Herpes Zoster - Ann Intern Med 2011

5/16/2018 Herpes Zoster - Ann Intern Med 2011 - slidepdf.com

http://slidepdf.com/reader/full/herpes-zoster-ann-intern-med-2011 1/16

I n t h e

C l i n i

cIn the Clinic

Prevention page ITC3-2

Screening page ITC3-5

Diagnosis page ITC3-6

Treatment page ITC3-8

Tool Kit page ITC3-14

Patient Information page ITC3-15

CME Questions page ITC3-16

Section EditorsDeborah Cotton, MD, MPHDarren Taichman, MDSankey Williams, MD

Science WriterJennifer F. Wilson

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 Self-

Assessment Program). Annals of Internal Medicine editors develop In the Clinic

from these primary sources in collaboration with the ACP’s Medical Education andPublishing divisions and with the assistance of science writers and physician writ-

ers. Editorial consultants from PIER and MKSAP provide expert review of the con-

tent. 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, diagno-

sis, and treatment of herpes zoster.

The information contained herein should never be used as a substitute for clinical

judgment.

© 2011 American College of Physicians

Herpes Zoster



I

What are the risk factors forherpes zoster?Herpes zoster can occur at any agein someone who has had varicella.Before vaccination became availablein 1995, almost all children con-tracted varicella and thus mostadults in the United States havebeen exposed. For example, anti-bodies to the virus are currently found in 95.5% of people aged 20to 29, 98.9% of people aged 30 to

39, and more than 99.6% of peopleover age 40 (2). Herpes zoster ismost common in people older than60 years who have age-related weakening of the immune system.It also occurs more often in im-munocompromised persons, includ-ing those treated with chemothera-py, radiotherapy, or steroids, andpersons with disease-related im-munosuppression from HIV/AIDS,diabetes mellitus, or cancer. Having varicella before 1 year of age also

increases the risk. Clinicians areonly rarely able to establish a trig-ger or proximate cause. Immunity develops once a person has herpeszoster, so recurrence is uncommon.Exposure to a person with herpeszoster can lead to varicella in a per-son who has not had varicella.Some research shows that the inci-dence of herpes zoster is increasing.

For example, a review of VeteransAffairs health records found thatthe incidence of herpes zoster inmen and women > 40 years of ageincreased from 3.1 episodes/1000persons per year in 2000 to5.2/1000 persons per year in 2007(R2 = 0.9743; P <0.001) (3).

Who should receive the vaccineagainst varicella zoster?Varivax, a varicella zoster virus vaccine, is recommended to prevent varicella in all children andadults who are seronegative forantibodies to varicella zoster virus.It remains unclear how the vac-cine affects the frequency andseverity of herpes zoster, but the vaccine can cause latent infectionof sensory neurons and subsequentherpes zoster (4, 5). Zostavax is aconcentrated formulation of Vari- vax that the U.S. Food and DrugAdministration (FDA) has ap-

proved to prevent herpes zosterand its complications in immuno-competent adults aged ≥60 years. The Advisory Committee on Im-munization Practices (ACIP) rec-ommends the vaccine for its ap-proved indications (6). A nationalsurvey of general internists andfamily physicians indicates thatmost primary care physicians

© 2011 American College of Physicians ITC3-2 In the Clinic Annals of Internal Medicine 1 March 2011

1. Schmader KE,Dworkin RH. Naturalhistory and treatmentof herpes zoster. JPain. 2008;9:S3-9.[PMID: 18166460]

2. Kilgore PE, Kruszon-Moran D, Seward JF,Jumaan A, Van LoonFP, Forghani B, et al.Varicella in Americansfrom NHANES III: im-plications for controlthrough routine im-munization. J MedVirol. 2003;70 Suppl1:S111-8.[PMID: 12627498]

3. Rimland D, MoannaA. Increasing inci-dence of herpeszoster among Veter-ans. Clin Infect Dis.2010;50:1000-5.[PMID: 20178416]

4. LaRussa P, SteinbergSP, Shapiro E, VazquezM, Gershon AA. Viralstrain identification invaricella vaccinees

with disseminatedrashes. Pediatr InfectDis J. 2000;19:1037-9.[PMID: 11099082]

5. Sharrar RG, LaRussa P,Galea SA, SteinbergSP, Sweet AR, KeatleyRM, et al. The post-marketing safety pro-file of varicellavaccine. Vaccine.2000;19:916-23.[PMID: 11115716]

6. Harpaz R, Ortega-Sanchez IR, SewardJF; Advisory Commit-tee on ImmunizationPractices (ACIP) Cen-ters for Disease Con-trol and Prevention

(CDC). Prevention of herpes zoster: recom-mendations of theAdvisory Committeeon ImmunizationPractices (ACIP).MMWR Recomm Rep.2008;57:1-30; quizCE2-4.[PMID: 18528318]

7. Hurley LP, Harpaz R,Daley MF, Crane LA,Beaty BL, Barrow J, etal. National survey of primary care physi-cians regarding her-pes zoster andthe herpes zostervaccine. J Infect Dis.2008;197 Suppl

2:S216-23.[PMID: 18419400]

8. Kerzner B, Murray AV,Cheng E, Ifle R, Har-vey PR, Tomlinson M,et al. Safety and im-munogenicity profileof the concomitantadministration of ZOSTAVAX and inacti-vated influenza vac-cine in adults aged50 and older. J AmGeriatr Soc.2007;55:1499-507.[PMID: 17908055]

Herpes zoster, a painful skin rash that is commonly known as shin-gles, occurs in approximately 1 million people in the United Statesannually (1). Herpes zoster can develop in anyone who has had

varicella (chickenpox). About 95% of the adult U.S. population has had vari-cella and thus can have herpes zoster. Approximately one third of persons will have an episode of herpes zoster, and the frequency increases with in-creasing age. Herpes zoster occurs when the varicella zoster virus, whichcauses both varicella and herpes zoster, is reactivated from its latent state in

the dorsal root or cranial nerve ganglia and spreads through the afferentnerve to the skin.

Both “zoster” (Greek) and “shingles” (French and Latin) translate to theEnglish word “belt,” which describes the characteristic narrow, band-likerash from the spine around to the front of the torso on just one side of thebody; it can also occur on the face, eyes, mouth, and ears. The rash includesskin inflammation and blisters, lasts about 2 to 4 weeks, and sometimescauses scarring and permanent pigment changes. Pain, which can be intenseand disabling, occurs frequently in the distribution of the rash.

Prevention



© 2011 American College of Physicians ITC3-3In the ClinicAnnals of Internal Medicine1 March 2011

recommend the vaccine againstherpes zoster for patients 60 to 79 years of age (n = 871; responserate, 69%) (7). Because it is a live vaccine, it is contraindicated insome people (see the Box: People Who Should Not Be VaccinatedAgainst Herpes Zoster).

The vaccine against herpes zostershould be given as a single, 0.65-mLdose subcutaneously in the deltoidregion of the arm. People need notbe asked or tested for previous vari-cella. The vaccine is indicated re-gardless of whether the person hashad a prior episode of herpes zoster,although people with active herpeszoster should wait until the rash hashealed before getting vaccinated. Abooster dose is not currently recom-

mended. Antiviral medications, suchas acyclovir and valacyclovir, shouldnot be used within 24 hours beforeor 14 days after vaccination. Themost common side effects are itch-ing; headache; and redness, pain,tenderness, and swelling at the injec-tion site. The vaccine can be given atthe same time as influenza vaccine without altering the immune re-sponse to either agent (8).

What is the evidence that thevaccine works?In the Shingles Prevention Study, investiga-tors enrolled 38 546 adults with a history of varicella who were ≥60 years of age into adouble-blind, randomized, controlled trial (RCT) to evaluate whether the vaccineagainst herpes zoster decreased the inci-dence and severity of herpes zoster. After amedian 3.1 years, the investigators found significantly reduced morbidity from herpes zoster and postherpetic neuralgia (9). Therewere 957 cases of herpes zoster, 315 amongvaccine recipients and 642 among placebo

recipients, and 107 cases of postherpetic neuralgia, 27 among vaccine recipients and 80 among placebo recipients. The vaccinereduced the burden of illness due to herpes zoster by 61.1% ( P<0.001), reduced the inci-dence of postherpetic neuralgia by 66.5%( P<0.001), and reduced the incidence of herpes zoster by 51.3 % ( P<0.001). The vaccinewas more effective in preventing herpes zoster for adults 60 to 69 years of age thanfor those 70 years or older, but it prevented

more postherpetic neuralgia in adults aged ≥ 70 years than in younger adults. Follow-upstudies indicate that the vaccine is effectivefor at least 6 years.

