The impact of varicella zoster virus: Chronic pain

doi:10.1016/S1386-6532(10)70003-2

Journal of Clinical Virology

Volume 48, Supplement 1, May 2010, Pages S8-S13

https://doi.org/10.1016/S1386-6532(10)70003-2 Get rights and content

SUMMARY

Herpes zoster (HZ) is a common condition that affects all age groups and both immunocompetent and immunocompromised individuals. However, it mainly impacts elderly and immunocompromised people and is associated with important and sometimes permanent detriment to quality of life and activities of daily living. Age-related decline in cell-mediated immunity (CMI) permits reactivation of varicella zoster virus (VZV) from latency. The risk of developing post-herpetic neuralgia (PHN) can be predicted using epidemiologically identified risk factors, thus indicating which patients may benefit most from protection by appropriate means, including vaccination.

Despite increasing knowledge of the pathology causing PHN, the management modalities for acute HZ pain and PHN remain inadequate. Public, and probably physician, understanding of HZ and its complications is poor, potentially leading to low utilisation of HZ vaccination and delayed presentation for treatment.

Introduction

Herpes zoster (HZ) is a common condition that affects all age groups and both immunocompetent and immunocompromised individuals.

HZ mainly impacts on elderly and immunocompromised people. Aging is a cause of deficient cell-mediated immunity (CMI), and it is a decline in zoster-specific CMI that permits reactivation of varicella zoster virus (VZV) from latency. The symptoms of HZ commence during its prodrome, i.e., before diagnosis can usually be made. By the time of rash appearance, leading to diagnosis and treatment, the inflammatory, immune and direct viral effects on the sensory neurons are already under way.

The elderly are highly sensitive to short periods of compromised health that can have a long-term impact on activities of daily living (ADL) and independence, including loss of ability to live independently.¹ The pain associated with HZ is complex; it may exhibit a number of components in one individual, and there are significant differences between individuals. A person's risk of developing post-herpetic neuralgia (PHN) can be predicted once the diagnosis of HZ is made – and indeed before it using epidemiologically identified risk factors.

This article reviews the complications associated with HZ, namely PHN and post-herpetic itch (PHI), and provides an overview of their epidemiology and current management strategies. Because older people represent a high-risk group for developing HZ, VZV vaccination and its potential to protect the elderly from HZ and PHN are also discussed.

Section snippets

HZ and PHN from a primary care perspective

The effective prevention and management of the condition require that both the at-risk public and their physicians know about HZ and its main complication, PHN, and are aware of the risk factors for its development. Two large international surveys have shown that, although the majority of older adults worldwide have heard of shingles (or its appropriate local translation), almost all consider themselves to be at low risk of developing it, and few are aware that long-lasting severe pain may

PHN: Pathogenesis, classification and measurement

PHN provides a human model of neuropathic pain and, indeed, it has been extensively studied to gain insights into its causality. It is also the second most common neuropathic pain condition used for trials of potential new treatments (after diabetic painful neuropathy) (Figure 1).¹⁰ PHN is attractive for research because it is common and results from a one-time injury with distinct diagnosis and time of onset. Because PHN most often occurs in older adults, autopsy examination of affected tissue

PHI (pruritus)

PHI is only recently attracting medical attention, although it has been a major complaint and source of disability for patients. It is reported by one third to one half of HZ patients and is more common after the occurrence of HZ rashes on the face or neck than on the torso.²⁹ It is usually mild or moderate in intensity. If the rash is accompanied by anaesthesia in the same area, patients may scratch painlessly often enough to self-injure. A report of such a case involved a 39-year-old woman

HZ in the context of aging

Changes in social environment and healthcare provision have led to increased longevity in developed nations. However, this is of little value to the individual or the community unless the quality of these additional years is good. In other words, ‘years have been added to life’, but ‘life must also be added to years’. Decade by decade, the age at which there is a decline from fully functional to severely dependent has risen such that full functionality is often now retained into the mid-70s;

Summary

HZ and PHN are common in older adults and are associated with important – sometimes permanent – detriment to QoL and ADL. Despite our increasing (albeit incomplete) knowledge of the pathology causing PHN, management modalities for acute HZ pain and PHN remain inadequate. The prevention of HZ and PHN has significant QoL implications. Public, and probably physician, understanding of HZ and its complications are poor, contributing to low HZ vaccination uptake.

The extent of the use of available

Conflict of interest

The GVF is a not-for-profit organization. The GVF Zoster Workshop was sponsored by educational grants from Novartis, Menarini, Sanofi-Pasteur and Merck.

Acknowledgments

We would like to thank Facilitate Ltd, Brighton, UK, for editorial assistance with the manuscript.

