Background Information

For more information, see the monograph:

Improving the Management of Varicella, Herpes Zoster and Zoster-associated Pain

Animal and in vitro Models

• 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)*

Latency

• 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)

• 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).

*Please refer to Recommendation and Statement Categories (page 3) of the monograph Improving the Management of Varicella, Herpes Zoster and Zoster-associated Pain for an explanation of the recommendations and statements.

For more information, see the monograph:

Improving the Management of Varicella, Herpes Zoster and Zoster-associated Pain

Epidemiology of Varicella

• 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)

Complications

• 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).

For more information, see the monograph:

Improving the Management of Varicella, Herpes Zoster and Zoster-associated Pain

Efficacy and Safety of Varicella Vaccine
Vaccination for women of childbearing age

• 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 Strategies

• 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)

• 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 ndividuals will provide valuable information but should not replace monitoring of the general vaccinated population in the USA (Rsearch need recommendation)

• 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).

Universal vaccination
Epidemiology of varicella in the USA following vaccine introduction
Strategies to improve vaccination rates in the USA

• 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)

Mathematical models of varicella incidence following universal childhood vaccination

• 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)

Targeted Vaccination

• 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)

• 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).

For more information, see the monograph:

Improving the Management of Varicella, Herpes Zoster and Zoster-associated Pain

Post-Exposure Prophylaxis

• 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

• 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)

Antiviral Treatment

• 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

• 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)

• 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)

• 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)

• 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)

• 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).

Prevention and Management of Varicella in the Pregnant Woman and Neonate

• 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)

• 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 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)

• Neonates (<28 days old) who are exposed to varicella post-natally should be administered prophylactic VZIG (Category 3 recommendation)

• 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)

Post-exposure prophylaxis in the pregnant woman
Antiviral prophylaxis

• 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).

   

For more information, see the monograph:

Improving the Management of Varicella, Herpes Zoster and Zoster-associated Pain

Rare Complications in the Immunocompetent Host

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/m 2 or 20 mg/kg every 8 hours for children) is warranted in the majority of these cases, based on anecdotal evidence (Category 3 recommendation)

Application of PCR to Understanding Pathogenesis and Risk Factors for Prolonged Zoster-associated Pain

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)

Mathematical Modelling of Zoster-associated Pain

It is important that clinicians recognize that acute and chronic pain and different chronic pain subtypes are engendered by different mechanisms (Category 3 recommendation)

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).

For more information, see the monograph:

Improving the Management of Varicella, Herpes Zoster and Zoster-associated Pain

Introduction

• 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)

Antiviral Therapy in Herpes Zoster

• 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)

• 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)

• There is no indication for the use of topical antiviral agents in the treatment of cutaneous herpes zoster (Category 1 recommendation)

• 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)

Antiviral Therapy in Herpes Zoster
Effect of time of initiation of antiviral therapy

• 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)

Corticosteroid Therapy in Herpes Zoster

• 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)

Antidepressant Treatment for Herpes Zoster

• 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)

Sympathetic Nerve Blocks and Other Agents to Treat Acute Pain in Herpes Zoster and for Prevention of PHN

• The presence of risk factors for the development of PHN should be assessed and documented for each patient (Category 3 recommendation)

• If the patient has severe acute pain, the following treatments may be beneficial: sympathetic nerve blocks, antidepressants, gabapentin and opioids (Category 3 recommendation)

• Studies are required to establish the role of gabapentin and other treatment modalities in the prevention of PHN (research need recommendation)

• 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).

   

For more information, see the monograph:

Improving the Management of Varicella, Herpes Zoster and Zoster-associated Pain

Herpes Zoster Ophthalmicus
Ocular complications of herpes zoster ophthalmicus

• It is strongly recommended that patients with obvious ocular involvement should be referred to an ophthalmologist (Category 3 recommendation)

Therapy for herpes zoster ophthalmicus

• To prevent ocular complications, antiviral therapy is recommended for all patients with herpes zoster ophthalmicus who present within 1 week of onset of lesions (Category 2 recommendation)

• 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)

• It is recommended that antiviral treatment of herpes zoster ophthalmicus is initiated up to 7 days following rash onset (Category 3 recommendation)

• It is not recommended that corticosteroid therapy (either topical or systemic) be prescribed except upon the advice of an ophthalmologist (Category 3
  recommendation)

• 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).

For more information, see the monograph:

Improving the Management of Varicella, Herpes Zoster and Zoster-associated Pain

Presentation and Complications of VZV Infections in the Immunocompromised
Herpes zoster
Abdominal herpes zoster

• Clinicians should be aware that in some immunocompromised individuals, herpes zoster might initially present as unexplained abdominal pain (Category 3 recommendation)

Atypical cutaneous lesions

• 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)

Pre-Exposure Vaccination in the Immunocompromised

• 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)

Post-Exposure Prophylaxis in the Immunocompromised

• Immunocompromised individuals should receive prophylaxis with VZIG as soon as possible but no later than 4 days following exposure to varicella (Category 1 recommendation)

• Post-exposure prophylaxis with varicella vaccine is not suitable for immuno-compromised individuals because of the risk of vaccine-induced varicella (Category 2 recommendation)

• 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/m 2 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)

Treatment of VZV Infections in the Immunocompromised
Antiviral therapy

• 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)

The place of oral antivirals

• Studies are recommended comparing valaciclovir and famciclovir with intravenous aciclovir for the management of immunocompromised individuals with VZV infections (Research need recommendation)

• 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 varicella

• 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)

Oral antiviral therapy for herpes zoster

• 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)

• Studies are recommended comparing valaciclovir and famciclovir with intravenous aciclovir in the management of immunocompromised individuals with herpes zoster (Research need recommendation)

VZV Ocular Infections in HIV-Infected Individuals

• 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

Antiviral-resistant VZV infections

• 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).

For more information, see the monograph:

Improving the Management of Varicella, Herpes Zoster and Zoster-associated Pain

Introduction

• 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)

• The development of effective pain management programmes for PHN patients, especially elderly patients, is of utmost importance (Research need recommendation)

First-Line Treatment of Established PHN
Physical measures

• 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)

• Efforts should be made to encourage treatment compliance in patients with established pain (Category 3 recommendation)

Analgesic therapy for established PHN

• 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)

Tricyclic antidepressants in PHN

• 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)

Anticonvulsants in PHN

• 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)

Lidocaine patch

• Administration of a topical local anaesthetic (e.g. lidocaine patch 5%) is recommended (Category 1 recommendation)

Second-Line Treatments for Established PHN
Analgesic therapy

• 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 antidepressants

• 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)

Capsaicin

• 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)

Other Treatment Approaches for Established PHN

• 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)

• Patients who fail to respond to several different treatment approaches despite monitored compliance should be referred to a pain management clinic (Category 3 recommendation)

• 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).

TENS

• TENS may be effective but evidence to support its efficacy is scarce (Category 3 recommendation).