The vaccine was designed to boostcell-mediated immune responses, which should keep latent varicellazoster virus from reactivating and

thus prevent herpes zoster. Thestrategy apparently was successful,because investigators found an en-hanced cytotoxic lymphocyte re-sponse 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 Preven-tion Study examined vaccine safety in themain study group of 38 546 participantsand included an adverse events substudy

of 6616 participants (11). More side effectsat the inoculation site, such as redness and tenderness, occurred in vaccine recipientsthan in the placebo recipients (48% vs.16%), but these effects were mostly mild or moderate. The frequency of serious adverseevents (1.4%) was the same in the vaccineand placebo groups.

An observational study of 75 761 vaccinat-ed and 227 283 unvaccinated people aged ≥ 60 years confirmed that the vaccineworks outside of a research setting in clini-cal practice (12). In these conditions, the

vaccine reduced the frequency of herpes zoster (hazard ratio [HR], 0.45 [95% CI, 0.42to 0.48]), herpes zoster involvement of theeye (HR, 0.37[CI, 0.23 to 0.61]), and hospi-talizations coded as herpes zoster (HR, 0.35[CI, 0.24-0.51]).

What are the barriers tovaccination?Fewer than 10% of eligible peoplein the United States receive the vaccine against herpes zoster (13),primarily due to cost and cost-ef-

fectiveness issues. It costs $100 to$300, which makes it the most ex-pensive vaccine recommended forolder adults. A cost-effectivenessmodel that compared varicellazoster vaccination with usual carefor healthy adults aged >60 yearsestimated that vaccination in-creased life expectancy by 0.0007 to0.0024 quality-adjusted life-years

9. Oxman MN, Levin MJ,Johnson GR,Schmader KE, StrausSE, Gelb LD, et al;Shingles PreventionStudy Group. A vac-cine to prevent her-pes zoster and pos-therpetic neuralgia inolder adults. N Engl JMed. 2005;352:2271-84. [PMID: 15930418]

10. Levin MJ, Barber D,Goldblatt E, Jones M,LaFleur B, Chan C, etal. Use of a live at-tenuated varicellavaccine to boostvaricella-specific im-mune responses inseropositive people55 years of age andolder: duration of booster effect. J In-fect Dis. 1998;178Suppl 1:S109-12.[PMID: 9852987]

11. Simberkoff MS, Ar-beit RD, Johnson GR,Oxman MN, Board-man KD, WilliamsHM, et al; ShinglesPrevention StudyGroup. Safety of her-pes zoster vaccine inthe shingles preven-tion study: a ran-domized trial. AnnIntern Med.2010;152:545-54.[PMID: 20439572]

12. Tseng HF, Smith N,Harpaz R, Bialek SR,Sy LS, Jacobsen SJ.Herpes zoster vac-cine in older adultsand the risk of sub-sequent herpeszoster disease. JAMA.2011;305:160-6.[PMID: 21224457]

People Who Should Not Be

Vaccinated Against Herpes

Zoster

People who have had a life-threatening allergic reaction togelatin or neomycin.

People who have a severe allergy toany component of the vaccine.

People with a weakened immune

system as a result of leukemia,lymphoma, or another blood orbone cancer.

People with HIV/AIDS who have T-cell counts <200.

People being treated with drugs thataffect the immune system,including high-dose steroids.

Women who are or might bepregnant.

Source: Centers for Disease Control and Prevention.




per person by preventing the acutepain of herpes zoster and posther-petic neuralgia (14). The cost-ef-fectiveness varied substantially withpatient age and often exceeded$100,000 per quality-adjusted life- year. Another modeling study esti-mated that the vaccine would be

reasonably cost-effective if it were<$200, it remained effective for >30 years, and people were vaccinatedbetween ages 60 to 69 years (15).

Reimbursement is also an issue. A2008 national survey of 301 generalinternists and 297 family medicinephysicians with a 72% response ratefound that 41% of providers strongly recommended the vaccine against her-pes zoster compared with 90% who

strongly recommended the vaccinesagainst influenza and pneumococcaldisease (16). Physicians reported thatthe main barriers to vaccination werethe high cost and reimbursementproblems. Just 45% of physiciansknew that Medicare pays for the vac-cine through Medicare Part D insteadof Medicare Part B, which pays physi-cians for nearly all other Medicareservices. Twelve percent of physicianshad stopped administering the vaccine

against herpes zoster in their officesbecause of cost and reimbursementissues.

Does childhood vaccination

against varicella prevent herpes

zoster?

In 1995, the United States imple-mented a vaccination program forchildren 12 to 18 months of age toprevent varicella. The National Im-munization Survey found that from

1997 to 2005, the percentage of children 19 to 35 months of age who received at least 1 dose of vari-cella vaccine increased from 26% to88%. By 2008, all but 2 states re-quired vaccination against varicella virus for children in child care set-tings or schools or both (see theBox: Recommendations for Varicel-la Vaccination).

The evidence about the effect onherpes zoster of childhood vaccina-tion against varicella is conflicting(17). One study suggested that thefrequency of herpes zoster increasedas vaccine coverage against varicellain children increased and the fre-quency of varicella decreased (18).Other studies have not confirmed

these findings. One study by theCenters for Disease Control andPrevention found that the incidenceof herpes zoster remained stable asthe incidence of varicella decreased(19). Another study compared her-pes zoster incidence rates between 2states with different rates of varicella vaccine coverage and determinedthat the higher incidence of herpeszoster in 1 state was due to increaseduse of childhood oral corticosteroids

for wheezing conditions, not differ-ences in vaccination rates (20). An-other study of immunocompromisedchildren who received varicella vac-cine found that the incidence of her-pes zoster 10 to 26 years later in thisgroup was similar to that of the gen-eral U.S. population in the prevac-cine era (21). Furthermore, Canadaand the United Kingdom report in-creasing rates of herpes zoster in theabsence of varicella vaccination pro-

grams, which suggests that risk fac-tors other than varicella vaccinationare involved.

When should low-dose acyclovirbe considered to prevent herpeszoster?Low-dose acyclovir may be used toprevent herpes zoster in immuno-compromised patients who cannotreceive the vaccine against varicellazoster virus because it contains a live virus. For example, the National

Comprehensive Cancer Network guidelines (22) recommend herpeszoster prophylaxis for patients re-ceiving bortezomib or bortezomib-based therapies and for recipients of allogenic transplants of peripheralblood stem cells. In 1 trial, re-searchers detected varicella zoster virus, presumably from reactivation,in 13% of patients with multiple

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.

13. Advisory Committeeon ImmunizationPractices. Recom-mended adult im-munization sched-ule: United States,2010. Ann InternMed. 2010;152:36-9.[PMID: 20048270]

14. Rothberg MB, Vi-rapongse A, Smith KJ.Cost-effectiveness of a vaccine to preventherpes zoster andpostherpetic neural-gia in older adults.Clin Infect Dis.2007;44:1280-8.[PMID: 17443464]

15. Hornberger J, Rober-tus K. Cost-effective-ness of a vaccine toprevent herpeszoster and posther-petic neuralgia inolder adults. Ann In-tern Med.2006;145:317-25.[PMID: 16954357]

16. Hurley LP, LindleyMC, Harpaz R, Stok-ley S, Daley MF,Crane LA, et al. Barri-ers to the use of her-pes zoster vaccine.Ann Intern Med.2010;152:555-60.[PMID: 20439573]

17 Reynolds MA, ChavesSS, Harpaz R, LopezAS, Seward JF. Theimpact of the vari-cella vaccinationprogram on herpeszoster epidemiologyin the United States:a review. J Infect Dis.2008;197 Suppl2:S224-7.[PMID: 18419401]



18 Yih WK, Brooks DR,Lett SM, Jumaan AO,Zhang Z, ClementsKM, et al. The inci-dence of varicellaand herpes zoster inMassachusetts asmeasured by the Be-havioral Risk FactorSurveillance System(BRFSS) during a pe-riod of increasingvaricella vaccinecoverage, 1998-2003. BMC PublicHealth. 2005;5:68.[PMID: 15960856]

19. Jumaan AO, Yu O,Jackson LA, BohlkeK, Galil K, Seward JF.Incidence of herpeszoster, before and af-ter varicella-vaccina-tion-associated de-creases in theincidence of varicel-la, 1992-2002. J In-fect Dis.2005;191:2002-7.[PMID: 15897984]

