chap! er 194 :: Varicella and Herpes Zoster Kenneth E. Schmader & Michael N. Oxman tie lies caused (ee ante the spss ay, bya ves (VZV). an acute, highly contagious that ocurs most often in childhood, tert at primary VZV infection of a Je individual, Varicella isthe ssp tb perish usually begins on the face and Bipand spreads rapt to the trunk, with Aivesparing ofthe extremities. Lesions are ‘tena rather than clustered, and progress fom rose-colored macules to papules, oles pustules, and erusts. In varicella in JRomast fo smallpox, lesions in all stages are mully present on the body at the same time, tnnormal children, systemic symptoms ane usually mild and serious complications arerare In adults and immunologically ‘compromised persons of any age, varicella ismoreikely to be associated! with life- threatening complications. + Where use of varicella vaccine in susceptible Juldeen and adults is widespread, the ‘idence of varicella is markedly reduced, hough breakthrough varicella may occur. EPIDEMIOLOGY EU TTTT Aer as nae distributed worldwide, but its age-specific ‘xiv ditfersin temperate versus tropical climates, {niinpopulations that have received varicella vaccine ae climates in the absence of varicella vacci- is endemic, with a regularly recurring nN Prevalence in winter and spring, and pert: wee that depend upon the accumulation of Sc ytbe persons. In Europe and North Americt in ca 2 cination era, 9 of cases occurTed in chile so inguuager than 10 years of age and Fewer than gg, VHluals older than the age of 15.' From 1988 10 tee there were: approximately. 11,000 hospitaliza- SSR death eased by Y hla each year in ted States. The risk of hospitalization and \WAANDHEBPES ZOSTER ATA.GLANCE i atannaoeimensinl Herpes zoster is characterized by unilateral, ddermatomal pain, and rash that results from reactivation and multiplication of endogenous VZV that had persisted in latent form within serany ger llewing an srl attack of © The erythematous, maculopapular, and vesicular lesions of herpes zoster are clustered rather than scattered because virus reaches the skin via sensory nerves rather than viremia. © Herpes zoster is most common in older adults and immunosuppressed individuals. # Pain is an important clinical manifestation of herpes zoster, and the most common debilitating, ‘complication is chronic pain or postherpetic neuralgia (PHN). ‘+ Antiviral therapy and analgesics reduce acute pain; lidocaine patch (5%), high dose capsaicin patch, gabapentin, pregabalin, opioids, and tricyclic antidepressants may reduce the pain of PHN. = Alive attenuated zoster vaccine reduces the incidence of herpes zoster by one-half and the incidence of PHN by two-thirds. death was much higher in infants and adults than in Children, and most varicella-elated deaths occurred in previously healthy people: In tropical and semitropi- eer countries, the mean age of varicella is higher and Susceptibility among adults to primary VZV infection js significantly greater than in temperate climates, High levels of susceptibility to varicella among adult immigrants from tropical climates are well docu: inunted in the US military, where many recruits from Puerto Rico and the Philippines have been seronegas tive. This is important for hospitals, where susceptible haalthcare workers may pose significant risk of nose ccomial varicella, ‘Widespread use of the varicella vaccine has mark- edly altered the epidemiology of varicella. In the Druted States, vaccine coverage rates among, sus: eptible children increased from OY» in 1995, when cep lla vaccine was licensed, to 88% in 2004." This Wasted ina marked decline in varicella casesand varicellacrelated hospitalizations. Prom 1995 through 2000, varicella cases reported to the Centers for Disease Control (CDC) declined by 71%-84% depending upon surveillance area; by 2005 the inci: dence of varicella had decreased by 90%, with a comparable decline in varicella-related hospitaliza- tions.” The decline was greatest among children aged 1-4 years, but cases declined in all age groups, including unvaccinated infants and adults, reflect- ing herd immunity. Varicella-related mortality has also declined substantially after introduction of the varicella vaccine, From 1990 to 1994, mortality from ricella decreased by 66% in all age groups under 50 years, with the greatest reduction (92%) among children 1-4 years of age! Varicella is highly contagious. Attack rates of 87% among susceptible siblings in households and nearly 70% among susceptible patients on hospital wards have been reported. More than 95% of cases of vari- cella are clinically apparent, although occasionally the exanthem may be $0 sparse and transient as to pass unnoticed. A typical patient is infectious for 1-2 days (rarely, 3-4 days) before the exanthem appears, and for 40rS days thereafter, that is, until the last crop of ves- icles has crusted. The immunocompromised patient, who may experience many successive crops of lesions for a week or more, is infectious for a longer period Of time. The mean incubation period of varicella is 14 or 15 days, with a range of 10-23 days. Iti often pro- longed in patients who develop varicella after passive immunization with varicella-zoster immune globu- lin (VZIG) or zoster immune plasma (ZIP), or after postexposure immunization with live attenuated Oka strain varicella vaccine.” The major route by which varicella is acquired and transmitted is thought to be the respiratory tract, but infection may also be spread by direct contact. Vari- cella crusts are not infectious, and the duration of infectivity of droplets containing virus is probably ted. Although the infectiousness of patients jcella is thought to depend largely upon virus shed from the mucous membranes of the upper respiratory tract, VZV has only rarely been cultured from pharyngeal secretions; however, VZV DNA ‘can be detected in the oropharynx of the majority of patients using polymerase chain reaction (PCR)- based assays.”” Natural varicella (Le., varicella caused by wilde type VZV) generally confers life-long immunity to the disease. Re-exposure to the virus boosts humoral and cell-mediated immune responses, but rarely leads to clinical illness. Most reported second attacks of varicella involve incorrect diagnoses; others may represent cutaneous dissemination in patients