Herpes zoster: Epidemiology, natural history, and common complications

Jeffrey M. Weinberg, MD New York, New York

Herpes zoster is a disease associated with aging that can signicantly impair quality of life for affected individuals. Anyone infected with varicella (chickenpox) virus in childhood is at risk for reactivation of dormant virus and the onset of zoster disease, although it occurs with increasing frequency in the elderly as a result of waning of cell-mediated immunity. The most common complication of herpes zoster is postherpetic neuralgia, which can cause chronic and debilitating pain. Current treatments can decrease the severity of zoster rash and pain but cannot prevent disease onset or completely eliminate the most frequent symptoms. The zoster vaccine may help prevent the onset of herpes zoster in the target population of those age 60 years and older. This summary reviews the epidemiology, pathogenesis, natural history, and common symptoms of zoster disease. ( J Am Acad Dermatol 2007;57:S130-5.)

erpes zoster, or shingles, is a disease that predominantly affects the elderly. It occurs as a result of aging-related waning of cellmediated immunity to varicella-zoster virus (VZV), the virus that also causes varicella and is dormant in everyone who has ever had it.1,2 The association between aging and vulnerability to VZV reactivation is apparent in the epidemiology of the disease: of the estimated 1 million cases of herpes zoster in the United States each year, approximately 50% occur in individuals aged 50 years or older.3 Although 10% to 20% of the US population overall will develop zoster in their lifetimes, 50% of persons reaching age 85 years can be expected to do so4; the incidence of herpes zoster increases dramatically, from a low of between 1.1 and 2.9 per 1000 person-years in people younger than 50 years to 4.6 and 6.9 per 1000 personyears, respectively, in the age groups 50 to 59 and 60 to 69 years. The age groups 70 to 79 and 80 years or older have the highest incidence, with 9.5 and 10.9 per 1000 person-years, respectively.5
From the Clinical Research Center, Department of Dermatology, St. Lukes-Roosevelt Hospital Center and Beth Israel Medical Center, and Department of Dermatology, Columbia University College of Physicians and Surgeons. Supported by an educational grant from Merck & Co., Inc. Disclosure: Dr Weinberg is a consultant and on the speakers bureau for Merck & Co., Inc. Accepted for publication August 11, 2007. Reprint requests: Jeffrey M. Weinberg, MD, Department of Dermatology, St. Lukes-Roosevelt Hospital Center, 1090 Amsterdam Ave, Suite 11D, New York, NY 10025. E-mail: jmw27@columbia.edu. 0190-9622/$32.00 2007 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2007.08.046

Acute zoster is painful, but does not incur lasting morbidity. However, there is a potential for neurologic and inammatory complications that cause patientseand physiciansegreat and lasting difculty. The relationship between zoster infection and destruction of neurons and satellite cells has been well established, with neurologic damage beginning even before the characteristic zoster rash appears.1,6 Postherpetic neuralgia, the most frequent complication of herpes zoster, can cause debilitating pain and impaired quality of life among the otherwise healthy elderly.7-9 The associated pain, furthermore, can continue long after the rash resolves, despite aggressive antiviral and/or pain therapy. In addition, when herpes zoster occurs in the first division of the trigeminal nerve, the patient develops herpes zoster ophthalmicus (HZO), and runs the risk of long-term vision complications related to inflammation or nerve damage.10 The zoster vaccine is indicated for the prevention of herpes zoster in adults age 60 years and older, and has been shown to reduce the incidence and severity of zoster, and the incidence of postherpetic neuralgia, in this population.3 However, despite the availability of a vaccine, zoster is still seen frequently in clinical practice. This review will describe the natural history of VZV, the usual course of zoster disease, its common complications, and their impact on the atrisk elderly population.

NATURAL HISTORY OF HERPES ZOSTER

VZV is a ubiquitous herpes virus that causes chickenpox in childhood.10 On resolution of the primary varicella infection, residual provirus segments travel from sensory nerve endings up sensory fibers,

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Fig 1. Natural history of herpes zoster: primary varicella infection induces immunity via development of antigens (not shown) and varicella-zoster virus (VZV)-specific memory T cells. T cellemediated immunity declines with age until, below threshold point (dashed line) risk for zoster reactivation increases. Exposure to zoster, whether as VZV reactivation or vaccination, boosts immunity and protects against subsequent episodes. Data from Arvin A. N Engl J Med 2005;352:2266-7.