20. Mullooly JP,Riedlinger K, Chun C,Weinmann S, Hous-ton H. Incidence of herpes zoster, 1997-2002. Epidemiol In-fect. 2005;133:245-53. [PMID: 15816149]

21. Hambleton S, Stein-berg SP, Larussa PS,Shapiro ED, GershonAA. Risk of herpeszoster in adults im-munized with vari-cella vaccine. J InfectDis. 2008;197 Suppl2:S196-9.[PMID: 18419397]

22. National Compre-hensive Cancer Net-work; guidelines. Ac-cessed atwww.nccn.org/in-dex.asp on January13, 2011.

23. San Miguel JF,Schlag R, KhuagevaNK, Dimopoulos MA,Shpilberg O, Kropff M, et al; VISTA TrialInvestigators. Borte-zomib plus melpha-lan and prednisonefor initial treatmentof multiple myelo-ma. N Engl J Med.2008;359:906-17.[PMID: 18753647]

24. Vickrey E, Allen S,Mehta J, Singhal S.Acyclovir to preventreactivation of vari-cella zoster virus(herpes zoster) inmultiple myelomapatients receivingbortezomib therapy.Cancer.2009;115:229-32.[PMID: 19090004]


myeloma who were treated withbortezomib-melphalan-prednisone,compared with 4% in patientstreated with melphalan-prednisonealone. However, with addition of acyclovir prophylaxis, the rate of varicella zoster virus decreased to3% in the bortezomib-treated pa-tients (23). In a retrospective study,

prophylactic acyclovir was associat-ed with no cases of varicella zoster virus reactivation in patients withmultiple myeloma who receivedbortezomib-based therapy (24). Adaily low dose of acyclovir that wasgiven until engraftment or discon-tinuation of immunosuppressionprevented herpes zoster in patients with allogeneic transplants of pe-ripheral blood stem cells during amedian 26.5 months of follow-up

(25). In a retrospective cohort

study, acyclovir until the end of im-munosuppressive therapy and ≥1 year after transplantation was asso-ciated with a decreased incidence of varicella zoster virus and with prevention of death and severe symp-toms related to varicella zoster virusafter allogeneic transplantation of hematopoietic stem cells (26). Cli-

nicians should prescribe low-doseoral acyclovir at 400 to 800 mg perday for these patients. Other antivi-ral agents, such as valacyclovir, 250or 500 mg/d, and famciclovir, 500mg/d, can also be used as prophy-laxis for varicella zoster virus. Al-though the risk for reactivation of varicella zoster virus increases withanti–tumor necrosis factor-α thera-py, antiviral prophylaxis is not yetrecommended for patients who re-

ceive this therapy (27).

depending on the cost of thescreening test. Knowledge of im-mune status may be useful becauseimmunocompetent adults who areseronegative should receive the vari-cella vaccine, not the zoster vaccine.

The ACIP does not recommendserologic testing for persons younger than age 13, and it advisesthat serologic testing may be con-sidered for persons ≥13 years whodo not have a history of varicella. Itdoes not recommend postvaccina-tion serologic testing in any group.

Can serologic tests help guidedecisions about vaccination forherpes zoster? Titers of serologic antibodiesagainst varicella zoster virus estab-

lish whether immunity is presentand thus could guide decisionsabout whether vaccination is need-ed (28). However, screening before vaccination is generally not neces-sary because nearly all older U.S.adults are seropositive and becauseit is safe to vaccinate persons al-ready immune to the disease. How-ever, it could be cost-effective

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

CLINICAL BOTTOM LINE

Screening




What symptoms are typical?

Herpes zoster is characterized by aband-like rash in the dermatome thatcorresponds to the affected nerve(Figure 1). The rash is unilateral anddoes not cross the midline. Overlap of lesions in adjacent dermatomes occursin 20% of patients. The most com-monly involved dermatomes are tho-racic, followed by cranial (especially

trigeminal), lumbar, and cervical.Sacral dermatomes are least frequently involved. Simultaneous involvementof noncontiguous dermatomes virtual-ly never occurs in the immunocompe-tent host, but finding a few isolatedskin lesions outside of the primary dermatome is not unusual. Diagnosisis more difficult in patients who haveneuralgic pain before skin lesions develop. Patients may report localizedsensations ranging from mild itching

or tingling to severe pain that precedesthe development of the skin lesions by 1 to 5 days, or occasionally even weeks. Pain that is provoked b y lighttouch may be present. Other possiblesymptoms include a general feeling of being unwell, headache, photophobia,and malaise. Significant fever is rare.

What tests should be used fordiagnosis?

When the clinical diagnosis of herpeszoster is not obvious, cliniciansshould order confirmatory laboratory testing (Table 1). Confirmation of thediagnosis is particularly important when antiviral therapy is planned.

What conditions can be confusedwith herpes zoster? The clinical appearance of fully developed herpes zoster is quite dis-tinct and mimicked by few other

Figure 1. Clusters of vesicles with sur-

rounding 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 dependent on the stage of the lesions, the quality of the specimen collected, and the time elapsed between specimen collection andinoculation of tissue culture. For maximum yield, fluid from fresh vesicles should be aspirated into a tuberculin syringe containingviral transport media and delivered immediately to the virology laboratory. If delivery to the laboratory is delayed, the specimenshould be refrigerated or stored on wet ice, not frozen. Growth of varicella zoster virus in tissue culture may take 3 to 14 days.

PCR 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. Inpatients with suspected varicella zoster virus myelitis and vasculopathy of zoster sine herpete, PCR on CSF is the test of choicealong with antibody testing for varicella zoster virus. The PCR test is the most sensitive and specific diagnostic test; however, it isnot widely available.

Antigen DFA is more sensitive than viral culture and is a suitable alternative when PCR is not available. Using a modified Tzanck technique,detection 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 Tzancksmear, DFA can distinguish between herpes simplex virus and varicella zoster virus. Additional advantages of DFA assay over viralculture are lower cost and more rapid turnaround time.

Serology Patients with herpes zoster will, by definition, be varicella zoster virus–seropositive at the onset of illness. Although some patientswill show a “boost” in varicella zoster virus antibody titer after an episode of herpes zoster, serology is not a very sensitive or spe-cific diagnostic method. Most laboratories use ELISA or latex agglutination methods. More sensitive assays, such as the fluorescentantibody to membrane antigen test and glycoprotein ELISA are not widely available. The latex agglutination test is generally moresensitive than ELISA for detecting varicella zoster virus antibody after natural infection or vaccination. Commercial ELISAs range insensitivity from 86% to 97% and range in specificity from 82% to 99% in detecting antibody after natural infection.

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

Diagnosis

Screening... Screening for serologic antibodies to the varicella zoster virus beforevaccination is generally not required because it is safe to vaccinate people whoare already immune to the disease. Screening provides information about the sta-tus of immunity that might, however, be useful to some people.





diseases. The skin diseases mostcommonly confused with herpeszoster are contact dermatitis,especially toxic dermatitis fromplant exposure, and zosteriformherpes simplex, especially in thesacral area. Immunocompetentpatients believed to have recurrentherpes zoster often have recurrent

herpes simplex infection instead.Consider an alternate diagnosis if the patient has a rash without painor dysesthesias, if the rash does notconform to a dermatomal distribu-tion, or if neuralgic pain persists without the typical skin eruption(Table 2). Additionally, becauseherpes zoster is a common sentineldisease for AIDS, clinicians may consider HIV serologic testing, es-pecially in young adults.

When should a specialist beconsulted for assistance orspecialized procedures to helpdiagnose herpes zoster? When the presentation of herpeszoster is atypical or complex, consultappropriate specialists for advice orspecialized diagnostic procedures. Aninfectious disease specialist or derma-tologist can provide assistance in rec-ognizing atypical presentations or

with procedures, such as viral cultureor skin biopsy. A herpes zoster rashthat resists healing may indicatebacterial infection. An ophthalmolo-gist can help diagnose herpes zosterinvolving the first division of thetrigeminal nerve, which is herpeszoster ophthalmicus (Figure 2). Thiscondition represents 10% to 25% of all cases of herpes zoster, and it hasno known correlation with age, gen-der, or severity of the skin rash. Cli-nicians should be aware that patients with herpes zoster may have oph-thalmic symptoms only, without thetypical skin rash. A common indica-tor of herpes zoster ophthalmicus isthe appearance of blisters on the tipof the nose, which is known asHutchinson sign. The occurrence of severe ear pain, facial muscle weak-ness, and rash identify the Ramsay-Hunt syndrome, an infection of thefacial nerve caused by varicella zoster virus. An otolaryngologist should beconsulted to help diagnose and treatthis syndrome, which can lead tohearing loss and permanent facialmuscle weakness, especially if treat-ment is delayed. Patients sometimesmisinterpret this syndrome as astroke.