with herpes zoster (see below). With severe immunocom- promise, reinfections manifested as varicella have been observed. In addition, persons who develop modified varicella (eg,, because they are infected early in infancy in the presence of maternal antibody or have been immunized with live attenuated vari. cella vaccine) may respond to exogenous exposure by developing a second, usually mild, episode of “break. through” varicella. > | PASE: A Herpes zoster occurs sporadically thoy, without seasonal prevalence, The ocen i‘ zoster is independent of the Prevalence ct thant and there is no convincing evidence thay ny ter can be acquired by contact with others PF nt varicella or herpes zoster. Rather, the incerta pes zoster is determined by factors thar och host-virus relationship. infers One strong risk factors older age Fig. oy, Incidence of herpes zoster is 15-30 pe 1g! Te years inall ages and 7-11 per 1,000 per yer Per over 60 years of age in European and Noah P studies.”” It is estimated that there are mane million new cases of herpes zoster in the Unie each year, more than half of which occur fee 260 years of age, and this number will ineesg population ages." she ‘Another major risk factor is cellular im, function. Immunosuppressed patients have ey) times greater risk of herpes zoster than a petent individuals of the same age. Imma Sive conditions associated with high rik of zoster include HIV infection, bone marrow taney leukemia and lymphoma, use of cancer chemother and use of corticosteroids. Herpes zoster is ap, nent and early “opportunistic infection” in ene infected with HIV, in whom itis often the fist sgn immune deficiency. Thus, HIV infection should bee sidered in individuals who develop herpes zoster Other factors reported to increase the risk of hes zoster include female sex,” physical trauma inte affected dermatome,* IL-10 gene polymorphises! and white race." Exposure to children and crs With cases of varicella have been reported to incre levels of VZV-CMI and confer protection against ht pes zoster" Second episodes of herpes zoster are uncommen immunocompetent persons, and third attacks ae ve) rare. Persons suffering more than one episode may immunocompromised, Immunocompetent pati suffering multiple episodes of herpes zoster-lke & ease are likely to be suffering, from recurrent 20st form herpes simplex virus infections.” Patients with herpes zoster are less contagious Patients with varicella, The rate at which user household contacts develop varicella after expos herpes zoster appears to be about one-thid of Bee observed following exposure to varicella." Virus isolated from vesicles and pustules in @ herpes zoster for up to 7 days after the ppm, the rash, and for much longer periods in imm: Promised individuals. Patients with sion dermatomal zoster appear to spread the Hy means of direct contact with their lesions yt transmission has also been documented.” Patio disseminated herpes zoster may also transtt ed tl via aerosols, so that airbome preco¥nn s 48 contact precautions, are required for SUP FE gt The effect of the marked reduction iO esad of varicella, due to widespread varicella > |‘E12 months] Lesa tnen moth mite ‘A. The epidemiology of herpes zoster and ‘etc neuralgia. The annual incidence cof herpes Uy 1900 persons in a general medical practice. en fttentage of patients with pain persisting after ptt the herpes zoster rash. These data afr net b® fEcplents in one lage, double bin treat- fete gaa’ ©: The proportion of patients ‘with posther- SEpgquaia acording to age. From Kost RG Suan Perna BE neuralgia: Pathogenesis weatrrern and N Engl Med 335:32, 1996 with permission) children, on the epidemiology of herpes zoster is unclear Inthe long term, the incidence of herpes zoster is likely t0 decline asthe cohorts of children now receiving varicella vaccine become adults; vaccine virus-associated herpes zoster will probably be less frequent and less severe in ‘older adults than wild-type virus-associated herpes 20% ter because the vaccine virus is highly attenuated. In the short term, the incidence of herpes zoster could increase because a decline in the incidence of varicella will reduce the adult population's exposure to VZV thereby redtuc- ing immune boosting, hastening the age-related decline in immunity to VZV, and thus increasing the age-specific risk of herpes zoster. However, recent studies of herpes zoster in populations with high rates of varicella vacci- zation have shown litle or no increase in the incidence of herpes zoster!" ETIOLOGY AND PATHOGENESIS VZV is a member of the herpesvirus family" Other members pathogenic for humans include herpes simplex Viruses type 1 (HSV-1) and type 2 (HSV-2); cytomegalo~ virus (CMV); Epstein-Barr virus (EBV); human herpes- virus-6 (HHV-6) and human herpesvirus-7 (HHV-7)- Which cause roseola; and Kaposi's sarcoma-associated herpesvirus, also called human herpesvirus type 8. All ally. indistinguishable herpesviruses are and share a numberof including the capacity that persis fr life. toestablish latent infections ‘The VZV genome encodes about 70 unique genes, ‘most of which have DNA sequence and functional omology to genes ofthe other herpesviruses." Imme- diate early (IE) gene products regulate VZV replica- tion. Early gene products, such as the virus-specific thymidine Kinase andthe viral DNA polymerase, sup- port viral replication. Late genes encode virus struc: Firal proteins that serve as targets for neutralizing, antibodies and cellular immune responses "There is only one VZV serotype. However, there segreg in their nucleotide sequences a id eype from vaccine virus strains, and to “Ainger- print” viruses isolated from individual patients zat VZV is through the mucosa of the upper Entry of ; Featory tract and oropharym nital multiplication occurs at ‘of entry, where VZV infects tonsil- lar T cells, virus via the blood and lymphatics ) nected T cells catty ial system, the major site of Selay VZV ‘rash formation.” “The incu i parally contain by feron, natural killer finnat defenses (eg, inter (NK) cells] and by d 'VZV-specific immune responses viduals, virus replication even- reshy overtime these developing host efenses, £0 ialthat about 2 weeks afte ondary) viremia and as ‘occur. Skin lesions appear in successive crops, reflect ing a cyctie viremia, which in the