminal nerve. The resultant dermal rash may extend from the nose and eye to the vertex
of the skull but rarely extends across the midline of the patient’s forehead.10 When the
nasociliary portion of the optic nerve is involved, which occurs in about 33% of patients
with herpes zoster ophthalmicus, there is a significant correlation with ocular
complications.8 Proliferation of VZV causes destruction of the ganglion but VZV is not
limited to the trigeminal nerve – it may travel to the central nervous system (CNS) where
it initiates necrosis in the corresponding sensory nuclei.11
Ocular complications of herpes zoster ophthalmicusJ It is strongly recommended that patients with obvious ocular involvement should be
referred to an ophthalmologist (category 3 recommendation).
The ocular complications of herpes zoster ophthalmicus may affect almost all structures of
the eye, including the orbit, conjunctiva, cornea, retina and optic nerve (Figure 1). The
complications are attributable to a number of mechanisms including virus replication and
dissemination, neuronal damage, ischaemic vasculitis and an inflammatory
granulomatous reaction.10 However, although much is known about manifestations of the
complications of herpes zoster ophthalmicus, less is known about the incidence and long-
term course of ocular involvement subsequent to it.
Conjunctiva. The most common manifestation is a non-specific conjunctivitis with a mixed
follicular and papillary reaction, which usually resolves within a week. Membranous
conjunctivitis can develop and lead to conjunctival scarring if inadequately treated.
Scleritis may occur during the acute phase of the
disease, but can also occur 2–3 months after the
rash has resolved.
Orbit. Complications may include proptosis,
chemosis and ocular motor palsies. The latter results
from localized spread of the virus within the orbit.10
Cornea. The complications are frequent and may be
both acute and chronic in nature. The cornea can
develop various signs of infection including an
epithelial or stromal keratitis. It develops shortly
after disease onset due to virus replication in the
corneal epithelium and occurs in 50% of patients with herpes zoster ophthalmicus. The
epithelial lesions can appear as small, slightly elevated, dendritic-shaped lesions that stain
slightly with fluorescein but vividly with rose Bengal. Because their shape resembles the
dendritic ulcerations seen in herpes simplex infections, they have been labelled
pseudodendrites. Later, corneal complications may result from host inflammatory
responses, and include anterior stromal infiltrates, sclerokeratitis, keratouveitis,
endotheleitis and disciform keratitis.
Uvea. The most frequently observed signal of intraocular involvement is mild-to-severe
anterior uveitis. It can occur independently of corneal or conjunctival disease and can
become chronic and recurrent. Patients with herpes zoster ophthalmicus-related iritis can
also develop elevated intraocular pressure due to inflammation or cellular damage.
70
FIGURE 1: Herpeszoster ophthalmicusinfection of theconjunctiva
Retina. Herpes zoster ophthalmicus can result in various retinal conditions, including
retinal haemorrhages, retinitis, ischaemic vasculitis and acute retinal necrosis syndrome.
The latter complication is discussed later in this chapter.
Optic nerve. The vasculitis associated with herpes zoster ophthalmicus may manifest in
the retina and optic nerve accompanied by central retinal vein occlusion, central retinal
artery occlusion, retinal vasculitis or ischaemic optic neuropathy.10 Herpes zoster
ophthalmicus-related optic neuropathy usually begins 1–4 weeks after the onset of rash
and can result in decreased visual acuity.
Therapy for herpes zoster ophthalmicusThe primary aim of treating herpes zoster ophthalmicus is to prevent the potentially severe
and sight-threatening ocular complications that can follow herpes zoster involving the
trigeminal nerve.
J To prevent ocular complications, antiviral therapy is recommended for all patients
with herpes zoster ophthalmicus who present within 1 week of onset of lesions.
Aciclovir (800 mg five times a day), valaciclovir (1000 mg three times daily for 7 days)
and famciclovir (500 mg three times daily) have been proven to reduce ocular
complications. Valaciclovir and famciclovir have the advantage of simpler dosing
schedules (category 2 recommendation).
J It is recommended that antiviral treatment of herpes zoster ophthalmicus is initiated up
to 7 days following rash onset (category 3 recommendation).
J It is not recommended that corticosteroid therapy (either topical or systemic) be
prescribed except upon the advice of an ophthalmologist (category 3
recommendation).
J It is recommended that a study is initiated to research the benefit of long-term antiviral
treatment on the outcome of herpes zoster ophthalmicus (research need
recommendation).
Antiviral treatmentThe use of antiviral therapies in the management of herpes zoster ophthalmicus limits virus
replication and has been shown to have benefit in preventing its ocular complications.
Aciclovir has proved to be effective in the treatment of acute herpes zoster ophthalmicus
in two placebo-controlled trials. In the first of these, oral aciclovir (600 mg five times daily
for 10 days) was compared with placebo in the treatment of immunocompetent patients
with herpes zoster ophthalmicus.12 Aciclovir treatment resulted in quicker resolution of
dermatomal signs and symptoms, and reduced acute zoster-associated pain, particularly
when treatment was initiated within 72 hours of lesion onset.12 In addition, aciclovir
significantly reduced the incidence and severity of several frequent early ocular
complications (Table 1).12 There was no effect on late complications, but this may have
been due to the suboptimal dosage used.
In the second aciclovir trial, 42 patients with acute herpes zoster ophthalmicus of less than
72 hours’ duration received either aciclovir (800 mg five times daily for 10 days) or placebo.1371
There was a significant reduction in eye disease persisting after 6 months with aciclovir. The
frequency and severity of complications during the early phase was also reduced but this
effect did not reach significance; it is possible that the failure to detect an effect was due to
the study not being of sufficient power.13
Although the results of the two studies
are somewhat in conflict, one showing
an early and the other a late effect,
aciclovir does appear to prevent the
complications of herpes zoster
ophthalmicus. These findings have been
followed by the investigation of both
valaciclovir and famciclovir in the
treatment of herpes zoster
ophthalmicus.
Valaciclovir has the potential to be as
effective as, or more effective than,
aciclovir for treating herpes zoster
ophthalmicus but with a simplified
dosing schedule. Valaciclovir results in
an aciclovir concentration in the
aqueous humour twice as high as that
after aciclovir administration.14
Moreover, corneal concentrations of
aciclovir correlate with plasma
concentrations.14 The potential for valaciclovir to reduce the complications of herpes
zoster ophthalmicus was suggested in a trial of 1141 patients with acute herpes zoster,
in which a small subset (119 patients) had herpes zoster ophthalmicus. There was a
trend to faster resolution of pain in herpes zoster ophthalmicus patients using
valaciclovir compared with aciclovir, but the sample size was too small to permit an
analysis of efficacy.15 Definitive evidence was obtained from a multicentre, randomized
trial comparing valaciclovir (1000 mg three times daily) with oral aciclovir (800 mg five
times daily for 7 days) in 110 immunocompetent patients with herpes zoster
ophthalmicus.14 The ocular complications were similar in the valaciclovir and aciclovir
groups, the most common being conjunctivitis affecting 54% and 52% of valaciclovir-
and aciclovir-treated patients, respectively (Table 2). The long-term outcomes of herpes
zoster ophthalmicus ocular complications were favourable and similar in the two
treatment groups, with only two patients (3.6%) in the valaciclovir group and one
patient (1.9%) in the aciclovir group experiencing ocular lesions that persisted for more
than 6 months. Thus, valaciclovir was as effective as aciclovir in preventing ocular
complications and the two treatments had similar tolerability.14
The safety and efficacy of famciclovir (500 mg three times daily) have also been compared
with oral aciclovir (800 mg five times daily for 7 days) in the treatment of herpes zoster
ophthalmicus.16 Famciclovir was well tolerated and demonstrated efficacy similar to
aciclovir in this study of 454 patients randomized to receive oral famciclovir 500 mg three
times daily or oral aciclovir 800 mg five times daily for 7 days and followed for up to
6 months. For the main outcome measure (loss of visual acuity), there was no significant72
TABLE 1: Ocularcomplications in herpeszoster ophthalmicuspatients receiving oralaciclovir (600 mg fivetimes daily) or placebo12
Aciclovir Placebo P-value ≤n (%) n (%)
Total patients (n) 36 35
Episcleritis 6 (17) 14 (40) Present at entry 1 (3) 7 (20) 0.0250 Developed after entry 5 (14) 7 (20) 0.2250
ScleritisAnterior 1 (3) 3 (9) Posterior 0 (0) 2(6)
Dendritiform keratopathy 12 (33) 21 (60) Present at entry 7 (19) 10 (29) 0.2670 Developed after entry 5 (14) 11 (31) 0.0319
Stromal keratitis (after entry) 9 (25) 19 (56) 0.0081 Mild 7 14 Moderate 2 5 Severe 0 1
Corneal scarring/vascularization 8 (22) 12 (34) 0.1934
Anterior uveitis (after entry) 6 (19) 18 (56) 0.0020 Mild 6 8 Moderate 0 8 Severe 0 2
Keratitic precipitates 7 (19) 17 (49) 0.0112 Mild 6 10 Moderate 0 5 Severe 1 2
Iris atrophy 1 4 (11) 0.1697
difference between groups. The percentage of patients who experienced one or more ocular
manifestation was similar for famciclovir (142/245, 58.0%) and aciclovir (114/196, 58.2%)
recipients, with no significant difference between groups (odds ratio [OR] 0.99; 95%
confidence interval [CI] 0.68, 1.45). The percentage of patients experiencing severe and
non-severe manifestations was also similar between groups, with no significant difference,
and the incidence of individual ocular manifestations was comparable between groups.
73
TABLE 2: Incidence of ocular complications ofherpes zoster ophthalmicusin patients treated withvalaciclovir (1000 mgthree times daily) or oralaciclovir (800 mg fivetimes daily), and untreatedhistorical controls14
Valaciclovir (n=56) Aciclovir (n=54) Historical untreated controls Complication Incidence (%) 95% CI Incidence (%) 95% CI Incidence (%)
Conjunctivitis 30 (54) 40–67 28 (52) 38–66 86
Superficial keratitisPunctate keratitis 22 (39) 26–53 26 (48) 34–62 51 Dendritic keratitis 6 (11) 4–22 6 (11) 4–23 51–60
Dendritic ulcer 3 (5) 1–15 1 (2) 0–10 –
Stromal keratitis 7 (13) 5–25 7 (13) 5–24 41–56
Uveitis 7 (13) 5–24 9 (17) 8–29 34–60
Elevated intraocular pressure 8 (14) 6–26 7 (13) 5–25 –
Episcleritis 4 (7) 2–17 1 (2) 0–10 40
Thus, antiviral treatment of herpes zoster ophthalmicus is effective in reducing the
incidence and severity of ocular complications, with valaciclovir and famciclovir being as
effective as aciclovir but having simpler dosing schedules.
SteroidsAs discussed in Chapter 6, corticosteroids reduce the acute pain associated with herpes
zoster, but there is no proven benefit upon the development of post-herpetic neuralgia
(PHN) or the ocular complications of herpes zoster ophthalmicus.
The unanswered questions over the utility of steroids in the treatment of herpes zoster
ophthalmicus, and the severity of the complications that might warrant such therapy, lead
to the recommendation that corticosteroids, either systemic or topical, should not be
prescribed to patients with herpes zoster ophthalmicus without prior consultation with an
ophthalmologist, to ensure that patients are receiving the most appropriate therapy to help
prevent ocular complications, the most common of which is cataracts.
Sympathetic nerve blocksA small, randomized trial in patients with herpes zoster ophthalmicus demonstrated that
sympathetic nerve blocks given within 14 days of rash onset reduced the severity of acute
pain.17 Patients were administered a stellate ganglion block (bolus dose [9.5 ml]
comprising equal parts 1% lignocaine and 0.5% marcaine injected onto the C5/C6
prevertebral fascia) or were untreated. The treated patients reported significant reductions
in pain at 1 hour (P<0.001), 2 weeks to 1 month (P<0.01), 6 weeks to 2 months (P<0.05)
and 3 months (P<0.01). No significant reduction in the pain experienced by the untreated
control patients was observed until 3 months; the authors considered this reduction to be
due to resolution of pain over time in herpes zoster ophthalmicus.17 While sympathetic
nerve blockade may be considered for patients with severe acute pain, close liaison with
local pain clinics would be necessary to ensure that treatment is commenced within
14 days of rash onset, and not all pain clinics would accept that the value of this treatment
is proven.
Acute Retinal NecrosisVZV-associated acute retinal necrosis (ARN) has been described in both
immunocompetent and immunocompromised patients. Since the advent of AIDS, a more
aggressive variant of this disease (sometimes termed rapidly progressive herpetic retinal
necrosis [RPHRN]) has been identified in HIV-infected individuals, thought to be due to
their reduced level of cell-mediated immunity.18,19 Visual changes associated with ARN
usually occur weeks to months after the onset of herpes zoster. ARN can follow either
herpes zoster ophthalmicus or herpes zoster in a remote dermatome. Furthermore, retinal
involvement is bilateral in over half of cases, suggesting that VZV reaches the CNS via
haematogenous spread, possibly with extension along nerve pathways within the anterior
visual system.18
ARN presents with multifocal necrotizing lesions, often initially involving the peripheral
retina. The granular, non-haemorrhagic lesions rapidly extend and coalesce, accompanied
by relatively little intraocular inflammation.20-22 The typical signs and symptoms of
ARN are listed in the text box (right).
Recurrences of ARN are rare.23
Diagnosis of ARN is generally clinical.
Although PCR analysis of vitreous biopsy
samples can be performed to confirm
presence of VZV,24,25 the time taken for
biopsy results to be obtained may be
unacceptable.
Treatment of ARNJ Intravenous aciclovir (10 mg/kg
every 8 hours, 500 mg/m2 every
8 hours for children) followed by the oral formulation is the treatment of choice for
acute retinal necrosis caused by VZV (category 2 recommendation). Valaciclovir
(1000 mg three times daily) and famciclovir (500 mg three times daily) should also be
considered for use in this situation.
