The varicella-zoster virus (VZV) is a

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1 Herpes Zoster Overview: Natural History and Incidence Bethany A. Weaver, DO, MPH The varicella-zoster virus (VZV) causes two diseases. The primary VZV infection, known as chickenpox, typically occurs during childhood. Herpes zoster infection results later in life from reactivation of VZV in the dorsal root ganglia. Herpes zoster characteristically results in a rash with a unilateral dermatomal distribution, which usually resolves within 2 to 4 weeks. If the infection does not resolve after its acute phase, long-term complications, such as postherpetic neuralgia, may develop. The author discusses the natural history and incidence of primary VZV infection and herpes zoster and details the epidemiology, clinical manifestation, diagnosis, and complications of this disease. J Am Osteopath Assoc. 2009;109(suppl 2):S2-S6 The varicella-zoster virus (VZV) is a single virus that causes two diseases (Figure 1). The primary VZV infection, also known as chickenpox, typically occurs during childhood. However, VZV infection persists for the infected individual s lifetime, and viral latency subsequently develops along the spinal cord in dorsal root ganglia. Later in life, the virus reactivates usually in a dermatomal distribution causing the secondary infection known as herpes zoster, which is also called shingles. 1 In the present article, the natural history and incidence of varicella zoster (ie, primary VZV infection) and herpes zoster are discussed. The epidemiology, This article was developed in part from an expert panel discussion held October 29, 2008, during the American Osteopathic Association s 113th Annual Convention and Scientific Seminar in Las Vegas, Nev.A video of the discussion is posted at under the Featured CME tab. Dr Weaver is medical director and infectious disease consultant at Armor Correctional Health Services in Tampa, Fla. Dr Weaver reports that she has no relevant financial relationships to disclose. Address correspondence to Bethany A. Weaver, DO, MPH, PO Box 89069, Tampa, FL bethanyg@u.washington.edu, clinical manifestation, diagnosis, and complications of herpes zoster are examined in detail. Varicella-Zoster Virus The primary mode of VZV transmission is via droplets or airborne particles. Thus, a child can spread the infection by simply coughing or breathing. In a typical household, there is an 85% risk of transmission of chickenpox to a susceptible sibling. 2 The infection is characterized by fever, malaise, and the typical diffuse rash. The average time from virus exposure to development of the rash is 14 to 15 days, though the time can be as short as 10 days or as long as 20 days. 2 The child or young adult becomes infectious approximately 48 hours before the onset of vesicle eruption and may remain infectious for 4 to 5 days after vesicle eruption. Approximately 10% of patients older than 15 years are considered susceptible for primary VZV infection. 2 The Advisory Committee on Immunization Practices of the United States Centers for Disease Control and Prevention revised the criteria for evidence of VZV immunity in The criteria for evidence of immunity now include documentation of age-appropriate administration of the live attenuated VZV vaccine, which should be given in one dose to children aged 12 months to 12 years, and in two doses to adolescents and adults. Evidence of immunity also includes laboratory test results indicating immunity or confirmation of chickenpox; diagnosis of chickenpox or verification of history of chickenpox by a healthcare provider; or verification of history of herpes zoster based on diagnosis by a healthcare provider. Such a diagnosis of herpes zoster should include a fairly accurate description of the rash. An individual may also be considered immune to VZV if he or she was born in the United States before 1980 unless that individual is pregnant or a healthcare worker. 2 Herpes Zoster Epidemiology Herpes zoster occurs as a more sporadic disease than does primary VZV infec- This supplement is supported by an independent educational grant from Merck & Co, Inc. S2 JAOA Supplement 2 Vol 109 No 6 June 2009