normal host is termi- nated after about 3 days by VZV-specific humoral and Saga immune responses. Virus ctculates in mono- uclear leukocytes, primarily lymphocytes. Even in Lncompliated varie, the secondary ete esl In the subclinical infection of many organs in addition to the skin, Effective host immune responses terminate ‘Viremla and limit the progression of varicella lesions in the skin and other organs. Humeral immunity to ZN protects against varicella. People with detectable serum antibody resulting from wild-type VZV infec- tion do not usually become ill after exogenous expo- sure, Cell-mediated immunity to VZV also develops uring the course of varicella, persists for many years, and protects against severe infections." PATHOGENESIS OF HERPES ZOSTER During the course of varicella, VZV passes from lesions in the skin and mucosal surfaces into the contiguous endings of sensory nerves and is transported centrip- tally up the sensory fibers to the sensory ganglia. Infected T cells may also carry virus to sensory ganglia hematogenously, In the ganglia, the virus establishes a latent infection that persists for life. Herpes zoster ‘occurs most often in dermatomes in which the rash of varicella achieves the highest density—those inner- vated by the first (ophthalmic) division of the trigemi- nal nerve and by spinal sensory ganglia from 1 to L2." Although the latent virus in the ganglia retains its potential for full infectivity, reactivation is sporadic and infrequent, and infectious virus does not appear to be present during latency. The mechanisms involved in reactivation of latent VZV are unclear, but reactivation has been associated with immunosuppression; emotional stress; irradiation of the spinal column; tumor involve: ‘ment of the cord, dorsal root ganglion, or adjacent strc- tures; local trauma; surgical manipulation of the spine; and frontal sinusitis (as a precipitant of ophthalmic zos- ter). Most important, though, is the decline in VZV. les and multinucleated giant cells similar to those seen in the cutaneous lesions of the disease. These changes ae indistinguishable from those produced by HSV, but whereas HSV rapidly spreads to infect the remaining, cells in the culture, the eytopathic effect of VZV remains focal. Cytopathic effects of VZV are generally not appar cent until several days after specimen inoculation. Mod= ifications of the cell culture assay in which vesicle uid Co lesion scrapings are centrifuged onto cells growing, ‘on coverslips at the bottom of thin glass-walled “shell” vials followed 24-72 hours later by fixation and stain ing with Muorescein- or enzyme-labeled monoclonal antibodies to VZV proteins, can confirm the presen of VZV relatively quickly, well before cytopathic effects are evident in conventional cell cultures, Immunofluorescent or immunoperoxidase staining ‘of cellular material from fresh vesicles or prevesicular lesions has become the diagnostic method of choice 8194-9 is I vesicle, acanthalysis, reticular degeneration. underlying Herpes zoster, histopathology. A. intraepidermal vesicle, iysis, "shows edema andvascuic 8. Mulmucieated giant ces with charactnstic nuclear changesin many centers; it can detect VZV significantly more ‘often and faster than virus culture, even relatively late in the disease when cultures are no longer positive.” Enzyme immunoassays provide another rapid and sensitive method for antigen detection. Detection of VZV DNA in clinical specimens follow ing amplifications by PCR provides the greatest assay sensitivity, very high specificity and rapid turnaround time. It has revolutionized the diagnosis of VZV infec- tions, and can distinguish among wild type and Oka vaccine strains of VZV and HSV." Serologic tests permit the retrospective diagnosis of varicella and herpes zoster when acute and convales- cent sera are available for comparison." These assays can also identify susceptible individuals who may be candidates for isolation or prophylaxis. The technique most commonly used is a solid-phase enzyme-linked immunosorbent assay (ELISA). However, this assay often lacks sensitivity and specificity, failing to detect antibody in people who are immune and sometimes yielding false-positive results in susceptible indi- viduals. Several more sensitive techniques have been developed to measure humoral responses to VZV. These include an immunofluorescence assay for anti- body to VZV-induced membrane antigens [fuorescent antibody to membrane antigen (FAMA)] that reliably distinguishes immune from susceptible adults and a latex agglutination test that is comparable in sensitiv ity and specificity to FAMA assays, but is much sim- pler to perform COMPLICATIONS LICATI yy Xela Nira ae In the normal child, varicella i rarely complicated. The ‘most common complication is the secondary bacterial infection of skin lesions, usually by Staphylococci or Streptococci, which may produce impetigo, furuncles, cellulitis, erysipelas, and, rarely, gangrene.” These local infections often lead to scarring and, rarely, to septicemia with metastatic infection of other organs. Bullous lesions may develop when vesicles are super- infected by Staphylococci that produce exfoliative toxins. Invasive group A streptococcal infections are particularly virulent. In the absence of varicella vac- 12 years, persons with chronic cutaneous or pulmonary disorders, perso receiving long-term salicylate therapy, and penor® short, intermittent, or aerosolized course of corticosteroids because these individuals are 3 increased risk for moderate-to-severe varicella.” Normal Adolescents and Adults. 