Antiviral treatmentThere have been no randomized trials of therapy in VZV-associated ARN. However,
intravenous aciclovir (10 mg/kg every 8 hours) for 7–10 days followed by 1–2 months of
oral aciclovir (400–800 mg five times a day) speeds the resolution of retinal lesions and
decreases the risk of disease in the other eye.23 Similarly, a clinical case report has
documented effective treatment of ARN with famciclovir (500 mg three times daily for
3 months) in an immunocompetent patient.26 Despite antiviral treatment, retinal
detachment occurs in most severe cases.
SummaryHerpes zoster ophthalmicus is observed in 1 in 5 patients with herpes zoster and up to
90% of these may experience ocular complications if left untreated. These complications
affect almost all of the structures of the eye and include conjunctivitis, scleritis, ocular
motor palsies, epithelial keratitis, stromal infiltrates, anterior uveitis and ARN.74
Signs and symptoms of acute retinal necrosis
• Pain
• Large white plaques in retinal periphery
• Photophobia
• Prominent vitritis
• Iritis
• Vascular sheathing
• Vitreous precipitates
• Necrotizing spreading retinal lesions
• Anterior uveitis
• 80% of cases become bilateral in 5–20 days
The use of antiviral therapies in the management of herpes zoster ophthalmicus to limit
VZV replication has been shown to have benefit in preventing the ocular complications of
herpes zoster ophthalmicus. Valaciclovir (1000 mg three times daily) and famciclovir
(500 mg three times daily) are as effective as aciclovir in preventing the ocular
complications of herpes zoster ophthalmicus, but their simpler dosing schedules make
them more suitable for use.
The efficacy of steroids in herpes zoster ophthalmicus remains in doubt. It is not, therefore,
recommended that corticosteroids, either systemic or topical, are prescribed in herpes
zoster ophthalmicus without prior consultation with an ophthalmologist.
Sympathetic nerve blocks may play a role in limiting the pain associated with herpes
zoster ophthalmicus; however, the evidence for this is inconclusive.
Patients presenting with VZV-associated ARN should be treated with intravenous aciclovir
(10 mg/kg every 8 hours); however, anecdotal evidence suggests that valaciclovir
(1000 mg three times daily) and famciclovir (500 mg three times daily) may be beneficial
in these patients.
References1. Ragozzino MW, Melton LJ, 3rd, Kurland LT et al. Population-based study of herpes zoster and its sequelae.
Medicine (Baltimore) 1982;61:310-316.2. Burgoon CFJ, Burgoon JS, Bladridge GD. The natural history of herpes zoster. JAMA 1957;164:265-269.3. Mahalingam R, Wellish M, Lederer D et al. Quantitation of latent varicella-zoster virus DNA in human
trigeminal ganglia by polymerase chain reaction. J Virol 1993;67:2381-2384.4. Pavan-Langston D. Ophthalmic zoster. In: Varicella-zoster virus: virology and clinical management. (Arvin A,
Gershon A, eds). Cambridge: Cambridge University Press, 2000.5. Kestelyn P, Stevens AM, Bakkers E et al. Severe herpes zoster ophthalmicus in young African adults: a marker
for HTLV-III seropositivity. Br J Ophthalmol 1987;71:806-809.6. Marsh RJ, Cooper M. Ophthalmic herpes zoster. Eye 1993;7:350-370.7. Womack LW, Liesegang TJ. Complications of herpes zoster ophthalmicus. Arch Ophthalmol 1983;101:
42-45.8. Harding SP, Lipton JR, Wells JC. Natural history of herpes zoster ophthalmicus: predictors of postherpetic
neuralgia and ocular involvement. Br J Ophthalmol 1987;71:353-358.9. Liesegang TJ. Varicella-zoster virus eye disease. Cornea 1999;18:511-531.10. Liesegang TJ. Diagnosis and therapy of herpes zoster ophthalmicus. Ophthalmology 1991;98:1216-1229.11. Linnemann CC, Jr, Alvira MM. Pathogenesis of varicella-zoster angiitis in the CNS. Arch Neurol
1980;37:239-240.12. Cobo LM, Foulks GN, Liesegang T et al. Oral acyclovir in the treatment of acute herpes zoster ophthalmicus.
Ophthalmology 1986;93:763-770.13. Harding SP, Porter SM. Oral acyclovir in herpes zoster ophthalmicus. Curr Eye Res 1991;10:177-182.14. Colin J, Prisant O, Cochener B et al. Comparison of the efficacy and safety of valaciclovir and acyclovir for
the treatment of herpes zoster ophthalmicus. Ophthalmology 2000;107:1507-1511.15. Beutner KR, Friedman DJ, Forszpaniak C et al. Valaciclovir compared with acyclovir for improved therapy
for herpes zoster in immunocompetent adults. Antimicrob Agents Chemother 1995;39:1546-1553.16. Tyring SK. Famciclovir for ophthalmic zoster: A randomized acyclovir-controlled study. Br J Ophthalmol
2001;85:576-581.17. Harding SP, Lipton JR, Wells JC et al. Relief of acute pain in herpes zoster ophthalmicus by stellate ganglion
block. BMJ (Clin Res Ed) 1986;292:1428.18. Ormerod LD, Larkin JA, Margo CA et al. Rapidly progressive herpetic retinal necrosis: a blinding disease
characteristic of advanced AIDS. Clin Infect Dis 1998;26:34-45; discussion 46-37.19. Hellinger WC, Bolling JP, Smith TF et al. Varicella-zoster virus retinitis in a patient with AIDS-related
complex: case report and brief review of the acute retinal necrosis syndrome. Clin Infect Dis 1993;16:208-212.
20. Garthy DS, Spalton DJ, Hykin PG. Acute retinal necrosis syndrome. Br J Ophthalmol 1991May;75(5):292-297.
21. Margolis TP, Lowder CY, Holland GN et al. Varicella-zoster virus retinitis in patients with the acquiredimmunodeficiency syndrome. Am J Ophthalmol 1991;112:119-131.
22. Engstrom RE, Jr., Holland GN, Margolis TP et al. The progressive outer retinal necrosis syndrome. A variantof necrotizing herpetic retinopathy in patients with AIDS. Ophthalmology 1994;101:1488-1502.
23. Blumenkranz MS, Culbertson WW, Clarkson JG et al. Treatment of the acute retinal necrosis syndrome withintravenous acyclovir. Ophthalmology 1986;93:296-300.
24. Short GA, Margolis TP, Kuppermann BD et al. A polymerase chain reaction-based assay for diagnosing75
varicella-zoster virus retinitis in patients with acquired immunodeficiency syndrome. Am J Ophthalmol1997;123:157-164.
25. Yamamoto S, Pavan-Langston D, Kinoshita S et al. Detecting herpesvirus DNA in uveitis using thepolymerase chain reaction. Br J Ophthalmol 1996;80:465-468.
26. Figueroa MS, Garabito I, Gutierrez C et al. Famciclovir for the treatment of acute retinal necrosis (ARN)syndrome. Am J Ophthalmol 1997;123:255-257.
76
Management RecommendationsCategory 1J Intravenous aciclovir therapy is the standard of care for immunocompromised patients
with disseminated varicella zoster virus (VZV) disease, including those with
complications such as varicella pneumonia.
The recommended doses are:
Immunocompromised adults with VZV infections: 10 mg/kg every 8 hours
UK: Immunocompromised children with VZV infections: 500 mg/m2 body surface area
every 8 hours. The dosage in children under 3 months of age is calculated on the basis
of body weight.
USA: Immunocompromised children with VZV infections: 20 mg/kg every 8 hours.
J Immunocompromised individuals should receive prophylaxis with varicella zoster
immune globulin (VZIG) as soon as possible but no later than 4 days following
exposure to varicella.
Category 2J In immunocompromised patients with suspected aciclovir-resistant VZV infection,
treatment with foscarnet (120–200 mg/kg/day, in two or three divided doses) should be
initiated unless renal failure is evident.
J It is recommended that suppressive antiviral therapy targeted at VZV should be
considered for transplant patients, especially in bone marrow transplant (BMT)
recipients and patients requiring immunosuppression for graft-versus-host disease
(GVHD). The recommended regimen is intravenous aciclovir (500 mg/m2 three times
a day) for 1 month followed by oral aciclovir (800 mg four times a day) for a further
6 months.
J It is recommended that the use of prophylactic varicella vaccination be considered in
selected groups of immunocompromised persons, such as those with leukaemia that
is in remission or who are undergoing haematopoietic stem cell transplantation.
However, varicella vaccine is not recommended in these patients for post-exposure
prophylaxis because of the risk of vaccine-induced varicella.
Category 3J Anecdotal evidence suggests that oral antiviral therapy may be appropriate for the
treatment of varicella in some immunocompromised individuals. In this setting, the
newer antivirals, valaciclovir (1000 mg three times daily for adults) and famciclovir
(500 mg three times daily for adults), are likely to be at least as effective as aciclovir
(800 mg four times daily). The minimum duration of therapy should be 7 days.77
MANAGEMENT OF VARICELLA ZOSTER VIRUS
INFECTIONS IN THE IMMUNOCOMPROMISED HOST8
J For some immunocompromised individuals, oral antiviral therapy may be appropriate
for the treatment of herpes zoster – in this setting, the newer antivirals, valaciclovir
(1000 mg three times daily for adults) and famciclovir (500 mg three times daily for
adults), are likely to be at least as effective as aciclovir (800 mg five times daily).
J Clinicians should be aware that in immunocompromised individuals, herpes zoster
might initially present as unexplained abdominal pain.
J Combined intravenous foscarnet (60 mg/kg three times per week) plus intravitreal
ganciclovir (400 mg twice per week) therapy is the best option for rapidly progressive
herpetic retinal necrosis. However, the dose of foscarnet to be used has not been
established in the clinical trial setting, and further dose-comparative studies should be
undertaken.
J It is recommended that VZV isolates obtained from hyperkeratotic papules and
ecthymatous lesions from HIV-positive individuals be submitted so that antiviral
susceptibility testing may be undertaken if clinically necessary.
Research needJ Studies are recommended comparing oral valaciclovir and famciclovir with
intravenous aciclovir for the management of immunocompromised individuals with
VZV infections.
J There is a need to define the patients for whom oral antiviral therapy might be used in
place of intravenous therapy.
IntroductionIn individuals who have defective or compromised cell-mediated immunity, VZV may
cause extensive cutaneous disease and invade visceral organs, especially the lungs, liver,
central nervous system (CNS) and bone marrow. The complications that may arise in
immunocompromised individuals can be severe and sometimes life-threatening, e.g.
pneumonitis and encephalitis.
Immunocompromised individuals at greater risk of developing severe varicella include
patients with lymphoproliferative malignancies (especially T-cell dysplasias), individuals
who have received either a BMT or solid organ transplant within the previous 12 months,
HIV-positive individuals with a significantly reduced CD4 cell count (<200 CD4
cells/mm3) and those receiving high doses of corticosteroids or cytotoxic chemotherapy.
Immunocompromised individuals who may be at lower risk of severe varicella include
those receiving short-term corticosteroid therapy, patients receiving long-term aspirin
therapy and those with chronic cutaneous, cardiac or pulmonary disease.
The potential severity of varicella and its attendant complications in the
immunocompromised patient emphasize the need for effective prevention and treatment
of disease, particularly in these populations. This chapter considers post-exposure
prophylaxis and treatment of varicella in this vulnerable patient group. Vaccination of
immunocompromised individuals is reviewed in Chapter 3.78
HIV-infected children who develop varicella are at increased risk of developing herpes
zoster soon after the initial varicella infection. These patients may also develop recurrent
disease – defined as new episodes of disseminated skin lesions in the absence of exposure
occurring at least 1 month after a previous attack.1 Such patients have modest decreases
in CD4 cell count, whereas low CD4 cell counts are associated with progressive varicella,
in which lesions continue to appear for at least 1 month.1
While many cases of herpes zoster in individuals with HIV/AIDS are similar to disease in
the otherwise healthy host, unusual presentations of herpes zoster may occur. Infections in
the immunocompromised host may have atypical features – large rash area, long-term
persistence, or recurrent outbreaks.2 Pain in these individuals may also be complicated by
AIDS neuropathy. Furthermore, the growing use of chemotherapy may result in an increase
in the reactivation of VZV, which is more likely to be severe or complicated than in the
otherwise healthy individual if untreated. The widespread use of potent antiretroviral
therapy has prevented the incidence of herpes zoster in individuals with HIV increasing
compared with that in the general population.
Other immunocompromised populations at greater risk of herpes zoster include those
receiving immunosuppressant medication, steroids or chemotherapy (transplant recipients,
patients with malignancies and patients with immune-mediated diseases such as
rheumatoid arthritis and systemic lupus erythematosus [SLE]). These groups of patients are
most likely to benefit from antiviral treatment.
Epidemiology of VZV Infections in the Immunocompromised VaricellaHIV-infected individualsThe prevalence and clinical presentation of varicella in children with HIV infection in
developed countries is similar to that in immunocompetent individuals, with respect to
likelihood of infection and proportion of severe cases and complications.3 In the European
Collaborative Study, approximately 130 HIV-infected children and 750 uninfected
children born to HIV-positive mothers were followed. There were no reports of severe
varicella in any of the children who were infected during the study period.4,5 However, in
children with AIDS, the proportion of severe cases and complications is greater.2
Since 95% of adults in developed countries are VZV-seropositive, most HIV-positive adults
will already have had varicella earlier in life. However, for those who are VZV-seronegative
and HIV-positive, the consequences of a primary VZV infection in adulthood are likely to
be serious. This situation could occur more frequently in rural areas of tropical countries,
which may have a larger susceptible adult population. However, there is a lack of data on
the prevalence of varicella in HIV-infected adults in those parts of the world.