Figure 2. Herpes zoster ophthalmicus.

25. Kim DH, Kumar D,Messner HA, MindenM, Gupta V, KuruvillaJ, et al. Clinical effica-cy of prophylacticstrategy of long-term low-dose acy-clovir for Varicella-Zoster virus infectionafter allogeneic pe-ripheral blood stemcell transplantation.Clin Transplant.2008;22:770-9.[PMID: 18707605]

26. Asano-Mori Y, KandaY, Oshima K, Kako S,Shinohara A, Naka-sone H, et al. Long-term ultra-low-doseacyclovir againstvaricella-zoster virusreactivation after al-logeneichematopoietic stemcell transplantation.Am J Hematol.2008;83:472-6.[PMID: 18266207]

27. Strangfeld A, ListingJ, Herzer P, LiebhaberA, Rockwitz K,Richter C, et al. Risk of herpes zoster inpatients withrheumatoid arthritistreated with anti-

TNF-alpha agents.JAMA. 2009;301:737-44. [PMID: 19224750]

28. Sauerbrei A, WutzlerP. Serological detec-tion of varicella-zoster virus-specificimmunoglobulin Gby an enzyme-linked immunosor-bent assay using gly-coprotein antigen. JClin Microbiol.2006;44:3094-7.[PMID: 16954232]

Table 2. Differential Diagnosis of Herpes Zoster

HSV Herpes simplex virus (HSV) is characterized by clusters of painful vesicles on theskin. It can occasionally occur in an elongated distribution that may mimic her-pes zoster, anywhere on the skin. HSV infection is sometimes misdiagnosed asherpes zoster. Patients who report multiple recurrences of herpes zoster (>2episodes) should have definitive virologic testing to distinguish between HSV andvaricella zoster virus. Recurrence of herpes zoster is rare in immunocompetentpersons; HIV-infected persons may have multiple episodes.

Allergic Contact dermatitis, such as reactions to rubber or nickel, or cutaneous reac-tions to topical medications, such as neomycin, can reactions cause localizedareas of erythema and vesiculation that may mimic herpes zoster. Contact

dermatitis does not, however, usually conform to a dermatomal distribution.Chemical Contact with toxic plants, such as poison ivy or poison oak, can cause painful

skin erythema and vesiculation in a band-like irritationpattern. Dermatitisfrom topical toxins does not, however, usually conform to a dermatomalpattern.

Zoster Some patients have neuralgic pain typical of herpes zoster but never developcutaneous lesions, a condition known as zoster sine herpete. Because there isno diagnostic test for this disorder, the incidence is not known. Other condi-tions that involve herpes without neuralgic pain without rash include varicellazoster virus meningitis, polyneuritis cranialis, myelitis, and vasculopathy. Insuch zoster cases, polymerase chain reaction testing on cerebrospinal fluid isrecommended.




acyclovir are all effective for treat-ing herpes zoster, although famci-clovir and valacyclovir are preferred

because they have simpler dosingschedules and better pharmacoki-netic characteristics (see the Box:Drugs for Patients With HerpesZoster Presenting Within 72Hours of Lesion Onset).

What complications should theclinician anticipate? The pain of herpes zoster is calledpostherpetic neuralgia when it persistsfor more than 3 months after the cu-taneous lesions of herpes zoster havecompletely resolved. The frequency of postherpetic neuralgia among people≥ 60 years of age is about 40% at 1month after rash onset, 13% at 3months, and about 7% at 1 year(29–32). The intensity of pain can vary from trivial to debilitating. Pos-therpetic neuralgia occurs more fre-quently with increasing age, more severe acute pain, and a larger surface

area with skin lesions (32, 33).

Herpes zoster can cause other seriouscomplications, including vision andhearing impairments and neurologiccomplications, including vasculopathy,myelitis, cranial and peripheral nervepalsies, and polyradiculitis. Bacterialsuperinfection of cutaneous lesions oc-casionally develops. Immunocompro-mised persons have an increased risk for varicella zoster infection of the

lungs, central nervous system, andbrain as well as life-threatening sec-ondary bacterial infection.

What antiviral drugs are availableto treat herpes zoster? Three orally administered antiviraldrugs are approved in the UnitedStates for treatment of herpeszoster in immunocompetent pa-tients. Famciclovir, valacyclovir, and

Drugs for Patients With Herpes

Zoster Presenting Within 72 Hours

of Lesion Onset

• Famciclovir, 500 mg orally 3 times aday for 7 days

• Valacyclovir, 1 g orally 3 times a dayfor 7 days

• Although the dosage given above isthe approved valacyclovir dosage forherpes zoster in the United States,valacyclovir 1.5 g twice a day is safeand effective for the treatment of uncomplicated herpes zoster inimmunocompetent patients over age18, and less frequent dosing mightimprove patient compliance (MadkanVK, 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 dayfor 7 days

• Prescribe acyclovir only if neitherfamciclovir nor valacyclovir is available,because acyclovir’s complicated dosingschedule reduces the likelihood of compliance and its pharmacokineticcharacteristics are inferior to those of famciclovir and valacyclovir.

29 Helgason S, Peturs-son G, Gudmunds-son S, Sigurdsson JA.Prevalence of pos-therpetic neuralgiaafter a first episodeof herpes zoster:prospective studywith long term fol-low up. BMJ.2000;321:794-6.[PMID: 11009518]

30. Bowsher D. The ef-fects of pre-emptivetreatment of pos-therpetic neuralgiawith amitriptyline: arandomized, double-blind, placebo-con-trolled trial. J PainSymptom Manage.1997;13:327-31.[PMID: 9204652]

31. McKendrick MW,McGill JI, Wood MJ.Lack of effect of acy-clovir on posther-petic neuralgia. BMJ.1989;298:431.[PMID: 2495051]

32. Yawn BP, Saddier P,Wollan PC, St SauverJL, Kurland MJ, Sy LS.A population-basedstudy of the inci-dence and compli-cation rates of her-pes zoster beforezoster vaccine intro-duction. Mayo ClinProc. 2007;82:1341-9.[PMID: 17976353]

33. Whitley RJ, Weiss HL,Soong SJ, Gnann JW.Herpes zoster: risk categories for per-sistent pain. J InfectDis. 1999;179:9-15.[PMID: 9841816]

34. Tyring S, BarbarashRA, Nahlik JE, Cun-ningham A, Marley J,Heng M, et al. Famci-clovir for the treat-ment of acute her-pes zoster: effects onacute disease andpostherpetic neural-gia. A randomized,double-blind, place-bo-controlled trial.Collaborative Famci-clovir Herpes ZosterStudy Group. AnnIntern Med.1995;123:89-96.[PMID: 7778840]

35. Shafran SD, TyringSK, Ashton R, De-croix J, Forszpaniak C, Wade A, et al.Once, twice, or threetimes daily famci-clovir comparedwith aciclovir for theoral treatment of herpes zoster in im-munocompetentadults: a random-ized, multicenter,double-blind clinicaltrial. J Clin Virol.2004;29:248-53.[PMID: 15018852]

Diagnosis... Varicella zoster virus produces a characteristic rash in the involveddermatome. Skin changes include an erythematous maculopapular rash followedby the appearance of clear vesicles for 3 to 5 days and subsequent pustulationand scabbing. Skin lesions heal within 2 to 4 weeks. Patients may report sensa-tions that range from mild itching or tingling to severe pain preceding the devel-opment of skin lesions. The clinical appearance of fully developed herpes zoster isquite distinct and mimicked by few other diseases. When the clinical diagnosis of herpes zoster is not obvious, clinicians should order confirmatory laboratory test-ing. Skin diseases commonly confused with herpes zoster include contact der-

matitis and herpes simplex virus infection. Consult with appropriate specialistswhen the presentation of herpes zoster is atypical or complex.