4 randor ed, controlled trial of acyclovir treatment of health adolescents 13-18 years of age found that early tert ment with oral acyclovir (800 mg five times 2 day 5 days) reduced the maximum number of lesion® time to cessation of new lesion formation comps" Placebo.” A randomized, placebo-controlled tri! 1 ofeon Gast 18 yeas of age) Adolescent (240 kg) oF adult specially with mild immune ‘emproise (29, use of inhaled glucocorticoids) Preonia Peary murecompromised ‘varicella or mid compromise “Severe varicella or severe compromise cydovirestant advanced AIDS) Regimen Ayo YOma/hgor 300mg m'eery thor Symptomsticteatmentalone of aay tayern ZO mora every Bh forS days rot to exceed 3 9/ ‘Acyclovir 20 mg/kg po four times a day x 5 days (not to exceed 3200ma/ay) Valoxlow 9 po vey Shor 7 aur Fanextow Sodma po cre 8 NF apt Ae 600ma po hens oo ays Aaya YO mpg Wey Bh 1.0 day Routine vie ot lot nat conmende. there ae campaton (9, puna west peumona 5 perrconmendaton stove Valacyclovir 1 g po every 8h for 7-10 days or Famciclovi 500 mg po every 8h for 7-10-days of ‘Acyclovir 890 mg po five times a day for 7-10 days ‘Acyclovir TO maykg W every 8h for 7-10 days Foscaret 40 mg/g V every 8 h until heated ‘Descour o preferably, famciclovir or valacyclovir, shouldbe considered for otherwise healthy perions at increased rk for moderate to seerevarcela (eg persons aged >12 years, persons with chronic cutaneous or pulmonary dsorders, persons tecening long term sacylate ‘Dengy. and persons receiving shor, intermattent of aerosolized courses of corticosteroid) From Marin M etal Prevention of varicella Recom ‘entaonso the Advisory Committee on Immunization Practices (ACI MMAR Recomm ep $6149, 2007) ‘Vat prepare suspension by grinding $00-mg valacyclow capets and suspending a cherry favored Suspension Structural Vehical USP NF 5501.3 mg/mL. or 50 mgmt in fts of 100 mL at time of dispensing cal ayclovir in healthy young adults with varicella ‘owed that early treatment (within 24 hours of rash rset) with oral acyclovir (800 mg five times a day for 7 days) significantly reduced the time to crusting of ‘esons, the extent of disease, and duration of symp- ‘Sas and fever.” Thus, routine treatment of varicella ‘® adults seems reasonable. Although not tested, it is “ely that famciclovir 500 mg PO q8h or valacyclovir LAW mg NO gh would be convenient and appropti- “substitutes for acyclovir in normal adolescents and ‘tults Many physicians do not prescribe oral acyclovir 222complicated varicella during pregnancy because "sk to the fetus of treatment is unknown. Other - recommend oral antiviral therapy for infec- ASSlathe thnd trimester when organogenesis is com- ‘Nee when there may be a heightened risk of varicella [ekmenia, and when infection can be spread to the ‘rn Intravenous acyclovir is often considered for Foynant women with varicella who have extensive ‘“reous and/or systemic disease. tions of Varicella in Normal Uncontrolled trials in immunocom yagest that carly pneumonia suggest thal oy reduce fever and tachy- Immunocompromised Patients. Controlled trials in immunocompromised patients with vari- cella demonstrated that treatment with IV acyclovir decreased the incidence of life-threatening. visceral complications when treatment was initiated. within 72 hours of rash onset.” Immune compromise, how- ever, isa continuum ranging from minimal to severe Intravenous acyclovir has been the standard of care for varicella in patients with substantial immunodefi- ‘ciency. Although oral therapy with famciclovir or vala- ‘cyclovir might suffice for patients with mild degrees ‘of immune impairment, there are no controlled clinical trials to guide the decision, TREATMENT OF HERPES ZOSTER TOPICAL THERAPY. During the acute phase of her- ‘zoster, the application of cool compresses, calamine fotion, cornstarch, or baking soda may help to allevi- ate local symptoms and hasten the drying of vesicular iesions. Occlusive ointments should be avoided, and creams or lotions containing glucocorticoids should trot be used. Bacterial superinfection of local lesions is . ‘and should be treated with warm soaks; ‘pacterial cellulitis requires systemic antibiotic therapy. ‘Topical treatment vith anaiieal agents isnot effective. [ANTIVIRAL THERAPY. The major goals of therapy inpatients with herpes zoster are to (1) limit the extent, arapation. and severity of pain and rash in the primaryos Ne crs saiscss iiss sitteeiemennil ‘satis ly Patient Group Normal ‘Age <50 years ‘Age 250 years and patients of any age with cranial nerve (€9, ophthalmic zoster) Immunocompromied Mild compromise including HIV infection Severe compromise Acyclovir resistant (eg, advanced ADS) Regimen Symptomatic treatment alone, Fameiclovir 600 mg PO every 8h for? days or Valacyclovir 1g PO every 8 hfor 7 days ot ‘Aeyclovit 800 mg PO times a day for 7 days? Famcclove $00 mg PO every 8h for 7 days or Valacyclovir 1 9 PO every 8 for 7 days of Acyclovir 600 -mg PO 5 times a day for 7 days" Famellov 500mg FO every Bhhfor 7-10 day or Valncylovi 1g PO every 8h for 7-10 dayor ‘Acyclovir 809 mg POS times a dy for 7-10 days ‘Aeslonr WO mg/kg V every Bh fo 7-10 days Fescarnet ao ma/gIV every Bhunti healed “Fameiclov ot valacyclovir are prefered because thes greater and mere reliable oral iow slabity result in higher blood levels of ante _cthity. the lower suscepibty of VZV (compared 1oHSV, andthe enstence of barnes tothe enty of antiviral agents nto Usices hat new, ‘OfVZV replication, dermatome; (2) prevent disease elsewhere; and (3) pre vent PHN. Normal Patients. Table 194-3 lists the current recommendations for treatment of herpes zoster. Randomized controlled trials indicate that oral acyclo- vir (800 mg five times a day for 7 days), famciclovir (600 mg, q 8 hours for 7 days), and valacyclovir (1 g, three times a day for 7 days) reduce time to rash heal ing, and the duration and severity of acute pain in ‘older adults with herpes zoster who are treated within 72 hours of rash onset.” In some studies, the duration of chronic pain was also reduced, but the FDA has not approved these agents for the prevention of PHN.”” Randomized controlled trials comparing acyclovir to valacyclovir, acyclovir to famciclovir, and valacyelo- vir to famciclovir demonstrated equivalent results in rash healing, acute pain, and the duration of chronic pain." All three drugs are acceptable agents for older adults, with cost and dosing schedule determining the choice of agent. However, the reduced sensitivity of VZV compared with HSV, the existence of barriers to the entry of antiviral agents into tissues that ate sites, of VZV replication, and the higher and more reliable blood levels of antiviral activity achieved, make fam. ciclovir or valacyclovir preferable to acyclovir for oral treatment of herpes zoster. Because of the lower risk of PHIN, antiviral therapy is less valuable of necessary for treatment of uncom plicated herpes zoster in healthy people younger than ‘50 years of age. The utility of antiviral agents is unproven if treatment is initiated more than 72 hours after 