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Reported QALYs lost/1000 cases in children for other vaccine preventable diseases include 3.1–3.5 for rotavirus [19], 4 for pneumonia [20], 8 for influenza [21], 19 for measles [22], 97 for pertussis [23], and 200 for meningococcal disease (for cases without sequelae) [24]. Although there have been many assessments of the clinical and economic burden of varicella, including detailed evaluations in European countries without universal vaccination [25] and the QoL burden of zoster and PHN has been emphasised [26], the effects of varicella on HRQoL of children have not been robustly assessed and, to our knowledge, have not been reported on hospitalised children and on carers of children with varicella. It has been proposed that QoL impact in childhood should carry greater weight in cost effectiveness evaluation [27] and previous studies evaluating the impact on carer HRQoL in other paediatric infectious diseases have found it to be a significant additional burden of disease [28,29,30].
Although usually benign, varicella can lead to serious complications and sometimes long-term sequelae. Vaccines are safe and effective but not yet included in immunisation programmes in many countries. We aimed to quantify the impact on health-related quality of life (HRQoL) in terms of quality-adjusted life years (QALY) in children with varicella and their families, key to assessing cost-utility in countries with low mortality due to this infection.
Children with varicella in the community and admitted to hospitals in Portugal were included over 18 months from January 2019. Children's and carers’ HRQoL losses were assessed prospectively using standard multi-attribute utility instruments for measuring HRQoL (EQ-5D and CHU9D), from presentation to recovery, allowing the calculation of QALYs.
Among 109 families with children with varicella recruited from attendees at a pediatric emergency service (community arm), the mean HRQoL loss/child was 2.0 days (95 % CI 1.9–2.2, n = 101) (mean 5.4 QALYs/1000 children (95 % CI 5.3–6.1) and 1.3 days/primary carer (95 % CI 1.2–1.6, n = 103) (mean 3.6 QALYs /1000 carers (95 % CI 3.4–4.4).
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Estimates for children’s QALYs lost using the CHU9D tool were well correlated with those obtained using EQ-5D, but substantially lower.
The impact of varicella on HRQoL is substantial. We report the first measurements of QALYs lost in hospitalised children and in the families of children both in the community and admitted to hospital, providing important information to guide vaccination policy recommendations.
Anti-varicella zoster virus and related anti-inflammation effects of ethanolic extract of Elaeocarpus sylvestris
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In the present study, we aim to investigate the VZV-antiviral efficacy, pain suppression, and the anti-inflammatory and antipyretic effects of ES.
and methods: Inhibition of VZV was evaluated by hollow fiber assays. Analgesic and antipyretic experiments were conducted using ICR mice and SD Rats, and anti-inflammatory experiments were conducted using Raw264.7 cells.
To evaluate the efficacy of ESE against VZV, we conducted antiviral tests. ESE inhibited cell death by disrupting virus and gene expression related to invasion and replication. In addition, ESE suppressed the pain response as measured by writhing and formalin tests and suppressed LPS-induced inflammatory fever. Further, ESE inhibited the phosphorylation of IκB and NF-κB in LPS-induced Raw264.7 cells and expression of COX-2, iNOS, IL-1β, IL-6, and TNF-α.
E. sylvestris shows potential as a source of medicine. ESE had a direct effect on VZV and an inhibitory effect on the pain and inflammation caused by VZV infection.
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Other viruses are also widely recognized by their modulation of nociceptor response. Herpesviruses, namely, herpes simplex virus 1 (HSV1), HSV2, and varicella-zoster virus (VZV) replicate in the DRG and trigeminal ganglia and move along primary afferents fibers to the skin, resulting in their characteristic skin lesions [36]. Specifically for HSV1, the interaction between the virus and 3-O-sulfated heparan sulfate [37] or nectin-1/HveC [38] are the main responsible for the viral entry into neurons (Fig. 1C).
Clinically, a variety of micro-organisms cause painful infections. Before seen as bystanders in the context of infections, recent studies have demonstrated that, as immune cells, nociceptors can sense pathogen-derived products. Nociceptors and immune cells, therefore, have evolved to communicate with each other to control inflammatory and host responses against pathogens in a complementary way. This interaction is named as neuroimmune communication (or axon-axon immune reflex) and initiates after the release of neuropeptides, such as CGRP and VIP by neurons. By this neurogenic response, nociceptors orchestrate the activity of innate and adaptive immune cells in a context-dependent manner. In this review, we focus on how nociceptors sense pathogen-derived products to shape the host response. We also highlight the new concept involving the resolution of inflammation, which is related to an active and time-dependent biosynthetic shift from pro-inflammatory to pro-resolution mediators, the so-called specialized pro-resolving lipid mediators (SPMs). At very low doses, SPMs act on specific receptors to silence nociceptors, limit pain and neurogenic responses, and resolve infections. Furthermore, stimulation of the vagus nerve induces SPMs production to regulate immune responses in infections. Therefore, harnessing the current understanding of neuro-immune communication and neurogenic responses might provide the bases for reprogramming host responses against infections through well balanced and effective immune response and inflammation resolution.