eventually lodging in the cranial or dorsal root ganglia. These viral fragments settle in neuronal or satellite cell nuclei, where they are protected from the high levels of antibody that persist in the circulation in response to the primary infection. This migration and colonization of virus along the neural route may in part explain why herpes zoster primarily affects the sensory ganglia and its rash is distributed locally along a sensory nerve dermatome.2 Once inside the neuronal nucleus, the virus remains latent and does not multiply, although it retains the ability to revert to an infectious state at any time.2 It is unclear what induces reactivation of VZV, but it is thought to occur when cell-mediated immunity decreases below a crucial level. This conviction is supported by evidence that, over time, even persons with apparent immunity to varicella exhibit T cells with reduced ability to proliferate and produce VZV-specific interferon gamma when exposed to VZV antigen in vitro.1 Furthermore, although memory CD4 and CD8 T cells are highly detectable in the young, who are largely resistant to herpes zoster, they are substantially diminished among the elderly and in immunocompromised individuals, groups that are more likely to develop herpes zoster. Periodic exposure to individuals with varicella provides a boost in immunity to VZV. When cellmediated immunity declines too far, zoster results. An episode of acute zoster does, however, boost the

Table I. Risk factors and potential risk factors for varicella-zoster virus reactivation
Prior VZV exposure (chickenpox, vaccine) Age [ 50 y Immunocompromised state Immunosuppressive drugs HIV/AIDS Bone-marrow or organ transplantation Cancer Chronic steroid therapy Psychologic stress Trauma
VZV, Varicella-zoster virus. Data from Arvin.10

individuals immunity to VZV; thus, recurrence of zoster is rare (Fig 1).1-3,11

RISK FACTORS FOR HERPES ZOSTER

Prior varicella is a prerequisite for herpes zoster, but other factors further increase risk (Table I).10 More than 90% of the US adult population has had varicella, which means the pool of individuals at risk for zoster is quite large.12 Older age further increases risk: most zoster disease occurs after age 45 years, and half of all cases reported are in individuals older than 60 years.3,5 This association with advancing years, as previously described, is a result of the agerelated decline in VZV-specific cell-mediated

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Fig 2. Herpes zoster lesions: dermatomal distribution and close-up view of vesicles. Copyright 2007 Photo Researchers, Inc. All rights reserved. Credit: Scott Camazine/Photo Researchers, Inc.

immunity. Childhood zoster is rare but not unheard of, with cases reported in children as young as 4 months. The incidence of zoster in children younger than 14 years is only 1.1 per 1000 person-years.5 Immunocompromised people or those receiving immunosuppressive drugs are also at increased risk for zoster.10 Thus, HIV-positive individuals have a higher incidence of zoster disease than individuals with a healthy immune system; one longitudinal study reported 29.4 cases per 1000 patient-years.13 Patients undergoing bone-marrow or organ transplantation and treated with immunosuppressives are also at increased risk for herpes zoster.10 Some reports have suggested that systemic steroid therapy can incite VZV reactivation as well, placing persons with conditions such as rheumatoid arthritis or lupus at increased risk.10 Finally, both trauma and stressful life circumstances have been suggested to play a role in development of herpes zoster.14,15

Beginning 4 days to 2 weeks before lesions appear, patients often note pain and paresthesia in what will become the zoster-affected dermatome. The pain can be intermittent or continuous, and has been described by patients variously as throbbing, sharp, stabbing, burning, or shooting pain.16 They may experience abnormal skin sensations such as tingling or itching. Malaise, dysesthesia, and itching are frequent elements of the prodrome as well.17 Rash Most patients exhibit thoracic distribution of zoster rash, with more than 50% of cases presenting with cutaneous lesions of the trunk.10,16 The rash generally appears proximally, then spreads distally along the affected dermatome. The initial lesions appear as erythematous papules, which turn into vesicles within 12 to 24 hours (Fig 2). New lesions generally appear over no more than 3 to 7 days, but the duration of the rash has been correlated with patient age (advancing age associated with longer duration) and site of infection (face healing more rapidly than other loci). The vesicles become pustules in about 3 days, and form scabs 7 to 10 days later.16,17 Virus persists in the lesions for only a few days and only infrequently spreads cutaneously, except in patients who are immunocompromised.16

ACUTE HERPES ZOSTER: SYMPTOMS AND DIAGNOSIS

Prodrome The characteristic feature of herpes zoster is a vesicular rash of unilateral distribution limited to 1 to 3 adjacent dermatomes. The onset of the rash, however, often is preceded by a prodromal phase.16