Treatment




36. Beutner KR, Fried-man DJ, Forszpaniak C, Andersen PL,Wood MJ. Valaci-clovir comparedwith acyclovir for im-proved therapy forherpes zoster in im-munocompetentadults. AntimicrobAgents Chemother.1995;39:1546-53.[PMID: 7492102]

37. Tyring SK, BeutnerKR, Tucker BA, An-derson WC, CrooksRJ. Antiviral therapyfor herpes zoster:randomized, con-trolled clinical trial of valacyclovir andfamciclovir therapyin immunocompe-tent patients 50years and older. ArchFam Med.2000;9:863-9.[PMID: 11031393]

38. Huff JC, Bean B, Bal-four HH Jr, Laskin OL,Connor JD, Corey L,et al. Therapy of her-pes zoster with oralacyclovir. Am J Med.1988;85:84-9.[PMID: 3044099]

39. Morton P, ThomsonAN. Oral acyclovir inthe treatment of herpes zoster ingeneral practice. N ZMed J. 1989;102:93-5. [PMID: 2648213]

40. McKendrick MW,McGill JI, White JE,Wood MJ. Oral acy-clovir in acute her-pes zoster. Br Med J(Clin Res Ed).1986;293:1529-32.[PMID: 3099943]

41. Wood MJ, Kay R,Dworkin RH, SoongSJ, Whitley RJ. Oralacyclovir therapy ac-celerates pain reso-lution in patientswith herpes zoster: ameta-analysis of placebo-controlledtrials. Clin Infect Dis.1996;22:341-7.[PMID: 8838194]

42. Li Q, Chen N, Yang J,Zhou M, Zhou D,Zhang Q, et al. An-tiviral treatment forpreventing posther-petic neuralgia.Cochrane DatabaseSyst Rev.2009:CD006866.[PMID: 19370655]

43. Gilden DH, BeinlichBR, Rubinstien EM,Stommel E, SwensonR, Rubinstein D, et al.Varicella-zoster virusmyelitis: an expand-ing spectrum. Neu-rology.1994;44:1818-23.[PMID: 7936229]

All 3 drugs reduce the duration of pain, presumably by limiting thedamage to the sensory nerves fromreplicating virus. Halting this repli-cation also shortens the duration of new lesion formation, acceleratescutaneous healing, and reduces theduration of viral shedding.

One RCT involving 419 immunocompetent adults with uncomplicated herpes zoster found that compared with placebo, famci-clovir reduced the median duration of pos-therpetic neuralgia from about 4 monthsto about 2 months (34). Another RCT com- paring 3 dose regimens of famciclovir (750mg once a day, 500 mg twice a day, or 250mg 3 times a day for 7 days) found themequally 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 cu-

taneous healing and acute pain. Still an-other RCT found valacyclovir and acyclovir equally effective for cutaneous healing(36). Valacyclovir was superior, however,for shortening the duration of acute painand the duration of postherpetic neural-gia. For example, fewer patients takingvalacyclovir experienced pain for 6 months(19.3%) when compared with patients tak-ing acyclovir (25.7%). A blinded RCT that compared valacyclovir and famciclovir found them therapeutically equivalent for the treatment of herpes zoster, but valacy-

clovir was more cost-effective ($83.90 vs$140.70 per course) (37).

If neither famciclovir nor valacy-clovir is available, clinicians shouldprescribe acyclovir.

Three clinical trials have demonstrated that oral acyclovir, initiated within 72hours of the onset of lesions at a dose of 800 mg, 5 times daily, reduces the durationof viral shedding, shortens the duration of new lesion formation, and accelerates cu-

taneous healing (38, 39, 40). One meta-analysis also found acyclovir superior to placebo for reducing the duration of herpes zoster–associated pain (41).

The role of antiviral treatment inpreventing postherpetic neuralgia isless clear. A recent Cochrane review concluded that oral acyclovirdoes not reduce the incidence of postherpetic neuralgia and that

evidence about other antiviral treat-ments is insufficient (42).

Clinical trials with antiviral drugshave focused on patients present-ing within 72 hours of lesion on-set. The value of antiviral therapy for patients presenting beyond 72hours has not been adequately

studied. Despite lack of evidence,however, antiviral therapy is rec-ommended for patients presentingmore than 72 hours after the on-set of rash with continued new vesicle formation or when thereare cutaneous, motor, neurologic,or ocular complications.

Cost–benefit considerations favortreatment of patients with herpeszoster who are older than age 50because of the higher risk forcomplications, especially posther-petic neuralgia, in older persons. Treatment is particularly advisedfor older patients with severe painand a large area of skin involve-ment, which are risk factors forprolonged pain. Antiviral therapy is optional for younger patients with mild pain and limited cuta-neous involvement because thesepatients are at relatively low risk for severe or protracted pain.

Topical antiviral therapy is ineffec-tive and thus is not recommended.

When should intravenousantivirals be given?Intravenous acyclovir should beadministered in patients withherpes zoster that is complicatedby central nervous system involvement, especially myelit is. This recommendation is basedon case reports and anecdotal ex-perience (43, 44). The dose forimmunocompetent individuals is10 to 15 mg/kg, every 8 hoursfor patients with normal renalfunction. For such manifestationsas delayed contralateral hemi-paresis, in which the role of ac-tive viral replication is less clear,the value of antiviral therapy isuncertain, but the potential



44. Peterslund NA. Her-pes zoster associat-ed encephalitis: clini-cal findings andacyclovir treatment.Scand J Infect Dis.1988;20:583-92.[PMID: 3222675]

45. Cobo M, Foulks GN,Liesegang T, Lass J,Sutphin J, WilhelmusK, et al. Observationson the natural histo-ry of herpes zosterophthalmicus. CurrEye Res. 1987;6:195-9. [PMID: 3493883]

46. Cobo Cobo LM,Foulks GN,Liesegang T, Lass J,Sutphin JE, Wilhel-mus K, et al. Oralacyclovir in thetreatment of acuteherpes zoster oph-thalmicus. Ophthal-mology.1986;93:763-70.[PMID: 3488532]

47. Herbort CP, BuechiER, Piguet B, Zo-grafos L, Fitting P.High-dose oral acy-clovir in acute her-pes zoster oph-thalmicus: the endof the corticosteroidera. Curr Eye Res.1991;10 Suppl:171-5.[PMID: 1864091]

48. Hoang-Xuan T, BüchiER, Herbort CP, DenisJ, Frot P, Thénault S,et al. Oral acyclovirfor herpes zosterophthalmicus. Oph-thalmology.1992;99:1062-70; dis-cussion 1070-1.[PMID: 1495785]

49. Liesegang TJ. Varicel-la zoster viral dis-ease. Mayo Clin Proc.1999;74:983-98.[PMID: 10918864]

50. Dworkin RH, Bar-bano RL, Tyring SK,Betts RF, McDermottMP, Pennella-Vaugh-an J, et al. A random-ized, placebo-con-trolled trial of oxycodone and of gabapentin foracute pain in herpeszoster. Pain.2009;142:209-17.[PMID: 19195785]

51. Berry JD, PetersenKL. A single dose of gabapentin reducesacute pain and allo-dynia in patientswith herpes zoster.Neurology.2005;65:444-7.[PMID: 16087911]

52 van Wijck AJ, Opstel-ten W, Moons KG,van Essen GA, Stolk-er RJ, Kalkman CJ, etal. The PINE study of epidural steroidsand local anaesthet-ics to prevent pos-therpetic neuralgia:a randomised con-trolled 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 ner vous sys-tem, is a risk for immunocom-promised persons but rarely occurs in immunocompetent in-dividuals. Consider intravenous

acyclovir for immunocompetentpatients with herpes zoster and visceral involvement, althoughthere are no data from prospec-tive studies to support thisrecommendation.

What are special considerationswhen treating herpes zosterophthalmicus?Herpes zoster ophthalmicus is par-ticularly serious because of the po-

tential for adverse ocular complica-tions with damage to the eye orsurrounding structures, includingstromal or neurotrophic keratitis,uveitis, scleritis or episcleritis, andretinal necrosis. In the absence of antiviral therapy, approximately 50%of patients with herpes zoster oph-thalmicus will develop some of thesecomplications (45). Controlled,prospective clinical trials have con-firmed that oral acyclovir therapy will reduce the frequency of late ocu-lar inflammatory complications fromapproximately 50% to 60% to ap-proximately 20% to 30% (46–48).Patients with herpes zoster oph-thalmicus should be treated with oralantiviral therapy even if lesions havebeen present for more than 72 hours.Consult an ophthalmologist for ap-propriate evaluation of the eye if there are any symptoms suggestingocular involvement. Certain ophthal-mologic complications may require

specific treatments. Systemic or topi-cal corticosteroids are indicated forsome of the ocular inflammatory phenomena that accompany herpeszoster ophthalmicus but should only be administered under the supervi-sion of an experienced ophthalmolo-gist (49). For patients with severeherpes zoster ophthalmicus, considerintravenous acyclovir for initial

therapy, although there are no datafrom controlled clinical trials to sup-port the superiority of this approachover oral antiviral therapy. Systemicantiviral therapy has largely replacedtopical antiviral preparations fortreatment of ocular complications as-sociated with herpes zoster oph-thalmicus.