Prevalence of infection in BMT recipientsBMT recipients have been reported as being at high risk of developing varicella
irrespective of the VZV serostatus of either the recipient or the donor.6-8 The prevention of
varicella in this population is discussed later in this chapter.
Herpes zoster Herpes zoster is more common in immunocompromised than in immunocompetent
individuals. Studies of HIV-positive individuals conducted in the late 1980s and early
79
1990s document that the incidence of herpes zoster varied from 2900–5100 per 100 000
patient-years.9-12 This compares with 130–480 new cases per 100 000 people per year in
the overall UK and USA populations.13-15 Thus the incidence is 15–25 times greater than
the rate in the general population and 3–7 times greater than that in the elderly.9 The
cumulative incidence of herpes zoster in HIV-infected individuals is estimated to be
30–40% over approximately 10 years of follow-up.9 Patients who present with herpes
zoster in areas of high HIV prevalence may have underlying HIV infection; therefore,
zoster may suggest HIV infection in susceptible individuals.16,17
Patients with malignancies are also an important population at increased risk of herpes zoster.
The strongest evidence of this comes from a study conducted from 1972–1980 in a cancer
care centre in Ontario, Canada. Patients were followed up for a minimum of
5 years.18 There were over 7000 new cancer cases per year, from which 811 cases of herpes
zoster were identified in 785 individuals with a median age of 57 years. The cumulative
incidence rate in this population 5 years after diagnosis was 625 per 100 000 patient-years,
some five times higher than in the general population. The study also found that risk for herpes
zoster is greater for patients with haematological malignancies than for those with solid
tumours, and is greatest for Hodgkin’s disease compared with all other malignancies.19,20
Bone marrow and solid organ transplant recipients are likely to be at increased risk of
herpes zoster but data on its incidence often come from small studies or retrospective
reviews. Despite this, it appears that BMT recipients are particularly at risk, with the
cumulative frequency of herpes zoster reported to range from 13% to 50% in the
28 months after BMT.8 The majority of cases occur within 12 months of transplantation,
with the highest incidence between 3 and 6 months after transplantation.21 Two
randomized, controlled studies have compared 6 months of aciclovir prophylaxis with
placebo.22,23 Aciclovir was effective in reducing the risk of herpes zoster in both studies
during the 6-month treatment period, but there were no differences between the groups
12 months post-transplant. This suggests that a long duration of antiviral prophylaxis is
needed to prevent herpes zoster in these patients.
The data on solid organ transplants are limited to surveys conducted in the 1960s and
1970s, in which different immunosuppressive regimens were employed. These studies
report that the frequency of herpes zoster was 7–14% in renal transplant recipients within
2–5 years of transplantation, and 22% after 6 years of follow-up in cardiac transplant
patients.9 Valaciclovir has not been studied for VZV prophylaxis, but when valaciclovir was
given for cytomegalovirus (CMV) prophylaxis in renal transplant recipients,24 no cases of
VZV were reported in the treatment arm.
Presentation and Complications of VZV Infections in theImmunocompromisedVaricellaThe reduced cellular immunity observed in the immunocompromised host results in
enhanced susceptibility to severe varicella and its associated complications compared
with immunocompetent individuals. Those more likely to be at high risk of developing
varicella and associated complications include:
• Individuals with AIDS
• Patients with malignancies
• BMT recipients80
• Solid organ transplant recipients
• Patients receiving high-dose corticosteroids
• Children with leukaemia.
Pneumonitis is the major complication of varicella among immunocompromised hosts
and is associated with appreciable mortality. The risk of it developing is inversely related
to lymphocyte count, and children with leukaemia appear to be particularly susceptible.25
Among these patients, varicella pneumonitis has an incidence of 32% and a mortality rate
of 31% in the absence of treatment.25
HIV-infected individualsThere are no published population-based studies, but a few case studies of varicella in
HIV-infected children have been reported.26-30 Complications and severity of varicella are
probably related to CD4 cell count; varicella-associated pneumonia and bacterial skin
infections are more severe in children with reduced CD4 cell counts (<200 CD4
lymphocytes per mm3 at presentation).27,28 In a study involving nine HIV-infected children,
aged between 9 months and 8 years, eight of the patients developed visceral dissemination
involving the lungs, two had liver involvement and one patient had brain and pancreas
involvement in addition to lungs and liver.27 During the initial episode of herpes zoster
infection, five were treated with intravenous aciclovir, three with oral aciclovir and one
patient did not receive aciclovir. Four of the nine patients developed secondary bacterial
infections, four developed chronic or recurrent varicella and one patient died following
progressive pneumonia. Despite this patient having received intravenous aciclovir, autopsy
findings also showed disseminated varicella zoster infection involving lung, liver, brain
and pancreas.27
When varicella occurs in HIV-infected adults and those with AIDS, it can result in
significant morbidity, including encephalitis and hepatitis.31 In a study of five HIV-positive
men who contracted varicella, two had complications characterized by severe headache
and meningismus, and one of these patients also exhibited hepatitis and
thrombocytopenia.31 All five responded to aciclovir therapy.
Although uncommon, the potentially serious nature of varicella and associated
complications in immunocompromised patients demonstrates the importance of
effectively treating those cases that do occur.
Herpes zoster Immunocompromised patients (e.g. BMT recipients) have an increased probability of
cutaneous and visceral dissemination of VZV compared with immunocompetent
individuals.32 Commonly reported complications in the immunocompromised include
VZV pneumonia, encephalitis, and hepatitis. The increased risk of complications in this
group is illustrated by observations of untreated herpes zoster. A study in 76 adults with
herpes zoster who had either lymphoma, a lymphoproliferative malignancy, or who had
undergone BMT or solid organ transplant, demonstrated that cutaneous dissemination
occurred in 32%, visceral dissemination in 9.5%, and two of these individuals died.33,34
In most instances, the clinical features of herpes zoster in HIV-positive individuals are
similar to those seen in the immunocompetent. However, a unique feature of herpes zoster
in those who are HIV-positive is the higher frequency of recurrence.10 In studies, 20–30%
81
of HIV-infected patients developed one or more subsequent episodes of herpes zoster,
which may have involved the same or different dermatomes.10,12 It is not clear whether these
patients were receiving aciclovir therapy. The probability of a recurrence within 1 year of
the index case is estimated to be 12% in these patients;35 this compares with a rate of second
recurrences in immunocompetent individuals of less than 5%.1 However, recent data from
an analysis of 1071 elderly subjects in the UK suggest a higher figure, of around 14%.36
Although studies have shown a variety of delayed-onset neurological complications,37
visceral dissemination of VZV as reported in other immunocompromised populations is
uncommon in HIV-infected individuals.
Evidence from some studies which show an apparent link between immunosuppression
and a higher incidence of post-herpetic neuralgia (PHN) is insubstantial. Immuno-
compromised and immunosuppressed individuals may be more at risk from other
complications (i.e. dissemination) than immunocompetent individuals.
Atypical generalized zosterAn unusual presentation of herpes zoster in the immunocompromised host is atypical
generalized zoster. Sufferers present with diffuse varicella-like skin lesions with limited
primary dermatomal involvement.38 Patients presenting with this are VZV seropositive
prior to rash development,38 thus the syndrome is due to reactivation of VZV, not primary
varicella. Herpes zoster begins with a limited area of involvement in the primary
dermatome, quickly followed by generalized cutaneous dissemination. Risk factors for
development of atypical generalized zoster appear to be the same as those for classic
herpes zoster, i.e. increasing age and reduced cell-mediated immunity.
Abdominal herpes zosterJ Clinicians should be aware that in some immunocompromised individuals, herpes zoster
might initially present as unexplained abdominal pain (category 3 recommendation).
A serious manifestation of herpes zoster in the immunocompromised individual is
abdominal herpes zoster. Patients present with severe, unexplained abdominal pain that
may precede the appearance of the cutaneous rash by hours or days.39,40 The diagnosis of
herpes zoster is usually not considered until the typical skin vesicles begin to appear,
usually in a thoracic dermatome. Abdominal herpes zoster is associated with a high
mortality rate, even when appropriate antiviral therapy is administered.
Autopsy studies have revealed a high frequency of abdominal visceral involvement in
patients with abdominal herpes zoster. Polymerase chain reaction (PCR) detection of VZV
in peripheral blood mononuclear cells and whole blood has been used in a few cases to
make the diagnosis of visceral VZV before the appearance of the rash.40
Chronic VZV encephalitisChronic VZV encephalitis is seen almost exclusively in patients with conditions involving
depressed cellular immune responses. In one study, two of 47 BMT patients with herpes
zoster developed encephalitis.41 Encephalitis may occur months after an episode of herpes
zoster, making a diagnosis problematic.42 The clinical presentation comprises headache,
fever, altered mental status, seizures, and focal neurological defects (including aphasia,
hemiplegia, and reduced visual field).43-45
82
Pathology studies reveal multifocal lesions in the white matter of the brain, near the grey-
white junction, with small-vessel vasculitis and nerve demyelination being observed.46,47
Magnetic resonance imaging (MRI) studies demonstrate plaque-like lesions in the white
matter, consistent with demyelination, and late development of ischaemic or
haemorrhagic infarcts of cortical and subcortical grey and white matter (Figure 1).48,49
Examination of CSF reveals mild mononuclear pleocytosis. VZV DNA has been amplified
from the CSF of encephalitis patients by PCR.50,51
The clinical course of chronic VZV encephalitis is
often deterioration and death in up to half of cases,41
although anecdotal reports have suggested benefit
from therapy with high-dose intravenous aciclovir.
Atypical cutaneous lesions J It is recommended that VZV isolates obtained
from hyperkeratotic papules and ecthymatous
lesions from HIV-positive individuals be
submitted for antiviral susceptibility testing
(category 3 recommendation).
VZV can cause a variety of atypical cutaneous lesions
in individuals with HIV infection and low CD4 cell
counts. One example is multiple hyperkeratotic
papules, measuring 3–20 mm in diameter, which follow no dermatomal pattern (Figure
2).52,53 These lesions may be chronic, persisting for months or years, and are sometimes
associated with aciclovir-resistant strains of VZV.54 A second type of dermatological
manifestation observed in HIV-positive individuals is ecthymatous VZV lesions (Figure 3).
Patients present with multiple, large (10–30 mm), punched-out ulcerations with a central
black eschar and a peripheral rim of vesicles.55,56
These atypical cutaneous lesions may be caused by antiviral-resistant
strains of VZV, and, thus, isolates obtained from these papules or lesions
should routinely be submitted for antiviral susceptibility testing.
Pre-Exposure Vaccination in the Immunocompromised J It is recommended that the use of prophylactic varicella
vaccination be considered in selected groups of
immunocompromised persons, such as those with leukaemia that
is in remission or who are undergoing haematopoietic stem cell
transplantation. However, varicella vaccine is not recommended
in these patients for post-exposure prophylaxis because of the risk
of vaccine-induced varicella (category 2 recommendation).
Clinical trials of the varicella vaccine were initially performed in
immunocompromised children because of the likely positive risk:benefit ratio. The vaccine
had been shown to be safe in trials in Japanese children and it was recognized that
protection against varicella would be of significant benefit to immunocompromised
children.57 A number of trials have documented seroconversion and protection following
varicella vaccination.22-2983
FIGURE 2:Hyperkeratotic papules of VZV lesions in anHIV-positive individual
FIGURE 1: MRI of thebrain or an HIV-positiveindividual with VZVencephalitis. Multifocalareas of infarction areshown: the long solidarrow shows a superficialwedge-shaped lesion.Open arrows indicatedeep ovoid lesions in thewhite matter. Short solidarrows show smallerlesions at junctions ofgrey and white matter
© 2
002.
Rep
rodu
ced
with
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, Gild
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H, K
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Med
2000
;342
(9):6
35-6
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Rep
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ced
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or Jo
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.
Leukaemic childrenVaricella vaccination has been shown to be safe and effective in selected groups of
immunocompromised children (including those with acute leukaemia, lymphoma and
malignancies). In studies conducted in Japan
between 1975 and 1983, a total of 330 children
with leukaemia were vaccinated with one dose of
vaccine.58-61 Two hundred and fifty-one children
were vaccinated during temporary suspension of
chemotherapy (i.e. for 1 week before and after
vaccination). Of these children, 18% had a mild,
varicella-associated rash and seroconversion
occurred in 91%. Of the remaining 79 children who
were immunized without suspension of
chemotherapy, 47% had a rash and seroconversion
occurred in 96%. Similar trials in Europe produced
comparable results.62-65 The vaccine-associated rash
observed in these trials is likely due to these patients’ reduced cell-mediated immunity.
A large study of vaccination of leukaemic children has been conducted in the USA and
Canada.66 Five hundred and seventy-five children with leukaemia were vaccinated (Figure 4).
Most received the VZVoka vaccine produced by Merck & Co Inc, although a few received
SmithKline Beecham’s (now GlaxoSmithKline) VZVoka-RIT vaccine. Chemotherapy was
suspended for 1 week before and 1 week after vaccination in 511 of the children; a further
64 had already completed therapy at the time of vaccination. To be eligible for the study,
the children had to be in remission for at least 1 year and have an absolute lymphocyte
count of at least 700 cells/mm3. Initially, vaccinees received a single dose of vaccine, but
18% of them failed to seroconvert. The schedule was subsequently changed to give two
doses of vaccine, 3 months apart, with chemotherapy suspended only for the first dose.
Following two doses, the seroconversion rate was 95%. Vaccine-associated rash occurred
2–6 weeks after vaccination; the incidence of this was lower in those no longer receiving
chemotherapy (5%) than in children whose chemotherapy had been suspended (50%).
