In the Clinic

Herpes Zoster
Prevention Screening Diagnosis Treatment Tool Kit Patient Information CME Questions
Section Editors Deborah Cotton, MD, MPH Darren Taichman, MD Sankey Williams, MD Science Writer Jennifer F. Wilson

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The content of In the Clinic is drawn from the clinical information and education resources of the American College of Physicians (ACP), including PIER (Physicians Information and Education Resource) and MKSAP (Medical Knowledge and SelfAssessment Program). Annals of Internal Medicine editors develop In the Clinic from these primary sources in collaboration with the ACPs Medical Education and Publishing divisions and with the assistance of science writers and physician writers. Editorial consultants from PIER and MKSAP provide expert review of the content. Readers who are interested in these primary resources for more detail can consult http://pier.acponline.org, http://www.acponline.org/products_services/ mksap/15/?pr31, and other resources referenced in each issue of In the Clinic. CME Objective: To review current evidence for the prevention, screening, diagnosis, and treatment of herpes zoster. The information contained herein should never be used as a substitute for clinical judgment. 2011 American College of Physicians

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1. Schmader KE, Dworkin RH. Natural history and treatment of herpes zoster. J Pain. 2008;9:S3-9. [PMID:18166460] 2. Kilgore PE, KruszonMoran D, Seward JF, Jumaan A, Van Loon FP, Forghani B, et al. Varicella in Americans from NHANES III: implications for control through routine immunization. J Med Virol. 2003;70 Suppl 1:S111-8. [PMID:12627498] 3. Rimland D, Moanna A. Increasing incidence of herpes zoster among Veterans. Clin Infect Dis. 2010;50:1000-5. [PMID:20178416] 4. LaRussa P, Steinberg SP, Shapiro E, Vazquez M, Gershon AA. Viral strain identification in varicella vaccinees with disseminated rashes. Pediatr Infect Dis J. 2000;19:1037-9. [PMID:11099082] 5. Sharrar RG, LaRussa P, Galea SA, Steinberg SP, Sweet AR, Keatley RM, et al. The postmarketing safety profile of varicella vaccine. Vaccine. 2000;19:916-23. [PMID:11115716] 6. Harpaz R, OrtegaSanchez IR, Seward JF; Advisory Committee on Immunization Practices (ACIP) Centers for Disease Control and Prevention (CDC). Prevention of herpes zoster: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2008;57:1-30; quiz CE2-4. [PMID:18528318] 7. Hurley LP, Harpaz R, Daley MF, Crane LA, Beaty BL, Barrow J, et al. National survey of primary care physicians regarding herpes zoster and the herpes zoster vaccine. J Infect Dis. 2008;197 Suppl 2:S216-23. [PMID:18419400] 8. Kerzner B, Murray AV, Cheng E, Ifle R, Harvey PR, Tomlinson M, et al. Safety and immunogenicity profile of the concomitant administration of ZOSTAVAX and inactivated influenza vaccine in adults aged 50 and older. J Am Geriatr Soc. 2007;55:1499-507. [PMID:17908055]

erpes zoster, a painful skin rash that is commonly known as shingles, occurs in approximately 1 million people in the United States annually (1). Herpes zoster can develop in anyone who has had varicella (chickenpox). About 95% of the adult U.S. population has had varicella and thus can have herpes zoster. Approximately one third of persons will have an episode of herpes zoster, and the frequency increases with increasing age. Herpes zoster occurs when the varicella zoster virus, which causes both varicella and herpes zoster, is reactivated from its latent state in the dorsal root or cranial nerve ganglia and spreads through the afferent nerve to the skin.

Both zoster (Greek) and shingles (French and Latin) translate to the English word belt, which describes the characteristic narrow, band-like rash from the spine around to the front of the torso on just one side of the body; it can also occur on the face, eyes, mouth, and ears. The rash includes skin inflammation and blisters, lasts about 2 to 4 weeks, and sometimes causes scarring and permanent pigment changes. Pain, which can be intense and disabling, occurs frequently in the distribution of the rash.

Prevention
What are the risk factors for herpes zoster? Herpes zoster can occur at any age in someone who has had varicella. Before vaccination became available in 1995, almost all children contracted varicella and thus most adults in the United States have been exposed. For example, antibodies to the virus are currently found in 95.5% of people aged 20 to 29, 98.9% of people aged 30 to 39, and more than 99.6% of people over age 40 (2). Herpes zoster is most common in people older than 60 years who have age-related weakening of the immune system. It also occurs more often in immunocompromised persons, including those treated with chemotherapy, radiotherapy, or steroids, and persons with disease-related immunosuppression from HIV/AIDS, diabetes mellitus, or cancer. Having varicella before 1 year of age also increases the risk. Clinicians are only rarely able to establish a trigger or proximate cause. Immunity develops once a person has herpes zoster, so recurrence is uncommon. Exposure to a person with herpes zoster can lead to varicella in a person who has not had varicella. Some research shows that the incidence of herpes zoster is increasing. For example, a review of Veterans Affairs health records found that the incidence of herpes zoster in men and women > 40 years of age increased from 3.1 episodes/1000 persons per year in 2000 to 5.2/1000 persons per year in 2007 (R2 = 0.9743; P <0.001) (3). Who should receive the vaccine against varicella zoster? Varivax, a varicella zoster virus vaccine, is recommended to prevent varicella in all children and adults who are seronegative for antibodies to varicella zoster virus. It remains unclear how the vaccine affects the frequency and severity of herpes zoster, but the vaccine can cause latent infection of sensory neurons and subsequent herpes zoster (4, 5). Zostavax is a concentrated formulation of Varivax that the U.S. Food and Drug Administration (FDA) has approved to prevent herpes zoster and its complications in immunocompetent adults aged 60 years. The Advisory Committee on Immunization Practices (ACIP) recommends the vaccine for its approved indications (6). A national survey of general internists and family physicians indicates that most primary care physicians

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recommend the vaccine against herpes zoster for patients 60 to 79 years of age (n = 871; response rate, 69%) (7). Because it is a live vaccine, it is contraindicated in some people (see the Box: People Who Should Not Be Vaccinated Against Herpes Zoster). The vaccine against herpes zoster should be given as a single, 0.65-mL dose subcutaneously in the deltoid region of the arm. People need not be asked or tested for previous varicella. The vaccine is indicated regardless of whether the person has had a prior episode of herpes zoster, although people with active herpes zoster should wait until the rash has healed before getting vaccinated. A booster dose is not currently recommended. Antiviral medications, such as acyclovir and valacyclovir, should not be used within 24 hours before or 14 days after vaccination. The most common side effects are itching; headache; and redness, pain, tenderness, and swelling at the injection site. The vaccine can be given at the same time as influenza vaccine without altering the immune response to either agent (8). What is the evidence that the vaccine works?
In the Shingles Prevention Study, investigators enrolled 38 546 adults with a history of varicella who were 60 years of age into a double-blind, randomized, controlled trial (RCT) to evaluate whether the vaccine against herpes zoster decreased the incidence and severity of herpes zoster. After a median 3.1 years, the investigators found significantly reduced morbidity from herpes zoster and postherpetic neuralgia (9). There were 957 cases of herpes zoster, 315 among vaccine recipients and 642 among placebo recipients, and 107 cases of postherpetic neuralgia, 27 among vaccine recipients and 80 among placebo recipients. The vaccine reduced the burden of illness due to herpes zoster by 61.1% (P<0.001), reduced the incidence of postherpetic neuralgia by 66.5% (P<0.001), and reduced the incidence of herpes zoster by 51.3 % (P<0.001). The vaccine was more effective in preventing herpes zoster for adults 60 to 69 years of age than for those 70 years or older, but it prevented

more postherpetic neuralgia in adults aged 70 years than in younger adults. Follow-up studies indicate that the vaccine is effective for at least 6 years.

People Who Should Not Be Vaccinated Against Herpes Zoster

People who have had a lifethreatening allergic reaction to gelatin or neomycin. People who have a severe allergy to any component of the vaccine. People with a weakened immune system as a result of leukemia, lymphoma, or another blood or bone cancer. People with HIV/AIDS who have Tcell counts <200. People being treated with drugs that affect the immune system, including high-dose steroids. Women who are or might be pregnant. Source: Centers for Disease Control and Prevention.