2 Reactivation VZV Latency in Dorsal Root Ganglia Spinal Cord Herpes Zoster Primary VZV Infection Figure 1. Primary varicella-zoster virus (VZV) infection (ie, chickenpox) typically occurs during childhood. Viral latency subsequently develops along the spinal cord in dorsal root ganglia. Later in life, the virus reactivates usually in a dermatomal distribution causing the secondary infection known as herpes zoster (ie, shingles). Sources: Arvin AM. Varicella-zoster virus. In: Knipe DM, Howley PM, eds. Fields Virology. Vol 2. 4th ed. Philadelphia, Pa: Lippincott Williams & Wilkins ( 2001: ; Straus SE, Oxman MN. Varicella and herpes zoster. In: Freedberg IM, Eisen AZ, Wolff K, et al, eds. Fitzpatrick s Dermatology in General Medicine. Vol 2. 5th ed. New York, NY: McGraw-Hill; 1999: tion. Primary VZV is transmitted from person to person by direct contact, inhalation of aerosols from vesicular fluid of skin lesions, or infected respiratory tract secretions that are aerosolized. Herpes zoster is typically transmitted person to person by direct contact. Because of its respiratory transmission, VZV can cause an epidemic among susceptible hosts. In the United States, more than 90% of adults are susceptible to herpes zoster infection, and there is no way to predict in whom the infection will reactivate. 1 The lifetime risk for development of herpes zoster is estimated to be approximately 30% meaning that the illness will occur in about one in three adults. 3,4 An estimated 1 million new cases of herpes zoster occur each year in the United States, 5 resulting in 50,000 to 60,000 hospitalizations. Recurrence of shingles is uncommon. Only an estimated 4% of patients will experience a second episode of shingles, and third episodes are even rarer. 5 The incidence and severity of herpes zoster increase with advancing age (Figure 2). 5 Approximately 40% to 50% of the 1 million new cases that occur each year develop in individuals who are at least 60 years of age. 5 Among individuals who reach age 85 years, as many as 50% will have experienced at least one episode of herpes zoster. 4,6 With each decade of life, the incidence rate of herpes zoster per thousand person-years steadily increases. The increased risk of herpes zoster associated with advancing age is at least partly caused by immunosenescence, the gradual deterioration of the immune system that is part of the natural aging process. Specific age-related decline in cell-mediated immunity to VZV also contributes to this increased risk. 7 In addition to the role played by advancing age, immunosuppression increases the risk for development of herpes zoster. In fact, herpes zoster is the earliest opportunistic infection observed in patients with human immunodeficiency virus (HIV)/AIDS as their CD4 T- cell count declines. Patients who are immunocompromised have earlier and increased manifestations of herpes zoster infection than those who are not immunocompromised The management of HIV/AIDS or other immunocompromising diseases may also contribute to herpes zoster development. For example, one of the most powerful risk factors for herpes zoster infection is the use of systemic corticosteroids, which are part of the standard management of most autoimmune diseases. Despite the increased risk of herpes zoster associated with immunosuppres- JAOA Supplement 2 Vol 109 No 6 June 2009 S3

3 Rate per 1000 person-years* (95% CI) Figure 2. Age-specific incidence rates (across both sexes) of herpes zoster from a healthcare claims database of more than 2.8 million individuals for the years , sex-adjusted to the 2000 United States population. Approximately 40% to 50% of the 1 million new cases of herpes zoster that occur each year develop in individuals who are 60 years of age or older. Source: Insinga RP, et al. The incidence of herpes zoster in a United States administrative database. J Gen Intern Med. 2005;20: sion, 70% to 80% of patients hospitalized for this condition are immunocompetent Clinical Manifestations As previously mentioned, herpes zoster is the consequence of the primary VZV infection reactivating after a period of dormancy in the dorsal root ganglia. Herpes zoster is characterized by a unilateral vesicular eruption in a dermatomal distribution, with thoracic and cranial and cervical distributions being the most common. Zoster lesions contain high concentrations of VZV, which can be spread to susceptible individuals by direct contact with the lesions. Localized herpes zoster is contagious from the time of rash eruption until the time of lesion crusting. The rate of transmission of herpes zoster infection is lower than that of primary VZV infection. 