14. Khanna KM et al: Immune control of herpes sLmplex virus during latency.

Curt Grin Irnrn,rn31 16:463, 2004 20. Patcl R Supporting the patient with genital HSV infection. FIerres 1187, 2004 23. Brown ZA et al: The acquisition of herp es simplex virus during pregnancy. N En!j Mcd 337:509, 1997 25. Kimberlin DW: Neonatal herpes simplex infection. Cls Mkr3bi2! Rcv 17:1, 2004 48, Wald A et al: The relationship between condom use and herpes simplex virus acquisition. Ann micro .lJed 143:707, 2005 52. Koellc DM, Wald A: Herpes simplex virus: The importance of asymptomaric shedd ing,J4nzirns.wb Chem.her45: I, 2000 CHAPTER 194 Varicella and Herpes Zoster Stephen E. Straus Michael N. Oxman Kenneth E. Schmader EPIDEMIOLOGY Epidemiology of Varicella Vancella is distributed worldwide, but its age-specific incidence differs in temperate versus tropical climates and in populat ions that have received varicella vaccine. In temperate climates in the absence of varicella vaccination, varicella is endemic, with a regularly recurring seasonal preval ence in winter and spring, and periodic epidemics that depend on the accumulat ion of susceptible persons. In Europe and North America in the pre-vaccination era, 90 percent of cases occurred in children younger than 10 years of age and fewer than 5 percent in individuals older than the age of 15. From 1988 to 1995, there were approximately 11 ,IX)0 hospitalizat ions and 100 deaths caused by variceila each year in the United States.2 The risk of hospitalization and death was much higher in infants and adults than in child ren, and most varicella-related deaths occ urred in previously healthy peoplc. In tropical and semi-tropical countries, the mean age of varicella is higher and suscept ibility among adults to primaiy varicellaz oster virus (VZV) infection is signffic andy greater than in temperate climates. Iligh levels of susceptibility to varicella among adult immigrants from tropical clim ates are well documented in the U.S. military where up to 40 percent of rec ruits from Puerto Rico and the Philipp ines have been seronegative. This is imp ortant for hospitals, where susceptible health care workers may pose a sigrufic ant risk of nosocomial varicella. Widespread use of the varicella vaccine has markedly altered the epidemiology of varicella. In the United States, vaccine coverage rates among susceptible child ren increased from 0 percent in 1995, when varicella vaccine was licensed, to 88 percent in 2004. This has resulted in a marked decline in varicella cases and vatic elIa-related hospitalizations. From 1995 through 2000, varicella cases reported to the Centers for Disease Control and Prev ention (CDQ dedined by 71 percent to 84 percent, depending on surveillance area, and by 2002 the incidence of vanc elIa had decreased from 2.63 to 0.92 cases/lOOt) person years.56 The decline was greatest among children aged 1 to 4 years, but cases declined in all age groups, including infants and adults. The annual varicella-related hospitalization rate in the United States declined from more than 0.5 per 10,000 from 1993 to 1995 to 0.1 per 10,000 by 2001. The dedine in varicella-related hospitalization rates was greatest among 0- to 4-year-old children, but rates also declined among youths aged5to 19 years and adults. Varicella is highly contagious. Attack rates of 87 percent among susceptible sibl ings in households and nearly 70 percent among susceptible patients on hospital wards have been reported. More than 95 percent of cases of varicella are clinically apparent, although occasionally the exant hem may be so sparse and transient as to pass unnoticed. A typical patient is infect ious for 1 to 2 days (rarely, 3 to 4 days) before the exanthem appears, and for 4 or 5 days thereafter, that is. until the last crop of vesides

has crusted. The imrnun ocompromised patient, who may exper ience many successive crops of lesions for 1 week or more, is infectious for a longer period of time. The mean incubat ion period of varicella is 14 or 15 days, with a range of 10 to 23 days. It is often prolonged in patients who develop varic elIa after passive immunization with varicella-zoster immune globulin VZIG) or zoster immune plasma, or active post- exposure immunization with live attenua ted Oka strain varicella vaccine.E 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. Varicella crusts are not infectious, and the duration of infectivity of droplets containing virus is probably quite limited. Although the inf ectiousness of patients with varicella is thought to depend largely upon virus shed from the mucous membranes of the upp er respiratory tract, VZV has only rarely been cultured from pharyngeal secretions; however, it can be detected in the orop haiynx of the majority of patients using polymerase chain reactionbased assays. Natural varicella (i.e., varicella caused by wild-type VZV) generally confers lifelong immunity to the disease. Re- exposure to the virus boosts humeral and cell-mediated immune responses but rarely leads to clinical illness. Most rep orted second attacks of varicella involve incorrect diagnoses; others may repres ent cutaneous dissemination in patients with herpes zoster (see Epidemiology of Herpes Zoster). With severe immunoc ompromise, re-infections manifested as varicella have been observed. In addition, persons who develop modified varicella (e.g., because they are infected early in infancy in the presence of maternal antib ody or have been immunized with live attenuated varicella vaccine) may res pond to exogenous exposure by develo ping a second, usually mild, episode of breakthrough varicelia. Epidemiology of Herpes Zoster Herpes zoster occurs sporadically througho ut the year without seasonal prevalence. The occurrence of herpes zoster is indep endent of the prevalence of varicella, and there is no convincing evidence that herp es zoster can be acquired by contact with other persons with varicella or herpes zost er. Rather, the incidence of herpes zoster is detemined by factors that influence the host-virus relationship. One strong risk factor is older age Q.ig 194- A). The incidence of herpes zoster is 1.5 to 3.0 per 1000 person years in all ages and 7 toll per 1000 per year in pers ons over 60 years of age in European and North American studies.u7 It is est imated that there arc more than a mill ion new cases of herpes zoster in the United States each year, more than oneC-) I > tz; = 1885

r Vadcdla (cilickenpox) and herpes zoster (shingles) are stirrct clinical entities caused by the vadcelazoster virus. Vancella, an acute, highly contagious exanthem that occurs most often in childh ood, is the result of primary infection of a susceptible individual. The rash usually begins on the face and scalp and spreads rapidly to the trunk. Lesions are scattered rather than dustered, and progress from rose-colored mactiles to papules, vesides, pustules, and crusts. In vancella. lesions in all stages are usually esent on the body at the same time. In normal children, senous complications are rare. In adults and in immunologically compromised persons, varicella is more likely to be associated with life-ttreatening complications. Where use of varicella vaccine in suscept ible children and adults is widespread, the incidence of varicella is markecly reduced.