The vaccine was designed to boost cell-mediated immune responses, which should keep latent varicella zoster virus from reactivating and thus prevent herpes zoster. The strategy apparently was successful, because investigators found an enhanced cytotoxic lymphocyte response specific for varicella zoster virus in elderly seropositive persons who received the vaccine (10). The vaccine also seems to be safe.
A secondary report of the Shingles Prevention Study examined vaccine safety in the main study group of 38 546 participants and included an adverse events substudy of 6616 participants (11). More side effects at the inoculation site, such as redness and tenderness, occurred in vaccine recipients than in the placebo recipients (48% vs. 16%), but these effects were mostly mild or moderate. The frequency of serious adverse events (1.4%) was the same in the vaccine and placebo groups. An observational study of 75 761 vaccinated and 227 283 unvaccinated people aged 60 years confirmed that the vaccine works outside of a research setting in clinical practice (12). In these conditions, the vaccine reduced the frequency of herpes zoster (hazard ratio [HR], 0.45 [95% CI, 0.42 to 0.48]), herpes zoster involvement of the eye (HR, 0.37[CI, 0.23 to 0.61]), and hospitalizations coded as herpes zoster (HR, 0.35 [CI, 0.24-0.51]).

What are the barriers to vaccination? Fewer than 10% of eligible people in the United States receive the vaccine against herpes zoster (13), primarily due to cost and cost-effectiveness issues. It costs $100 to $300, which makes it the most expensive vaccine recommended for older adults. A cost-effectiveness model that compared varicella zoster vaccination with usual care for healthy adults aged >60 years estimated that vaccination increased life expectancy by 0.0007 to 0.0024 quality-adjusted life-years

9. Oxman MN, Levin MJ, Johnson GR, Schmader KE, Straus SE, Gelb LD, et al; Shingles Prevention Study Group. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med. 2005;352:227184. [PMID:15930418] 10. Levin MJ, Barber D, Goldblatt E, Jones M, LaFleur B, Chan C, et al. Use of a live attenuated varicella vaccine to boost varicella-specific immune responses in seropositive people 55 years of age and older: duration of booster effect. J Infect Dis. 1998;178 Suppl 1:S109-12. [PMID:9852987] 11. Simberkoff MS, Arbeit RD, Johnson GR, Oxman MN, Boardman KD, Williams HM, et al; Shingles Prevention Study Group. Safety of herpes zoster vaccine in the shingles prevention study: a randomized trial. Ann Intern Med. 2010;152:545-54. [PMID:20439572] 12. Tseng HF, Smith N, Harpaz R, Bialek SR, Sy LS, Jacobsen SJ. Herpes zoster vaccine in older adults and the risk of subsequent herpes zoster disease. JAMA. 2011;305:160-6. [PMID:21224457]

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Recommendations for Varicella Vaccination

Children*: http://aapredbook.aappublications.org/ resources/IZSchedule0-6yrs.pdf) Adolescents*: http://aapredbook.aappublications.org/ resources/IZSchedule7-18yrs.pdf Adults: www.annals.org/content/152/1/36.full .pdf+html *Published by the American Academy of Pediatrics. Advisory Committee on Immunization. Practices.

per person by preventing the acute pain of herpes zoster and postherpetic neuralgia (14). The cost-effectiveness varied substantially with patient age and often exceeded $100,000 per quality-adjusted lifeyear. Another modeling study estimated that the vaccine would be reasonably cost-effective if it were <$200, it remained effective for >30 years, and people were vaccinated between ages 60 to 69 years (15). Reimbursement is also an issue. A 2008 national survey of 301 general internists and 297 family medicine physicians with a 72% response rate found that 41% of providers strongly recommended the vaccine against herpes zoster compared with 90% who strongly recommended the vaccines against influenza and pneumococcal disease (16). Physicians reported that the main barriers to vaccination were the high cost and reimbursement problems. Just 45% of physicians knew that Medicare pays for the vaccine through Medicare Part D instead of Medicare Part B, which pays physicians for nearly all other Medicare services. Twelve percent of physicians had stopped administering the vaccine against herpes zoster in their offices because of cost and reimbursement issues. Does childhood vaccination against varicella prevent herpes zoster? In 1995, the United States implemented a vaccination program for children 12 to 18 months of age to prevent varicella. The National Immunization Survey found that from 1997 to 2005, the percentage of children 19 to 35 months of age who received at least 1 dose of varicella vaccine increased from 26% to 88%. By 2008, all but 2 states required vaccination against varicella virus for children in child care settings or schools or both (see the Box: Recommendations for Varicella Vaccination).

13. Advisory Committee on Immunization Practices. Recommended adult immunization schedule: United States, 2010. Ann Intern Med. 2010;152:36-9. [PMID:20048270] 14. Rothberg MB, Virapongse A, Smith KJ. Cost-effectiveness of a vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. Clin Infect Dis. 2007;44:1280-8. [PMID:17443464] 15. Hornberger J, Robertus K. Cost-effectiveness of a vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. Ann Intern Med. 2006;145:317-25. [PMID:16954357] 16. Hurley LP, Lindley MC, Harpaz R, Stokley S, Daley MF, Crane LA, et al. Barriers to the use of herpes zoster vaccine. Ann Intern Med. 2010;152:555-60. [PMID:20439573] 17 Reynolds MA, Chaves SS, Harpaz R, Lopez AS, Seward JF. The impact of the varicella vaccination program on herpes zoster epidemiology in the United States: a review. J Infect Dis. 2008;197 Suppl 2:S224-7. [PMID:18419401]

The evidence about the effect on herpes zoster of childhood vaccination against varicella is conflicting (17). One study suggested that the frequency of herpes zoster increased as vaccine coverage against varicella in children increased and the frequency of varicella decreased (18). Other studies have not confirmed these findings. One study by the Centers for Disease Control and Prevention found that the incidence of herpes zoster remained stable as the incidence of varicella decreased (19). Another study compared herpes zoster incidence rates between 2 states with different rates of varicella vaccine coverage and determined that the higher incidence of herpes zoster in 1 state was due to increased use of childhood oral corticosteroids for wheezing conditions, not differences in vaccination rates (20). Another study of immunocompromised children who received varicella vaccine found that the incidence of herpes zoster 10 to 26 years later in this group was similar to that of the general U.S. population in the prevaccine era (21). Furthermore, Canada and the United Kingdom report increasing rates of herpes zoster in the absence of varicella vaccination programs, which suggests that risk factors other than varicella vaccination are involved. When should low-dose acyclovir be considered to prevent herpes zoster? Low-dose acyclovir may be used to prevent herpes zoster in immunocompromised patients who cannot receive the vaccine against varicella zoster virus because it contains a live virus. For example, the National Comprehensive Cancer Network guidelines (22) recommend herpes zoster prophylaxis for patients receiving bortezomib or bortezomibbased therapies and for recipients of allogenic transplants of peripheral blood stem cells. In 1 trial, researchers detected varicella zoster virus, presumably from reactivation, in 13% of patients with multiple

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myeloma who were treated with bortezomib-melphalan-prednisone, compared with 4% in patients treated with melphalan-prednisone alone. However, with addition of acyclovir prophylaxis, the rate of varicella zoster virus decreased to 3% in the bortezomib-treated patients (23). In a retrospective study, prophylactic acyclovir was associated with no cases of varicella zoster virus reactivation in patients with multiple myeloma who received bortezomib-based therapy (24). A daily low dose of acyclovir that was given until engraftment or discontinuation of immunosuppression prevented herpes zoster in patients with allogeneic transplants of peripheral blood stem cells during a median 26.5 months of follow-up (25). In a retrospective cohort

study, acyclovir until the end of immunosuppressive therapy and 1 year after transplantation was associated with a decreased incidence of varicella zoster virus and with prevention of death and severe symptoms related to varicella zoster virus after allogeneic transplantation of hematopoietic stem cells (26). Clinicians should prescribe low-dose oral acyclovir at 400 to 800 mg per day for these patients. Other antiviral agents, such as valacyclovir, 250 or 500 mg/d, and famciclovir, 500 mg/d, can also be used as prophylaxis for varicella zoster virus. Although the risk for reactivation of varicella zoster virus increases with antitumor necrosis factor- therapy, antiviral prophylaxis is not yet recommended for patients who receive this therapy (27).

Prevention... Although herpes zoster (shingles) can occur at any age in people
who have had varicella (chickenpox), it occurs most commonly in people older than 60 years who have age-related immune system weakening and in people who are immunocompromised. Experts recommend a live-virus vaccine to prevent varicella in children and adults who do not have antibodies against varicella zoster virus. They also recommend a concentrated formulation of the vaccine against varicella to prevent herpes zoster in adults 60 years of age. Because it contains a live virus, the vaccine against herpes zoster is contraindicated in some people, including those with a weakened immune system. Low-dose acyclovir can prevent herpes zoster in immunocompromised patients who cannot receive the vaccine against varicella zoster. The effect on herpes zoster of the vaccination program against childhood varicella remains unclear.