13 Figure 3 displays the stages of clinical manifestation of herpes zoster. In the initial stage of herpes zoster infection, known as the prodromal phase, patients may report such symptoms as headache, pain, malaise, and acute photophobia before the rash appears. After the prodromal phase, the acute phase is characterized by the dermatomal rash. The herpes zoster rash is typically unilateral, not crossing the midline of the body. 4,13 The rash may be accompanied by unbearable itching, altered sensitivity to touch, or allodynia (ie, pain at the site provoked by innocuous stimuli). Pain may also be felt before the rash develops. Age Group, y In some cases, patients experience the allodynia, pain, itching, and burning without a rash ever developing a condition known as zoster sine herpete. Initially, the rash is erythematous and maculopapular, but it progresses to take the form of coalescing clusters of clear vesicles containing high concentrations of VZV. 4,13 The rash typically lasts 7 to 10 days and fully heals within 2 to 4 weeks. However, permanent scarring and altered pigmentation occur in some cases. If the infection does not resolve after the acute phase, complications, such as postherpetic neuralgia (PHN), may develop. 4,13 Diagnosis A diagnosis of herpes zoster is often made based on the localization and morphologic characteristics of the rash. However, the rash associated with herpes zoster is sometimes confused with that of herpes simplex virus (HSV). Physicians should keep in mind that a rash that is recurrent in the same dermatome is most likely HSV. A comparison of VZV and HSV is available elsewhere in this supplement to JAOA The Journal of the American Osteopathic Association. 14 The varicella-zoster virus can be collected from lesions and identified using tissue culture, but this is a time-consuming process, and false-negative results may occur because viable virus is difficult to obtain from cutaneous lesions. Polymerase chain reaction (PCR) can be used to detect the DNA of VZV from collected lesion material. However, this technique is not widely available. Direct fluorescent antibody staining of VZV-infected cells obtained by scraping the base of the lesion is a rapid and sensitive method for diagnosis of herpes zoster. This technique is useful for evaluation of atypical skin lesions to guide early treatment decisions. When the symptoms of allodynia, pain, burning, and itching manifest without the rash, herpes zoster is especially difficult to diagnose. As a result of its localization, pain is often misdiagnosed as a gallbladder attack or appendicitis and is mismanaged until a rash develops. Results of recent studies 15,16 suggest that PCR can be used to positively identify VZV DNA in patients blood before symptoms manifest. Thus, PCR has potential application as a diagnostic tool for identifying patients who are in the prodromal phase of herpes zoster and patients who have zoster sine herpete, allowing these individuals to receive treatment before rash and nerve damage develop. Complications Postherpetic neuralgia is a common and potentially debilitating complication of herpes zoster that is difficult to manage. It is characterized by pain or dysesthesia that persists after resolution of the rash. Postherpetic neuralgia occurs in 10% to 18% of patients with herpes zoster, and the risk for development of this complication increases with advancing age. 17 The severity of pain in PHN ranges from mild to excruciating, and it can be constant, intermittent, or triggered by such stimuli as clothes touching the skin. S4 JAOA Supplement 2 Vol 109 No 6 June 2009