 Herpes zoster is characterized by unilate ral, dermatomal pain and rash as the result of the reactivation of endogenous varicefla-zoster virus that had persisted in latent form within sensory ganglia alter an earlier attack of vahcella. The erythemataus, maculopapular, and vesicular lesions of herpes zoster are clustered rather than scattered because virus reaches the skin via sensory nerves. Herpes zoster is most common in older adults arid imrnunosuppressed individuals. Pain is the most important dinical manif estation of herpes zoster, and the most common complication is chronic pain or postherpetic neuralgia. Antiviral therapy and analgesics aid acute pain control; lidocaine patch (5 percent), gabapentin, pregabalin, opioids, and tnc yclic antidepressants reduce postherp etic neuralgia. The zoster vaccine reduces the incidence of herpes zoster by one- ha and the incidence of postherpetic neuralgia by tw-thirds. half of which occur in persons 60 years of age or older, and this number increase as the population ages.H.14 Another major risk factor is cellular imm une dysfunction. Ininiunosuppressed patients have a 20 to 100 times greater risk of herpes zoster than immunocomp etent individuals of the same age. Tmm unosuppressive conditions associated with high risk of herpes zoster include human inimunodeficiency virus (HI)) inf ection, bone marrow transplant, leukem ia and lyrnphorna, use of cancer chem otherapy, and use of corticosteroids. Herpes zoster is a prominent and early opportunistic infection in persons inf ected with HtV in whom it is often the first sign of immune deficiency. Thus, HIV infection should be considered in ind ividuals who develop herpes zoster. Other factors reported to increase the risk of herpes zoster include female sex,7 physical trauma in the affected derrnatome,13 interleukin 10 gene polym orphisms, and black race,16,17 but confirmation is required. Exposure to children and contact with cases of vanc elia have been reported to confer prot ection against herpes zoster.17,2u Second episodes of herpes zoster are uncommon in immunocompetent pers ons, and third attacks are very rare. Persons suffering more than one epis ode may be immunocompromised. Imm unocompetent patients suffering mult iple episodes ot herpes zosterlike disease are likely to be suffering from recurrent zosteriform herpes simplex vir us (HSV) infections.21 Patients with herpes zoster are less contagious than patients with varicella. The rate at which susceptible household contacts develop varicella after exposure to herpes zoster appears to be about one- third of the rate observed after exposure to varicella. Virus can be isolated from vesides and pustules in uncomplicated herpes zoster for up to 7 days after the appearance of the rash, and for much longer periods in immunocompromised individuals. Patients with uncomplicated dermatomal zoster appear to spread the infection by means of direct contact with their lesions. Patients with disseminated herpes zoster may, in addition, transmit the infection in aerosols, so that airborne precautions, as well as contact precaut ions, are required for such patients. The effect of the marked reduction in the incidence of varicella, due to wides pread varicella vaccination of children, on the epidemiology of herpes zoster is unc lear. In the long term, the incidence of herpes zoster is likely to decline as the co orts of children now receiving the vaccine become adults; vaccine virus-associated herpes zoster will probably he less freq uent and less severe in older adults than wild-type virusassociated herpes zoster because the vaccine virus is highly attenua ted. In the short term, the incidence of herpes zoster could increase because a dec line in the incidence of varicella will red uce the adult populations exposure to VZV, thereby reducing immune boosting, hastening the age-related decline in immun ity to VZ\ and thus increasing the age- specific risk of herpes zoster. However, recent studies of herpes zoster in populat ions with high rates of varicella vaccinat ion have shown little or no increase in the incidence of herpes zoster.61222

ETIOLOGY AND PATHOGENESIS VZV is a member of the herpesvirus fami ly. Other members pathogenic for hum ans include HSV-l

and HSV-2; cytomega lovirus; Epstein-Barr virus; human herpesvirus-6 (HHV-6) and HHV-7, which cause roseola; and Kaposi sarcomaassoc iated herpesvirus, also called HHV-8. All herpesviruses are morphologically indistinguishable and share a number of prope rties, including the capacity to establish latent infections that persist for life. The VZV genome encodes approxim ately 70 unique genes, most of which have DNA sequence and functional hom ology to genes of the other herpesvir uses. Immediate early gene products regu late VZV replication. Early gene products, such as the virus-specific thymidine kinase and the viral DNA polymerase, support vir al replication. Late genes encode virus structural proteins that serve as targets of antibody and ccllubr immune responses. There is only one VZV serotype. Alt hough viruses isolated from individual cases of varicella or herpes zoster worldw ide are basically similar, minor variat ions in their nucleotide sequences allow one to distinguish wild-type from vacc ine virus strains, and to fingerprint vir uses isolated from individual patients. Pathogenesis of Varicella Entry of VZV is through the mucosa of the upper respiratory tract and orophary nx. Initial multiplication at this portal of entry results in dissemination of small amounts of virus via the blood and lymphatics (the primary viremia). This virus is cleared by cells of the reticu loendothclial system, the major site of virus replication during the remainder of the incubation period. VARICELLA AND HERPES ZOSTER