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In 10% to 15% of cases, zoster affects the rst division of the trigeminal nerve,7 producing the characteristic and usually painful zoster rash on the forehead, periocular area, and nose. Such a rash is known as HZO. Ocular complications of HZO are among the most dangerous consequences of zoster disease, placing patients at risk for sight impairment or vision loss caused by nerve damage or ocular pathology.12 Pain and sensation Approximately 60% to 90% of patients with zoster experience local neuritic pain16 and hypersensitivity in association with the acute herpetic rash. This pain is likely a result of an immediate nociceptive response: local inflammation and tissue damage stimulate the primary afferent neurons of the skin and subcutaneous tissue, which manifests neurologically as pain.18 It may also be a function of direct neurolytic injury to heavily infected axons and cell bodies, or intraneural hemorrhage secondary to inflammation. The pain often increases as the rash develops but then declines as the rash begins to heal.19 In addition, allodynia and hyperalgesia may be present, adding to patient discomfort during acute herpes zoster. Pain associated with zoster disease resolves within several days for many patients, although the degree of pain can be variable. Acute pain is also correlated with an increased risk of postherpetic neuralgia.19,20 Diagnosis The features of zoster disease are so characteristic that a diagnosis is generally made clinically, based on the presence of prodromal pain and/or itching and the dening zoster rash. For patients presenting in the prodromal period, the pain and dysesthesia may require differentiation from other pain sources, such as trauma, myocardial ischemia, renal colic, gallbladder disease, or dental pain.17 Atypical lesions, furthermore, may require laboratory confirmation, which sometimes is obtained from viral culture (often difficult to recover from swabs) or more readily from direct immunofluorescence assay. Recently, nested and real-time polymerase chain reaction testing of samples from skin lesions have proved valuable for identifying VZV, with more rapid amplification than other methods and high sensitivity.21 These laboratory techniques are most valuable for differentiating VZV from zosteriform herpes simplex, a herpes simplex viral infection that mimics zoster disease.

Table II. Potential complications of varicella-zoster virus can contribute to chronic pain and impairment
Neurologic Postherpetic neuralgia Motor paralysis Meningoencephalitis Transverse myelitis Cerebral vasculitis Cranial palsy Ocular Lid ulceration Conjunctivitis, keratitis, uveitis Optic neuritis Retinal necrosis Secondary glaucoma Visceral Pneumonitis Myocarditis Hepatitis Esophagitis
Data from Wood and Easterbrook.16

Encephalitis, myelitis, and nerve palsies have been reported among patients with zoster. Motor paralysis can be a particularly disquieting outcome, although it is rare, occurring in less than 5% of patients.19 Ramsay Hunt syndrome can present with hearing loss, vertigo, and facial paresis, and cerebral arteritis leading to stroke, delayed even months after the acute infection has been reported.17 The most common and challenging complications of herpes zoster, however, are postherpetic neuralgia and HZO with ocular complications. Postherpetic neuralgia, chronic and debilitating pain that persists long after the zoster rash has cleared, is more likely to occur with advancing age, in patients with a painful prodrome, in those with more severe pain or rash during the acute phase, and in those whose rash is distributed across multiple dermatomes.19,22,23 Postherpetic neuralgia affects up to 34% of those with zoster in the general population, but about 60% to 70% of patients age 60 years and older who develop zoster.24 HZO results when VZV reactivates in the rst (ophthalmic) branch of the trigeminal (fth) nerve.16 Of those with HZO, as many as 71% may develop ocular complications.25 Although blindness is rare, HZO is associated with a substantial complication rate, and permanent ocular damage and vision loss can occur.10 Patients with ocular involvement should be referred to an ophthalmologist. Postherpetic neuralgia Postherpetic neuralgia is thought to arise when nociceptors, sensitized during acute zoster infection,

COMPLICATIONS OF HERPES ZOSTER

Potential outcomes of zoster disease A number of complications of zoster disease have been described in the literature (Table II).