CLINICAL BOTTOM LINE

Screening
Can serologic tests help guide decisions about vaccination for herpes zoster? Titers of serologic antibodies against varicella zoster virus establish whether immunity is present and thus could guide decisions about whether vaccination is needed (28). However, screening before vaccination is generally not necessary because nearly all older U.S. adults are seropositive and because it is safe to vaccinate persons already immune to the disease. However, it could be cost-effective depending on the cost of the screening test. Knowledge of immune status may be useful because immunocompetent adults who are seronegative should receive the varicella vaccine, not the zoster vaccine. The ACIP does not recommend serologic testing for persons younger than age 13, and it advises that serologic testing may be considered for persons 13 years who do not have a history of varicella. It does not recommend postvaccination serologic testing in any group.

18 Yih WK, Brooks DR, Lett SM, Jumaan AO, Zhang Z, Clements KM, et al. The incidence of varicella and herpes zoster in Massachusetts as measured by the Behavioral Risk Factor Surveillance System (BRFSS) during a period of increasing varicella vaccine coverage, 19982003. BMC Public Health. 2005;5:68. [PMID:15960856] 19. Jumaan AO, Yu O, Jackson LA, Bohlke K, Galil K, Seward JF. Incidence of herpes zoster, before and after varicella-vaccination-associated decreases in the incidence of varicella, 1992-2002. J Infect Dis. 2005;191:2002-7. [PMID:15897984] 20. Mullooly JP, Riedlinger K, Chun C, Weinmann S, Houston H. Incidence of herpes zoster, 19972002. Epidemiol Infect. 2005;133:24553. [PMID:15816149] 21. Hambleton S, Steinberg SP, Larussa PS, Shapiro ED, Gershon AA. Risk of herpes zoster in adults immunized with varicella vaccine. J Infect Dis. 2008;197 Suppl 2:S196-9. [PMID:18419397] 22. National Comprehensive Cancer Network; guidelines. Accessed at www.nccn.org/index.asp on January 13, 2011. 23. San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, et al; VISTA Trial Investigators. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008;359:906-17. [PMID:18753647] 24. Vickrey E, Allen S, Mehta J, Singhal S. Acyclovir to prevent reactivation of varicella zoster virus (herpes zoster) in multiple myeloma patients receiving bortezomib therapy. Cancer. 2009;115:229-32. [PMID:19090004]

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Screening... Screening for serologic antibodies to the varicella zoster virus before vaccination is generally not required because it is safe to vaccinate people who are already immune to the disease. Screening provides information about the status of immunity that might, however, be useful to some people.

CLINICAL BOTTOM LINE

Diagnosis
What symptoms are typical? Herpes zoster is characterized by a band-like rash in the dermatome that corresponds to the affected nerve (Figure 1). The rash is unilateral and does not cross the midline. Overlap of lesions in adjacent dermatomes occurs in 20% of patients. The most commonly involved dermatomes are thoracic, followed by cranial (especially trigeminal), lumbar, and cervical. Sacral dermatomes are least frequently involved. Simultaneous involvement of noncontiguous dermatomes virtually never occurs in the immunocompetent host, but finding a few isolated skin lesions outside of the primary dermatome is not unusual. Diagnosis is more difficult in patients who have neuralgic pain before skin lesions develop. Patients may report localized sensations ranging from mild itching or tingling to severe pain that precedes the development of the skin lesions by 1 to 5 days, or occasionally even weeks. Pain that is provoked by light touch may be present. Other possible symptoms include a general feeling of being unwell, headache, photophobia, and malaise. Significant fever is rare. What tests should be used for diagnosis? When the clinical diagnosis of herpes zoster is not obvious, clinicians should order confirmatory laboratory testing (Table 1). Confirmation of the diagnosis is particularly important when antiviral therapy is planned. What conditions can be confused with herpes zoster? The clinical appearance of fully developed herpes zoster is quite distinct and mimicked by few other

Figure 1. Clusters of vesicles with surrounding erythema, characteristic of early herpes zoster.

Table 1. Laboratory Studies for Diagnosing Herpes Zoster

Viral culture A viral culture is 30% to 70% sensitive and 100% specific for varicella zoster virus. Recovery of varicella zoster virus is highly de pendent on the stage of the lesions, the quality of the specimen collected, and the time elapsed between specimen collection and inoculation of tissue culture. For maximum yield, fluid from fresh vesicles should be aspirated into a tuberculin syringe containing viral transport media and delivered immediately to the virology laboratory. If delivery to the laboratory is delayed, the specimen should be refrigerated or stored on wet ice, not frozen. Growth of varicella zoster virus in tissue culture may take 3 to 14 days. PCR is useful for detecting varicella zoster virus DNA in fluids and can be used to detect the DNA in fluid taken from the vesicles. In patients with suspected varicella zoster virus myelitis and vasculopathy of zoster sine herpete, PCR on CSF is the test of choice along with antibody testing for varicella zoster virus. The PCR test is the most sensitive and specific diagnostic test; however, it is not widely available. DFA is more sensitive than viral culture and is a suitable alternative when PCR is not available. Using a modified Tzanck technique, cells are scraped from the base of the lesion with a scalpel blade or the bevel edge of a large-gauge needle, smeared on a glass slide, then stained by using fluorescein-conjugated monoclonal antibodies to detect viral glycoproteins. Unlike a traditional Tzanck smear, DFA can distinguish between herpes simplex virus and varicella zoster virus. Additional advantages of DFA assay over viral culture are lower cost and more rapid turnaround time. Patients with herpes zoster will, by definition, be varicella zoster virusseropositive at the onset of illness. Although some patients will show a boost in varicella zoster virus antibody titer after an episode of herpes zoster, serology is not a very sensitive or specific diagnostic method. Most laboratories use ELISA or latex agglutination methods. More sensitive assays, such as the fluorescent antibody to membrane antigen test and glycoprotein ELISA are not widely available. The latex agglutination test is generally more sensitive than ELISA for detecting varicella zoster virus antibody after natural infection or vaccination. Commercial ELISAs range in sensitivity from 86% to 97% and range in specificity from 82% to 99% in detecting antibody after natural infection.

PCR

Antigen detection

Serology

CSF = cerebrospinal fluid; DFA = direct fluorescent antigen; ELISA = enzyme-linked immunosorbent assay; PCR = polymerase chain reaction.

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diseases. The skin diseases most commonly confused with herpes zoster are contact dermatitis, especially toxic dermatitis from plant exposure, and zosteriform herpes simplex, especially in the sacral area. Immunocompetent patients believed to have recurrent herpes zoster often have recurrent herpes simplex infection instead. Consider an alternate diagnosis if the patient has a rash without pain or dysesthesias, if the rash does not conform to a dermatomal distribution, or if neuralgic pain persists without the typical skin eruption (Table 2). Additionally, because herpes zoster is a common sentinel disease for AIDS, clinicians may consider HIV serologic testing, especially in young adults. When should a specialist be consulted for assistance or specialized procedures to help diagnose herpes zoster? When the presentation of herpes zoster is atypical or complex, consult appropriate specialists for advice or specialized diagnostic procedures. An infectious disease specialist or dermatologist can provide assistance in recognizing atypical presentations or

with procedures, such as viral culture or skin biopsy. A herpes zoster rash that resists healing may indicate bacterial infection. An ophthalmologist can help diagnose herpes zoster involving the first division of the trigeminal nerve, which is herpes zoster ophthalmicus (Figure 2). This condition represents 10% to 25% of all cases of herpes zoster, and it has no known correlation with age, gender, or severity of the skin rash. Clinicians should be aware that patients with herpes zoster may have ophthalmic symptoms only, without the typical skin rash. A common indicator of herpes zoster ophthalmicus is the appearance of blisters on the tip of the nose, which is known as Hutchinson sign. The occurrence of severe ear pain, facial muscle weakness, and rash identify the RamsayHunt syndrome, an infection of the facial nerve caused by varicella zoster virus. An otolaryngologist should be consulted to help diagnose and treat this syndrome, which can lead to hearing loss and permanent facial muscle weakness, especially if treatment is delayed. Patients sometimes misinterpret this syndrome as a stroke.

Figure 2. Herpes zoster ophthalmicus.