Only 10% of vaccinees developed rash after the second dose. Although the frequency of
the rash was high, it was much less severe than natural varicella.67 To minimize the severity
of the rash, vaccinees with 50 lesions or more were offered high-dose oral aciclovir
(800 mg five times daily). The rate and severity of vaccine-associated rash were higher in the
US studies than in the Japanese. This may be attributable to the more immunosuppressive
chemotherapy regimens used for leukaemia treatment in the USA and Canada.66 A similar
explanation may account for the need for two vaccine doses in the US and Canadian study.
In addition to documenting seroconversion, the study also provided evidence for vaccine
efficacy. Of 123 leukaemic vaccinees who had a household exposure to varicella, 86%
were completely protected and 14% had mild (median 100 lesions) breakthrough disease.
Over an 11-year follow-up period, 87% of vaccinated individuals remained seropositive
and there was no evidence that the incidence or severity of breakthrough varicella
increased with time.68
84
FIGURE 3:Echthymatous VZVlesions in an HIV-positiveindividual54
© R
epro
duce
d w
ith p
erm
issi
on, J
acob
son
MA
, Ber
ger T
G, F
ikrig
Set
al.A
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resi
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icel
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oste
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rus
infe
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ter
chro
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the
acqu
ired
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unod
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1990
;112
:187
-191
.Am
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ans.
Children with solid organ transplantsVaccination of children prior to or after solid organ transplantation results in
seroconversion in the majority of individuals. In a small study, 34 children (17 in renal
failure and 17 post-renal transplant) were immunized with one dose of the VZVoka-RIT
vaccine produced by SmithKline Beecham.69 The overall seroconversion rate was 85%, the
rate being equal in both groups. One child
developed a mild, vaccine-associated rash and three
developed mild varicella within 2–4 years. In 68
children with renal or hepatic failure, vaccination
with one dose of the SmithKline Beecham VZVoka-RIT
vaccine resulted in a 50% seroconversion rate and a
second dose gave an 85% seroconversion rate.70
There were no cases of varicella during the 6-year
follow-up period.70
Children with BMTVaccination also results in seroconversion after BMT. Seroconversion was seen in eight of
nine susceptible children immunized 12–23 months after they received a BMT.71
Seroconversion in immunocompromised versus immunocompetent childrenSeroconversion rates in immunocompromised children vaccinated with the varicella
vaccine are similar to the rate observed in immunocompetent children. In a study
conducted in Mexico, 67 immunocompromised and 33 immunocompetent children with
no clinical history of varicella or herpes zoster were vaccinated with live attenuated
varicella vaccine.72 The immunocompromised group comprised children with leukaemia,
solid tumours, chronic renal failure and cirrhosis. Serum IgG antibodies against VZV were
measured by ELISA at baseline, 3-months post-vaccination and 6-months post-
vaccination. Thirty-six (53.7%) of the immunocompromised and 22 (66%) of the
immunocompetent children had positive VZV-ELISA
results at baseline. Among VZV-seronegative
children, seroconversion at 6-months post-
vaccination was demonstrated in 90.3% of the
immunocompromised and 100% of the
immunocompetent children (Figure 5). Three of the
immunocompromised children had a mild rash
symptomatic of varicella following vaccination.72
Vaccination in immunocompromised adultsWhile the potential benefit of varicella vaccination
has been demonstrated in selected groups of
immunocompromised children, there is little data on the efficacy and safety of varicella
vaccine in immunocompromised adults.
One randomized study has indicated that the risk of developing zoster is significantly
reduced when inactivated varicella vaccine is administered prior to haematopoietic stem
cell transplantation and for the first 90 days thereafter.73 In this study, patients received the
vaccine 30 days before transplantation, and again at Days 30, 60 and 90 after
transplantation. Zoster subsequently developed in 7 of 53 vaccinated and 19 of 58
unvaccinated patients (13% versus 33%; P=0.001). The mean stimulation index (defined
85
FIGURE 4: Vaccinationof leukaemic children66
Patients
Single dose of vaccine
Vaccine-associated rash
Second dose of vaccine
Vaccine-associated rash
Chemotherapy suspended (n=511)Chemotherapy completed (n=64)
18% did not seroconvert
50% in those whose chemotherapy had been suspended
Seroconversion in 95%
Incidence of rash 10%
5% in those no longer receiving chemotherapy
FIGURE 5: Antibodytitres measured by ELISAat baseline, 3 months and6 months after varicellavaccination in healthy andimmunocompromisedchildren who were VZVseronegative at baseline72
43.5
32.5
2
1.51
0.5
00 3
ELIS
A u
nits
6
HealthyImmunocompromised
Months
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and
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-87.
as the in vitro CD4 T-cell proliferation response to VZV) was significantly higher in patients
who did, rather than did not, receive the vaccine at 90 days, 120 days and 12 months.
Increases in the stimulation index above 1.6 correlated with a reduced risk of zoster.73
Post-Exposure Prophylaxis in the ImmunocompromisedJ Immunocompromised individuals should receive prophylaxis with VZIG as soon as
possible but no later than 4 days following exposure to varicella (category 1
recommendation).
J Post-exposure prophylaxis with varicella vaccine is not suitable for immuno-
compromised individuals because of the risk of vaccine-induced varicella (category 2
recommendation).
J Extended antiviral suppression for VZV infections should be considered in transplant
patients, especially BMT recipients and patients requiring immunosuppression for
GVHD. The recommended regimen is intravenous aciclovir (500 mg/m2 three times a
day) for 1 month followed by oral aciclovir (800 mg four times a day) for a further
6 months (category 2 recommendation).
Transmission of VZV to susceptible individuals is difficult to prevent as those infected are
contagious 24–48 hours prior to clinical signs of disease. Thus, it is necessary to undertake
post-exposure prophylaxis in immunocompromised individuals who are at risk of severe
varicella and have had significant exposure to VZV.
VZIG post-exposure prophylaxis The only product licensed for post-exposure prophylaxis of varicella is VZIG, which
continues to be the mainstay of prophylaxis in immunocompromised individuals. Studies
performed in the 1960s and 1970s proved the efficacy of VZIG in modifying or preventing
VZV infections if administered soon after exposure (within 96 hours).
Although VZIG is widely used as post-exposure prophylaxis against varicella in
immunocompromised individuals, there is no evidence that VZIG is better than natural
immunity in these patients. If administered within 96 hours of exposure, VZIG reduces the
incidence of disease complications, lessens the severity of the disease and increases the
proportion of immunocompromised patients who experience subclinical varicella.74 In
some instances, VZIG appears to prolong the incubation period of varicella with the result
that a proportion of treated children develop varicella up to 28 days after its
administration. VZIG may be given to immunocompromised individuals who do not have
a clear history of varicella and are exposed to VZV, although VZIG has no antiviral effect
when given after the onset of rash.
The usual route of administration is intramuscular injection. In the UK, VZIG
administration is targeted only at those who are VZV-seronegative. Serum immune
globulin may also be administered intravenously (IVIG) to those with bleeding disorders.
Peak and trough VZV titres are comparable after administration of either VZIG or IVIG.75
If an individual receiving VZIG does not develop clinical varicella, subsequent VZV
exposures should also prompt VZIG prophylaxis unless active immunity is documented by
serological testing, as immunity derived from a subclinical infection is not known to be
86
protective. Between 25% and 50% of all immunocompromised VZIG recipients may
remain susceptible to varicella after its administration.74
VZIG has been used successfully as post-exposure prophylaxis in a variety of different
immunocompromised populations
(mostly children), including renal and
liver transplant recipients and those
with leukaemia or solid tumours.74,76,77
In one study, VZIG was administered to
2412 immunocompromised children
(<16 years of age) with a range of
underlying illnesses (including
leukaemia, non-Hodgkin’s lymphoma
and Hodgkin’s disease) within 4 days of
exposure to VZV.74 Varicella subsequently
occurred in 561 children (454 clinical
varicella, 107 subclinical). However, in
these immunocompromised children, VZIG reduced the incidence of pneumonia,
encephalitis and death from varicella 10-fold, and was associated with milder disease and
a higher incidence of subclinical varicella compared with historical controls (Table 1).74,78,79
Immunocompromised individuals should receive post-exposure prophylaxis with VZIG as
soon as possible, but no later than 4 days following exposure to varicella. If varicella develops,
the patient should be treated with intravenous antiviral compounds at least initially.
In settings where VZIG is not available, other modalities of prophylaxis, such as antiviral
compounds, should be considered. Recent studies have suggested that post-exposure
prophylaxis using antiviral compounds may also be of use in immunocompromised
patients, particularly when used in conjunction with VZIG.2,80 Oral aciclovir was a safe
and effective adjunctive adjunct to VZIG for post-exposure prophylaxis following VZV
exposure in 12 children receiving corticosteroid treatment for chronic renal disease.80 In
this small study, eight patients (10 separate VZV exposures) received oral aciclovir
(40 mg/kg/day) in conjunction with VZIG, and four patients (six separate VZV exposures)
received VZIG alone. None of the eight patients who received aciclovir plus VZIG
developed varicella, and one developed humoral immunity to VZV despite absence of
clinical disease. In comparison, one of the patients who received VZIG alone developed
varicella. No adverse reactions were seen with aciclovir prophylaxis. These data suggest
that aciclovir co-administered with VZIG may be more protective than VZIG alone.
Aciclovir prophylaxis BMT recipients are likely to be at high risk of primary (varicella) and recurrent (herpes
zoster) VZV infection irrespective of the VZV serostatus of the patient or donor.6,7 In an
observational study, low-dose aciclovir and ganciclovir were shown to be effective at
delaying VZV infection following allogeneic BMT.
One hundred and fifty-one BMT recipients received low-dose aciclovir or ganciclovir for
prophylaxis against herpes simplex virus (HSV) or CMV disease. Patients who were HSV
seropositive received either oral aciclovir (400 mg three times daily) or intravenous
87
TABLE 1: Varicellafollowing VZIGadministration to exposedimmunocompromisedchildren versus historicalcontrols74,78,79
Disease category VZIG Historic control (no VZIG) n (% of evaluable)* Expected n (%)†
Clinical varicella 1–10 pox 56 (13) 0 (0) 11–50 pox 132 (31) 23 (5) 51–100 pox 59 (13) 41 (9) >100 pox 178 (42) 390 (86)
Unknown 29 (1.2) Subclinical varicella 107 (4.4) 14 (~3)
Total 561 (23) 468
Pneumonitis 13 (2.9)†† 113 (25)††
Encephalitis 2 (0.4)†† 15 (3.3)††
Death 3 (0.6)†† 32 (7)††
*Adapted from Levin et al.74 Total number receiving VZIG = 2412†Data from Feldman et al.78 for pox number and subclinical varicella, and from Ross79 for pneumonitis, encephalitisand death
††Per cent of varicella cases
aciclovir (250 mg three times a day) up to the day of engraftment, followed by oral
aciclovir (200 mg three times a day) for at least 6 months following transplantation. CMV
seropositive patients received intravenous ganciclovir (5 mg/kg three times weekly) from
engraftment to Day 84.8 None of the patients developed VZV infection whilst receiving
either aciclovir or ganciclovir (P<0.0001 compared with historic controls). However,
when antiviral prophylaxis ended, 21 of 121 (17%)
patients developed VZV infection, five of which
occurred within 5 weeks of the end of therapy. The
cumulative incidence of VZV infection was 13% at
12 months, 32% at 24 months and 38% at 28
months following transplantation (Figure 6).8
The investigators concluded that 3–6 months, low-
dose aciclovir or ganciclovir was effective at
delaying VZV infection following BMT, even though
the therapies did not appear to affect the overall
incidence of VZV infection. This delay may allow
the patient time to develop sufficient immunity to
overcome varicella infection after cessation of
prophylaxis, which may reduce the incidence of
associated complications. Therefore, antiviral
suppression of varicella may be warranted in certain
high-risk patients, including those undergoing BMT.
More studies are needed to investigate whether
longer periods of prophylaxis than those analysed in
this study would further reduce or prevent
susceptibility to VZV reactivation.
Prophylaxis with aciclovir has been documented to
prevent herpes zoster in allogeneic BMT recipients in
two placebo-controlled trials. In the first trial,
intravenous aciclovir (250 mg/m2 three times per day)
starting 5 days before transplant and continued for
5 weeks, was followed by oral aciclovir (400 mg
three times daily) for 6 months.81 Herpes zoster
developed in 5 of 22 placebo recipients but there
were no cases in the 20 aciclovir recipients.
In the second study,82 in which aciclovir was given primarily for the prevention of CMV
disease, a variety of regimens were used:
• Intravenous aciclovir (500 mg/m2, three times a day for 1 month) followed by oral
aciclovir (800 mg four times a day for a further 6 months)
• Intravenous aciclovir (500 mg/m2, three times a day) followed by oral placebo
• Low-dose oral aciclovir (200 or 400 mg, four times a day) followed by placebo.
The probability of VZV disease by Day 210 of the trial was lower with the use of
intravenous aciclovir followed by oral aciclovir (3%) than with the other two regimens
(both 9%).82 While these results are encouraging, an earlier, placebo-controlled study did
not document an overall reduction in the incidence of herpes zoster in allogeneic BMT88
FIGURE 6: Cumulativeincidence of VZVinfection (a) following BMT and (b) followingcessation ofaciclovir/ganciclovirprophylaxis8
500.940
0.730
0.520
0.310
0.10Es
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Years following cessation of aciclovir/ganciclovir
121 15 11 017825
Number at risk
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0.520
0.310
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ZV
0 2 3 76541
Years following allogeneic BMT
151 43 27 03121678
Number at risk
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recipients given intravenous aciclovir (5 mg/kg three times daily) for 23 days followed by
oral aciclovir (800 mg four times daily) for 6 months.23 However, the balance of evidence
suggests that aciclovir prophylaxis can prevent herpes zoster in BMT recipients.