4 Prodromal Phase Acute photophobia, pain, headache, malaise Resolution Acute Phase Dermatomal rash, pain, unbearable itching, altered sensitivity to touch Complications May or may not occur; common complication is postherpetic neuralgia. Figure 3. Clinical manifestations of herpes zoster. In the initial stage of herpes zoster (ie, prodromal phase), patients may experience headache, pain, malaise, and acute photophobia before the rash appears. After the prodromal phase, the acute phase is characterized by the dermatomal rash, as well as by pain, unbearable itching, and altered sensitivity to touch. The rash typically heals within 2 to 4 weeks. If the infection does not resolve after the acute phase, complications, such as postherpetic neuralgia, may develop. Sources: Oxman MN. Clinical manifestations of herpes zoster. In: Arvin AM, Gershon AA, eds. Varicella-Zoster Virus: Virology and Clinical Management. Cambridge, England: Cambridge University Press; 2000: Copyright 2000 Cambridge University Press. Reprinted with permission. Harpaz R, et al. Prevention of herpes zoster: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2008;57(RR-5):1-30,CE Although allodynia affects 45% to 55% of patients with herpes zoster, it may affect as many as 90% of those with PHN. 18 The pain associated with herpes zoster or PHN may last for a few minutes or occur as chronic pain. The duration of PHN has been found to be inconsistent, ranging from 30 days to 6 months or longer after rash onset. In some cases, the pain persists for years Postherpetic neuralgia adversely affects the patient s quality of life as a result of its potential to interfere with sleep, work, and other activities of daily living, leading to social withdrawal and depression. 4 In a study by Katz and Melzack, 21 in which patients were asked to compare the pain associated with PHN with other types of pain they had experienced, pain associated with PHN was ranked as more severe than labor pain, postsurgical pain, arthritis pain, and chronic cancer-related pain. Pathologic mechanisms believed to cause the transition from uncomplicated herpes zoster to PHN include axonal and cell-body degeneration, atrophy of the spinal cord dorsal horn, scarring of the dorsal root ganglia, and loss of epidermal innervations in the affected region. In addition to PHN, other neurologic complications that can result from herpes zoster include chronic sensory loss at the site of the rash, limb weakness, and autonomic dysfunction related to the site of the rash (eg, bladder dysfunction if the rash has sacral dermatomal distribution). More severe neurologic complications include en ceph alitis, meningitis, and myelitis. Bacterial superinfection, particularly with methicillin-resistant Staphylococcus aureus, can also occur. Disseminated disease, with a mortality rate as high as 40%, is a complication that is observed mainly in patients who are immunosuppressed. 4 Herpes zoster ophthalmicus, which is prevalent in 10% to 25% of patients with herpes zoster, can occur when reactivation of latent VZV involves the first division of the trigeminal nerve. 4 Ophthalmic herpes zoster is a severe complication that is difficult to manage. Affected patients require admission to the hospital and administration of intravenous acyclovir and, in some cases, intravenous immunoglobulin. Even after aggressive management, patients may have long-term sequelae, including vision loss and pain related to the location of the rash, stemming from herpes zoster ophthalmicus. Keratitis occurs in approximately two-thirds of patients with herpes zoster ophthalmicus. 4 Conclusion Herpes zoster infection results from the reactivation of VZV in the dorsal root ganglia. It typically results in a rash with a unilateral dermatomal distribution, which usually resolves within 2 to 4 weeks. Herpes zoster may or may not lead to PHN or other long-term complications, depending on the case. References 1. Gnann Jr JW, Whitley RJ. Clinical practice. Herpes zoster [review]. N Engl J Med. 2002;347: Marin M, Guris D, Chaves SS, Schmid S, Seward JF; Advisory Committee on Immunization Practices (ACIP). Prevention of varicella: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2007;56(RR-4):1-40. Available at: /mmwrhtml/rr5604a1.htm. Accessed March 16, Yawn BP, Saddier P, Wollan PC, St Sauver JL, Kurland MJ, Sy LS. A population-based study of the incidence and complication rates of herpes zoster before zoster vaccine introduction [pub- JAOA Supplement 2 Vol 109 No 6 June 2009 S5