The incubating infection is partially contained by innate host defenses (e.g., interferon, natural killer cells) and by developing VZV-specific immune res ponses. In most individuals, virus repl ication eventually overwhelm these developing host defenses, so that app roximately 2 weeks after infection, a much larger (secondary) viremia and associated symptoms and lesions occ ur. Skin lesions appear in successive crops, reflecting a cyclic viremia, which in the normal host is terminated after approximately 3 days by VZV-speciflc hunieral and cellular immune res ponses. Virus circulates in mononu lear leukocytes, primarily lymphoc ytes. Even in uncomplicated varicella, the secondary viremia results in the sub-clinical infection of many organs in addition to the skin. Effective host imm une responses terminate viremia and limit the progression of varicella les ions in the skin and other organs. Hum eral immunity to VZV protects against varicella. People with detecta ble serum antibody do not usually bec ome ill after exogenous exposure. Cell-mediated immunity to VZV also develops during the course of varicella, persists for many years, and protects against severe infections.24 Pathogenesis of Herpes Zoster During the course of varicella, VZV passes horn lesions in the skin and muc osal surfaces into the contiguous endi ngs of sensory nerves and is transp orted centripetally up the sensory fibers to the sensory ganglia. In the gang lia, the virus establishes a latent infect ion that persists for life. Herpes zoster occurs most often in dermatomes in which the rash of varicella achieves the highest density those innervated by the first (ophthalmic) division of the tng eminal nerve and by spinal sensory ganglia horn Ti to L2 (H 4-2). A FIGURE 194-2 Varicclla and herpes ioster. A. During primary varicella-zoster virus (VZ) infection (varicella or chickenpox), virus in! ccts sensory ganglia. B. VZV persists in a latent phase within ganglia far the life of the individual. C. With diminished immune function, VZV re-activates within sensory ganglia, des cends through sensory nerves, and replicates ri skin. A BC

= a) 0 Co =
More than 1 year 6-12 months 16 months Less than 1 month -Ill

Ii...
Age (years) Months after onset of zoster Age (years) A FIGURE 194-1 A. The epidemiology of herpes iosler and postherpetic neuralgia. The annual incidence of herpes zoster per 1000 persons in a general medical practice. B. The percentage of patients with pain persisting alter the onset of the herpes zoster rash. These data are from the placebo recipients in one large, double-blind treatment study. C. The proportion of patients with postherpetic neuralgia according to age. rom Kost RG, Straus SE: Postherpetic neuralg ia: Pathogenesis, treatment, and prevention. N Engi J Med 335:32, 1996, with permission.) A

LI
B C Chickenpox Latent phase Herpes zoster

1887

Although the latent virus in the gang lia retains its potential for Full infectivi ty, re-activation is sporadic and infreq uent, and infectious virus does not appear to be present during latency. The mechanisms involved in re-activation of latent VZV are unclear, but re-activation has been associated with immunosupp ression; emotional stress; irradiation of the spinal column; tumor involvement of the cord, dorsal root ganglion, or adjac ent structures; local trauma; surgical manipulation of the spine; and frontal sin usitis (as a precipitant of ophthalmic zoster). Most important, though, is the decline in VZV-specific cellular immun ity that occurs with increasing age. VZV may also re-activate without producing overt disease. The small quantity of viral antigens released duri ng such contained re-activations would be expected to stimulate and sustain host immunity to VZV.26 When VZV-specific cellular immunity falls below some critical level, re-activated c.z virus can no

longer be contained. Virus multiplies and spreads within the gang lion, causing rzeuronal necrosis and int ense inflanunation, a process that is often accompanied by severe neuralgia.2 Infect ious VZV then spreads antidrornically down the sensory nerve, causing intense neuritis, and is released from the sensory nerve endings in the skin, where it prod uces the characteristic duster of zoster vesides. Spread of the ganglionic infection proximally along the posterior nerve root to the meninges and cord results in local leptomeningitis, cerebrospinal fluid pleoc ytosis, and segmental myelitis. Infection of motor neurons in the anterior horn and inflammation of the anterior nerve root account For the local palsies that may acc ompany the cutaneous eruption, and ext ension of infection within the central nerv ous system (CNS) may result in rare complications of herpes zoster e.g., meni ngoencephalitis, transverse myelitis). Pathogenesis of Pain in Herpes Zoster and Postherpetic Neuralgia Pain is a major symptom of herpes zost er. It often precedes and generally acc ompanies the rash, and it frequently persists after the rash has healeda complication known as postizerpetic neur algia (PHK). A number of different but overlapping mechanisms appear to be involved in the pathogenesis oF pain in herpes zoster and PHN (F I Injury to the peripheral nerve and to neurons in the ganglion triggers afferent pain signals. Inflammation in the skin triggers nociceptive signals that further amplify cutaneous pain. The abundant release of excitatory amino acids and neuropeptides induced by the sustained barrage of afferent impulses during the prodrome and acute phase of herpes zoster may cause excitotoxic injury and the loss of inhibitory iriterneurons in the spinal dorsal horn. Damage to neurons in the spinal cord and ganglion, and to the peripheral nerve, is important in the pathogenesis of PHN. Damaged prim ary afferent nerves may become spont aneously active and hypersensitive to peripheral stimuli, and also to sympat hetic stimulation. Excessive nociceptor activity and ectopic impulse generation may. in turn, sensitize CNS neurons, augmenting and prolonging central res ponses to innocuous as well as noxious Ascending spinottialamic fibers Skin or mucous membrane stimuli. Clinically, these mechanisms res ult in allodynia [pain and/or unpleasant sensations elicited by stimuli that are normally not painful (e.g., light touch)] with little or no sensory loss. The anatomic and functional changes responsible for PHN appear to be establ ished early in the course of herpes zost er. This would explain the correlation of initial pain severity and the presence of prodrumal pain with the subsequent development of P1-IN, and the failure of antiviral therapy to fully prevent PHN (see Treatment). CLINICAL FINDINGS Clinical Findings of Varicella