What drugs can be used forcontrol of acute pain? The pain of herpes zoster can sig-nificantly reduce functional statusand health-related quality of life.Clinicians should not underesti-mate the severity of the neuralgicpain and should keep in mind thateven patients with relatively limitedskin involvement can have severesymptoms. Therefore, aggressive

pain management is warranted.Early efforts to attenuate acutepain may reduce the risk for pos-therpetic neuralgia.

For some patients, over-the-counter medications, such as acet-aminophen or ibuprofen, are ade-quate for pain relief. If moderateto severe herpes zoster pain is notrelieved by antiviral agents com-bined with oral analgesic medica-tions, then clinicians should con-sider prescribing additionaltherapies. Short-acting narcoticanalgesics, such as oxycodone,should be prescribed on a sched-uled rather than on an as-neededbasis. Early in the course of dis-ease, it may be helpful to add an-ticonvulsants, such as gabapentin,or tricyclic antidepressants, al-though the anticholinergic sideeffects of some tricyclic antide-pressants, such as amitriptyline,

can cause serious problems inolder adults.

One RCT found controlled-release oxy-codone 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 withherpes zoster diminished with a single 900-mg dose of gabapentin (51). In addition,neural blockade may be prescribed. One



53. He L, Zhang D, ZhouM, Zhu C. Corticos-teroids for prevent-ing postherpeticneuralgia. CochraneDatabase Syst Rev.2008:CD005582.[PMID: 18254083]

54. Wood MJ, JohnsonRW, McKendrick MW,

Taylor J, Mandal BK,Crooks J. A random-ized trial of acyclovirfor 7 days or 21 dayswith and withoutprednisolone fortreatment of acuteherpes zoster. N EnglJ Med. 1994;330:896-900. [PMID: 8114860]

55. Whitley RJ, Weiss H,Gnann JW Jr, TyringS, Mertz GJ, PappasPG, et al. Acyclovirwith and withoutprednisone for thetreatment of herpeszoster. A random-ized, placebo-con-trolled trial. The Na-tional Institute of Allergy and Infec-tious Diseases Col-laborative AntiviralStudy Group. AnnIntern Med.1996;125:376-83.[PMID: 8702088]

56. Yawn BP, Saddier P,Wollan PC, St SauverJL, Kurland MJ, Sy LS.A population-basedstudy of the inci-dence and compli-cation rates of her-pes zoster beforezoster vaccine intro-duction. Mayo ClinProc. 2007;82:1341-9.[PMID: 17976353]


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

Topical capsaicin should not be usedfor acute herpes zoster because it canexacerbate the pain, but it can beused to treat postherpetic neuralgia.

What is the role of corticosteroidsin treating herpes zoster? A Cochrane review concluded that no evi-dence supports the use of corticosteroidsto prevent postherpetic neuralgia (53).Nevertheless, some experienced physicians prescribe oral corticosteroids because they believe that these drugs provide other symptomatic benefits for patients. OneRCT found that adding prednisolone to

acyclovir improved rash healing and re-duced moderate to severe pain but not mild pain during the acute phase of dis-ease; however, prednisolone did not reducethe 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 con-ferred a significant reduction in pain (55).

Consider adding a 10- to 14-day ta-pering course of oral prednisone

(e.g., starting at 60 mg daily) to an-tiviral therapy in patients with her-pes zoster older than 50 years of age who have moderate to severe pain atpresentation; however, rememberthat corticosteroid therapy can causepotentially serious adverse effects.Prednisone should also not be usedfor patients in whom steroid therapy is relatively contraindicated, such asin patients with diabetes mellitus,osteoporosis, or gastritis. Do not use

corticosteroids without concomitantantiviral therapy.

What nondrug therapies should beconsidered when managing herpeszoster?Basic symptomatic measures may beused to soothe and protect the involved skin (see the Box: NondrugMeasures for Managing HerpesZoster). Advise patients that involved

and uninvolved skin in the affecteddermatome may temporarily have in-creased sensitivity and tenderness.

When should patients behospitalized?Most patients with herpes zostercan be managed as outpatients;however, those with disseminated

herpes zoster infection or ocularinvolvement may need to be hos-pitalized for observation, support-ive care, and intravenous acyclovirtherapy. Scattered cutaneous vesi-cles appearing beyond the primary or adjacent dermatomes are not anindication for hospitalization.

When should a specialist beconsulted?Nearly 1 in 4 patients have sometype of herpes zoster–related compli-cation (56). The most commoncomplication is postherpetic neural-gia, and because this can be very dif-ficult to manage, consulting a painspecialist may be helpful. Consult aneurologist for assistance with therare patient who develops such neu-rologic complications as vasculopathy or myelitis. Consider an ophthalmol-ogy consult for all patients with her-pes zoster ophthalmicus, includingthose without complications. For

guidance managing antiviral drugtherapy, consider consulting an in-fectious disease specialist.

What should patients know abouttheir episode of herpes zoster?Patients should learn ways to sootheand protect the involved skin as wellas what to expect regarding the po-tential for chronic pain and the risk for virus transmission. Patients needto be psychologically prepared to

manage chronic pain and should beinstructed to contact the physician if pain-control measures are ineffectiveor inadequate. The dosing regimenfor analgesic medications is impor-tant to managing pain, and around-the-clock pain control is usually superior to as-needed dosing.

Patients with herpes zoster shouldlearn about the risk for varicella

Nondrug Measures for Managing

Herpes Zoster

• Keep cutaneous lesions clean and dryto reduce the risk for bacterialsuperinfection.

• Wash rash with soap and water andthen carefully pat dry.

• Warm or cool astringent soaks may besoothing.

• Consider using a sterile, occlusive,nonadherent dressing to protect thelesions and promote healing,especially in patients with herpeszoster with increased skin sensitivity.

• Wear loose-fitting clothing forcomfort.

• Remember that topical creams orointments (including topical acycloviror penciclovir) have no role in themanagement of herpes zoster.



57. Sawyer MH, Cham-berlin CJ, Wu YN,Aintablian N, WallaceMR. Detection of varicella-zoster virusDNA in air samplesfrom hospital rooms.J Infect Dis.1994;169:91-4.[PMID: 8277202]

58. Garner JS. Guidelinefor isolation precau-tions in hospitals.

The Hospital Infec-tion Control Prac-tices Advisory Com-mittee. InfectControl Hosp Epi-demiol. 1996;17:53-80. [PMID: 8789689]

59. Kuroiwa Y, Furukawa T. Hemispheric in-farction after herpeszoster ophthalmicus:computed tomogra-phy and angiogra-phy. Neurology.1981;31:1030-2.[PMID: 6973708]

60. Eidelberg D, SotrelA, Horoupian DS,Neumann PE,Pumarola-Sune T,Price RW. Thrombot-ic cerebral vascu-lopathy associatedwith herpes zoster.Ann Neurol.1986;19:7-14.[PMID: 3004319]

61. Reshef E, GreenbergSB, Jankovic J. Her-pes zoster oph-thalmicus followedby contralateralhemiparesis: reportof two cases and re-view of literature. JNeurol NeurosurgPsychiatry.1985;48:122-7.[PMID: 3884741]

62. Verghese A, SugarAM. Herpes zosterophthalmicus andgranulomatous angi-itis. An ill-appreciat-ed cause of stroke. JAm Geriatr Soc.1986;34:309-12.[PMID: 3485127]

63. Nagel MA, Cohrs RJ,Mahalingam R, Well-ish MC, Forghani B,Schiller A, et al. Thevaricella zoster virusvasculopathies: clini-cal, CSF, imaging,and virologic fea-tures. Neurology.2008;70:853-60.[PMID: 18332343]

64. Cheung WC, YuenKY, Chang CM,Cheng KP. Herpeszoster associated en-cephalitis in dialysispatients. J Infect.1991;23:169-74.[PMID: 1753116]


zoster virus transmission. Transmis-sion of the virus can cause varicellain a person who is seronegative forherpes zoster. Patients cannotacutely transmit herpes zoster toanother individual. The risk fortransmission of varicella zoster virus is probably less from a person with herpes zoster than from a per-

son with varicella. Patients with ac-tive herpes zoster should avoidcontact with susceptible infants orsmall children, susceptible pregnant women, or potentially susceptibleimmunocompromised individuals. The virus is transmitted primarily through direct contact. It also canbe transmitted through the air, par-ticularly from patients with dissem-inated herpes zoster. For example, varicella zoster virus DNA was de-

tectable in air samples from thehospital rooms of 9 of 13 patients with herpes zoster (57). Authoritiesrecommend standard precautionsand use of gloves when touchingthe lesions of patients with local-ized zoster. Severely immunocom-promised patients who developdermatomal zoster should beplaced on strict isolation, both air-borne and contact, until lack of contagion becomes clear. All pa-

tients with disseminated zostershould be on airborne and contactisolation (58).