1 onset. Nevertheless, we believe that it is prudent to tiate antiviral therapy even if more than 72 hours have ‘lapsed after rash onset in patients who have Zoster involving cranial nerves e.g, ophthalmic zoster) ‘or who continue to have new vesicle formation.” ‘Ophthalmic zoster represents a special therapeutic challenge because of the risk of ocular complications. Examination by an ophthalmologist should be sought in most cases. Oral acyclovir has been shown in a ton: domized, controlled trial to be effective in preventing ‘ocular complications of ophthalmic zoster" Famcih vir and valacyclovir appear to have efficacy compare ble to that of acyclovir in the treatment of ophthalmic zoster, and are preferred for the reasons cited above." Immunocompromised Patients. random: ized, double-blind, placebo-controlled trial in immu: ocompromised patients with herpes zoster showed that IV acyclovir (300 mg/m? qh for 7 days) halted Progression of the disease, both in patients with local: {zed herpes zoster and in patients with cutaneous div semination prior to treatment. Acyclovir accelerated the rate of clearance of virus from vesicles and math: cally reduced the incidence of visceral and progressive cutaneous dissemination. Pain subsided faster in 3) clovir recipients, and fewer reported PHN, but these differences were not statistically significant. Clinical trials comparing IV acyclovir to IV vidarabine for the treatment of herpes zoster in immunocompromise! Patients showed that acyclovir was significantly more effective and less toxic.” In patients with mild inv ocompromise and localized heepes zoster oral a¢yl0- vir, valacyclovir, or famciclovir will usually suffice” A randomized, controlled trial of oral famciclovit vee sus oral acyclovir in patients with localized herpes 70%" {er following bone marrow or organ transplantation & ‘cancer chemotherapy showed that the two treatmest® were equivalent in rash healing and loss of acute pa and that both were well tolerated.” ANTI-INFLAMMATORY THERAPY, The po sibility that PHIN' might be caused by inflammatio sensory ganglion and contiguous neutal st" {ures provided the rationale for the use of ghee? ticoids during the acute phase of herpes zoster if 2 attempt to further reduce acute pain and prevent PHN:iajocived controlled tals, however, showed that Matin OF RIUCOCOTICOLE 10 ey ll not othe incidence of ehvonie pain”! However, utleokds did rexluice acute pain in most tras, prone teal of acyclovir andl prednisone, the tine Ammintetuptes sep, return to baseline daily aetiv> wut cessation of analgesic therapy was reduce! in ants who receives glucocorticoids. Consequert Pipe experts alvoxate oral glucovorticoids f0F other: Ate healthy alder adults whose rash is complicated ‘haderateto-severe pain and who have to contra: Pacations to hicocorticolds.”” Others believe that he eonmon adverse effects of glucocorticolds argue paint their routine tse in older patients with herpes seter We agree andl do not recommend the tse of glu Aorticoids In this setting, Glucocorticoids, in combi (ation with effective antiviral therapy, may Improve ihotor outcomes and acute pain in VZV-induced facial quralysis and cranial polyneuritis, where compression Ffatlected nerves may contribute to disability ty ANALGESICS, Greater severity of acute pain is a tisk factor for PHN, and acute pain may contribute to ‘cmntral sensitization and the genesis of chronic pain. Therefore, aggressive pain control is both reasonable and humane.” The severity of acute herpes zoster pain should be determined using simple standardized pain ales, Clinicians should prescribe nonopiate or opl- ate analgesics with the goal of limiting the severity of fain oless than 3 or 4 on a O-to-10 scale, and to a level that does not interfere with sleep. The choice, dosage, and schedule of drugs are governed by the patient's pain severity, underlying conditions, and response to specific drugs. A randomized controlled trial of oxy codone, gabapentin, or placebo in older adults with herpes zoster showed that oxycodone, but not paba- Ponti, provided significantly greater pain relief than Flicebo in patients. with moderate-to-severe pain.” This tial was not powered to analyze PHN, and there ate no other controlled trials of the effect of treatment With opioids or gabapentin during the acute phase of herpes zoster on the subsequent development of PHN. Actossover study of a single dose of 900 mg of gabap- tntin during the acute phase of herpes zoster showed Breater pain relief than placebo.” If pain control Remains inadequate, regional or local anesthetic nery’ ‘Mocks should be consicered for acute pain control.” A tandomized controlled trial demonstrated that 4 ‘ingle epidural Injection of corticosteroids and local in the acute phase of herpes zoster did not Prevent the subsequent development of PHN. UVa aces Lyra Once established, PHI is difficult to teat, Fortunately it elves ‘spontaneously in most patiens, although requires several months (Fig: fas have advocated a wide range of treater ie many oral and topical medications, epidural Pune ‘of local anesthetic and glucocorticoids, acue ure, biofeedback, subcutaneous injections Of tre saminolone, ta (TENS), spinal istration of a var pair relet in PHIN for the followis pregabalin, tricyclic antide analgesics, tramadol, lidocaine patch 5%, and concentration capsaicin patch "' The choice of these nedications should be guided by the adverse event profiles, potential for drug interacti comorbidities and trea these agents provi a ef (defined as reduction of pain to below 4 on 4 0-10 point scale or bby 50% on a visual analog or Likert scale ‘of patients, These modalities are now rec evidence-based pharmacotherapy for PHN in practice management guidelines.” TOPICAL THERAPY. Topical anesthesia delivered by means of a 5% lidocaine patch has been shown in controlled clinical trials to produce significant pain relief in patients with PHN, The 10 * Hem lidocaine patch contains 5% lidocaine base, adhesive, and other Ingredients on a polyester backing, tis easy to use al is not associated with systemic lidocaine toxicity Up to three patches are applied over the affected ares for 12 hours a day. The disadvantages of the patch are application site reactions, such as skin redness of rash, ‘and substantial cost, Futectic mixture