Similarly, data from a series of trials of aciclovir for the prevention of CMV infection and
disease in liver transplant recipients suggest that it has the potential to minimize the risk
of herpes zoster. In these trials, intravenous and oral aciclovir prevented VZV infection and
reactivation.8,83,84
One study has advocated treatment of HIV-positive individuals who develop recurrent or
progressive herpes zoster with intravenous aciclovir followed by lifelong oral
prophylaxis.85 However, potent antiretroviral therapy may preserve or restore immune
function so that continual prophylaxis of opportunistic infections, including herpes zoster,
will no longer be necessary.
An alternative approach for the prophylaxis of herpes zoster is varicella vaccination. In 14
VZV-seropositive patients undergoing BMT, the use of a varicella vaccine during the early
post-transplantation period (administered in three doses at 1, 2 and 3 months) boosted
VZV-specific cellular immunity and decreased the severity of herpes zoster.86 A trial of a
modified approach, in which one dose of vaccine is given prior to BMT and three doses
are given after transplantation, is underway.
Despite efforts to prevent varicella in immunocompromised patients, passive prophylaxis
can sometimes fail, and unrecognized exposures to VZV can occur. Consequently, antiviral
treatment after the onset of clinical disease is a key component of the management of
varicella in immunocompromised patients. Antiviral therapy requires continual
reassessment, regardless of how the patient is immunocompromised.
Aciclovir has proven useful and has become the drug of choice in this setting. Early treatment
with it stops VZV viraemia and virus replication in skin, shortens the duration of virus shedding
and new lesion formation, and speeds lesion healing.2,87 The intervention appears to
compensate for the delayed acquisition of virus-specific immunity in patients in whom the
cell-mediated immune responses that are necessary to limit primary VZV infection are altered.
There is a limited window of opportunity for antiviral therapy to affect the outcome of
varicella. In the immunocompetent host, most virus replication has ceased by 72 hours
after rash onset. In immunocompromised patients, however, duration of virus replication
and virus shedding is extended. This limited chance to affect disease outcome means that
aggressive management of disease in these patients is justifiable and necessary. This has
been emphasized by studies investigating the impact of untreated varicella. In a study of
127 children with leukaemia and varicella who were not treated with antivirals, 28% of
the patients developed varicella-associated pneumonia, with a mortality rate of 7%.88
Treatment of VZV Infections in the Immunocompromised Antiviral therapy In immunocompetent individuals, post-exposure administration of antiviral therapy with
aciclovir is effective in reducing the severity of varicella and herpes zoster. Antiviral
therapy suppresses virus replication, and in immunocompetent hosts allows immune
responses to develop. Consequently, protective immunity may develop without the
89
associated severe clinical symptoms. However, in immunocompromised individuals, there
are few specific data available on the efficacy of antiviral post-exposure prophylaxis. In
these patients, immunity to VZV may not develop during administration of aciclovir, and
residual virus infection may still cause severe disease after prophylaxis is stopped. Despite
the lack of data, some physicians believe that aciclovir is effective in immunocompromised
patients and recent studies support this.87 The primary reason to treat herpes zoster in
immunocompromised hosts is to prevent life-threatening visceral dissemination. Alleviation
of acute pain and prevention or amelioration of post-herpetic neuralgia (PHN) are also
desirable therapeutic goals, as they are for immunocompetent patients.
J Intravenous aciclovir therapy is the standard of care for immunocompromised patients
with disseminated VZV disease, including those with complications such as varicella
pneumonia (category 1 recommendation).
Intravenous aciclovir treatment in the immunocompromisedVaricellaIntravenous aciclovir (10 mg/kg for adults and 500 mg/m2 or 20 mg/kg for children every
8 hours) remains the standard of care for the treatment of varicella in the immunocompromised,
including those within 9–12 months of BMT. Such therapy prevents virus dissemination,
reduces visceral complications,89 and in severe cases of varicella, reduces the duration of
prolonged attacks.27,13 Early treatment (within 24 hours of rash onset) with intravenous
aciclovir (500 mg/m2 every 8 hours for 5–7 days) significantly lowers the probability of
pneumonitis and death in immunocompromised children with varicella.25,88 In a very small
study of 20 paediatric cancer patients with varicella,25 a higher number of placebo recipients
(five of 11) developed pneumonia compared with the aciclovir recipients (none of seven).25
Intravenous aciclovir should be administered to transplant recipients and HIV-positive
individuals with low CD4 cell counts with varicella whether or not it is initiated within
24 hours of rash onset.
Early treatment is important to limit the chance of visceral dissemination; patients with
evidence of visceral dissemination before starting aciclovir therapy have a poorer
prognosis than those with none.90
Herpes zosterIntravenous aciclovir is used consistently for the highest-risk patients with localized or
disseminated herpes zoster, based on evidence from one placebo-controlled trial33 and
three comparative studies with vidarabine.91-93
In the placebo-controlled study, immunocompromised patients (those with
lymphoproliferative or other cancers, BMT or renal transplant recipients, or those with
primary immune deficiency) were enrolled into the trial up to 45 days after the onset of
localized herpes zoster provided they had new vesicles forming.33 Patients in the aciclovir
arm received a 7-day intravenous course of aciclovir (1500 mg/m2/day). There was no
significant effect of aciclovir on rash healing or on the resolution of acute pain, and this
was still the case when the analysis was confined to those patients randomized within
72 hours of rash onset, although it should be noted that the number of patients in this
subset was small. However, aciclovir did prevent further potentially life-threatening
cutaneous and visceral dissemination.33
90
In a study of aciclovir (10 mg/kg at 8-hour intervals for 7 days) and vidarabine (continuous
12-hour infusion of 10 mg/kg/day for 7 days) in 73 cancer patients with disseminated
herpes zoster, there were no differences between the treatment groups in rates of
cutaneous healing, resolution of acute neuritis or frequency of PHN,94 although aciclovir-
treated patients were discharged from hospital earlier. These data suggest that both
intravenous aciclovir and intravenous vidarabine are effective for treatment of
disseminated herpes zoster in immunocompromised individuals.
In the comparative studies of aciclovir and vidarabine,91-93 there was no discernible
advantage of vidarabine; in one trial, aciclovir was more effective. Moreover, aciclovir was
associated with fewer side-effects and was easier to administer.93 Consequently,
intravenous aciclovir remains the standard therapy for the treatment of recurrent VZV
infection in the immunocompromised host. There are no controlled trials in the peer-
reviewed literature comparing intravenous aciclovir with oral aciclovir, famciclovir or
valaciclovir for the treatment of herpes zoster in the immunocompromised host.
The place of oral antiviralsJ Studies are recommended comparing valaciclovir and famciclovir with intravenous
aciclovir for the management of immunocompromised individuals with VZV infections
(research need recommendation).
J There is a need to define the patients for whom oral antiviral therapy might be used in
place of intravenous therapy (research need recommendation).
Oral antiviral therapy in varicellaJ Anecdotal evidence suggests that oral antiviral therapy may be appropriate for the
treatment of varicella in some immunocompromised individuals. In this setting, the newer
antivirals, valaciclovir (1000 mg three times daily for adults) and famciclovir (500 mg three
times daily for adults), are likely to be at least as effective as aciclovir (800 mg four times
daily). The minimum duration of therapy should be 7 days (category 3 recommendation).
Although standard management of immunocompromised patients with varicella involves
intravenous aciclovir, this approach is expensive, has a negative effect on patient quality
of life, and is inconvenient to the recipient and their family.95 There is also a risk of
intravenous catheter-related complications such as phlebitis and secondary infection.
Consequently, the role of oral antiviral therapies for the treatment of varicella in less
immunocompromised individuals has gained interest.
To date, there have been no controlled trials in the peer-reviewed literature of oral
aciclovir, valaciclovir or famciclovir for the treatment of varicella in the
immunocompromised host. There are, however, anecdotal reports and small studies that
suggest such therapy may be adequate in some patients.16
In such circumstances, the newer oral antiviral therapies – valaciclovir and famciclovir –
are likely to be as effective as or more effective than oral aciclovir. Indeed, oral valaciclovir
(1000 mg three times a day) provides comparable systemic exposure, but reduced peak
aciclovir concentrations, compared with intravenous aciclovir (5 mg/kg three times a day)
in immunocompromised cancer patients, without adverse effects.96 In fact, Cohen et al1
recommended that these newer oral antiviral compounds should be considered alongside
91
oral aciclovir for treatment of varicella in some immunocompromised individuals. Oral
valaciclovir, famciclovir or aciclovir for 7 days was recommended for those taking
continuous or intermittent high-dose corticosteroids and those taking low-dose daily
cytotoxic chemotherapy.1 However, there are no paediatric formulations of valaciclovir
and famciclovir currently available.
Sequential intravenous–oral antiviral therapyConsidering the potential benefit of oral antiviral therapy in immunocompromised patients,
an approach using sequential intravenous–oral antiviral therapy may also prove effective.
A study was conducted in 26 immunocompromised children to assess the efficacy of
sequential intravenous and oral aciclovir.95 Intravenous aciclovir treatment was initiated at
1500 mg/m2/day in three equal doses. Concurrent management included reducing
immunosuppressive therapies (mercaptopurine, methotrexate, corticosteroids, cyclosporin)
by 50%, or stopping administration of these therapies. Sixteen of the patients had a
documented exposure to VZV. Eleven of these 16 (69%) received VZIG in addition to
intravenous aciclovir. Patients receiving 48 hours of intravenous therapy were deemed eligible
to switch to oral aciclovir (20 mg/kg four times daily) if they were afebrile, had no new lesion
formation within the previous 24 hours, had no internal organ involvement, and were able
to tolerate oral medication. Upon switching to oral aciclovir, patients were observed in
hospital for a further 24 hours; if their condition did not deteriorate, they were discharged.
Twenty five of the 26 patients successfully switched from intravenous to oral therapy after
4 days (exact 4.1±1.2 [mean±SD] days). Varicella resolved in all 25 children who switched
to oral aciclovir, and none of the patients required resumption of intravenous therapy.95
Considering that sequential intravenous–oral antiviral therapy for immunocompromised children
with severe varicella may decrease the duration of hospitalization and hence reduce the
associated inconvenience and high cost, this multi-modal therapy merits further investigation.
Oral antiviral therapy for herpes zosterJ For some immunocompromised individuals, oral antiviral therapy may be appropriate for
the treatment of herpes zoster – in this setting, the newer antivirals, valaciclovir (1000 mg
three times daily for adults) and famciclovir (500 mg three times daily for adults), are
likely to be at least as effective as aciclovir (800 mg five times daily) (category 3
recommendation).
J Studies are recommended comparing valaciclovir and famciclovir with intravenous
aciclovir in the management of immunocompromised individuals with herpes zoster
(research need recommendation).
The disadvantages of intravenous therapy (e.g. cost, risk of infection) have driven the
search for effective alternatives. Evidence is now emerging that some HIV-infected patients
(with normal CD4 cell counts) and other immunocompromised patients with herpes zoster
respond well to oral antiviral therapy.87,97 Patients who may be eligible for oral antiviral
therapy include HIV-infected individuals and those receiving:
• High-dose corticosteroids (intermittent or continuous)
• Low-dose cytotoxic chemotherapy (daily cyclophosphamide, methotrexate, 6-MP and
azathioprine).92
A double-blind study compared famciclovir (500 mg three times daily) with oral aciclovir
(800 mg five times daily) for 10 days for treatment of localized dermatomal herpes zoster in
immunocompromised patients.87 Patients were randomized following BMT, solid organ
transplantation, or cancer chemotherapy. Famciclovir and aciclovir were equivalent with
respect to the proportion of patients experiencing new lesion formation whilst receiving
treatment (77% versus 73% for famciclovir and aciclovir groups, respectively). In addition,
there were no significant differences
observed between the treatment groups
with respect to time to cessation of new
lesion formation, time to full crusting
and time to loss of acute pain (Table 2).87
Both oral antiviral therapies appeared to
reduce the risk of cutaneous or visceral
dissemination of herpes zoster. The
number of patients developing
disseminated zoster was low in both
treatment groups (famciclovir 3% [two
patients] aciclovir 8% [six patients]).
These results are similar to historical data
reported for intravenous aciclovir in
immuncompromised patients.33
The two oral agents were well tolerated.
This safety profile, combined with the
efficacy results, suggests that oral antiviral therapy offers a convenient alternative to
intravenous therapy. Valaciclovir (1000 mg three times daily) will probably be at least as
effective as aciclovir in this patient group. In neutropenic patients, valaciclovir (1000 mg
8-hourly) produced systemic aciclovir exposure comparable with that produced by
5 mg/kg aciclovir administered by 1-hour intravenous infusion every 8 hours (Figure 7).96
The efficacy of valaciclovir in this and other immunocompromised patient groups should
be established in clinical trials.
In a study of sorivudine (40 mg daily for 10 days)
versus aciclovir (800 mg five times daily for 10 days) in
170 HIV-positive patients presenting with herpes
zoster, sorivudine was effective and well tolerated.97 In
this study, the median CD4 cell count was 171
cells/mm3; 34% of the population had a CD4 cell
count of <100 cells/mm3 and 45% had CD4 cell
counts of >200 cells/mm3. Sorivudine was significantly
superior to aciclovir for several parameters, including
time to cessation of new vesicle formation and time to
total lesion crusting. Both aciclovir and sorivudine
were well tolerated and not associated with serious
clinical adverse events, and adverse event profiles
were not different between recipients. However, a
number of fatal adverse reactions have been reported
in Japan associated with the use of sorivudine in
patients already receiving the anticancer drug
5-fluorouracil.