What other complications shoulda clinician look for after an episodeof herpes zoster?Contralateral hemiparesisVaricella zoster virus can inducecentral nervous system angiitis,resulting in stroke-like symptoms with hemiparesis occurring con-tralateral to the antecedent trigemi-

nal zoster. The pathogenesis of thisrare disorder is believed to be directinvasion of cerebral arteries by vari-cella zoster virus along the first division of the trigeminal nerve, re-sulting in inflammation of theinternal carotid artery or one of itsbranches on the side ipsilateral tothe rash. Contralateral hemiparesisoccurs as a late complication of

herpes zoster ophthalmicus, withthe average interval from rash toonset of neurologic symptomsabout 7 weeks. Intervals of up to 6months have been reported. Clini-cians should evaluate patients withhemiparesis that follows an episodeof herpes zoster ophthalmicus by weeks or months for possible vari-

cella zoster virus–related centralnervous system vasculitis. Imagingstudies usually show changes con-sistent with brain infarction (59).Angiography is usually diagnostic,showing inflammation, narrowing,and thrombosis of the proximalbranches of the anterior or middlecerebral artery (60). Many patients with unifocal or multifocal vascu-lopathy due to varicella zoster virushave transient ischemic attacks

(TIAs), mental status changes, orboth within weeks to months afterzoster and before frank infarctiondevelops. Magnetic resonance im-aging (MRI) usually shows one ormore ischemic lesions, magneticresonance angiography may show arterial stenosis, and examination of cerebrospinal fluid (CSF) usually shows mononuclear pleocytosis andeven oligoclonal bands.

Multifocal vasculopathyDissemination of varicella zoster virus to the central nervous systemcan cause multifocal vasculopathy in immunologically intact individ-uals on rare occasions; this occur-renc is more common in immuno-compromised patients. Considerthe possibility of varicella zoster virus multifocal vasculopathy inpatients with altered mental statusor focal neurologic findings dur-ing or after an episode of herpes

zoster. The clinical presentation ismost often TIA; stroke; or acuteor subacute delirium that may beaccompanied by other signs, in-cluding headache, meningismus,fever, ataxia, or seizures. Even inthe absence of a history of rash,multifocal vasculopathy is a possi-ble cause of TIA or stroke inadults; 40% of patients with



65. Ormerod LD, LarkinJA, Margo CA, PavanPR, Menosky MM,Haight DO, et al.Rapidly p rogressiveherpetic retinalnecrosis: a blindingdisease characteris-tic of advancedAIDS. Clin Infect Dis.1998;26:34-45; dis-cussion 46-7.[PMID: 9455507]

66. Garweg J, BöhnkeM. Varicella-zostervirus is strongly as-sociated with atypi-cal necrotizing her-petic retinopathies.Clin Infect Dis.1997;24:603-8.[PMID: 9145733]

67. Blumenkranz MS,Culbertson WW,Clarkson JG, Dix R.

Treatment of theacute retinal necro-sis syndrome withintravenous acy-clovir. Ophthalmolo-gy. 1986;93:296-300.[PMID: 3703498]

68. Palay DA, SternbergP Jr, Davis J, Lewis H,Holland GN, MielerWF, et al. Decrease inthe risk of bilateralacute retinal necro-sis by acyclovir ther-apy. Am J Ophthal-mol. 1991;112:250-5.[PMID: 1882936]

69. Crapotta JA, Free-man WR. Visual out-come in acute reti-nal necrosis [Letter].Retina. 1994;14:382-3. [PMID: 7817036]

70. Galindez OA,Sabates NR, WhitacreMM, Sabates FN.Rapidly p rogressiveouter retinal necrosiscaused by varicellazoster virus in a pa-tient infected withhuman immunodefi-ciency virus. Clin In-fect Dis.1996;22:149-51.[PMID: 8824984]

71. Schliefer K, GümbelHO, Rockstroh JK,Spengler U. Manage-ment of progressiveouter retinal necrosiswith cidofovir in ahuman immunodefi-ciency virus-infectedpatient. Clin InfectDis. 1999;29:684-5.[PMID: 10530469]

72. Ragozzino MW,Melton LJ 3rd, Kur-land LT, Chu CP, Per-ry HO. Risk of cancerafter herpes zoster: apopulation-basedstudy. N Engl J Med.1982;307:393-7.[PMID: 6979711]


varicella zoster virus vasculopathy have no history of zoster rash(63). Signs may occur from 30days before to 6 months afteracute herpes zoster, and multifocal vasculopathy has been reported inpatients who were appropriately treated with antiviral therapy dur-ing the acute episode of herpes

zoster (64). The most consistentdiagnostic criterion for varicellazoster virus vasculopathy is evi-dence of ischemic lesions on MRIor computed tomography of thebrain with a CSF positive for varicella zoster virus on poly-merase chain reaction (PCR) assay or varicella zoster virus IgG.Examination of CSF reveals in-creased opening pressure, in-creased protein, and lymphocytic

pleocytosis, although the absenceof pleocytosis does not rule out varicella zoster virus vasculopathy. The PCR assay for varicella zoster virus DNA and anti–varicellazoster virus IgG antibody in CSF are often positive; detection of thelatter is more sensitive than detec-tion of the latter. Computed to-mography or MRI of the brain isoften abnormal, showing ischemiclesions. Histopathologic studies

suggest that the pathogenesis of diffuse disease of the central nerv-ous system is small-vessel vasculi-tis. The role of antiviral therapy for herpes zoster vasculitis has notbeen studied in a prospective fash-ion, but there are anecdotal re-ports of successful treatment withintravenous acyclovir.

Acute retinal necrosisAcute retinal necrosis is most oftencaused by varicella zoster virus, al-

though a similar syndrome hasbeen attributed to herpes simplex virus. Consider varicella zoster virusretinitis in a patient with acute vi-sual changes and a history of her-pes zoster. Both immunocompetentand immunocompromised patientshave experienced acute retinalnecrosis, but most recent case re-ports have involved patients with

AIDS (65). Acute retinal necrosiscan be a late complication of thedisease. Visual changes usually oc-cur weeks to months after anepisode of acute herpes zoster. Theprevious zoster may have been inany dermatome (not necessarily trigeminal), suggesting that varicel-la zoster virus reaches the retina by

the hematogenous route. Varicellazoster virus has been cultured fromretinal biopsy specimens, and anti-gens and nucleic acids have beendetected in vitreous humor andretinal tissue (66). The characteris-tic funduscopic examination revealsgranular, yellowish, nonhemorrhag-ic lesions that rapidly extend andcoalesce, often resulting in retinaldetachment. There is a relative lack of intraocular inflammatory

changes. In immunocompetent pa-tients, acyclovir therapy improvesthe clinical outcome. In conjunc-tion with an ophthalmologist, pre-scribe intravenous acyclovir, 10mg/kg to 15 mg/kg, every 8 hours,for 10 to 14 days (for patients withnormal renal function), followed by oral valacyclovir, 1 g, 3 times a day,for 4 to 6 weeks. The suggestedtreatment regimen is based on an-ecdotal experience and uncontrolled

clinical trials (67–69). In immuno-compromised patients, the optimalantiviral therapy and duration foracute retinal necrosis remain un-clear. Responses to intravenousacyclovir or ganciclovir have beeninconsistent and disappointing. Im-proved preservation of vision in pa-tients treated with a combination of intravenous ganciclovir plus foscar-net, with or without intravitreal an-tivirals, or with cidofovir alone hasbeen reported (70, 71).