of local anesth jes (EMLA) cream applied once a day over the affected area under an occlusive dressing, Is an alternative method of delivering topical anesthesia ‘A single I-hour application of a high-concentration capsaicin patch (8%) compared with a low-concen- tration control patch significantly reduced pain from PHN from the second week after the capsaicin appli- ‘cation throughout a subsequent 12-week period.” The high-concentration patch was generally well tolerated iAdiverse events include increases in pain associated {vith patch application (usually transient) and appli- Mitiomaite reactions (eg. erythema). The role of the highconcentration capsaicin patch in the treatment GLPHIN is yet to be clearly established, partly because fis long-term benefits are not yet known. However, this intervention has promise because a single 1-hour pplication may yiek several weeks of pain reduction RAL AGENTS. Gabapentin has been shown to ORAL AGENTS gauepuntcsin tt patients with PHN. ‘compared t0 12%-23% in patients receiving pl ‘ti Frequent adverse effects of gab apentin include somnolence, dizziness, and periph ‘edema. Pregabal has been shown to pretuee © pe oF greater pain relief in 50% of patents with PHN com 20% in . fo 3 Ta ee reported for prezabal licated dose titration sched- ster onset of ule ada faster ovwe' own. to produce moderate CAs have been eal ain relict in 44-67% of elderly patients withPHN in several randomized, controlled trials." Nortriptyline and desipramine are preferred alterna- tives to amitriptyline because they cause fewer cardiac adverse effects, sedation, cognitive impairment, ortho- static hypotension, and constipation in the elderly.” ‘Treatment with scheduled opioids may also reduce PHN. In a randomized, placebo-controlled crossover trial of sustained-retease oxycodone in patients with PHN, patients reported significant pain relief when {treated with opioid compared to placebo." In a cross- ‘over study in patients with PHN, both controlled release morphine and TCAs provided significant pain relief compared to placebo." In this trial, patients pre- ferred treatment with opioid analgesics to either TCAS or placebo, despite a greater incidence of adverse effects and more dropouts during opioid treatment. The use of combinations of these drugs for PHN is common in clinical practice and undergoing increas- ing investigation. In a crossover trial, patients with iabetic polyneuropathy or PHN were to daily active placebo (lorazepam), s morphine, gabapentin, and a combination of gaba- pentin and morphine."? Combination therapy with morphine and gabapentin produced greater pain relief than either agent alone or placebo, but with an increase in adverse effects (constipation, sedation, and dry mouth). Ina crossover trial, patients with diabetic poly- neuropathy or PHN were randomized to receive one of three sequences of daily oral gabay tyline, and a combination of the two. therapy with gabapentin and nortriptyline produced greater pain relief than either agent alone. The most common adverse event was dry mouth secondary to nortriptyline. These results suggest that combination therapy may benefit some individuals with PHN who have responded to one of the agents chosen, but at the risk of increased adverse effects than with either drug alone. PREVENTION REVENTI RZ resN VARICELLA VACCINE. Several studies conducted in Europe, Japan, and the United States from the early 1970s through the early 1990s demonstrated that live attenuated (Oka strain) VZV vaccines were immuno- genic and efficacious in protecting susceptible children against varicella, Although breakthrough cases of vari- cella were observed following subsequent exposure to wild-type VZV, they were relatively mild.” Similar results were obtained in adults when two doses were given 4-8 weeks apart. Vaccinated children and adults developed breakthrough varicella caused by wild-type VZV at arate of Yee-3% pe year compared tan attack rate of B%=13% Fin unvaccinal ren. the basis of thee data, the FDA licensed the Oka/ Merck varicella vaccine in the United States in 1995. In 2005, the FDA approved a combined measles, mumps, rubella, and varicella vaccine (MMRV) for routine immunization of children 12 months to 12 years of age. oN Because of Ue frequency of breakthrough yy caused by wild-type VZV, the Advisory Common Immunization Practices (ACIP) now recommenges"® (O.5-mL. doses of varicella vaccine fot healt aged 212 months, adolescents, and adults witnen’ dence of immunity.” For children aged 12 mong 12 years, the recommended minimum interval tere, the two doses is 3 months, although the secon." ray be administered as soon a5 28 days afer te ge For persons aged >13 years, the recommended mum interval is 4 weeks. Single-antigen varie cine is approved for use among healthy persons 212 months. Combination MMRV vaccine is apprey for use among healthy children aged 12 mame c 12 years. Because of the increased severity of variety in adults, susceptible adults should be identified sj vaccinated. High priority should be given to vaccine ing adults who may be at increased risk for exposun ey transmission and who do not have evidence of img nity, including (1) health care providers, 2) househoty contacts of immunocompromised persons, including susceptible pregnant women, (3) persons who live work in environments in which transmission of VZV is likely (e.,, teachers, day care employees, residents and staff in institutional settings), (4) persons who live or work in environments in which transmissin has been reported (e.g., college students, inmates and staff members of correctional institutions, and military personnel), (5) nonpregnant women of childbearing age, (6) adolescents and adults living in households with children, and (7) international travelers. Second dose catch-up varicella vaccination is recommended for children, adolescents, and adults who previously received only one dose.”* The immunity to varicella induced by varicella va: cine is not as solid as that induced by wild-type VZV infection, and the duration of vaccine-induced imm nity is not yet known. However, a high percentage cf children followed long-term have remained seropest tive! Recent experience in clinical practice indicates that vaccine efficacy in children is modestly lower than that reported in clinical trials, and outbreaks of brea} through varicella in schools and day care centers 4? occur.'