93
Famciclovir Aciclovir500 mg 3 x/day 800 mg 5 x/day
n=71 n=77
Time to full crusting Patients in analysis 71 77 Patients with event 60 60 Median (days) 8 9 Hazard ratio 1.26 95% confidence interval (0.88, 1.82)*
Time to complete healing Patients in analysis 71 77 Patients with event 56 57 Median (days) 20 21 Hazard ratio 0.9895% confidence interval (0.67, 1.42)*
Time to loss of acute phase pain Patients in analysis 64 69 Patients with event 39 36 Median (days) 14 17 Hazard ratio 1.1195% confidence Interval (0.71, 1.75)*
*No significant difference
FIGURE 7: Meansteady-state plasmaaciclovir concentrationsover time followingadministration of oralvalaciclovir (1000 mgthree times daily) orintravenous aciclovir toneutropenic patients(5 mg/kg every 8 hours)96
25
20
15
10
5
00 1 3 4 5 6 7
Aci
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once
ntra
tion
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)
121110982
Time (hours)
35
30
IV aciclovir (5 mg/kg)Oral valaciclovir (1000 mg)
TABLE 2: Lesion healingand resolution of acutepain in immuno-compromised patientsreceiving either oralaciclovir (800 mg fivetimes daily) or famciclovir(500 mg three timesdaily)87
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VZV Ocular Infections in HIV-Infected IndividualsJ Combined intravenous foscarnet (60 mg/kg three times per week) plus intravitreal
ganciclovir (400 mg twice per week) therapy is the best option for rapidly progressive
herpetic retinal necrosis (category 3 recommendation). However, the dose of foscarnet
to be used has not been established in the clinical trial setting, and further dose-
comparative studies should be undertaken.
The reduced level of cell-mediated immunity in herpes zoster patients who are HIV-positive
may lead to a higher level of unchecked virus replication and hence more frequent and serious
complications. VZV infection, and particularly herpes zoster ophthalmicus, is often the first
manifestation of HIV infection. Sellitti et al98 conducted a retrospective review of 112 herpes
zoster ophthalmicus patients to determine the incidence of HIV infection in patients
presenting with the complication. Twenty-nine of the 112 herpes zoster ophthalmicus
patients (26%) were HIV-positive. All 29 patients were younger than 50 years at the time of
herpes zoster ophthalmicus diagnosis. Acute retinal necrosis following herpes zoster
ophthalmicus was observed in five of the 29 immunocompromised patients, and none of
the remaining 83 patients.98 The authors recommended that all patients younger than
50 years presenting with herpes zoster ophthalmicus be tested for HIV serostatus, and that
HIV-infected patients should be monitored for acute retinal necrosis.98
Margolis et al99 reported a retrospective study on the incidence of ocular complications in
48 HIV-positive individuals with herpes zoster ophthalmicus. All patients had received
either oral or intravenous aciclovir. The median CD4 lymphocyte count for the study
population was 48 cells/mm3 (range 2–490 cells/mm3).99 The prevalence of ocular
complications is shown in Table 3. In addition to these complications, two patients (4%)
developed PHN, and two (4%) zoster-associated CNS disease.99 The authors reported that
although the overall level of complications was lower than expected for the study
population, those caused by active virus replication – chronic infectious pseudodendritic
keratitis and CNS disease – were
particularly devastating to the patients
involved and difficult to manage.99 This
highlights the need for effective
treatment to limit the VZV replication in
patients with HIV infection.
Rapidly progressive herpetic retinal necrosisRapidly progressive herpetic retinal necrosis (RPHRN) is a syndrome caused by VZV
infection, and is observed almost exclusively in patients with HIV infection (CD4 cell
count <100/mm3). Presentation is with multifocal necrotizing lesions involving the
peripheral retina. The granular, non-haemorrhagic lesions rapidly extend and coalesce,
and progress to full thickness retinal necrosis (Figure 8). In HIV-positive patients, bilateral
blindness ensues within days or weeks.100-110
For RPHRN in individuals with AIDS, combination therapy with intravenous ganciclovir (5 mg/kg
twice per day) plus systemic foscarnet may improve the outcome, and prevent involvement of
the other eye.101-105 However, visual acuity may still be reduced.101 More encouraging results
were reported in a single case report on the use of cidofovir (5 mg/kg weekly for 2 weeks and
subsequently once every 2 weeks as maintenance dose); the patient’s visual acuity improved and
stabilized (for at least 16 months) following five treatment cycles (10 weeks).106
94
TABLE 3: Prevalenceand nature of ocularcomplications of herpeszoster ophthalmicus inHIV-positive patientsreceiving aciclovir99
Ocular complication Prevalence (%)
Mild or no ocular involvement 31 Stromal keratitis (usually mild) 35 Chronic infectious pseudodendritic keratitis 4 Iritis 50 Raised intraocular pressure 6 Progressive outer retinal necrosis 4
Antiviral-resistant VZV infectionsJ In immunocompromised patients with suspected
aciclovir-resistant VZV infection, treatment with foscarnet
(120–200 mg/kg/day, in two or three divided doses)
should be initiated unless renal failure is evident
(category 2 recommendation).
VZV resistant to aciclovir has been reported as a clinical
problem only in HIV-positive individuals with long-term,
chronic VZV infection.54,107 These individuals frequently
experience persistent or recurrent VZV infections, which may
be atypical in presentation (e.g. ecthymatous VZV
lesions).55,56 The resistant isolates are often cross-resistant to
penciclovir (the prodrug of famciclovir). This occurs as most
drug-resistant isolates have an altered or deleted thymidine
kinase gene. Aciclovir and penciclovir require activation by
virus thymidine kinase prior to inhibiting the virus polymerase. Therefore, alternative drugs
that act to directly inhibit the DNA polymerase, such as foscarnet or cidofovir, are often
effective as second-line treatments.
The efficacy of foscarnet in the setting of aciclovir-resistant VZV was shown in a recent
review of 18 HIV-positive individuals with chronic VZV lesions.108 Thirteen of these
patients received intravenous foscarnet (120–200 mg/kg/day, in two or three divided
doses). Ten patients (77%) experienced initial complete healing of their lesions, although
herpes zoster reoccurred after a mean of 110 days in five.
While foscarnet can be effective, there have been rare instances of foscarnet resistance in
VZV.109 Cidofovir may be a suitable alternative for infections caused by foscarnet and
nucleoside analogue-resistant strains.110
SummaryImmunocompromised individuals who have impaired cell-mediated immunity are at great
risk of developing life-threatening varicella and its associated complications. Consequently,
both post-exposure prophylaxis and aggressive treatment of varicella, if it does occur, are
warranted in this group.
The efficacy and safety of VZIG as prophylaxis for varicella in immunocompromised
populations have been well documented and, as such, remains the mainstay of post-
exposure prophylaxis in this population. Recent studies have indicated that post-exposure
prophylaxis with aciclovir is effective, particularly if used in combination with VZIG, and
it is recommended that this combination is used in immunocompromised patients to
improve the outcome following exposure to varicella.
Long-term oral antiviral therapy for suppression of VZV may be of value in organ transplant
patients, especially BMT recipients and patients requiring immunosuppression for GVHD.
It should be noted that post-exposure prophylaxis with varicella vaccine is not suitable for
the immunocompromised. 95
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When prophylaxis fails or unwitting exposure occurs, aggressive treatment of varicella
with antiviral compounds is necessary and has been well documented. Intravenous
antiviral therapy with aciclovir (10 mg/kg for adults and 500 mg/m2 or 20 mg/kg for
children every 8 hours) remains the standard of care for immunocompromised patients
and those presenting with complications such as varicella-associated pneumonia. In the
profoundly immunocompromised with suspected aciclovir resistance, therapy with
foscarnet (120–200 mg/kg/day, in two or three divided doses) is recommended in the first
instance.
Studies suggest that oral antiviral therapy may be appropriate for the treatment of varicella in
some immunocompromised individuals, which may help alleviate the cost, inconvenience
and negative impact on patients’ quality of life associated with intravenous therapy. As is the
case for varicella in the immunocompetent, valaciclovir (1000 mg three times daily) and
famciclovir (500 mg three times daily) in adults will probably be at least as effective as
aciclovir (800 mg five times daily).
In immunocompromised hosts, the primary reason to treat herpes zoster is to prevent visceral
dissemination, which can be fatal. Alleviation of acute pain and prevention or amelioration
of PHN are also desirable therapeutic goals, as they are for immunocompetent patients.
Dissemination of herpes zoster is more likely to occur in immunocompromised individuals
than in the immunocompetent of the same age. However, despite the greater impact of
herpes zoster, there have been fewer studies conducted in these populations than in
immunocompetent groups.
Prophylactic treatment with intravenous or oral antivirals, potentially administered
sequentially, is recommended in transplant patients to prevent the development of herpes
zoster in the period immediately following transplantation when they are at their most
immunocompromised and, therefore, most at risk of severe herpes zoster and its associated
complications.
Intravenous aciclovir (10 mg/kg every 8 hours) should be considered the standard of care for
immunocompromised patients with herpes zoster. In those with suspected aciclovir
resistance, therapy with foscarnet (120–200 mg/kg/day, in two or three divided doses) should
be initiated, unless renal failure is evident. In rare situations where foscarnet-resistant VZV is
encountered, cidofovir may be a suitable therapeutic alternative.
Preliminary evidence suggests that oral antiviral therapy is appropriate for the treatment of
herpes zoster in some immunocompromised individuals. Famciclovir (500 mg three times
daily for adults) is as effective as aciclovir (800 mg five times daily) in the treatment of herpes
zoster in the immunocompromised. Valaciclovir (1000 mg three times daily for adults) may
well be at least as effective as oral aciclovir and famciclovir but this hypothesis has yet to be
tested in a clinical trial.
References1. Cohen JI, Brunell PA, Straus SE et al. Recent advances in varicella-zoster virus infection. Ann Intern Med
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4. Newell M. Personal communication.5. Conant M, Wood MJ. Management Strategies in Herpes: Herpesvirus and HIV Infection – Co-factors and
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43. Gray F, Mohr M, Rozenberg F. Varicella-zoster virus encephalitis in acquired immunodeficiency syndrome: areport of four cases. Neuropathol Appl Neurobiol 1992;18:502-514.
44. Janssen RS, Saykin AJ, Kaplan JE. Nuerological complications of human immunodeficiency virus infection inpatients with lymphadenopathy syndrome. Ann Neurol 1988;23:49-55.
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46. Kleinschmidt-DeMasters BK, Amlie-Lefond C, Gilden DH. The patterns of varicella zoster virus encephalitis. Hum Pathol 1996;27:927-938.
47. Morgello S, Block GA, Price RW et al. Varicella-zoster virus leukoencephalitis and cerbral vasculopathy. ArchPathol Lab Med 1988;112:173-177.
48. Lentz D, Jordan JE, Pike GB et al. MRI in varicella zoster virus leukoencephalitis in the immunocompromisedhost. J Comput Assist Tomogr 1993;17:313-316.
49. Aygun N, Finelli DA, Rodgers MS et al. Multifocal varicella-zoster virus leukoencephalitis in a patient withAIDS: MR findings. Am J Neuroradiol 1998;19:1897-1899.
50. Gilden DH, Kleinschmidt-DeMasters BK, LaGuardia JJ et al. Neurologic complications of the reactivation ofvaricella-zoster virus. N Engl J Med 2000;342:635-645.
51. Iten A, Chatelard P, Vuadens P et al. Impact of cerebrospinal fluid PCR on the management of HIV-infectedpatients with varicella-zoster virus infection of the central nervous system. J Neurovirol 1999;5:172-180.
52. Tronnier M, Plettenberg A, Meigel WN et al. Recurrent verrucous herpes zoster in an HIV patient.Demonstration of the virus by immunofluorescence and electron microscopy. Eur J Dermatol 1994;4:604-607.
53. Vaughan-Jones SA, McGibbon DH, Bradbeer CS. Chronic verrucous varicella-zoster infection in a patient withAIDS. Clin Exp Dermatol 1994;19:327-329.
54. Jacobson MA, Berger TG, Fikrig S et al. Acyclovir-resistant varicella zoster virus infection after chronic oralacylovir therapy in patients with the acquired immunodeficiency syndrome (AIDS). Ann Intern Med1990;112:187-191.
55. Gilson IH, Barnett JH, Conant M et al. Disseminated ecthymatous herpes varicella zoster virus infection inpatients with acquire immunodeficiency syndrome. J Am Acad Dermatol 1989;20:637-642.
56. Alessi E, Cusini M, Zerboni R. Unusual varicella zoster virus infection in patients with the acquiredimmunodeficiency syndrome. Arch Dermatol 1988;124:1011-1013.
57. Annunziato PW, Gershon AA. Primary immunization against varicella. In: Varicella-Zoster Virus: Virology andClinical Management. (Arvin A, Gershon AA, eds). Cambridge: Cambridge University Press, 2000: 460-476.
58. Takahashi M, Gershon AA. Varicella vaccine. In: Vaccines. 2nd edn. (Plotkin SA, Mortomer EA, eds).Philadelphia PA: WB Saunders, 1994: 387-417.
59. Sato Y, Miyano T, Kawauchi K et al. Use of live varicella vaccine in children with acute leukemia and malignantlymphoma. Biken J 1984;27:111-113.
60. Nunoue T. Clinical observations on varicella-zoster vaccinees treated with immunosuppressants for amalignancy. Biken J 1984;27:115-118.
61. Konno T, Yamaguchi Y, Minegishi M et al. A clinical trial of live attenuated varicella vaccine (Biken) in childrenwith malignant diseases. Biken J 1984;27:73-75.
62. Ninane J, Latinne D, Heremans-Bracke MT et al. Live varicella vaccine in severely immunodepressed children.Postgrad Med J 1985;61:97-102.
63. Haas RJ, Belohradsky B, Dickerhoff R et al. Active immunization against varicella of children with acuteleukaemia or other malignancies on maintenance chemotherapy. Postgrad Med J 1985;61:69-72.
64. Heath RB, Malpas JS. Experience with the live Oka-strain varicella vaccine in children with solid tumours.Postgrad Med J 1985;61:107-111.
65. Heller L, Berglund G, Ahstrom L et al. Early results of a trial of the Oka-strain varicella vaccine in children withleukaemia or other malignancies in Sweden. Postgrad Med J 1985;61:79-83.