PRODROME OF VARICELI.A In young child ren, prodromal symptoms are unconi

escending noradrenergic and serotoninergic inhibitory fibers

A FIGURE 194-3 Pathway of normal pain perception. Noxious stimuli activate tree nerve endings in the skin to generate signals that are conveyed through unmyehnated C fibers (rec4 and small AS fibers to the neurenal bodies in the segmental dorsal root ganglia, then proximally to the dorsal horn of the spinal cord, where they form synapses with second-order neurons. Spinal cord neurons are subject to powerful descending inhibitory signals from the brain (blue), mediated by the blogenic amines serotonin ani nore pinephrine. Drugs that potentiate the central effects of biogenic aniines, such as tricyclic antidepress ant drugs, may act by enhancing these descending pathways. Endogenous opiates also contribute to descending inhibitory input. The net result of peripheral atferent input and

descending inhibitory input is prede cephalad, joining other ascending fibers in the contralateral spinothalamic tract (orange). biform abon from the spinothalamic tract is integrated with input from brainslem and cortical areas for the perception of specitic aspects of pain as well as more general affective components of pain perception.

mon. In older children and adults, the rash is often preceded by 2 to 3 days of fever, chills, malaise, headache, anorexia, severe backache, and, in some patients, sore throat and dry cough. RASH OF VARICEIIA In unvaccinated pers ons, the rash begins on the face and scalp and spreads rapidly to the trunk, with relative sparing of the extremities (g b4-4). New lesions appear in succ essive crops, but their distribution rem ains central. The rash tends to be denser in the small of the back and bet ween the shoulder blades than on the scapulae and buttocks and more profuse on the medial than on the lateral aspects of the limbs. ft is not uncommon to have a few lesions on the palms and soles, and vesicles often appear earlier and in larger numbers in areas of inflamm ation, such as diaper rash or sunburn. A striking feature of varicella lesions is their rapid progression, over as little as 12 hours, from rosecolored macuies to papu les, vesides, pustules, and crusts (see F. 1 i--4). The typical vesicle of vancella is 2 to 3 mm in diameter and elliptical, with its long axis parallel to the folds of the skin. The early vesicle is superficial and thin-walled, and it is surrounded by an irr egular area of erythema, which gives the lesions the appearance of a dewdrop on a rose petal. The vesicular fluid soon bec omes cloudy with the influx of inflamm atory cells, which convert the vesicle to a pustule (see F 1 -4). The lesion then dries, beginning in the center, first prod ucing an umbilicated pustule and then a crust. Crusts fall off spontaneously in I to 3 weeks, leaving shallow pink depress ions that gradually disappear. Scarring is rare unless the lesions were traumatized by the patient or superinfected with bac eria. Healing lesions may leave hypopigm ented spots that persist for weeks to months. Vesicles also develop in the mucous membranes of the mouth, nose, phary nx. larynx, trachea, gastrointestinal tract, urinary tract, and vagina. These mucosal vesicles rupture so rapidly that the vesicular stage may he missed. Ins tead, one sees shallow ulcers 2 to 3 mm in diameter. A distinctive feature of varicella is the simultaneous presence, in any one area of the skin, of lesions in all stages of dev elopment. Careful prospective studies have shown that the average number of lesions in healthy children ranges frnm 250 to 500; secondary cases resulting from household exposure are more sev ere than primary cases resulting from exposure at school, presumably because more intense and prolonged exposure at home results in a higher virus inoculum. Fever usually persists as long as new lesions continue to appear, and its height is generally proportional to the severity of the rash. It may be absent in mild cases or rise to 40.5C (1O5F) in severe cases with extensive rash. Prol onged fever or recurrence of fever after defervescence may signify a secondary bacterial infection or another complicat ion. The most distressing symptom is pruritus, which is usually present throughout the vesicular stage. The varicella vaccine alters the natur al history of the rash. A small percenta ge of vaccinees develop breakthrough varicella after exposure to people with active VZV infections. The usual breakt hrough rash is predominately maculop apular with fewer lesions (i.e., less than 60) and fewer vesicles than the rash of natural varicella. The incidence and severity of fever is also less than that in natural varicella. Clinical Findings of Herpes Zoster PRODROME OF HERPES ZOSTER Pain and paresthesia in the in volved dermatome often precede the eruption by several days and vary from superficial itching, tingling, or burning to severe, deep, bori ng, or lancinating pain. The pain may be constant or intermittent, and it is oft en accompanied by tenderness and hyp eresthesia of the skin in the involved dermatome. The pre-eruptive pain of herpes zoster may simulate pleurisy, myocardial infarction duodenal ulcer, cholecystitis, biliary or renal colic, app endicitis, prolapsed intervertebral disk, or early glaucoma, and this may lead to serious misdiagnosis and misdirected interventions. Prodromal pain is uncomm on in inirnunocompetent

persons younger than 30 years of age, but it occ urs in the majority of persons with herp es zoster over the age of 60 years. A few patients experience acute segmental neuralgia without ever developing a cut aneous eruptiona condition known as zosler sine herpese. RASH OF HERPES ZOSTER The most dist inctive feature of herpes zoster is the loc alization and distribution of the rash, which is nearly always unilateral and is generally limited to the area of skin innerv ated by a single sensory ganglion (Fig. 194-5). The area supplied by the trigemin al nerve, particularly the ophthalmic divis ion, and the trunk from T3 to L2 are most frequently affected; the thoracic region alone accounts for more than one-half of all reported cases, and lesions rarely occur distal to the elbows or knees.1115 Although the individual lesions of herp es zoster and varicella are indistinguisha ble, those of herpes zoster tend to evolve more slowly and usually consist of closely grouped vesicles on an erythemat ous base, rather than the more discrete, randomly distributed vesicles of varicella. This difference reflects intraneural spread of virus to the skin in herpes zoster, as opposed to viremic spread in varicella. Herpes zoster lesions begin as erythemat ous macules and papules that often first appear where superficial branches of the affected sensory nerve are given off, for example, the posterior primary division and the lateral and anterior branches of the anterior primary division of spinal nerves. Vesiclcs form within 12 to 24 hours and evolve into pustules by the third day. These dry and crust in 7 to 10