*** Ina prospective, population-based st vaccine effectiveness for prevention of all disease W2* 78.9% (95% Cl, 69:7%-85.3%); for prevention of mode ate disease was 92% (50-500 lesions) and for preve™, tion of severe disease and physician visits was 100% A CDC analysis of 10 years of surveillance data fet varicella (1995-2004) stowed that the annual rate o breakthrough varicella significantly increased with time since vaccination, from 1.6 cases per 1,000 pers years (95% CL 1.2-2.0) within 1 year after eoctnalens, 9.0 per 1.000 person-years (95% Cl, 69-11.7) at 5 and 582 per 1,000 pemeyaate (95% CI, 360-960) at 9 years." Although most breakthrough varie in children are characterized by mild disease, fecent reports indicate that 25%:-07's of breabthvous? cases are not mild and are clinically similar to ¥*" cella in unvaccinated children.” Interestingly: of breakthrough varicella in household settings" halfas contagious as cases of varicella in unvacciates Persons, although the minority of breakthrough child‘ons oF more Were aS Contagious as cases in 01 sth 8) persons. In adults, approximately 20% of ee ose detectable antibodies to VZV over time, coc 0 to be partially protected.""""* Of the 48 ees of varicella vaccine distributed between ie] Mind 2005, there were 25,306 adverse events "52.7/100,000 doses distributed) to the FDA's ‘Adverse Event Reporting System and the for Disease Control and Prevention (CDC)"" Gay which were nonserious events, mainly minor injection site reactions.” Serious adverse tate were rare (2.6/100,000 doses distributed) and, ve majority a causal relationship between the ser inverse event and varicella vaccine could not be zoster has been reported in vaccinees, totit occurs at a significantly lower frequency than ‘ostet in persons of similar age following, werellacaused by wild-type VZV. Cases of laboratory {onfmed herpes zoster in vaccines from several ‘tulies included some cases caused by reactivation of the vaccine virus and others caused by reactivation of tritype virus acquired prior to vaccination as a con- sequence of unrecognized varicella. POSTEXPOSURE PROPHYLAXIS = AND INFECTION CONTROL. Patients with varicella and herpes zoster may transmit VZV to susceptible individuals. Preventive measures include the varicella vaccine, investigational high-titer zoster immune glob- ula (VariZIG), and postexposure chemoprophylaxis with acyclovir. Active immunization with the live attenuated vari- cela vaccine is effective in preventing illness or modi- ‘ying varicella severity in children if used within 3 days after exposure." Whereas protection afforded by 2o4er immune globulin is transient, varicella vaccine induces long-lasting (active) immunity to VZV and Protection against subsequent exposures. Therefore, ‘he ACIP recommends varicella vaccine for postexpo- ‘ure prophylaxis in unvaccinated persons without evi- ‘of immunity.” Passive immunization with VZIG was an effec: tive preventive strategy, but the production of VZIG tas been discontinued inthe United States. An ‘svestigational VZIG, VariZIG, is available under an ‘estgational new drug, application (IND). The ‘stigational VariZIG is a purified human immune ‘¢buln prepared from plasma containing high levels quately to VZV (immunoglobulin class G {IgG)). tae oust can be requested for patients who have frag Posed to varicella and who are at increased risk ra disease ‘and complications.” sumeProphylaxis with acyclovir also has bess tulled in susceptible children following household eto varicella. Children who received poops, with sJovir experienced fewer ar : vere cases of \Jartcella that children in the con- ang 24?" However, appropriate timing is critical, Cal to varicella may not be achieved, espe they With early postexposure treatment, In addition, 's concern that resistant strains of VZV may be by promiscuous application of this approach. Hence, postexposure antiviral chemotherapy is not Tecommended for routine use in children. Infection control practices for VZV increase in impor- tance with the age and compromised immune status of the exposed, susceptible individual. There is no need to prevent exposure of susceptible normal children to VZV, but careful isolation procedures should be enforced to prevent infection of susceptible immuno- compromised patients, newborn infants, and adults, particularly women of childbearing age. Exposure of susceptible immunocompromised patients to VZV warrants reduction in the dosage of glucocorticoids and other immunosuppressive drugs, and adminis- tration of investigational VariZIG. Hospital and long- term care facility personnel without a clear history of varicella or herpes zoster should be tested for antibody to VZV, and susceptible personnel vaccinated against varicella. Appropriate leave from work should be insti- tuted following VZV exposure of any susceptible per- sonnel who are not vaccinated. In hospitals, airborne ‘and contact precautions are recommended until all lesions are crusted for patients with varicella, immu- nocompromised patients with localized herpes zoster, and any patient with disseminated herpes zoster." Contact precautions are recommended for immuno- ‘competent patients with localized herpes zoster PREVENTION OF HERPES ZOSTER ZOSTER VACCINE. Until universal varicella vacci- nation greatly reduces the number of people latently infected with wild-type VZV, prevention of herpes zoster must be aimed at preventing reactivation and spread of the latent wild-type VZV. Long-term sup- pressive acyclovir treatment is only practical in immu- nocompromised patients at proven risk of developing herpes zoster within a defined time period, for exam- ple, in the year following bone marrow or solid organ transplantation. Other strategies must be devised for the general population. ‘One approach to the prevention of herpes zoster is the stimulation of immunity to VZV, which wanes in the elderly and in other high-risk individuals. Studies of healthy adults over 55 years of age with a history of varicella have demonstrated an increase in VZV-specific T lymphocytes and humoral immu- nity after vaccination with live attenuated VZV vac- Cine that is similar to the increase observed after an episode of herpes zoster.