Table 2. Differential Diagnosis of Herpes Zoster

HSV Herpes simplex virus (HSV) is characterized by clusters of painful vesicles on the skin. It can occasionally occur in an elongated distribution that may mimic herpes zoster, anywhere on the skin. HSV infection is sometimes misdiagnosed as herpes zoster. Patients who report multiple recurrences of herpes zoster (>2 episodes) should have definitive virologic testing to distinguish between HSV and varicella zoster virus. Recurrence of herpes zoster is rare in immunocompetent persons; HIV-infected persons may have multiple episodes. Contact dermatitis, such as reactions to rubber or nickel, or cutaneous reactions to topical medications, such as neomycin, can reactions cause localized areas of erythema and vesiculation that may mimic herpes zoster. Contact dermatitis does not, however, usually conform to a dermatomal distribution. Contact with toxic plants, such as poison ivy or poison oak, can cause painful skin erythema and vesiculation in a band-like irritationpattern. Dermatitis from topical toxins does not, however, usually conform to a dermatomal pattern. Some patients have neuralgic pain typical of herpes zoster but never develop cutaneous lesions, a condition known as zoster sine herpete. Because there is no diagnostic test for this disorder, the incidence is not known. Other conditions that involve herpes without neuralgic pain without rash include varicella zoster virus meningitis, polyneuritis cranialis, myelitis, and vasculopathy. In such zoster cases, polymerase chain reaction testing on cerebrospinal fluid is recommended.

Allergic

Chemical

Zoster

25. Kim DH, Kumar D, Messner HA, Minden M, Gupta V, Kuruvilla J, et al. Clinical efficacy of prophylactic strategy of longterm low-dose acyclovir for VaricellaZoster virus infection after allogeneic peripheral blood stem cell transplantation. Clin Transplant. 2008;22:770-9. [PMID:18707605] 26. Asano-Mori Y, Kanda Y, Oshima K, Kako S, Shinohara A, Nakasone H, et al. Longterm ultra-low-dose acyclovir against varicella-zoster virus reactivation after allogeneic hematopoietic stem cell transplantation. Am J Hematol. 2008;83:472-6. [PMID:18266207] 27. Strangfeld A, Listing J, Herzer P, Liebhaber A, Rockwitz K, Richter C, et al. Risk of herpes zoster in patients with rheumatoid arthritis treated with antiTNF-alpha agents. JAMA. 2009;301:73744. [PMID:19224750] 28. Sauerbrei A, Wutzler P. Serological detection of varicellazoster virus-specific immunoglobulin G by an enzymelinked immunosorbent assay using glycoprotein antigen. J Clin Microbiol. 2006;44:3094-7. [PMID:16954232]

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29 Helgason S, Petursson G, Gudmundsson S, Sigurdsson JA. Prevalence of postherpetic neuralgia after a first episode of herpes zoster: prospective study with long term follow up. BMJ. 2000;321:794-6. [PMID:11009518] 30. Bowsher D. The effects of pre-emptive treatment of postherpetic neuralgia with amitriptyline: a randomized, doubleblind, placebo-controlled trial. J Pain Symptom Manage. 1997;13:327-31. [PMID:9204652] 31. McKendrick MW, McGill JI, Wood MJ. Lack of effect of acyclovir on postherpetic neuralgia. BMJ. 1989;298:431. [PMID:2495051] 32. 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. Mayo Clin Proc. 2007;82:1341-9. [PMID:17976353] 33. Whitley RJ, Weiss HL, Soong SJ, Gnann JW. Herpes zoster: risk categories for persistent pain. J Infect Dis. 1999;179:9-15. [PMID:9841816] 34. Tyring S, Barbarash RA, Nahlik JE, Cunningham A, Marley J, Heng M, et al. Famciclovir for the treatment of acute herpes zoster: effects on acute disease and postherpetic neuralgia. A randomized, double-blind, placebo-controlled trial. Collaborative Famciclovir Herpes Zoster Study Group. Ann Intern Med. 1995;123:89-96. [PMID:7778840] 35. Shafran SD, Tyring SK, Ashton R, Decroix J, Forszpaniak C, Wade A, et al. Once, twice, or three times daily famciclovir compared with aciclovir for the oral treatment of herpes zoster in immunocompetent adults: a randomized, multicenter, double-blind clinical trial. J Clin Virol. 2004;29:248-53. [PMID:15018852]

Diagnosis... Varicella zoster virus produces a characteristic rash in the involved dermatome. Skin changes include an erythematous maculopapular rash followed by the appearance of clear vesicles for 3 to 5 days and subsequent pustulation and scabbing. Skin lesions heal within 2 to 4 weeks. Patients may report sensations that range from mild itching or tingling to severe pain preceding the development of skin lesions. The clinical appearance of fully developed herpes zoster is quite distinct and mimicked by few other diseases. When the clinical diagnosis of herpes zoster is not obvious, clinicians should order confirmatory laboratory testing. Skin diseases commonly confused with herpes zoster include contact dermatitis and herpes simplex virus infection. Consult with appropriate specialists when the presentation of herpes zoster is atypical or complex.

CLINICAL BOTTOM LINE

Treatment
What complications should the clinician anticipate? The pain of herpes zoster is called postherpetic neuralgia when it persists for more than 3 months after the cutaneous lesions of herpes zoster have completely resolved. The frequency of postherpetic neuralgia among people 60 years of age is about 40% at 1 month after rash onset, 13% at 3 months, and about 7% at 1 year (2932). The intensity of pain can vary from trivial to debilitating. Postherpetic neuralgia occurs more frequently with increasing age, more severe acute pain, and a larger surface area with skin lesions (32, 33). Herpes zoster can cause other serious complications, including vision and hearing impairments and neurologic complications, including vasculopathy, myelitis, cranial and peripheral nerve palsies, and polyradiculitis. Bacterial superinfection of cutaneous lesions occasionally develops. Immunocompromised persons have an increased risk for varicella zoster infection of the lungs, central nervous system, and brain as well as life-threatening secondary bacterial infection. What antiviral drugs are available to treat herpes zoster? Three orally administered antiviral drugs are approved in the United States for treatment of herpes zoster in immunocompetent patients. Famciclovir, valacyclovir, and acyclovir are all effective for treating herpes zoster, although famciclovir and valacyclovir are preferred because they have simpler dosing schedules and better pharmacokinetic characteristics (see the Box: Drugs for Patients With Herpes Zoster Presenting Within 72 Hours of Lesion Onset).

Drugs for Patients With Herpes Zoster Presenting Within 72 Hours of Lesion Onset
Famciclovir, 500 mg orally 3 times a day for 7 days Valacyclovir, 1 g orally 3 times a day for 7 days Although the dosage given above is the approved valacyclovir dosage for herpes zoster in the United States, valacyclovir 1.5 g twice a day is safe and effective for the treatment of uncomplicated herpes zoster in immunocompetent patients over age 18, and less frequent dosing might improve patient compliance (Madkan VK, Arora A, Babb-Tarbox M, et al. Open-label study of valacyclovir 1.5 g twice daily for the treatment of uncomplicated herpes zoster in immunocompetent patients 18 years of age or older. J Cutan Med Surg. 2007;11:89-98. [PMID: 1751192]). Acyclovir, 800 mg orally 5 times a day for 7 days Prescribe acyclovir only if neither famciclovir nor valacyclovir is available, because acyclovirs complicated dosing schedule reduces the likelihood of compliance and its pharmacokinetic characteristics are inferior to those of famciclovir and valacyclovir.

