Advances in the understanding of the pathogenesis and epidemiology of herpes zoster
Introduction
Varicella zoster virus (VZV) causes two distinct diseases, chickenpox (varicella) and shingles (herpes zoster [HZ]). The link between these two diseases has been understood for over 100 years and is based on two observations: (a) VZV remains latent in human neurons for decades after varicella infection and (b) sufficient VZV-specific cellmediated immunity (CMI) is necessary to maintain latency.
The segmental nature of HZ and its origin in individual sensory ganglia were appreciated when ganglionitis was observed during autopsies performed on patients with HZ in the early 20th century. In 1892, von Bokay1, 2 recorded cases of varicella in children exposed to adults with HZ, and the link between varicella and HZ was later proven by an analysis of isolates from a patient who had had varicella followed by HZ some years later. These isolates had identical molecular profiles.3, 4
Before the introduction of varicella vaccination, there were 4 million cases of varicella per year in the USA, with an incidence of 15–16 cases per 1,000 population.5 The varicella vaccine was licensed in the USA in 1995, and consequently the incidence of varicella has been reduced by 76–87% in the period 1995–2000.6 There are over 1 million cases of HZ in the USA each year, with an estimated lifetime attack rate of 30%.7
This article reviews the epidemiology of varicella in temperate and tropical climates, and the ability of current diagnostic techniques to provide information about its molecular epidemiology. Our contemporary understanding of viral pathogenesis and the major theories explaining latency and reactivation will also be examined. An understanding of the risk factors and complications associated with HZ, particularly in older people, will be discussed in relation to primary healthcare management.
Section snippets
Epidemiology
VZV is unique among the human alphaherpes viruses in that it is transmitted via the airborne route, leading to a typical winterspring seasonality pattern of primary infection for varicella.8 VZV can also be transmitted by fomites from skin lesions of varicella and HZ. HZ does not follow a seasonal pattern and does not occur in epidemics because it results from the reactivation of each patient's latent endogenous virus; therefore, the incidence rate of HZ is generally more stable than that of
Pathogenesis of VZV infection
The highly infectious VZV enters the body via the respiratory tract and spreads rapidly from the pharyngeal lymphoid tissue to circulating T lymphocytes. During the incubation period of 10–21 days, the virus arrives at the skin, causing the typical vesicular rash of varicella. Infection results in lifelong immunity against clinically apparent second episodes of varicella in the vast majority of individuals.21
The immune response to VZV infection has three components:
- (1)
Innate immunity. Experiments
Latency
All herpesviruses have the ability to establish latency, thereby providing a reservoir to facilitate the infection of new generations of susceptible individuals.
Two hypotheses have been proposed to explain how VZV gains access to the dorsal root ganglia (DRG) and cranial root ganglia (CRG) to establish latency:
- (1)
Cell-free VZV is produced in the epidermis and infects the intraepidermal projections of sensory neurons. The virus then travels by retrograde transport in axons to reach cell bodies,
Reactivation
Viral gene transcription products are required to establish and maintain latency, but host factors subsequently determine whether or not the virus remains latent. There are a number of potential triggers of reactivation, including expression of the ORF61 protein and the presence of mediators of inflammation. Different viral genes are expressed during latent and lytic infection. The ORF61 gene product is necessary and sufficient to induce the switch between the two states: latency and lytic
Risk factors for HZ
Risk factors for HZ are shown in Table 1, the most important being older age.36, 37, 38, 39, 40, 41, 42, 43, 44
In the general population, the incidence of HZ is two to three per 1,000 patients per year. Lifetime risk in the general population is about 30% and, in those surviving to 85 years of age, at least 50% will have had HZ. The lifetime risk increases with age, with an odds ratio (OR) of 1.20 (1.10–1.31) per 5-year interval in those aged >65 years.45 This is most likely due to declining
Complications of HZ
The complications of HZ can be divided into four groups – cutaneous, visceral, neurological and ocular (Table 2),49 with the incidence of all complications increasing with age. After PHN, ocular complications are the most common,46 and the virus can infect any of the structures within the eye.50
Neurological complications associated with HZ are common. PHN, defined as pain lasting after the rash has disappeared (often considered when pain is present for 90 days after the onset of rash), is
Summary
Primary infection with VZV causes varicella, whereas reactivation of the latent virus causes HZ. The recent demonstration of co-infection of the same host (and indeed even the same cell) with different strains of VZV, and the further possibility of recombination between the viruses, adds complexity to our understanding of the natural history of VZV infection.
VZV evades the host's immune system and spreads throughout the body, with the potential to cause serious problems in the immunocompromised
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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