Is herpes zoster associated with anincreased risk for cancer?Herpes zoster is not a marker forcancer (72). A thorough history and physical examination are war-ranted for all patients with herpeszoster, but additional laboratory and imaging studies are not, un-less clinically indicated.



I n

t h

e

C l i n

i cTool KitIn the Clinic

Herpes Zoster

PIER Moduleswww.pier.acponline.org

PIER module on herpes zoster. PIER modules provide evidence-based,updated information on current diagnosis and treatment in an electronicformat designed for rapid access at the point of care.

Patient Information

www.annals.org/intheclinic/toolkit-herpeszoster.html

Patient Information material that appears on the following pages forduplication 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 Guidelineswww.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 onImmunization Practices (ACIP) vaccine recommendations, from theCenters 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.

1 March 2011Annals of Internal MedicineIn the Clinic ITC3-14© 2011 American College of Physicians

Treatment... Three orally administered antiviral drugs are approved in the UnitedStates for treatment of herpes zoster in immunocompetent patients. Famciclovir,valacyclovir, and acyclovir are all effective for treatment of herpes zoster, al-though famciclovir and valacyclovir are preferred because of a simplified dosingschedule and improved pharmacokinetic characteristics. Administer intravenousacyclovir to patients with herpes zoster that is complicated by central nervoussystem involvement. Intravenous acyclovir may also be warranted for severe casesof herpes zoster ophthalmicus. Aggressive, early pain management is warranted toreduce 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 pos-therpetic neuralgia, but the anti-inflammatory effects may provide other sympto-matic benefit. Conservative measures may soothe and protect involved skin. Mostepisodes of herpes zoster can be managed on an outpatient basis. Patients withdisseminated herpes zoster infection or with ocular involvement, however, mayneed to be hospitalized. Consult a specialist when diagnosis or management isunclear or complicated.




In the Clinic

Annals of Internal Medicine

P a t i e n t I n f o r m a t i o n

THINGS YOU SHOULD KNOWABOUT 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 dormantin the nerve cell and can reactivate later in life.

• Herpes zoster can occur at any age, but it is mostcommon among people 50 years of age and older.

• People who have medical conditions or take medica-tions that suppress their immune system are at in-creased risk for herpes zoster.

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 for2 to 4 weeks.

• Symptoms can include a general feeling of being

unwell, headache, chills.

How is herpes zoster diagnosed?• Your doctor will diagnose herpes zoster after per-

forming a physical examination and analyzing yoursymptoms. Sometimes laboratory tests are per-formed to confirm the diagnosis.

• Your doctor may consult with a specialist who hasspecial knowledge of diagnosing and treating com-plications of herpes zoster.

How is it treated?• Three orally administered antiviral drugs are ap-

proved in the United States for treatment of herpeszoster in healthy patients: famciclovir, valacyclovir,and acyclovir.

• Treatment is shown to reduce the duration of painand accelerate the healing of the rash.

• Early treatment may reduce the risk for complications.

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 orsharp pain or itchiness in the area where the herpeszoster rash appeared. It can sometimes be severeenough that it disrupts sleep and makes everydayactivities difficult.

• Herpes zoster can also cause other serious complica-tions, including vision loss; ear pain; and inflamma-tion of the spinal cord, which causes weakness inlegs and arms and back pain.

Can herpes zoster be prevented?• 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 zosterduring their lifetime; risk increases with age.

• The herpes zoster vaccination also prevents posther-petic neuralgia.

For More Informationwww.aad.org/public/publications/pamphlets/viral_herpes_zoster.htmlInformation 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.htmInformation on varicella vaccination and herpes zostervaccination from the Centers for Disease Control andPrevention.

www.ninds.nih.gov/disorders/shingles/shingles.htmInformation on herpes zoster from the National Institute of

Neurological Disorders and Stroke.

www.vzvfoundation.org/chickenq&a.htmlwww.vzvfoundation.org/shingles&phn.htmlInformation on varicella and on herpes zoster and postherpetic

neuralgia from the Varicella Zoster Virus Research Foundation.



CME Questions

1 March 2011Annals of Internal MedicineIn the Clinic ITC3-16© 2011 American College of Physicians

Questions are largely from the ACP’s 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.

1. A 75-year-old man is hospitalized with a1-day history of fever, painful rash, andconfusion. The patient has Crohn diseasetreated with prednisone and 6-

mercaptopurine. The corticosteroid dosewas recently escalated and then taperedfor treatment of a disease flare.

On physical examination, the patientappears ill and confused. Temperature is37.9°C (100.3°F), blood pressure is120/70 mm Hg, pulse rate is 110/min,and respirations are 28/min and shallow.Arterial oxygen saturation is 90% onambient air. A prominent vesicular rash ispresent on the chest in a dermatomalpattern, and multiple vesicular lesions of a similar nature are scattered on the

trunk, arms, and legs. Examination of thelungs discloses scattered crackles. Resultsof laboratory studies are as follows:leukocyte count, 5200/µL (5.2 × 109/L)with a normal differential; blood ureanitrogen, 34 mg/dL (12.1 mmol/L);creatinine, 2.3 mg/dL (203.3 µmol/L);alanine aminotransferase, 95 U/L; andaspartate aminotransferase, 98 U/L.

A chest radiograph shows bilateralinterstitial infiltrates. Lumbar puncture isperformed. The cerebrospinal fluid (CSF)leukocyte count is 48/µL (48 × 106/L)

with 10% polymorphonuclear cells, 70%lymphocytes, and 20% monocytes;protein is 90 mg/dL (900 mg/L), andglucose is 70 mg/dL (3.9 mmol/L) (plasmaglucose is 110 mg/dL [6.1 mmol/L]). Gramstain and culture of the CSF and bloodand urine cultures are negative.

In addition to replacement of cortico-steroids in stress doses, which of thefollowing is the most appropriatetreatment?

A. IV acyclovirB. Foscarnet

C. Herpes zoster vaccineD. Valganciclovir

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

of shingles 1 year ago that was treatedwith famciclovir. He has a history of alcoholism and intermittent injectiondrug use. He has lost approximately 3.0

kg (6.6 lb) over the past 3 months. Hehas had increased fatigue but deniesfever, chills, lymphadenopathy, jaundice,or change in his bowel habits. He takesno medications.

On physical examination, temperature is37.0°C (98.6°F), and BMI is 28. Oralmucous membranes are normal. There isno jaundice, lymphadenopathy, orhepatosplenomegaly. Direct fluorescentantibody test is positive for varicella-zoster virus.

Which of the following is the most likely

underlying disease?

A. Cirrhosis

B. Diabetes mellitusC. Hepatitis BD. Hepatitis C

E. HIV infection

3. A 68-year-old woman is evaluated duringa routine examination. She states thatlast year she had a painful rash on theright side of her back that was self-limited. She does not recall a history of childhood chickenpox. She takes no

medications and has no allergies. Vital signs are normal, and the physicalexamination is unremarkable. Completeblood count, liver enzymes, and serumchemistry studies are all normal. She isscheduled to receive her annual influenzavaccination today.

Which of the following is the mostappropriate vaccine administration strategyto prevent herpes zoster in this patient?

A. Zoster vaccination if negative forvaricella antibodies

B. Zoster vaccination if positive forvaricella antibodies

C. Zoster vaccination nowD. Zoster vaccination now and in 6

months

E. Zoster vaccination is not indicated

4. A 70-year-old man has a 1-day history of a painful rash on his chest. Three daysbefore the rash became apparent, hedeveloped severe pain and paresthesias

in the same area. The remainder of theexamination is unremarkable.

In addition to appropriate analgesicagents, which of the following should begiven at this time?

A. Corticosteroids

B. Oral famciclovirC. Intravenous acyclovirD. Topical penciclovir

5. A 64-year-old man is evaluated for aright-sided headache with which heawoke yesterday. It began as a dull ache

over his right forehead and has graduallyincreased in intensity. He also notes someright eye discomfort, sensitivity to light,and that his eye is red.

Vital signs are normal. The patient isuncomfortable and prefers to have thelights dimmed. The right eye has diffuselyinjected conjunctiva, and the corneaappears clear. The left eye is normal. Thepupils are equal and reactive. Visualacuity is normal. Cranial nerves areintact.

Which of the following is the most likely

diagnosis?

A. Herpes simplex virus keratitisB. Herpes zoster ophthalmicusC. Scleritis

D. Trigeminal neuralgia

Documents

Herpes Zoster - Ann Intern Med 2011