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All 3 drugs reduce the duration of pain, presumably by limiting the damage to the sensory nerves from replicating virus. Halting this replication also shortens the duration of new lesion formation, accelerates cutaneous healing, and reduces the duration of viral shedding.
One RCT involving 419 immunocompetent adults with uncomplicated herpes zoster found that compared with placebo, famciclovir reduced the median duration of postherpetic neuralgia from about 4 months to about 2 months (34). Another RCT comparing 3 dose regimens of famciclovir (750 mg once a day, 500 mg twice a day, or 250 mg 3 times a day for 7 days) found them equally effective for cutaneous healing of herpes zoster and resolution of acute pain (35). This trial also found that famciclovir and acyclovir were equally effective for cutaneous healing and acute pain. Still another RCT found valacyclovir and acyclovir equally effective for cutaneous healing (36). Valacyclovir was superior, however, for shortening the duration of acute pain and the duration of postherpetic neuralgia. For example, fewer patients taking valacyclovir experienced pain for 6 months (19.3%) when compared with patients taking acyclovir (25.7%). A blinded RCT that compared valacyclovir and famciclovir found them therapeutically equivalent for the treatment of herpes zoster, but valacyclovir was more cost-effective ($83.90 vs $140.70 per course) (37).

evidence about other antiviral treatments is insufficient (42). Clinical trials with antiviral drugs have focused on patients presenting within 72 hours of lesion onset. The value of antiviral therapy for patients presenting beyond 72 hours has not been adequately studied. Despite lack of evidence, however, antiviral therapy is recommended for patients presenting more than 72 hours after the onset of rash with continued new vesicle formation or when there are cutaneous, motor, neurologic, or ocular complications. Costbenefit considerations favor treatment of patients with herpes zoster who are older than age 50 because of the higher risk for complications, especially postherpetic neuralgia, in older persons. Treatment is particularly advised for older patients with severe pain and a large area of skin involvement, which are risk factors for prolonged pain. Antiviral therapy is optional for younger patients with mild pain and limited cutaneous involvement because these patients are at relatively low risk for severe or protracted pain. Topical antiviral therapy is ineffective and thus is not recommended. When should intravenous antivirals be given? Intravenous acyclovir should be administered in patients with herpes zoster that is complicated by central nervous system involvement, especially myelitis. This recommendation is based on case reports and anecdotal experience (43, 44). The dose for immunocompetent individuals is 10 to 15 mg/kg, every 8 hours for patients with normal renal function. For such manifestations as delayed contralateral hemiparesis, in which the role of active viral replication is less clear, the value of antiviral therapy is uncertain, but the potential

If neither famciclovir nor valacyclovir is available, clinicians should prescribe acyclovir.

Three clinical trials have demonstrated that oral acyclovir, initiated within 72 hours of the onset of lesions at a dose of 800 mg, 5 times daily, reduces the duration of viral shedding, shortens the duration of new lesion formation, and accelerates cutaneous healing (38, 39, 40). One metaanalysis also found acyclovir superior to placebo for reducing the duration of herpes zosterassociated pain (41).

The role of antiviral treatment in preventing postherpetic neuralgia is less clear. A recent Cochrane review concluded that oral acyclovir does not reduce the incidence of postherpetic neuralgia and that

36. Beutner KR, Friedman DJ, Forszpaniak C, Andersen PL, Wood MJ. Valaciclovir compared with acyclovir for improved therapy for herpes zoster in immunocompetent adults. Antimicrob Agents Chemother. 1995;39:1546-53. [PMID:7492102] 37. Tyring SK, Beutner KR, Tucker BA, Anderson WC, Crooks RJ. Antiviral therapy for herpes zoster: randomized, controlled clinical trial of valacyclovir and famciclovir therapy in immunocompetent patients 50 years and older. Arch Fam Med. 2000;9:863-9. [PMID:11031393] 38. Huff JC, Bean B, Balfour HH Jr, Laskin OL, Connor JD, Corey L, et al. Therapy of herpes zoster with oral acyclovir. Am J Med. 1988;85:84-9. [PMID:3044099] 39. Morton P, Thomson AN. Oral acyclovir in the treatment of herpes zoster in general practice. N Z Med J. 1989;102:935. [PMID:2648213] 40. McKendrick MW, McGill JI, White JE, Wood MJ. Oral acyclovir in acute herpes zoster. Br Med J (Clin Res Ed). 1986;293:1529-32. [PMID:3099943] 41. Wood MJ, Kay R, Dworkin RH, Soong SJ, Whitley RJ. Oral acyclovir therapy accelerates pain resolution in patients with herpes zoster: a meta-analysis of placebo-controlled trials. Clin Infect Dis. 1996;22:341-7. [PMID:8838194] 42. Li Q, Chen N, Yang J, Zhou M, Zhou D, Zhang Q, et al. Antiviral treatment for preventing postherpetic neuralgia. Cochrane Database Syst Rev. 2009:CD006866. [PMID:19370655] 43. Gilden DH, Beinlich BR, Rubinstien EM, Stommel E, Swenson R, Rubinstein D, et al. Varicella-zoster virus myelitis: an expanding spectrum. Neurology. 1994;44:1818-23. [PMID:7936229]

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44. Peterslund NA. Herpes zoster associated encephalitis: clinical findings and acyclovir treatment. Scand J Infect Dis. 1988;20:583-92. [PMID:3222675] 45. Cobo M, Foulks GN, Liesegang T, Lass J, Sutphin J, Wilhelmus K, et al. Observations on the natural history of herpes zoster ophthalmicus. Curr Eye Res. 1987;6:1959. [PMID:3493883] 46. Cobo Cobo LM, Foulks GN, Liesegang T, Lass J, Sutphin JE, Wilhelmus K, et al. Oral acyclovir in the treatment of acute herpes zoster ophthalmicus. Ophthalmology. 1986;93:763-70. [PMID:3488532] 47. Herbort CP, Buechi ER, Piguet B, Zografos L, Fitting P. High-dose oral acyclovir in acute herpes zoster ophthalmicus: the end of the corticosteroid era. Curr Eye Res. 1991;10 Suppl:171-5. [PMID:1864091] 48. Hoang-Xuan T, Bchi ER, Herbort CP, Denis J, Frot P, Thnault S, et al. Oral acyclovir for herpes zoster ophthalmicus. Ophthalmology. 1992;99:1062-70; discussion 1070-1. [PMID:1495785] 49. Liesegang TJ. Varicella zoster viral disease. Mayo Clin Proc. 1999;74:983-98. [PMID:10918864] 50. Dworkin RH, Barbano RL, Tyring SK, Betts RF, McDermott MP, Pennella-Vaughan J, et al. A randomized, placebo-controlled trial of oxycodone and of gabapentin for acute pain in herpes zoster. Pain. 2009;142:209-17. [PMID:19195785] 51. Berry JD, Petersen KL. A single dose of gabapentin reduces acute pain and allodynia in patients with herpes zoster. Neurology. 2005;65:444-7. [PMID:16087911] 52 van Wijck AJ, Opstelten W, Moons KG, van Essen GA, Stolker RJ, Kalkman CJ, et al. The PINE study of epidural steroids and local anaesthetics to prevent postherpetic neuralgia: a randomised controlled trial. Lancet. 2006;367:219-24. [PMID:16427490]

benefits probably outweigh any potential risks. Dissemination of herpes zoster to visceral organs, including the liver and lungs, as well as the central nervous system, is a risk for immunocompromised persons but rarely occurs in immunocompetent individuals. Consider intravenous acyclovir for immunocompetent patients with herpes zoster and visceral involvement, although there are no data from prospective studies to support this recommendation. What are special considerations when treating herpes zoster ophthalmicus? Herpes zoster ophthalmicus is particularly serious because of the potential for adverse ocular complications with damage to the eye or surrounding structures, including stromal or neurotrophic keratitis, uveitis, scleritis or episcleritis, and retinal necrosis. In the absence of antiviral therapy, approximately 50% of patients with herpes zoster ophthalmicus will develop some of these complications (45). Controlled, prospective clinical trials have confirmed that oral acyclovir therapy will reduce the frequency of late ocular inflammatory complications from approximately 50% to 60% to approximately 20% to 30% (4648). Patients with herpes zoster ophthalmicus should be treated with oral antiviral therapy even if lesions have been present for more than 72 hours. Consult an ophthalmologist for appropriate evaluation of the eye if there are any symptoms suggesting ocular involvement. Certain ophthalmologic complications may require specific treatments. Systemic or topical corticosteroids are indicated for some of the ocular inflammatory phenomena that accompany herpes zoster ophthalmicus but should only be administered under the supervision of an experienced ophthalmologist (49). For patients with severe herpes zoster ophthalmicus, consider intravenous acyclovir for initial

therapy, although there are no data from controlled clinical trials to support the superiority of this approach over oral antiviral therapy. Systemic antiviral therapy has largely replaced topical antiviral preparations for treatment of ocular complications associated with herpes zoster ophthalmicus. What drugs can be used for control of acute pain? The pain of herpes zoster can significantly reduce functional status and health-related quality of life. Clinicians should not underestimate the severity of the neuralgic pain and should keep in mind that even patients with relatively limited skin involvement can have severe symptoms. Therefore, aggressive pain management is warranted. Early efforts to attenuate acute pain may reduce the risk for postherpetic neuralgia. For some patients, over-thecounter medications, such as acetaminophen or ibuprofen, are adequate for pain relief. If moderate to severe herpes zoster pain is not relieved by antiviral agents combined with oral analgesic medications, then clinicians should consider prescribing additional therapies. Short-acting narcotic analgesics, such as oxycodone, should be prescribed on a scheduled rather than on an as-needed basis. Early in the course of disease, it may be helpful to add anticonvulsants, such as gabapentin, or tricyclic antidepressants, although the anticholinergic side effects of some tricyclic antidepressants, such as amitriptyline, can cause serious problems in older adults.
One RCT found controlled-release oxycodone to be effective for acute pain relief in herpes zoster within 2 weeks of onset (50). A double-blind, crossover RCT found that the severity of pain associated with herpes zoster diminished with a single 900mg dose of gabapentin (51). In addition, neural blockade may be prescribed. One