D HGURE 194-4 Varicella. A. A full spectrum of lesionsthat is, erythematous papules, vesides rdewdrops on rose petals), crusts, and erosions at sites of excoriationis seen in a child with a Ipical case of varicella. B. A wider range of lesions. including many large pustLdes, is seen in a 21year-old woman who was feble as well as toxic and had vahcella pneumonills.
C-) I>=

1889

S
days. The crusts generally persist for 2 to 3 weeks (see Fi. l.5l3) In normal iridiv iduals, new lesions continue to appear for 1 to 4 days (occasionally for as long as 7 days). The rash is most severe and lasts longest in older people, and is least severe and of shortest duration in children. Between 10 percent and 15 percent of reported cases of herpes zoster involve the ophthalmic division of the trigerninal nerve (see I 94-5C).3 The rash of ophthalmic zoster may extend from the level of the eye to the vertex of the skull. hut it terminates sharply at the midline of the forehead. When only the suprat rochicar and supraorbital branches are involved, the eye is usually spared. Tnv olvement of the nasociliary branch. which innervates the eye as well as the tip and side of the nose, provides VZV with direct access to intraocular struct ures. Thus, when ophthalmic zoster inv oLves the rip and the side of the nose. careful attention must be given to the condition of the eye. The eye is involved in 30 percent to 40 percent of patients with ophthalmic zoster. Comeal sensat ion is generally impaired and when imp airrnent is severe, it may lead to neur otrophic keratitis and chronic ulceration. Herpes zoster affecting the second and third divisions of the trigeminal nerve (Fig 4-6) as well as other cranial nerves may produce symptoms and lesions in the mouth, ears, pharynx, or larynx. The so-called Ra,nsai Hunt spndr,ne (facial palsy, in combination with herpes zoster of the external ear or tyrnpanic memb rane, with or without tinnitus, vertigo, and deafness), results from involvement of the facial and auditory nerves. PAIN OF HEIWES ZOSTER Although the rash is important, pain is the cardinal problem posed by

herpes zoster, especially in the elderly. Most patients experience derrnat ornal pain or discomfort during the acute phase (30 days from rash onset) that ranges from mild to severe. Patients des cnbc their pain or discomfort as burning, deep aching, tingling, itching, or stabbing. For some patients, the pain intensity is so great that words such as horribk or excruaa ling are used to describe the experience. Acute herpes zoster pain is associated with decreased physical functioning, emotional distress, and decreased social functioning.52 HERPES ZOSTER IN ThE IMMUNOCOMPROM ISED HOST Except for PHN, most serio us complications of herpes zoster occ ur in immunocompromised persons. These complications include necrosis of skin and scarring (F:. 194-7) and cutan eous dissemination with an incidence as high as 25 percent to 50 percent. App roximately 10 percent of patients with cutaneous dissemination also manifest widespread (P. 1 -d), often fatal, visc eral dissemination, particularly to the lungs, liver, and brain. HIV-infcctcd patients arc fairly unique in their tendency to suffer multiple recurr ences of herpes zoster as their HIV inf ection progresses; herpes zoster may rec ur in the same or different dermatomes or in several contiguous or non-contiguo us dennatoines. Herpes zoster in pat ients with acquired immunodeficiency syndrome (AIDS) may be severe, with cutaneous and visceral dissemination. Patients with AIDS may also develop chronic verrucous, hyperkeratotic (Fig. I 4-9), or ecthymatous cutaneous lesions caused by acyclovir-resistant VZV. DIAGNOSIS OF VAICELLA Varicella can usually be diagnosed readily on the basis of the appearance and evolution of its characteristic rash (see Ft I 4-4), particularly when there is a history of exposure within the prec eding 2 to 3 weeks.

*
., i-. ,i. -

b
. C, iI I] A FIGURE 194-5 Herpes zoster. A. Early involvement of a thoracic dermatome with erythema within the dermatome and areas of grouped vesicle formation. B. Later involvement with crusted sites on the back, where the eruption first appealed, and many confluent hemorrhagic vesicles and hullae on the lateral chest wall, where the eruption appeared rme recently; some vesicles are also seen outside the involved dermatome, representing hematogenous dissemination, a not uncommon occurrence. C. Ophthalmic zoster, Note the involvement of the tip of the nose, which frequently signals involvement of the eye.

A FIGURE 194-6 Cephalic herpes zoster with facial palsy (Hunt syndrome). A 60-year-old woman with right-sided facial palsy and vesicles on her (A) tongue and (B) soft palate. 1890

A FiGURE 194-7 A. ute, necrotic herpes zost er (viving the lirt and secuid distributions at the fifth cranial nerve in a woman with lymphoma recetvi rig cytotodc chemotherapy. B. Dense scar formation

and temporal musde wasting several weeks later. from Straus SE et al: Vicella-zoster infections: Bio gy, natural histixy, treatment and prevention. Am lriem MedlOR:221 1988 with permission.)

A FIGURE 194-8 The back of a patient with chronic lyrnphocytic leukemia and disseminated herpes zoster. (From Straus SE et al: Varicellai oster infections: Biology, natural history, treatm ent and prevention. Ann Intern Med 108221, 1988 with permission.)
Disseminated herpes zoster may be mistaken for varicella when there is widespread dissemination of VZV from a small, painless area of herpes zoster or from the affected sensory ganglion in the absence of an obvious dermatomal eruption. This is nor infrequent in prof oundly immunosuppressed, seroposit ive persons (see ig [94-7). Disseminated HSV infections may res emble varicella; however, there is often an obvious concentration of lesions at and surrounding the site of the primary or recurrent infection (e.g., the mouth or external genitalia), and there may be marked toxicity and encephalitis. The remaining differential diagnoses of varicelliform rashes are listed in Brr< I I. The character, distribution, and evolution of the lesions, together with a careful epidemiologic history, usually differentiate these diseases from van