66. LaRussa P. Experience with live-attenuated varicella-zoster vaccines. Contrib Microbiol 1999;3:173-192.67. Gershon AA, LaRussa P, Steinberg S. The varicella vaccine. Clinical trials in immunocompromised individuals.
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Pediatr Nephrol 1994;8:190-192.70. Giacchino R, Marcellini M, Timitilli A et al. Varicella vaccine in children requiring renal or hepatic
transplantation. Transplantation 1995;60:1055-1056.71. Sauerbrei A, Prager J, Hengst U et al. Varicella vaccination in children after bone marrow transplantation. Bone
Marrow Transplant 1997;20:381-383.72. Morales-Castillo ME, Alvarex-Munoz MT, Solorzano-Santos F et al. Live varicella vaccine in both
immunocompromised and healthy children. Arch Med Res 2000;31:85-87.73. Hata A, Asanuma H, Rinki M et al. Use of an inactivated varicella vaccine in recipients of hematopoietic-cell
transplants. N Engl J Med 2002;347:26-34.74. Levin MJ, Nelson WL, Preblud SR. Clinical trials with varicella-zoster virus immunoglobulins. London:
Academic Press, 1986.75. Paryani SG, Arvin AM, Koropchak CM et al. Comparison of varicella zoster antibody titers in patients given
intravenous immune serum globulin or varicella zoster immune globulin. J Pediatr 1984;105:200-205.76. Lynfield R, Herrin JT, Rubin RH. Varicella in pediatric renal transplant patients. Pediatrics 1992;90:216-220.77. McGregor RS, Zitelli BJ, Urbach AH. Varicella in pediatric orthotopic liver tranplant recipients. Pediatrics
1989;82:256-261.78. Feldman S, Hughes WT, Daniel CB. Varicella in children with cancer: Seventy-seven cases. Pediatrics 1975;56:
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79. Ross H. Modification of chickenpox in family contacts by administration of gamma globulin. N Engl J Med1962;267:369-376.
80. Goldstein SL, Somers MJ, Lande MB et al. Acyclovir prophylaxis of varicella in children with renal disease receivingsteroids. Pediatr Nephrol 2000;14:305-308.
81. Lundgren G, Wilczek H, Lonnqvist B et al. Acyclovir prophylaxis in bone marrow transplant recipients. Scand JInfect Dis Suppl 1985;47:137-144.
82. Prentice HG, Gluckman E, Powles RL et al. Impact of long-term acyclovir on cytomegalovirus infection and survivalafter allogeneic bone marrow transplantation. European Acyclovir for CMV Prophylaxis Study Group. Lancet1994;343:749-753.
83. Singh N, Yu VL, Mieles L et al. High-dose acyclovir compared with short-course preemptive ganciclovir therapy toprevent cytomegalovirus disease in liver transplant recipients. A randomized trial. Ann Intern Med 1994;120:375-381.
84. Winston DJ, Wirin D, Shaked A et al. Randomised comparison of ganciclovir and high-dose acyclovir for long- termcytomegalovirus prophylaxis in liver-transplant recipients. Lancet 1995;346:69-74.
85. Wood MJ. Antivirals in the context of HIV disease. J Antimicrob Chemother 1996;37 (Suppl B):S97-S112.86. Redman RL, Nader S, Zerboni L et al. Early reconstitution of immunity and decreased severity of herpes zoster in
bone marrow transplant recipients immunized with inactivated varicella vaccine. J Infect Dis 1997;176:578-585.87. Tyring S, Belanger R, Bezwoda W et al. A randomized, double-blind trial of famciclovir versus acyclovir for the
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90. Balfour HH, Jr. Intravenous acyclovir therapy for varicella in immunocompromised children. J Pediatr1984;104:134-136.
91. Shepp DH, Dandliker PS, Meyers JD. Treatment of varicella-zoster virus infection in severely immunocompromisedpatients. A randomized comparison of acyclovir and vidarabine. N Engl J Med 1986;314:208-212.
92. Vilde JL, Bricaire F, Leport C et al. Comparative trial of acyclovir and vidarabine in disseminated varicella-zostervirus infections in immunocompromised patients. J Med Virol 1986;20:127-134.
93. Whitley RJ, Gnann JW, Jr, Hinthorn D et al. Disseminated herpes zoster in the immunocompromised host: acomparative trial of acyclovir and vidarabine. The NIAID Collaborative Antiviral Study Group. J Infect Dis1992;165:450-455.
94. Whitley RJ. Therapeutic approaches to varicella-zoster virus infections. J Infect Dis 1992;166 (Suppl B):S51-S57.95. Carcao MD, Lau RC, Gupta A et al. Sequential use of intravenous and oral acyclovir in the therapy of varicella in
immunocompromised children. Pediatr Infect Dis J 1998;17:626-631.96. Hoglund M, Ljungman P, Weller S. Comparable aciclovir exposures produced by oral valaciclovir and intravenous
aciclovir in immunocompromised cancer patients. J Antimicrob Chemother 2002;47:855-856.97. Gnann JW, Jr., Crumpacker CS, Lalezari JP et al. Sorivudine versus acyclovir for treatment of dermatomal herpes
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98. Sellitti TP, Huang AJ, Schiffman J et al. Association of herpes zoster ophthalmicus with acquired immunodeficiencysyndrome and acute retinal necrosis. Am J Ophthalmol 1993;116:297-301.
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100. Austin RB. Progressive outer retinal necrosis syndrome: a comprehensive review of its clinical presentation,relationship to immune system status, and management. Clin Eye Vis Care 2000;12:119-129.
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103. Yang CM, Wang WW, Lin CP. Progressive outer retinal necrosis syndrome as an early manifestation of humanimmunodeficiency virus. J Formos Med Assoc 1999;98:141-144.
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99
Management RecommendationsFirst-line treatment of established post-herpetic neuralgiaCategory 1J Tricyclic antidepressants, such as amitriptyline or nortriptyline (initiated at 10–25 mg
and increasing weekly by 25 mg [10 mg if patient >65 years or frail]), relieve pain in
some patients. It is recommended that these treatments be initiated at a low dose for
acute herpes zoster-associated pain. If post-herpetic neuralgia (PHN) develops, the
dose should be increased gradually until pain control is achieved or side-effects
become intolerable.
J Gabapentin is recommended as an effective treatment for PHN and can be titrated
from 300–900 mg/day up to 3600 mg/day (provided there is unimpaired renal
function).
J Administration of a topical local anaesthetic (e.g. lidocaine patch 5%) is
recommended.
Category 3J Encouragement, counselling and education on quality-of-life matters should be given
to patients with established PHN, as should cold packs and advice on clothing and
lifestyle.
J Efforts should be made to encourage treatment compliance in patients with established
pain.
J Analgesia using paracetamol with or without a weak opioid is effective and
recommended in established pain, but there is no evidence to support the use of non-
steroidal anti-inflammatory drugs (NSAIDs) in the treatment of PHN.
Second-line treatment of established PHNCategory 1J Topical capsaicin (0.025% or 0.075%) may be effective in some patients and they
should receive advice on its use and side-effects to achieve compliance.
Category 2J Stronger opioids (including oxycodone, morphine and methadone) may be considered
for therapy of PHN, but, as they are usually administered in a pain clinic, cannot be
considered as first-line therapy.
J If a first-line tricyclic antidepressant fails, any of the available non-tricyclics may be
tried, such as venlafaxine or maprotiline. Selective serotonin reuptake inhibitors
(SSRIs) such as fluoxetine, paroxetine or sertraline may also be effective in some
patients.100
MANAGING ESTABLISHED PAIN IN HERPES ZOSTER9
Category 3J Transcutaneous electrical nerve stimulation (TENS) may be effective but evidence to
support this is scarce.
J With persistent pain, topical preparations, tricyclic antidepressants, gabapentin and
opioids may be effective if used in combination. It is recommended that this approach
be based upon the physician’s experience and the condition of the individual patient.
J Additional approaches to consider in established PHN include nerve blocks, and
topical aspirin in ether. Some patients may wish to consider complementary or
alternative medicine, such as homeopathy, faith healing or acupuncture, although
there is no evidence to support these approaches.
J Patients who fail to respond to several different treatment approaches despite
monitored compliance should be referred to a pain management clinic.
Research needsJ Cost-benefit analysis of different treatment modalities and management techniques
utilized in established PHN would be beneficial to assess the clinical impact and cost
of therapeutic alternatives.
J The development of effective pain management programmes for PHN patients,
especially elderly patients, is of utmost importance.
IntroductionJ Cost-benefit analysis of different treatment modalities and management techniques
utilized in established PHN would be beneficial to assess the clinical impact and cost
of therapeutic alternatives (research need recommendation).
J The development of effective pain management programmes for PHN patients,
especially elderly patients, is of utmost importance (research need recommendation).
PHN, the ongoing pain that follows the resolution of herpes zoster, can result in significant
morbidity that interferes with the activities of daily living.1 It can manifest as one or more
of:
• Spontaneous aching or burning or paroxysmal shooting pains
• Allodynia (pain evoked by application of a mild, normally non-noxious, stimulus – this
may be static or dynamic)
• Hyperalgesia (severe pain evoked by application of a normally mildly painful stimulus).
In addition to being severe, PHN is often prolonged. Approximately 22% of patients with
herpes zoster still have spontaneous and/or evoked pain 3 months after rash appearance.2
At 1 year, about 5–10% still have PHN and by this stage further spontaneous resolution is
limited.2 Such is the frequency of herpes zoster that at any one time, the estimated
prevalence of PHN in the UK is 200 000 cases.2 Thus, many patients will suffer moderate-
to-severe pain which can last for many years and in some cases for life.
Aciclovir and, by inference, other antivirals cannot treat established PHN.3,4 The ongoing
discomfort and distress caused to patients by established PHN highlight the need for
effective treatment and management. Work published on tricyclic antidepressants,
101
opioids,5,6 anticonvulsants including gabapentin,7 topical lidocaine,8 and topical
capsaicin6 documents their varying degrees of effectiveness for established PHN. With the
increasing number of therapy options available, successful PHN treatment is likely to be
be multimodal.
First-Line Treatment of Established PHNPhysical measuresJ Encouragement, counselling and education on quality-of-life matters should be given
to patients with established PHN, as should cold packs and advice on clothing and
lifestyle (category 3 recommendation).
J Efforts should be made to encourage treatment compliance in patients with established
pain (category 3 recommendation).
Patients with established PHN should receive encouragement, counselling and education
on quality-of-life matters. When discussing treatments for PHN, the importance of
compliance should be emphasized.
Physical measures can offer benefit to the patient with PHN.9 Cold packs can give
temporary relief of symptoms in patients who do not have cold allodynia. They must be
applied frequently and with a layer such as a cotton towel between the pack and the skin.
A protective layer, such as plastic ‘artificial skin’ sprays between the skin and clothing may
reduce tactile allodynia from the rubbing of clothes.
Analgesic therapy for established PHNJ Analgesia using paracetamol, with or without a weak opioid, is effective and
recommended in established pain, but there is no evidence to support the use of
NSAIDs in PHN (category 3 recommendation).
Paracetamol is well tolerated and is a suitable first-line analgesic in PHN.10 When pain
relief is insufficient with paracetamol alone, codeine may be added as their combination
produces a significant increase in analgesia.11
Although it has been argued for a number of years that neuropathic pain is unresponsive
to opiates, non-blinded studies suggest that patients with PHN may obtain significant pain
relief from opioid analgesics, leading to the wider use of these agents in the treatment of
PHN.5,12,13 The higher potency opioid analgesics (e.g. morphine) are probably best
administered in a multidisciplinary pain clinic, as monitoring and dose titration against
pain relief are essential. If opioids do not provide significant analgesia, they should be
discontinued to prevent dependence.
Oxycodone may provide significant relief from PHN. A cross-over trial compared
controlled-release oxycodone with placebo in 50 patients with PHN of at least moderate
intensity for an average of 31 months. The initial dose of oxycodone was 10 mg every
12 hours increasing to a maximum of 30 mg every 12 hours over 4 weeks. The average
dose in the last week was 45 mg per day. Patients treated with oxycodone exhibited
significantly greater pain relief (P<0.0001), and reduction of allodynia (P=0.0004)
compared with those receiving placebo.6 This study provides justification for opioid
administration in patients with established PHN. However, the side-effects of opioids,102
which include respiratory depression, constipation, sedation, nausea and vomiting, may
be problematic. A further side-effect of concern is delirium which may be a barrier to the
use of this class of drug.
Another analgesic, tramadol, a weak opioid m-receptor agonist and monoamine re-uptake
inhibitor, has shown potential in the treatment of established PHN. In a pilot study, nine
out of 10 patients reported tramadol as providing pain relief described as satisfactory or
very satisfactory.14,15 However, tramadol should not be co-administered with
antidepressants because of the risk of serotonin syndrome.
Tricyclic antidepressants in PHNJ Tricyclic antidepressants, such as amitriptyline or nortriptyline (initiated at 10–25 mg
and increasing weekly by 25 mg [10 mg if patient >65 years or frail]), relieve pain in
some patients. The dose should be increased gradually until pain control is achieved
or side-effects become intolerable (category 1 recommendation).
The place of tricyclic antidepressants in
the first-line treatment of PHN has been
established in a number of clinical
trials.16-22 These demonstrate an
analgesic effect on chronic neuropathic
pain that is independent of their
antidepressant action (Table 1), and an
effect on sodium channels in primary
afferent fibres. In reviews of treatments
for PHN, Volmink et al23 and McQuay
et al24 concluded that both amitriptyline
and desipramine are effective at relieving pain in PHN.13,23-25 The starting dose of
amitriptyline should be 25 mg (10 mg in frail patients) as a single night-time dose.26 The
dose should be increased by 25 mg at weekly intervals until either it achieves pain relief or
adverse effects become problematic. The maximum dose is 150 mg. Patients should be
warned to expect a dry mouth and drowsiness.