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RCT showed that epidural injection of 80 mg methylprednisolone acetate and 10 mg bupivacaine in addition to antiviral therapy and oral analgesics was slightly more effective than antivirals and analgesics in reducing zoster-associated pain at 1 month but not at 3 or 6 months (52).

and uninvolved skin in the affected dermatome may temporarily have increased sensitivity and tenderness. When should patients be hospitalized? Most patients with herpes zoster can be managed as outpatients; however, those with disseminated herpes zoster infection or ocular involvement may need to be hospitalized for observation, supportive care, and intravenous acyclovir therapy. Scattered cutaneous vesicles appearing beyond the primary or adjacent dermatomes are not an indication for hospitalization. When should a specialist be consulted? Nearly 1 in 4 patients have some type of herpes zosterrelated complication (56). The most common complication is postherpetic neuralgia, and because this can be very difficult to manage, consulting a pain specialist may be helpful. Consult a neurologist for assistance with the rare patient who develops such neurologic complications as vasculopathy or myelitis. Consider an ophthalmology consult for all patients with herpes zoster ophthalmicus, including those without complications. For guidance managing antiviral drug therapy, consider consulting an infectious disease specialist. What should patients know about their episode of herpes zoster? Patients should learn ways to soothe and protect the involved skin as well as what to expect regarding the potential for chronic pain and the risk for virus transmission. Patients need to be psychologically prepared to manage chronic pain and should be instructed to contact the physician if pain-control measures are ineffective or inadequate. The dosing regimen for analgesic medications is important to managing pain, and aroundthe-clock pain control is usually superior to as-needed dosing. Patients with herpes zoster should learn about the risk for varicella

Nondrug Measures for Managing Herpes Zoster

Keep cutaneous lesions clean and dry to reduce the risk for bacterial superinfection. Wash rash with soap and water and then carefully pat dry. Warm or cool astringent soaks may be soothing. Consider using a sterile, occlusive, nonadherent dressing to protect the lesions and promote healing, especially in patients with herpes zoster with increased skin sensitivity. Wear loose-fitting clothing for comfort. Remember that topical creams or ointments (including topical acyclovir or penciclovir) have no role in the management of herpes zoster.

Topical capsaicin should not be used for acute herpes zoster because it can exacerbate the pain, but it can be used to treat postherpetic neuralgia. What is the role of corticosteroids in treating herpes zoster?
A Cochrane review concluded that no evidence supports the use of corticosteroids to prevent postherpetic neuralgia (53). Nevertheless, some experienced physicians prescribe oral corticosteroids because they believe that these drugs provide other symptomatic benefits for patients. One RCT found that adding prednisolone to acyclovir improved rash healing and reduced moderate to severe pain but not mild pain during the acute phase of disease; however, prednisolone did not reduce the frequency of postherpetic neuralgia or the time to complete cessation of pain (54). Another RCT involved only participants >50 years age and found that combined acyclovir and prednisone therapy conferred a significant reduction in pain (55).

Consider adding a 10- to 14-day tapering course of oral prednisone (e.g., starting at 60 mg daily) to antiviral therapy in patients with herpes zoster older than 50 years of age who have moderate to severe pain at presentation; however, remember that corticosteroid therapy can cause potentially serious adverse effects. Prednisone should also not be used for patients in whom steroid therapy is relatively contraindicated, such as in patients with diabetes mellitus, osteoporosis, or gastritis. Do not use corticosteroids without concomitant antiviral therapy. What nondrug therapies should be considered when managing herpes zoster? Basic symptomatic measures may be used to soothe and protect the involved skin (see the Box: Nondrug Measures for Managing Herpes Zoster). Advise patients that involved

53. He L, Zhang D, Zhou M, Zhu C. Corticosteroids for preventing postherpetic neuralgia. Cochrane Database Syst Rev. 2008:CD005582. [PMID:18254083] 54. Wood MJ, Johnson RW, McKendrick MW, Taylor J, Mandal BK, Crooks J. A randomized trial of acyclovir for 7 days or 21 days with and without prednisolone for treatment of acute herpes zoster. N Engl J Med. 1994;330:896900. [PMID:8114860] 55. Whitley RJ, Weiss H, Gnann JW Jr, Tyring S, Mertz GJ, Pappas PG, et al. Acyclovir with and without prednisone for the treatment of herpes zoster. A randomized, placebo-controlled trial. The National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. Ann Intern Med. 1996;125:376-83. [PMID:8702088] 56. 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. Mayo Clin Proc. 2007;82:1341-9. [PMID:17976353]

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57. Sawyer MH, Chamberlin CJ, Wu YN, Aintablian N, Wallace MR. Detection of varicella-zoster virus DNA in air samples from hospital rooms. J Infect Dis. 1994;169:91-4. [PMID:8277202] 58. Garner JS. Guideline for isolation precautions in hospitals. The Hospital Infection Control Practices Advisory Committee. Infect Control Hosp Epidemiol. 1996;17:5380. [PMID:8789689] 59. Kuroiwa Y, Furukawa T. Hemispheric infarction after herpes zoster ophthalmicus: computed tomography and angiography. Neurology. 1981;31:1030-2. [PMID:6973708] 60. Eidelberg D, Sotrel A, Horoupian DS, Neumann PE, Pumarola-Sune T, Price RW. Thrombotic cerebral vasculopathy associated with herpes zoster. Ann Neurol. 1986;19:7-14. [PMID:3004319] 61. Reshef E, Greenberg SB, Jankovic J. Herpes zoster ophthalmicus followed by contralateral hemiparesis: report of two cases and review of literature. J Neurol Neurosurg Psychiatry. 1985;48:122-7. [PMID:3884741] 62. Verghese A, Sugar AM. Herpes zoster ophthalmicus and granulomatous angiitis. An ill-appreciated cause of stroke. J Am Geriatr Soc. 1986;34:309-12. [PMID:3485127] 63. Nagel MA, Cohrs RJ, Mahalingam R, Wellish MC, Forghani B, Schiller A, et al. The varicella zoster virus vasculopathies: clinical, CSF, imaging, and virologic features. Neurology. 2008;70:853-60. [PMID:18332343] 64. Cheung WC, Yuen KY, Chang CM, Cheng KP. Herpes zoster associated encephalitis in dialysis patients. J Infect. 1991;23:169-74. [PMID:1753116]

zoster virus transmission. Transmission of the virus can cause varicella in a person who is seronegative for herpes zoster. Patients cannot acutely transmit herpes zoster to another individual. The risk for transmission of varicella zoster virus is probably less from a person with herpes zoster than from a person with varicella. Patients with active herpes zoster should avoid contact with susceptible infants or small children, susceptible pregnant women, or potentially susceptible immunocompromised individuals. The virus is transmitted primarily through direct contact. It also can be transmitted through the air, particularly from patients with disseminated herpes zoster. For example, varicella zoster virus DNA was detectable in air samples from the hospital rooms of 9 of 13 patients with herpes zoster (57). Authorities recommend standard precautions and use of gloves when touching the lesions of patients with localized zoster. Severely immunocompromised patients who develop dermatomal zoster should be placed on strict isolation, both airborne and contact, until lack of contagion becomes clear. All patients with disseminated zoster should be on airborne and contact isolation (58). What other complications should a clinician look for after an episode of herpes zoster?
Contralateral hemiparesis

herpes zoster ophthalmicus, with the average interval from rash to onset of neurologic symptoms about 7 weeks. Intervals of up to 6 months have been reported. Clinicians should evaluate patients with hemiparesis that follows an episode of herpes zoster ophthalmicus by weeks or months for possible varicella zoster virusrelated central nervous system vasculitis. Imaging studies usually show changes consistent with brain infarction (59). Angiography is usually diagnostic, showing inflammation, narrowing, and thrombosis of the proximal branches of the anterior or middle cerebral artery (60). Many patients with unifocal or multifocal vasculopathy due to varicella zoster virus have transient ischemic attacks (TIAs), mental status changes, or both within weeks to months after zoster and before frank infarction develops. Magnetic resonance imaging (MRI) usually shows one or more ischemic lesions, magnetic resonance angiography may show arterial stenosis, and examination of cerebrospinal fluid (CSF) usually shows mononuclear pleocytosis and even oligoclonal bands.
Multifocal vasculopathy