S100A9 plays a pivotal role in a mouse model of herpetic neuralgia via TLR4/TNF pathway
2020, Brain, Behavior, and Immunity
Citation Excerpt :
Herpetic neuralgia is the most important symptom of herpes zoster disease, which is caused by Varicella zoster Virus (VZV) reactivation in the dorsal root (DRGs) or trigeminal ganglia post primary infection (Nagel and Gilden, 2014; Opstelten et al., 2010). Herpes zoster affects approximately 25% of the population and the resulting neuralgia is clinically characterized by a painful blistering skin rash which negatively impacts the quality of life of the individuals and the disease management is challenging and often unsatisfactory (Johnson, 2010; Opstelten et al., 2010). Mice are resistant to VZV infection, however herpes simplex virus type-1 (HSV-1) has been employed to infect animals.
Herpetic neuralgia is a painful condition following herpes zoster disease, which results from Varicella-zoster virus reactivation in the dorsal or trigeminal sensory ganglia. Nevertheless, the pathophysiological mechanisms involved in herpetic neuralgia are not well understood. Recently, we identified, that neuroimmune-glia interactions in the sensory ganglion is a critical mechanism for the development of herpetic neuralgia. Here, we investigate the contribution of S100A9, a well-known pro-inflammatory molecule produced by myeloid cells, for the development of herpetic neuralgia using a murine model of HSV-1 infection. We found that cutaneous HSV-1 infection results in an increase of S100A9 expression in the Dorsal Root Ganglia (DRGs). Infiltrating neutrophils into the DRGs were the main source of S100A9 post HSV-1 infection. Functionally, genetic or pharmacological inhibition of S100A9 impairs the development of HSV-1 infection-induced mechanical pain hypersensitivity. Finally, we found that the pronociceptive role of S100A9 in herpetic neuralgia depends on the TLR4/TNF pathway. These results unraveled previously unknown mechanisms involved in the pathophysiology of herpetic neuralgia and indicate that S100A9 might be an important target for novel therapies aiming acute herpetic neuralgia.
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Varicella-zoster virus early infection but not complete replication is required for the induction of chronic hypersensitivity in rat models of postherpetic neuralgia
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Herpes zoster, the result of varicella-zoster virus (VZV) reactivation, is frequently complicated by difficult-to-treat chronic pain states termed postherpetic neuralgia (PHN). While there are no animal models of VZV-induced pain following viral reactivation, subcutaneous VZV inoculation of the rat causes long-term nocifensive behaviors indicative of mechanical and thermal hypersensitivity. Previous studies using UV-inactivated VZV in the rat model suggest viral gene expression is required for the development of pain behaviors. However, it remains unclear if complete infection processes are needed for VZV to induce hypersensitivity in this host. To further assess how gene expression and replication contribute, we developed and characterized three replication-conditional VZV using a protein degron system to achieve drug-dependent stability of essential viral proteins. Each virus was then assessed for induction of hypersensitivity in rats under replication permissive and nonpermissive conditions. VZV with a degron fused to ORF9p, a late structural protein that is required for virion assembly, induced nocifensive behaviors under both replication permissive and nonpermissive conditions, indicating that complete VZV replication is dispensable for the induction of hypersensitivity. This conclusion was confirmed by showing that a genetic deletion recombinant VZV lacking DNA packaging protein ORF54p still induced prolonged hypersensitivities in the rat. In contrast, VZV with a degron fused to the essential IE4 or IE63 proteins, which are involved in early gene regulation of expression, induced nocifensive behaviors only under replication permissive conditions, indicating importance of early gene expression events for induction of hypersensitivity. These data establish that while early viral gene expression is required for the development of nocifensive behaviors in the rat, complete replication is dispensable. We postulate this model reflects events leading to clinical PHN, in which a population of ganglionic neurons become abortively infected with VZV during reactivation and survive, but host signaling becomes altered in order to transmit ongoing pain.

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The impact of varicella zoster virus: Chronic pain

SUMMARY

Introduction

Section snippets

HZ and PHN from a primary care perspective

PHN: Pathogenesis, classification and measurement

PHI (pruritus)

HZ in the context of aging

Summary

Conflict of interest

Acknowledgments

Pain

Vaccine

Pain

Pain

Neurobiol Dis

Pain

Neuroscience

J Pain

Pain

Vaccine

Lancet Infect Dis

Curr Opin Immunol

Blood

Hum Immunol

Curr Opin Immunol

Vaccine

Herpes zoster and quality of life: a self-limited disease with severe impact

Neurology

Public knowledge and awareness of herpes zoster: Results of a global survey

Gerontology

Patient awareness of herpes zoster: The global herpes zoster survey - a preliminary report

Herpes

Herpes zoster and postherpetic neuralgia: incidence and risk indicators using a general practice research database

Fam Pract

Risk factors for postherpetic neuralgia in patients with herpes zoster

Neurology

Do herpes zoster patients receive antivirals? A Dutch National Survey in General Practice

Fam Pract

Antiviral treatment for preventing postherpetic neuralgia

Cochrane Database Syst Rev