IGURE 194-9 Chronic verr ucous lesions of herpes zoster despite long-term acydow treatm ent in a patient with advanced acquired immunodeficiency synd rome.J sed with permission from David Paar, MD.) celIa. When aiiy doubt exists, the clinic al impression should receive laboratory confirmation. DIAGNOSIS OF HERPES ZOSTER In the pre-eruprive stage, the prodromal pain of herpes zoster is often confused with other causes of localized pain. Once the eruption appears, the charact er and dermatomal location of the rash, coupled with dermatomal pain or disc omfort, usually makes the diagnosis obvious (see fi. 194-5 and A cluster of vesicles, particularly near the mouth or genitals, may represent herpes zoster, but it may also be a recurr ent HSV infection.2 Zosteriform herpes simplex is often impossible to distinguish from herpes zoster on clinical grounds. A history of multiple recurrences at the same site is common in herpes simplex
Ii -

Box 194-1 Differential Diagnosis L 1891 VARICELLA Most Likely Vesicular exantliems of coxsackie viruses and echoruses Impetigo Insect bites Contact dermatitis Consider Papular urticana Erythema multiforrne

Drug eruptions Disseminated herpes simplex Scabies Always Rule Out Secondary syphihs Disseminated herpes zoster Dermatitis herpetiformis Smallpox and other poxviruses

HERPES ZOSTER Most Likely Zosteritcrm herpes simplex Contact dermatitis Insect bites Burns Consider Papular urticana Erythema rnultiforme Drug eruptions Scabies Always Rule Out Bullous pemphigoid Pernphigus vulqaria Dermatitis herpetifmis Epidermolysis bullosa herpetilormis

but does not occur in herpes zoster in the absence of profound and clinically obvio us immune deficiency. ox 94-1 lists other considerations in the differential diagnosis of herpes zoster LABORATORYTESTS The lesions of varicella and herpes zoster are indistinguishable by histopathology (Fig. 14-JU). The presence of mukinuc leated giant cells and epitheial cells cont aming acidophilic intranuclear inclusion bodies (see F I *1- I K) distinguishes the cutaneous lesions produced by V7.V from all other vesicular eruptions (e.g., those caused by vanola and other poxvir uses, and by coxsackie viruses and echov iruses) except those produced by HSV (see H. 1 in Chap. 193). These cells can be demonstrated in Tzanck smears prepared at the bedside; material is scraped from the base of an early vesicle spread on a glass slide, fixed in acetone or methanol, and stained with hematoxy lin-cosin. Giemsa, Papanicolaou, or Para gon multiple stain. Punch biopsies provide more reliable material for histologic examination than Tzanck smears and facilitate diagnosis in the prevesicular stage and in atypical lesions such as the chronic verrucous les ions produced by acyclovir-resistant VZV in patients with Al[)S (see I The detinitive diagnosis of WV infect ion, as well as the differentiation of VZV from HSV, is accomplished by the isolation of virus in cell cultures inocul ated with vesicle fluid, blood, cereb rospinal fluid or infected tissue, or by the direct identification of VZV antigens or nucleic acids in these specimens. Virus isolation is the only technique that yields infectious VZV for further analys is, such as determination of its sensitivi ty to antiviral drugs; however, VZV is extremely labile, and only 30 percent to 60 percent of cultures from proven cases are generally positive. To maximize vir us recovety, specimens should be inocu lated into cell culture immediately. It is important to select new vesicles containi ng dear fluid for aspiration, because the probability of isolating VZV diminishes rapidly as lesions become pustular. VZV is almost never isolated from crusts.

VZV can be isolated and propagated in vitro in monolayer cultures of a variety of human (and certain simian) cells. The cyt opathic effects induced by the replicati ng virus in such cell cultures are charact erized by the formation of acidophilic intranuclear inclusion bodies and multin udeated giant cells similar to those seen in the cutaneous lesions of the disease. These changes are indistinguishable from those produced by HSV, but whereas HSV rapidly spreads to infect the remaini ng cells in the culture, the cytopathic eff ect of VZV remains focal. (ytopathic eff ects of VZV are generally not apparent until several days after specimen inoculat ion. Modifications of the cell culture ass ay in which veside fluid or lesion scrapi ngs are centrifuged onto cells growing on coverslips at the bottom of thin glasswalled ashell vials followed 24 to 72 hours later by fixation and staining with fluorescein- or enzymelabeled monoc lonal antibodies to VZV proteins, can confirm the presence of WV relatively quickly, well before cytopathic effects are evident in conventional cell cultures,34 Irninunofluorescent or immunoperoxi dase staining of cellular material from fresh vesicles or prevesicular lesions has become the diagnostic method of choice 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 prov ide another rapid and sensitive method for antigen detection. Detection of WV DNA in clinical specimens after aniplitications by pol ymerase chain reaction provides the greatest assay sensitivity, very high specificity, and rapid turn-around time. It has revolutionized the diagnosis of VZV infections.S4 Serologic tests permit the retrospect ive diagnosis of varicella and herpes zoster when acute and convalescent sera are available for comparison. These assays can also identify suscept ible individuals who may be candid ates for isolation or prophylaxis. The technique most commonly used is a solidphase enzyme-linked immuno sorbent assay. This assay, however, often lacks sensitivity and specificity and does not detect antibody in people who are immune, and soinetinies yield falsepositive results in susceptible ind ividuals. Several more sensitive techn iques have been developed to measu re humoral responses to VZV. These include an immunofluoresccncc assay for antibody to VZV-induced memb rane antigens (fluorescent antibody to membrane antigen) that reliably disting uishes immune from susceptible adults and a latex agglutination test that is comparable in sensitivity and specificity to fluorescent antibody to membrane antigen assays but is much simpler to perform.36 I A F

A FIGURE 194-10 Herpes zoster, histopathology. A. lntraepidermal vesicle, acantholysis, reticular degenerahon; underlying dermis shows edema and vascul itis. B. Multinucleated giant cells with characteristic nuclear changes. 1892