™ These findings suggested that vaccination of older persons may be useful in eventing herpes zoster and its complications." A Prcent VA Cooperative Study (the Shingles Prevention Study) tested the hypothesis that vaccination against VZV would decrease the incidence and/or sev of herpes zoster and PHN among, older adults study enrolled 38,546 adults 60 years of age or oldes ina randomized, double-blind, placebo-controlled tral of a live attenuated Oka /Merck VZV vaccine of tmuch greater potency than the currently licensed var- jealla vaccine. Atotal of 957 confirmed cases of herpes poster (315 among vaccine recipients and 612 among Placebo recipients) and 107 cases of PHN (27 among,Vaccine recipients and 80 among placebo recipients) Were included in the efficacy analysis. The zoster Vaccine reduced the burden of illness due to herpes Zoster by 61.1% (P <0.001), reduced the incidence of PHN by 66.5% (P <0.001), and reduced the incidence of herpes zoster by 51.3% (P <0.001), Reactions at the injection site were more frequent among vaccine recipients but were generally mild. The proportion of subjects reporting serious adverse events, and rates of hospitalization and death were comparable in vac- cine and placebo recipients." Furthermore, the 20s- ter vaccine neither caused nor induced herpes zoster in recipients. This landmark study showed that the zoster vaccine markedly reduced morbidity from her- Pes zoster and PHN among older adults. The FDA licensed the zoster vaccine for the prevention of her- Pes zoster in adults 60 years of age and older in 2006. ‘The ACIP of the CDC unanimously recommended the vaccine for the prevention of herpes zoster and its complications, including PHN, in immunocompetent adults 60 years of age and older, irrespective of a his- tory of herpes zoster." Zoster vaccine has now been added to the US schedule of routinely recommended adult immunizations.” The zoster vaccine may be administered without ‘screening for a history of varicella or herpes zoster, nor should one conduct serologic testing for varicella immunity before vaccination.” Persons known to be VZN seronegative should be vaccinated against vari- cella according to current recommendations,” Older adults who have PHN or who have a current episode ‘of herpes zoster may ask to be vaccinated, but zoster vaccination is not indicated to treat acute herpes z0s- ter or PHN, Some patients may want to receive 20s- ter vaccine after a recent episode of herpes zoster has resolved. The optimal time to immunize an individual after a recent episode of herpes zoster is unknown, and. the clinical diagnosis of herpes zoster is not always cor- rect. The authors believe that an interval of 3-5 years after the onset of a well-documented case of herpes zoster is reasonable. A history of anaphylactic reaction to any of the vac- cine components is a contraindication to the vaccine. Neomycin is a vaccine component but contact derma- titis due to neomycin does not represent anaphylaxis and therefore is not a contraindication to zoster vacci- nation. The zoster vaccine should not be given to per- sons who have severe acute illness, including active untreated tuberculosis, until the illness has subsided. Persons with leukemia, lymphomas, or other ‘malig- nant neoplasm affecting the bone marrow or lymphatic system, or with AIDS or other clinical manifestations of HIV infection, incising those with CD4* ‘T-lympho- «¢yte counts $200 per mm’ and/or <15% of total lym: phocytes should not receive zoster vaccine.” Persone on immunosuppressive therapy, including high-dose corticosteroid therapy, should not receive the vaccine, The ACIP defines high-dose corticosteroids as 20 mg ‘or more per day of oral prednisone or equivalent for 14 days or more Low doses of methotrexate (s0.4 mg/kg/week), azathioprine (33.0 mg/kg/day), ‘or 6-mercaptopurine (S1.5 mg/kg/day) are not con. sidered to have significant immunosuppression.” ON When considering the 20st Vaccine, ig, ay express concems. about tranam Aky ne virus to other individuals Transmission Ye requires the development of a vesicular nt Vg ing vaccine virus after vaccination If tae ht there is no transmission. Zoster vaca, ° 2 vesicular rashes are very unustal. In tee Prevention Study, vesicular lesions at ghey site were observed! in 20 of 19.270 vacant 2 a median of 3-4 days after vaccination and ny 19,276 placebo recipients, Neither vaccine n°! wild-type VZV were detected by DNA Pepe" in the few specimens that were available fr 2 Transmission of vaccine virus from recipients vaccine to susceptible household contacts ae ne documented. Thus, immunocompetent olde st in contact with immunosuppressed patients go> receive zoster vaccine to reduce the risk that thy develop herpes zoster and transmit wikttype\on their susceptible immunosuppressed conta fy the same reasons, adult contacts of suscep a nant women and infants should receive zostervanee Zoster vaccine recipients with susceptible pesos ‘or immune compromised contacts need not tikes. special precautions following vaccination, exces the rare situation that a vesicular rash deveays 2 which case standard contact precautions ae ade Eligible residents and personnel in nursing hemes i other facilities housing older adults should abo vaccinated against herpes zoster. However, VZVse~ negative persons (e.g., health care workers from tnp- cal countries who have not had varicella) shuld © vaccinated against varicella, These recommendatus are consistent with those of the ACIR2 Inthe uni event that an immunocompromised contact develops! significant illness caused by vaccine virus he/she bbe treated with standard anti-VZV agents (acyl: valacyclovir, or famciclovir), With the development of the varicella and rs vaccines, antiviral therapy, and neuropathic pin ‘ments, clinicians now have multiple effective {o reduce human suffering from varicella and ber zoster. ACKNOWLEDGMENT ace? Dedicated to the memory of Stephen F. Straus thor of this chapter in previous editions. © DVD contains references and additions conte pe 4 Nguyen HO, fosrsan AO, Seward Fee ue ity due to var after implementabon 450, lation inte sed Staten N Engl] Ml 3 ef 7. Seward JF et 1i. Varicella disease aftet nH Yaticella vaccine in the United States 19°" * Jmain AO ta: incidenc of rps 0s \ Jumaan AO etal: alter vaticela-acrinationassocned oA *