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Table III. Postherpetic neuralgia can present with a range of neurologic pain symptoms
Intermittent or continuous, deep or superficial Throbbing or stabbing Spontaneous aching or burning Paroxysm Allodynia Hyperalgesia Intense itching
Data from Johnson and Whitton.17

fail to return to their prezoster state, or when a persistent subclinical threshold state of central hypersensitization develops in which neurons are more easily stimulated than normal.18 Postherpetic neuralgia has been variously dened: denitions share persistent pain post-rash, but differ in how long the pain must persist post-rash to be classied as postherpetic neuralgia. Cut points used to discriminate postherpetic neuralgia have ranged from 1 to 6 months after onset of zoster.26 The presentation of postherpetic neuralgia is heterogeneous (Table III): patients may present with continuous or intermittent pain, which may be spontaneous, evoked, or evoked in response to stimuli that are not normally painful (allodynia). Some patients may present with intense itching.17 Postherpetic neuralgia is a chronic and debilitating condition that can seriously impair the health and quality of life among the affected elderly. Like zoster disease itself, the risk for postherpetic neuralgia increases with advancing age. Choo et al22 reported a 14.7-fold increase in prevalence of pain 30 days after the acute rash among their patients aged 50 years and older compared with patients younger than 50 years. Ragozzino et al7 observed that the average age of persons with postherpetic neuralgia in Rochester, Minn, was 67 years. Symptoms frequently associated with postherpetic neuralgia include chronic fatigue, anorexia, weight loss, and insomnia.9 The persistent pain and discomfort often interfere with activities of daily living, limiting patients social interaction and ability to work or tend to household chores. These challenges may lead to psychologic problems, including depression and difficulty concentrating. Oster et al27 reported that 385 respondents completing a questionnaire assessing pain and its impact on life activities experienced long-standing and severe pain that diminished their health-related quality of life, despite the use of medication. The pain interfered moderately to severely with their ability to participate in general activities, and with their mood and enjoyment of life (Fig 3). Mauskopf et al28 also related

Fig 3. Extent and degree of impact of postherpetic neuralgia pain on health-related quality-of-life parameters measured with the EuroQol scale. Reprinted from Oster et al,27 with permission from the American Pain Society.

postherpetic neuralgia to impaired health-related quality of life. In a study involving 1141 adults aged 50 years or older with zoster pain treated with valacyclovir or acyclovir, this group measured impact of pain on 6 dimensions of well-being using a generic quality-of-life instrument, the Nottingham Health Profile. It was observed that 8 weeks after rash onset, zoster pain significantly diminished quality-of-life measures for energy, sleep, and global quality-of-life score (P \ .01).27 These consistent ndings across multiple studies establish postherpetic neuralgia as a substantial problem among the elderly. Herpes zoster ophthalmicus HZO is not in and of itself sight threatening or difcult to treat, but if the eye becomes involved, the risk to the patient increases, and the patient should be referred to an ophthalmologist. The ocular sequelae can be focused at the eyelid/conjunctiva (blepharoconjunctivitis, secondary Staphylococcus infection), episclera/sclera (episcleritis/scleritis), cornea (punctate epithelial keratitis, dendritic keratitis, anterior stromal keratitis, neurotrophic keratopathy), anterior chamber (uveitis), retina (necrosis), or cranial nerves (optic neuritis, oculomotor palsies), with different degrees of associated damage or impairment. The most serious complications develop from involvement of the nasociliary branch of the cranial nerve, which innervates the globe.29

CONCLUSION
Herpes zoster carries signicant morbidity, and is both more common and associated with greater harm in the elderly and/or in immunocompromised individuals. Acute herpes zoster is painful, and a

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substantial portion of these patients will develop long-lasting complications associated with ongoing pain and other morbidity. Available antiviral and pain medications help reduce the severity of zoster rash and diminish pain, but have limited efcacy in preventing the complications and pain entirely; in fact, in some cases zoster-related pain actually worsens over time.9 Furthermore, patients with prolonged postherpetic neuralgia have a variety of constitutional symptoms, such as fatigue, weight loss, and depression, and become progressively more socially isolated as they try to cope with the pain and limitations associated with the disease. Chronic morbidity and ocular damage related to ophthalmic zoster infection can lead to fear, caution, and confinement among the already guarded elderly. The risk of blindness, although small, is real. Given the current risk prole and limitations of available symptomatic therapies, prevention may prove to be the key to reducing the health and economic costs of herpes zoster. As we attempt to help patients deal with the challenges of acute and chronic zoster disease, universal application of the zoster vaccine to the target population may be a rst step toward reducing the burden of this terrible disease. The vaccine has the potential to reduce the risk of active zoster disease and thereby reduce the challenging and life-altering sequelae that it can leave in its wake, thereby preserving quality of life for the increasing number of US citizens older than 60 years. Ensuring widespread vaccination among this population is the next step in protecting against zoster morbidity, gaining better health and emotional well-being for the 35 million elderly persons in the United States at risk for this debilitating disease.
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