Complications of Varicella In the normal child, vancella is rarely complicated. The most common complic ation is the secondary bacterial infection of skin lesions, usually by staphylococci or streptococci, which may produce imp etigo, furuncles, cellulitis, ezysipelas, and, rarely, gangrene. These local infecd ons often lead to scarring and, rarely, to septicemia with metastatic infection of other organs. Bullous lesions may dev elop when vesicles are superinfected by staphylococci that produce exfoliative toxins. Invasive group A streptococcal inf cctions are particularly virulent. In the absence of varicella vaccination, up to one-

third of invasive group A streptococc al infections are associated with vanc ella; they usually occur within 2 weeks of the onset of the vancella rash.sz Wides pread varicella vaccination appears to have markedly reduced the percentage of invasive group A streptococcal hospitali zations associated with varicella in the United States,3 Secondary bacterial pneumonia, otitis media, and suppurative meningitis are rare complications and typically res pond to appropriate antibiotic therapy. However, bacterial superinfection is common and potentially life-threateni ng in icukopenic patients. Other comp lications reflect a basic defect in the cap acity of the host to limit VZV replication and dissenunation.4 In adults, fever and constitutional symptoms are more prominent and prol onged, the rash of varicella is more prof use, and complications are more freq ucnt.4 High rates of complications have been reported in adults not born in the United States (i.e., adults born in Mexico),4 Primary varicella pneumonia is the major complication of adult vanc ella. Some patients are virtually asympt omatic. but others develop severe respir atory embarrassment, with cough, dyspnea, tachypnea. high fever, pleuritic chest pain, cyanosis, and hemoptysis I to 6 days after onset of the rash. The severi ty of the symptoms usually exceeds the physical findings, but the roentgenogram typically reveals diffuse, peribronchial nodular densities throughout both lung fields with a tendency to concentrate in the perthilar regions and at the bases. The mortality in adults with frank varic dlla pneumonia has been estimated to be between 10 percent and 30 percent, but it is less than 10 percent if immunoc ompromised patients are excluded.42

TABLE 1941 Complications of Herpes Zoster CUTANEOUS IhSCERAL Pneumonitis Hepatitis Esophagitis Gastritis Pericarditis Cystitis Arthntis Varicella during pregnancy is a threat to both mother and Fetus.4 Dissemin ated infection and varicella pneumonia may result in maternal death, but neither the incidence nor the severity of vanicella pneumonia appear to be significantly inc reased by pregnancy. The fetus may die as a consequence of premature labor or maternal death caused by severe vanicella pneumonia, but varicella during pregn ancy does not, othervise, substantially increase fetal mortality. Nevertheless, even in uncomplicated varicella, matern al viremia can result in intrauterine (congenital) VZV infection, and a charact eristic constellation of congenital abnorm alities.43 Peninatal varicella (i.e., vanc ella occurring within 10 days of birth) is more serious than varicella in infants inf ected even a few weeks later. The morbidity and mortality of vatic ella are markedly increased in irnmunoc ompromised patients. Tn these patients, continued virus replication and dissemin ation result in a prolonged high-level viremia, a more extensive rash, a longer period of new vesicle formation, and cliiii cally significant visceral dissemination. Immunosuppressed and glucocorricoidt reated patients may develop pneumonia, hepatitis, encephalitis, and hemorrhagic complications of varicella, which range in severity from mild febnle purpura to sev ere and often fatal purpura fulminans and malignant varicella. CNS complications of varicdlla occur in fewer than 1 in 1000 cases; they inc lude several distinct syndromes. Vanc elIa-associated Reye syndrome (acute encephalopathy with fatty degeneration of the liver) typically occurs 2 to 7 days after the appearance of the rash. In the past, from 15 percent to 40 percent of all cases of Reyc syndrome occurred in ass ociation with varicella, particularly when aspirin was administered for fe
EUR0L0GIC Postherpetic neuralgia

 Meninoencephalitis Transverse niyelitis Peripheral nerve palsies Motor Autonomic Cranial nerve palsies Sensy loss Deafness Ocular complications Granulomatous angiitis (causing contra- lateral hemiparesis) ver, with mortality as high as 40 perc ent.M Acute cerebellar ataxia is more common than the other neurologic complications of varicella, occurring in I in 4000 cases, and is more benign. Enc ephalitis is much tess common, occurr ing in I in 33,000 cases, but it freq uently causes death or permanent neurologic sequelae. The pathogenesis of cerebellar ataxia and encephalitis rem ains obscure, hut in many cases it is possible to detect VZV antigens, VZV antibodies, and VZV DNA in the cereb rospinal fluid of patients, suggesting direct infection of the CNS.35 Although elevated aminotransferase levels are common, clinical hepatitis is rare except as a complication of progress ive vanicella. Other rare complications of varicella include myocarditis, glomeru lonephnitis, orchitis, pancreatitis, gast ritis and ulcerative lesions of the bowel, arthritis, Henoch-Schnlein vasc ulitis, optic neuritis, keratitis, and iritis. The pathogeriesis of many of these complications has not been delineated, but direct parenchymal or endovascular VZV infection, or vasculitis induced by VZV antigen-antibody complexes, app ear to be responsible in most cases. Complications of Herpes Zoster (ThL i94-1) The sequelac of herpes zoster include cut aneous, ocular, neurologic, and visceral complications. Most complications of herpes zoster are associated with the spread of VZV from the initially involved sensory ganglion, nerve, or skin, either via the bloodstream or by direct neural extension. The rash may disseminate aft er the initial dermatomal eruption has become apparent. When immunocompet ent patients are carefully examined, it is Bacterial siermnfection Scamng Zoster gangrenosum Cutaneous dissemination Li