Varicella zoster virus can induce central nervous system angiitis, resulting in stroke-like symptoms with hemiparesis occurring contralateral to the antecedent trigeminal zoster. The pathogenesis of this rare disorder is believed to be direct invasion of cerebral arteries by varicella zoster virus along the first division of the trigeminal nerve, resulting in inflammation of the internal carotid artery or one of its branches on the side ipsilateral to the rash. Contralateral hemiparesis occurs as a late complication of

Dissemination of varicella zoster virus to the central nervous system can cause multifocal vasculopathy in immunologically intact individuals on rare occasions; this occurrenc is more common in immunocompromised patients. Consider the possibility of varicella zoster virus multifocal vasculopathy in patients with altered mental status or focal neurologic findings during or after an episode of herpes zoster. The clinical presentation is most often TIA; stroke; or acute or subacute delirium that may be accompanied by other signs, including headache, meningismus, fever, ataxia, or seizures. Even in the absence of a history of rash, multifocal vasculopathy is a possible cause of TIA or stroke in adults; 40% of patients with

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varicella zoster virus vasculopathy have no history of zoster rash (63). Signs may occur from 30 days before to 6 months after acute herpes zoster, and multifocal vasculopathy has been reported in patients who were appropriately treated with antiviral therapy during the acute episode of herpes zoster (64). The most consistent diagnostic criterion for varicella zoster virus vasculopathy is evidence of ischemic lesions on MRI or computed tomography of the brain with a CSF positive for varicella zoster virus on polymerase chain reaction (PCR) assay or varicella zoster virus IgG. Examination of CSF reveals increased opening pressure, increased protein, and lymphocytic pleocytosis, although the absence of pleocytosis does not rule out varicella zoster virus vasculopathy. The PCR assay for varicella zoster virus DNA and antivaricella zoster virus IgG antibody in CSF are often positive; detection of the latter is more sensitive than detection of the latter. Computed tomography or MRI of the brain is often abnormal, showing ischemic lesions. Histopathologic studies suggest that the pathogenesis of diffuse disease of the central nervous system is small-vessel vasculitis. The role of antiviral therapy for herpes zoster vasculitis has not been studied in a prospective fashion, but there are anecdotal reports of successful treatment with intravenous acyclovir.
Acute retinal necrosis

Acute retinal necrosis is most often caused by varicella zoster virus, although a similar syndrome has been attributed to herpes simplex virus. Consider varicella zoster virus retinitis in a patient with acute visual changes and a history of herpes zoster. Both immunocompetent and immunocompromised patients have experienced acute retinal necrosis, but most recent case reports have involved patients with

AIDS (65). Acute retinal necrosis can be a late complication of the disease. Visual changes usually occur weeks to months after an episode of acute herpes zoster. The previous zoster may have been in any dermatome (not necessarily trigeminal), suggesting that varicella zoster virus reaches the retina by the hematogenous route. Varicella zoster virus has been cultured from retinal biopsy specimens, and antigens and nucleic acids have been detected in vitreous humor and retinal tissue (66). The characteristic funduscopic examination reveals granular, yellowish, nonhemorrhagic lesions that rapidly extend and coalesce, often resulting in retinal detachment. There is a relative lack of intraocular inflammatory changes. In immunocompetent patients, acyclovir therapy improves the clinical outcome. In conjunction with an ophthalmologist, prescribe intravenous acyclovir, 10 mg/kg to 15 mg/kg, every 8 hours, for 10 to 14 days (for patients with normal renal function), followed by oral valacyclovir, 1 g, 3 times a day, for 4 to 6 weeks. The suggested treatment regimen is based on anecdotal experience and uncontrolled clinical trials (6769). In immunocompromised patients, the optimal antiviral therapy and duration for acute retinal necrosis remain unclear. Responses to intravenous acyclovir or ganciclovir have been inconsistent and disappointing. Improved preservation of vision in patients treated with a combination of intravenous ganciclovir plus foscarnet, with or without intravitreal antivirals, or with cidofovir alone has been reported (70, 71). Is herpes zoster associated with an increased risk for cancer? Herpes zoster is not a marker for cancer (72). A thorough history and physical examination are warranted for all patients with herpes zoster, but additional laboratory and imaging studies are not, unless clinically indicated.

65. Ormerod LD, Larkin JA, Margo CA, Pavan PR, Menosky MM, Haight DO, et al. Rapidly progressive herpetic retinal necrosis: a blinding disease characteristic of advanced AIDS. Clin Infect Dis. 1998;26:34-45; discussion 46-7. [PMID:9455507] 66. Garweg J, Bhnke M. Varicella-zoster virus is strongly associated with atypical necrotizing herpetic retinopathies. Clin Infect Dis. 1997;24:603-8. [PMID:9145733] 67. Blumenkranz MS, Culbertson WW, Clarkson JG, Dix R. Treatment of the acute retinal necrosis syndrome with intravenous acyclovir. Ophthalmology. 1986;93:296-300. [PMID:3703498] 68. Palay DA, Sternberg P Jr, Davis J, Lewis H, Holland GN, Mieler WF, et al. Decrease in the risk of bilateral acute retinal necrosis by acyclovir therapy. Am J Ophthalmol. 1991;112:250-5. [PMID:1882936] 69. Crapotta JA, Freeman WR. Visual outcome in acute retinal necrosis [Letter]. Retina. 1994;14:3823. [PMID:7817036] 70. Galindez OA, Sabates NR, Whitacre MM, Sabates FN. Rapidly progressive outer retinal necrosis caused by varicella zoster virus in a patient infected with human immunodeficiency virus. Clin Infect Dis. 1996;22:149-51. [PMID:8824984] 71. Schliefer K, Gmbel HO, Rockstroh JK, Spengler U. Management of progressive outer retinal necrosis with cidofovir in a human immunodeficiency virus-infected patient. Clin Infect Dis. 1999;29:684-5. [PMID:10530469] 72. Ragozzino MW, Melton LJ 3rd, Kurland LT, Chu CP, Perry HO. Risk of cancer after herpes zoster: a population-based study. N Engl J Med. 1982;307:393-7. [PMID:6979711]

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Treatment... Three orally administered antiviral drugs are approved in the United
States for treatment of herpes zoster in immunocompetent patients. Famciclovir, valacyclovir, and acyclovir are all effective for treatment of herpes zoster, although famciclovir and valacyclovir are preferred because of a simplified dosing schedule and improved pharmacokinetic characteristics. Administer intravenous acyclovir to patients with herpes zoster that is complicated by central nervous system involvement. Intravenous acyclovir may also be warranted for severe cases of herpes zoster ophthalmicus. Aggressive, early pain management is warranted to reduce acute and postherpetic neuralgia. Short-acting narcotic analgesics, such as oxycodone, should be prescribed on a scheduled rather than an as-needed basis. Adding oral corticosteroids to antiviral therapy may not reduce the risk for postherpetic neuralgia, but the anti-inflammatory effects may provide other symptomatic benefit. Conservative measures may soothe and protect involved skin. Most episodes of herpes zoster can be managed on an outpatient basis. Patients with disseminated herpes zoster infection or with ocular involvement, however, may need to be hospitalized. Consult a specialist when diagnosis or management is unclear or complicated.

CLINICAL BOTTOM LINE

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PIER Modules
www.pier.acponline.org PIER module on herpes zoster. PIER modules provide evidence-based, updated information on current diagnosis and treatment in an electronic format designed for rapid access at the point of care.

Tool Kit
Herpes Zoster

Patient Information
www.annals.org/intheclinic/toolkit-herpeszoster.html Patient Information material that appears on the following pages for duplication and distribution to patients. www.niaid.nih.gov/topics/shingles/Pages/Default.aspx www.ninds.nih.gov/disorders/shingles/shingles.htm Patient information on herpes zoster from the National Institute of Allergy and Infectious Diseases and from the National Institute of Neurological Disorders and Stroke. www.nlm.nih.gov/medlineplus/shingles.html MEDLINE Plus information about herpes zoster for patients, including an interactive tutorial available in both English and Spanish.