5 lished correction appears in Mayo Clin Proc. 2008; 83:255]. Mayo Clin Proc. 2007;82: Available at: /content/82/11/1341.long. Accessed March 16, Harpaz R, Ortega-Sanchez IR, Seward JF. Prevention of herpes zoster: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2008;57(RR-5):1-30,CE2-4. Available at: /preview/mmwrhtml/rr57e0515a1.htm?s_cid=rr57e0 515_e. Accessed March 11, Insinga RP, Itzler RF, Pellissier JM, Saddier P, Nikas AA. The incidence of herpes zoster in a United States administrative database. J Gen Intern Med. 2005;20: Available at: medcentral.nih.gov/articlerender.fcgi?tool=pubmed &pubmedid= Accessed March 16, Schmader KE. Epidemiology and impact on quality of life of postherpetic neuralgia and painful diabetic neuropathy [review]. Clin J Pain. 2002;18: Burke BL, Steele RW, Beard OW, Wood JS, Cain TD, Marmer DJ. Immune responses to varicellazoster in the aged. Arch Intern Med. 1982;142: Gnann JW, Whitley RJ. Natural history and treatment of varicella-zoster in high-risk populations. J Hosp Infect. 1991;18(suppl A): Gnann JW Jr, Whitley RJ. Clinical practice. Herpes zoster. N Engl J Med. 2002;347: Available at: /5/340. Accessed April 29, Gershon AA. Prevention and treatment of VZV infections in patients with HIV. Herpes. 2001;8: Smitten AL, Choi HK, Hochberg MC, Suissa S, Simon TA, Testa MA, Chan KA. The risk of herpes zoster in patients with rheumatoid arthritis in the United States and the United Kingdom. Arthritis Rheum. 2007;57: Available at: http: //www3.interscience.wiley.com/cgi-bin/fulltext / /HTMLSTART. Accessed April 29, Gupta G, Lautenbach E, Lewis JD. Incidence and risk factors for herpes zoster among patients with inflammatory bowel disease. Clin Gastroenterol Hepatol. 2006;4: Oxman MN. Clinical manifestations of herpes zoster. In: Arvin AM, Gershon AA, eds. Varicella- Zoster Virus: Virology and Clinical Management. Cambridge, England: Cambridge University Press; 2000: Oxman MN. Herpes zoster pathogenesis and cell-mediated immunity and immunosenescence. J Am Osteopath Assoc. 2009;109(suppl 2):S13-S Dobec M, Bossart W, Kaeppeli F, Mueller- Schoop J. Serology and serum DNA detection in shingles. Swiss Med Wkly. 2008;138: Engelmann I, Petzold DR, Kosinska A, Hepkema BG, Schulz TF, Heim A. Rapid quantitative PCR assays for the simultaneous detection of herpes simplex virus, varicella zoster virus, cytomegalovirus, Epstein-Barr virus, and human herpesvirus 6 DNA in blood and other clinical specimens [published correction appears in J Med Virol. 2008;80:1505; 2008;80:2177]. J Med Virol. 2008;80: Choo PW, Galil K, Donahue JG, Walker AM, Spiegelman D, Platt R. Risk factors for postherpetic neuralgia. Arch Intern Med. 1997;157: De Moragas JM, Kierland RR. The outcome of patients with herpes zoster. AMA Arch Derm. 1957;75: Watson PN, Evans RJ. Postherpetic neuralgia. A review. Arch Neurol. 1986;43: Kost RG, Straus SE. Postherpetic neuralgia pathogenesis, treatment, and prevention. N Engl J Med. 1996;335: Katz J, Melzack R. Measurement of pain. Surg Clin North Am. 1999;79: Video of Supplement s Content Available Online The contents of this supplement to JAOA The Journal of the American Osteopathic Association were developed mainly from an expert panel discussion held October 29, 2008, during the American Osteopathic Association s 113th Annual Convention and Scientific Seminar in Las Vegas, Nev. A video of the discussion is posted at under the Featured CME tab. Members of the AOA can access the video using their AOA identification numbers and DO-Online passwords. Alternatively, registered users of CE Medicus can access the video at Healthcare professionals who are not registered on CE Medicus can obtain a user name and password by clicking on the Register Free Now link at S6 JAOA Supplement 2 Vol 109 No 6 June 2009