Although amitriptyline has become the most widely used antidepressant for the treatment
of PHN, it is associated with a large number of adverse effects, especially in the elderly
(e.g. anticholinergic side-effects and orthostatic hypotension).13,27 To address this, Watson
and colleagues22 performed a double-blind crossover trial comparing amitriptyline with
nortriptyline in 31 patients with PHN. There were no differences between the two
antidepressants with regard to relief of skin pain, mood, disability, satisfaction, or
preference between the two drugs. However, intolerable side-effects were more common
with amitriptyline. Thus, nortriptyline is a suitable alternative, especially for those who
may experience side-effects with the latter.
Anticonvulsants in PHNJ Gabapentin is recommended as an effective treatment for PHN and can be titrated
from 300–900 mg/day up to 3600 mg/day (provided there is unimpaired renal
function) (category 1 recommendation).103
TABLE 1: Summary ofcontrolled trials ofantidepressant therapiesin PHN6,17–22
Treatment Patients (n) Positive pain relief reported (%)
Amitriptyline17 24 67 Placebo 5 Amitriptyline18 34 47 Placebo 8 Desipramine19 19 63 Placebo 11 11 Amitriptyline20 15 60 Zimelidine 7 Amitriptyline21 32 44 Maprotiline 18 Amitriptyline22 31 58 Nortriptyline 55
Evidence for the benefit of anticonvulsants in PHN was lacking until the publication of a
report by Rowbotham and colleagues5 of a large-scale clinical trial evaluating the use of
gabapentin in this indication. This randomized, double-blind study comparing gabapentin
(titrated to a maximum dose of 3600 mg daily) with placebo in 229 patients with PHN7 had
a primary efficacy outcome of change in average daily pain score, based upon an
11-point Likert pain scale (0=no pain, 10=worst possible pain). Patients receiving
gabapentin exhibited a significant reduction in average daily pain score from 6.3 to 4.2
compared with 6.5 to 6.0 for the placebo group (P<0.001).7 Gabapentin was found to be
effective not only in pain control but also in the treatment of sleep interference associated
with PHN, which in turn improved mood and quality of life. Gabapentin was associated with
somnolence, dizziness, ataxia, peripheral oedema, and infection. However, the number of
withdrawals due to side-effects was similar to that seen with placebo. Similar results were
seen in another multicentre, randomized, double-blind, placebo-controlled trial involving
334 patients with PHN.28 Patients who received gabapentin (either 1800 or 2400 mg/day
in three divided doses) showed significantly greater improvements in pain scores and
measures of sleep quality than those who received placebo.28
Gabapentin has not been directly compared with other treatments for PHN. However, its
efficacy has been compared with tricyclic antidepressants using the ‘number needed to
treat‘ (NNT) method.24 The comparison used data from the gabapentin trials and from a
review of tricyclic antidepressants. The analysis indicated that gabapentin was as effective
and safe as tricyclic antidepressants but with fewer contraindications to its use. The
placebo-controlled study, therefore, supports the use of gabapentin as a first-line therapy
for the treatment of the pain of established PHN. The FDA in the USA has also approved
gabapentin for use in the treatment of PHN.
Other anticonvulsants have been less well studied in PHN. For example, lamotrigine
reduced hyperalgesia and allodynia in experimental studies,29 and anecdotal reports
indicate that lamotrigine was effective in neuropathic pain, including central pain, which
is notoriously difficult to treat.29 However, this effect occurred at comparatively high doses
(up to 600 mg/day). Side-effects of lamotrigine are similar to those of other
anticonvulsants, but dermatological complications may be more common and more
severe.30 The risk of developing adverse effects can be reduced by prescribing a low initial
dose (25–50 mg/day) and increasing the dose slowly. Carbamazepine was ineffective at
relieving continuous pain in an uncontrolled study.31
Lidocaine patchJ Administration of a topical local anaesthetic (e.g. lidocaine patch 5%) is
recommended (category 1 recommendation).
Topical lidocaine has been shown to provide effective pain relief in established PHN.
There have been a number of double-blind, vehicle-controlled studies on the efficacy of
topical lidocaine in the treatment of PHN.8,32,33 In these studies, 5% lidocaine, either as a
gel or as a non-woven patch, provided moderate or better pain relief in more than half of
patients compared with vehicle controls.8,32,33 In the most recent of these studies, the
lidocaine patch gave pain relief in patients with established PHN. In the trial,33 the
lidocaine patch provided greater pain relief than the vehicle control, with patients
receiving the lidocaine patch remaining on treatment 3.7-fold longer than on the vehicle104
patch. All of the patients in the study had previously been successfully treated with topical
lidocaine. Upon completion of the study, 78.1% (25/32) of the lidocaine-patch group
preferred the treatment patch to previous treatment they had received, compared with
9.4% (3/32) of the control group (P<0.001).32
There is minimal systemic uptake and no need for dose escalation with use of the patch
which, combined with the rapid onset of relief, makes the lidocaine patch a useful option
for relieving the pain of PHN. Lidocaine patches and gabapentin are the only treatments
with a specific approval for the treatment of PHN by the FDA in the USA.
In countries where lidocaine is not available, EMLA cream under an occlusive dressing
may be effective.34
Second-Line Treatments for Established PHNAnalgesic therapyJ Stronger opioids (including oxycodone, morphine and methadone) may be considered
for therapy of PHN, but, as they are usually administered in a pain clinic, cannot be
considered as first-line therapy (category 2 recommendation).
Alternative tricyclic antidepressantsJ If a first-line tricyclic antidepressant fails, any of the available non-tricyclics may be
tried, such as venlafaxine or maprotiline. SSRIs such as fluoxetine, paroxetine or
sertraline may also be effective in some patients (category 2 recommendation).
Amitriptyline may cause significant anticholinergic side-effects in the elderly or it may fail
to offer sufficient pain relief. Similarly, patients may experience unacceptable sedation
from nortriptyline. Thus, an alternative tricyclic antidepressant, such as desipramine, may
be considered.35 In a randomized, double blind, placebo-controlled trial, 6 weeks of
desipramine treatment (mean dose 167 mg/day) resulted in significant improvements in
PHN.17 Furthermore, desipramine has a less toxic side-effect profile than amitriptyline,
especially with respect to anticholinergic effects.27
Maprotiline is also thought to have fewer side-effects than amitriptyline;36 both have been
compared in the treatment of established PHN in a double-blind, randomized trial.21
Maprotiline relieved PHN (steady pain, brief pain and pain on skin contact) but was not
as effective as amitryptiline. Moreover, more patients receiving maprotiline experienced
side-effects, many of which were more severe, than those in the amitryptiline group.
Therefore, it is recommended that amitryptiline should be the first choice of tricyclic
antidepressant to treat PHN, but, if it fails agents such as maprotiline should be used.29
If a patient tolerates a full dose of the first tricyclic antidepressant over a trial period of
2–4 weeks, there is little justification for trying a second tricyclic antidepressant, except as
third-line therapy. If a first-line tricyclic antidepressant is not tolerated, any of the available
non-tricyclics may be tried, such as venlafaxine or maprotiline. SSRIs such as fluoxetine,
paroxetine or sertraline may also be effective in some patients and can be considered as
second-line treatments.
105
CapsaicinJ Topical capsaicin (0.025% or 0.075%) may be effective in some patients and they
should receive advice on its use and side-effects to achieve compliance (category 1
recommendation).
The place of topical capsaicin is still not completely resolved. Capsaicin (N-Vanillyl-8-
methyl-6-(E)-noneamide) is a pungent derivative of hot chilli peppers. Its application to
sensory nerve tissue first stimulates then inhibits (by causing depletion of the
neurotransmitter substance P) activity in nociceptive C fibres. Topical applications of
concentrations varying from 0.025% to 0.075% have been studied in a number of painful
conditions including osteoarthritis of the knee and PHN. A 0.075% preparation of
capsaicin has been reported to provide a significant benefit in the treatment of PHN.23 In
contrast, McQuay and Moore25 reviewed its use and concluded that there was no
evidence of significant improvement in pain relief following capsaicin treatment. These
disparate results are likely to be due to the problem of placebo-blinding in controlled
studies of capsaicin, because of the burning sensation associated with the active treatment.
Topical capsaicin is not a first-line choice for the treatment of patients with PHN. For
many, there is a lack of compliance due to the burning sensation experienced following
application.13
Other Treatment Approaches for Established PHNJ With persistent pain, topical preparations, tricyclic antidepressants, gabapentin and
opioids may be effective if used in combination. It is recommended that this approach
be based upon the physician’s experience and the condition of the individual patient
(category 3 recommendation).
J Patients who fail to respond to several different treatment approaches despite
monitored compliance should be referred to a pain management clinic (category 3
recommendation).
J Additional approaches to consider in established PHN include nerve blocks, and
topical aspirin in ether. Some patients may wish to consider complementary or
alternative medicine, such as homeopathy, faith healing or acupuncture, although
there is no evidence for these approaches (category 3 recommendation).
Sympathetic nerve blocksAlthough sympathetic nerve blocks may be effective in relieving acute zoster-associated
pain, they do not appear to provide prolonged pain relief in patients with established
PHN.7,37 Studies by Colding38 and Nurmikko et al39 have demonstrated little or no benefit
from the use of sympathetic nerve blocks in the treatment of PHN. This lack of efficacy may
be explained in part by evidence which suggests only a limited role for the sympathetic
nervous system in the pain and allodynia experienced in PHN.39,40
In contrast, intrathecal administration of methylprednisolone was found to be effective for
the treatment of PHN in a study of 270 patients who had had PHN for at least 1 year; the
population was restricted to those patients with long-lasting pain that was resistant to
conventional treatments.41 Patients were randomized to one of three groups:106
• Methylprednisolone and lidocaine (3 ml of 3% lidocaine with 60 mg methylprenisolone)
• Lidocaine alone
• No treatment.
Treatment was once weekly for 4 weeks. Pain was evaluated at the end of the 4-week study
period, then at 4 weeks, 1 year and 2 years later. At the end of the study, patients in the
methylprednisolone–lidocaine group had a decrease in the pain area and intensity, and
their use of diclofenac was 70% lower than at baseline, suggesting that this treatment may
be of benefit in PHN.41 However, this study has received much criticism because of the
perceived serious risk of intrathecal methylprednisolone administration. Until
confirmation from properly-conducted studies is available, this treatment cannot be
advised.
TENSJ TENS may be effective but evidence to support its efficacy is scarce (category 3
recommendation).
Evidence for the efficacy of TENS is scarce but it may be beneficial in some patients and
has little risk.42,43 However, TENS should be part of a larger management programme that
includes other modalities.44
N-methyl-D-aspartate (NMDA) receptor antagonistsThere have been no controlled trials of the N-methyl-D-aspartate (NMDA) receptor
antagonist ketamine in PHN but evidence that it may be effective for reducing pain comes
from a non-comparative trial in five patients.45 Continuous subcutaneous infusion of
ketamine was effective in relieving the spontaneous pain and allodynia of PHN. However,
itching and painful indurations at the injection site were common and other side-effects
included nausea, fatigue and dizziness. Another NMDA antagonist, dextramethorphan
(mean dose 439 mg/day), did not reduce pain in 13 patients with established PHN when
compared with placebo, although the antagonist was effective in diabetic neuropathy in
the same trial.46
Topical aspirin in etherThe evidence that other treatments can ameliorate established PHN is often poor. There
has been a limited number of studies on aspirin suspended in ether, chloroform or
acetone.47-49 Although these therapies can help some patients, there are doubts about the
extent of clinical benefit, especially as the trials have been of short duration. There are also
concerns about the safety of the mixtures.
Alternative and complementary medicineAcupuncture was shown to have no effect on pain resolution in a placebo-controlled trial
involving 62 individuals; patients in both treatment groups experienced similar levels of
pain relief.50 Faith healing may offer benefit to some patients but this non-invasive
approach has not been tested in formal studies.
SummaryPHN can result in significant morbidity and interfere with patients’ activities of daily living.
It can manifest as spontaneous pain (aching or burning in nature), allodynia or 107
hyperalgesia. Not only is PHN potentially severe, it is often prolonged with some 5–10%
of patients still experiencing pain at 1 year after rash appearance. This ongoing discomfort
and distress emphasize the need for effective management and treatment.
First-line therapy for PHN may include analgesics, such as paracetamol or a weak opioid,
and tricyclic antidepressants, such as amitriptyline or nortriptyline, initiated at 10–25 mg
and increasing weekly by 25 mg. Gabapentin (up to 3600 mg per day provided there is
unimpaired renal function) is also recommended as an effective first-line treatment for
PHN. However, other anticonvulsants have been less well studied for the treatment of
PHN. Physical measures such as cold packs have been shown to offer pain relief to some
patients. In addition, patients with established PHN should receive encouragement,
counselling, and education on quality-of-life matters and the importance of treatment
compliance.
If a first-line tricyclic antidepressant fails to provide pain relief, or the patient experiences
unacceptable side-effects, treatment with any of the other available tricyclics should be
considered. Other first-line treatments that have been shown to be of use in PHN include
topical lidocaine patches or capsaicin and stronger opioid analgesics such as oxycodone
or tramadol.
Alternative approaches to consider in the second-line treatment of PHN that does not
respond to the therapies described above include nerve blocks, homeopathy, topical
aspirin in ether, faith healing, acupuncture, TENS and referral to a pain management clinic.
In summary, effective treatment of established PHN is likely to be multimodal and may involve:
• Tricyclic antidepressants (amitriptyline initiated at 10–25 mg)
• Anticonvulsants (gabapentin titrated from 300–900 mg daily up to 3600 mg every
24 hours provided there is unimpaired renal function)
• Opioids (oxycodone, morphine and methadone)
• Topical agents (lidocaine or capsaicin).
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