Clinical Guidelines
www.journals.uchicago.edu/doi/full/10.1086/510206 Recommendations released in 2007 for the management of herpes zoster, developed by the International Association for the Study of Pain, Neuropathic Pain Institute, and VZV Research Foundation. www.cdc.gov/vaccines/vpd-vac/shingles/default.htm#clinical Clinical information on herpes zoster, including Advisory Committee on Immunization Practices (ACIP) vaccine recommendations, from the Centers for Disease Control and Prevention. www.cdc.gov/mmwr/preview/mmwrhtml/rr5705a1.htm 2008 recommendations of the ACIP on the prevention of herpes zoster. www.cdc.gov/mmwr/preview/mmwrhtml/rr5604a1.htm 2007 recommendations of the ACIP on the prevention of varicella. www.annals.org/content/152/1/36.full ACIP 2010 recommended U.S. adult immunization schedule.

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THINGS YOU SHOULD KNOW ABOUT HERPES ZOSTER

What is herpes zoster?
Herpes zoster, commonly known as shingles, is a painful skin rash caused by the varicella zoster virus. Varicella zoster virus is the same virus that causes chickenpox. A person who had had chickenpox is at risk for herpes zoster because the virus lies dormant in the nerve cell and can reactivate later in life. Herpes zoster can occur at any age, but it is most common among people 50 years of age and older. People who have medical conditions or take medications that suppress their immune system are at increased risk for herpes zoster.

In the Clinic Annals of Internal Medicine

What are the symptoms?

Painful, itchy tingling skin and rash with blisters. Rash is usually limited to a small area on one side of the body, usually on the trunk or face, and lasts for 2 to 4 weeks. Symptoms can include a general feeling of being unwell, headache, chills.

What are the complications?

The main complication is pain called postherpetic neuralgia that lasts after the rash heals. Postherpetic neuralgia causes severe skin sensitivity, called allodynia, which is described as a burning or sharp pain or itchiness in the area where the herpes zoster rash appeared. It can sometimes be severe enough that it disrupts sleep and makes everyday activities difficult. Herpes zoster can also cause other serious complications, including vision loss; ear pain; and inflammation of the spinal cord, which causes weakness in legs and arms and back pain.

How is herpes zoster diagnosed?

Your doctor will diagnose herpes zoster after performing a physical examination and analyzing your symptoms. Sometimes laboratory tests are performed to confirm the diagnosis. Your doctor may consult with a specialist who has special knowledge of diagnosing and treating complications of herpes zoster.

Can herpes zoster be prevented?

How is it treated?
Three orally administered antiviral drugs are approved in the United States for treatment of herpes zoster in healthy patients: famciclovir, valacyclovir, and acyclovir. Treatment is shown to reduce the duration of pain and accelerate the healing of the rash. Early treatment may reduce the risk for complications.

For More Information

www.aad.org/public/publications/pamphlets/viral_herpes_zoster.html

Information on herpes zoster, available in pamphlet form from the American Academy of Dermatology.
www.cdc.gov/vaccines/vpd-vac/varicella/default.htmwww.cdc.gov/ vaccines/vpd-vac/shingles/default.htm

Information on varicella vaccination and herpes zoster vaccination from the Centers for Disease Control and Prevention.
www.ninds.nih.gov/disorders/shingles/shingles.htm

Information on herpes zoster from the National Institute of Neurological Disorders and Stroke.
www.vzvfoundation.org/chickenq&a.html www.vzvfoundation.org/shingles&phn.html

Information on varicella and on herpes zoster and postherpetic neuralgia from the Varicella Zoster Virus Research Foundation.

Patient Information

A live vaccine to prevent herpes zoster is available. The Advisory Committee on Immunization Practices recommends a dose for most adults 60 years of age who have a good immune system. Without vaccination, approximately one third of healthy adults have an episode of herpes zoster during their lifetime; risk increases with age. The herpes zoster vaccination also prevents postherpetic neuralgia.

CME Questions

1. A 75-year-old man is hospitalized with a 1-day history of fever, painful rash, and confusion. The patient has Crohn disease treated with prednisone and 6mercaptopurine. The corticosteroid dose was recently escalated and then tapered for treatment of a disease flare. On physical examination, the patient appears ill and confused. Temperature is 37.9C (100.3F), blood pressure is 120/70 mm Hg, pulse rate is 110/min, and respirations are 28/min and shallow. Arterial oxygen saturation is 90% on ambient air. A prominent vesicular rash is present on the chest in a dermatomal pattern, and multiple vesicular lesions of a similar nature are scattered on the trunk, arms, and legs. Examination of the lungs discloses scattered crackles. Results of laboratory studies are as follows: leukocyte count, 5200/L (5.2 109/L) with a normal differential; blood urea nitrogen, 34 mg/dL (12.1 mmol/L); creatinine, 2.3 mg/dL (203.3 mol/L); alanine aminotransferase, 95 U/L; and aspartate aminotransferase, 98 U/L. A chest radiograph shows bilateral interstitial infiltrates. Lumbar puncture is performed. The cerebrospinal fluid (CSF) leukocyte count is 48/L (48 106/L) with 10% polymorphonuclear cells, 70% lymphocytes, and 20% monocytes; protein is 90 mg/dL (900 mg/L), and glucose is 70 mg/dL (3.9 mmol/L) (plasma glucose is 110 mg/dL [6.1 mmol/L]). Gram stain and culture of the CSF and blood and urine cultures are negative. In addition to replacement of corticosteroids in stress doses, which of the following is the most appropriate treatment?

of shingles 1 year ago that was treated with famciclovir. He has a history of alcoholism and intermittent injection drug use. He has lost approximately 3.0 kg (6.6 lb) over the past 3 months. He has had increased fatigue but denies fever, chills, lymphadenopathy, jaundice, or change in his bowel habits. He takes no medications. On physical examination, temperature is 37.0C (98.6F), and BMI is 28. Oral mucous membranes are normal. There is no jaundice, lymphadenopathy, or hepatosplenomegaly. Direct fluorescent antibody test is positive for varicellazoster virus. Which of the following is the most likely underlying disease?

4. A 70-year-old man has a 1-day history of a painful rash on his chest. Three days before the rash became apparent, he developed severe pain and paresthesias in the same area. The remainder of the examination is unremarkable. In addition to appropriate analgesic agents, which of the following should be given at this time?

A. Corticosteroids B. Oral famciclovir C. Intravenous acyclovir D. Topical penciclovir

5. A 64-year-old man is evaluated for a right-sided headache with which he awoke yesterday. It began as a dull ache over his right forehead and has gradually increased in intensity. He also notes some right eye discomfort, sensitivity to light, and that his eye is red. Vital signs are normal. The patient is uncomfortable and prefers to have the lights dimmed. The right eye has diffusely injected conjunctiva, and the cornea appears clear. The left eye is normal. The pupils are equal and reactive. Visual acuity is normal. Cranial nerves are intact. Which of the following is the most likely diagnosis?

A. Cirrhosis B. Diabetes mellitus C. Hepatitis B D. Hepatitis C E. HIV infection

3. A 68-year-old woman is evaluated during a routine examination. She states that last year she had a painful rash on the right side of her back that was selflimited. She does not recall a history of childhood chickenpox. She takes no medications and has no allergies. Vital signs are normal, and the physical examination is unremarkable. Complete blood count, liver enzymes, and serum chemistry studies are all normal. She is scheduled to receive her annual influenza vaccination today. Which of the following is the most appropriate vaccine administration strategy to prevent herpes zoster in this patient?

A. Herpes simplex virus keratitis B. Herpes zoster ophthalmicus C. Scleritis D. Trigeminal neuralgia

A. IV acyclovir B. Foscarnet C. Herpes zoster vaccine D. Valganciclovir

2. A 37-year-old man is evaluated for a 6day history of a painful eruption on his left posterior thorax. He had an episode

A. Zoster vaccination if negative for varicella antibodies B. Zoster vaccination if positive for varicella antibodies C. Zoster vaccination now D. Zoster vaccination now and in 6 months E. Zoster vaccination is not indicated

Questions are largely from the ACPs Medical Knowledge Self-Assessment Program (MKSAP, accessed at http://www.acponline.org/products_services/mksap/15/?pr31). Go to www.annals.org/intheclinic/ to complete the quiz and earn up to 1.5 CME credits, or to purchase the complete MKSAP program.

2011 American College of Physicians

ITC3-16

In the Clinic

Annals of Internal Medicine

1 March 2011