not uncommon to have at least a few vesicles in areas distant from the inv olved and immediately adjacent dermat omes. The disseminated lesions usually appear within a week of the onset of the segmental eruption and, if few in numb er, are easily overlooked. More extens ive dissemination (with 25 to 50 lesions or more), producing a varicella-like erupt ion (generalized herpes zoster; see Ft; ) 1-7), occurs in 2 percent to 10 percent of unselected patients with localized zost er, most of whom have immunologic defects as a result of acquired irnmunod eficiency as seen with HIV infection, underlying malignancy particularly lymp homas), or immunosuppressive thera py. If the rash spreads widely from a small, painless area of herpes zoster, the initial dermatomal presentation may go unnoticed, and the ensuing disseminated eruption may be mistaken for varicella. When the dermatomal rash is particul arly extensive, as it often is in severely immunocompromised patients, there may be superficial gangrene with del ayed healing and subsequent scarring (see Fig. 194.78). Secondary bacterial inf ection may also delay healing and cause scarring. The eye is involved in 20 percent to 70 percent of patients with ophthalmic zost er, with a wide range of possible complic ations. VZV is also the principle cause of acute retinal necrosis, a fulminant sight-threatening disease observed prim anly in otherwise healthy individuals.46

Herpes zoster may be attended by a variety of neurologic complications (see Lihir 194-1). of which PHN is the most common and important.47 PHNI has been variably defined as any pain after rash healing or any pain I month, 3 months, 4 months, or 6 months after rash onset, with most recent definitions focusing on 90 to 120 days after rash onset.4541 In clinic and community studi es, the overall incidence of PHN is 8 percent to 15 percent, depending on the definition (see i 194_l).2850. Age is the most significant risk factor for PHN (see Fig. 4-l). Clinically significant pain lasting 3 months or more is rare in immunocompetent persons younger than 50 years of age, but complicates 12 percent to 15 percent of cases of herpes zoster in persons 60 years of age and older.4 Other risk factors for PHN inc lude the presence of prodromal pain, severe pain during the acute phase of herpes zostcr, greater rash severity more extensive sensory abnormalities in the affected dermatonie and, possibly, ophthalmic (as opposed to thoracic or abdominal) herpes zoster.2 Increasing age, greater acute pain severity, prese nce of prodromal pain, and greater rash severity have each been reported to be independent predictors of PHN.9 The positive predictive value of each factor alone was low, hut, together, the posit ive predictive value was almost 50 perc ent. Conversely, 90 percent to 95 perc ent of patients with herpes zoster who had none of these risk factors developed PHN. PHN usually remits spontaneo usly over several months but, as with PHN itself, the risk of long-lasting PHt also increases with increasing age. Patients with PHN may suffer from constant pain (described as 1,urning, athi ng, throbbing), intermittent pain (stabb ing, shooting), and/or stimulus-evoked pain, including allodynia (render, bunting, stabbing). Allodynia pain elicited by stimuli that are normally not painful) is a particularly disabling component of the disease that is present in approxim ately 90 percent of patients with PHN. Patients with allodynia may suffer sev ere pain after even the lightest touch of the affected skin by things as trivial as a breeze or a piece of clothing. These subt ypes of pain may produce disordered sleep, depression, anorexia, weight loss, chronic fatigue, and social isolation, and they often interfere with dressing, bathi ng, general activity, traveling, shopping, cooking, and housework. TREATMENT Antivira Agents The nucleoside analogues acyclovir, farnc iclovir, valacyclovir, and brivudin and the pyrophosphate analog foscamet show efficacy in treating VZV infections. Acydovir is a guanosine analog that is sel ectively phosphotylated by VZV thymid ine kinases (it is a poor substrate for cell ular thymidine kinase) and thus is concentrated in infected cells. Cellular enz ymes then convert acyciovir monophosp hate to acyclovir triphosphate, which interferes with viral DNA synthesis by inh ibiting viral DNA polyrnerase. VZV is approximately 10-fold less sensitive to acyclovir than HSV (see Chap. 232). Two prodrugs, valacyclovir and fanic idovir, are better and more reliably abs orbed than acyclovir after oral administ ration. Thus, they produce much higher blood levels of antiviral activity and permit less frequent dosing than acyclovir. Because of their superior pharinacokin etics and the lower sensitivity of VZV compared with I-ISV, famciclovir, or vala cyclovir are preferred to acyclovir for oral therapy of VZV infections. Acyclov ir-resistant varicella and herpes zoster have been documented in patients with advanced AIDS (see 4-9). Because of the mechanism of acyclovir resist ance in VZV (mutations in the viral thymidine kinase gene), these infections are cross-resistant to ganciclovir, valacyc lovir, famciclovir, and penciclovir. They usually respond to foscamet, 40 mg intravenously every 8 hours; howe ver, the infections commonly recur aft er treatment has ended. Treatment of Varicella TOPICAL THERAPY In normal children, varicella is generally benign and self- limited. Cool compresses or calamine lotion locally, oral antihistamines, and tepid baths with baking soda or colloid al oatmeal (3 cups per tub of water) may relieve itching. Creams and lotions containing glucocorticoids and occlusive ointments should not be used. Antip yretics may be needed, but salicylates must be avoided because of their associa tion with Reye syndrome. Minor bacterial infections are treated with wann soaks. Bacterial cellulitis requires systemic antimicrobial therapy that is effective against S1a1,hvlococcus aurcus and group A -hemolytic streptococcus.

ANTI VIRAL THERAPY Normal Children. i-t-2) A large randomized, cont rolled trial of acyclovir treatment of healthy children 2 to 12 years of age found that early treatment (within 24 hours of the appearance of rash) with oral acyclovir (20 mg/kg four times a day for 5 days) modestly reduced the maximum number of lesions, the time to cessation of new lesion formation, and the duration of the rash, fever, and constitutional symptoms when comp ared with placebo.53 Treatment initia ted more than 24 hours after rash onset was not effective. Because varicella is a relatively benign infection in children and the clinical benefits of treatment arc modest, it does not require routine acyc lovir treatinent. However, many have favored its use when cost is not a conc ern, when it can be begun in time to benefit the patient (within 24 hours of rash onset), and when there is a perc eived need to speed resolution of the infection so that parents can comforta bly return to work. Because secondary cases among susceptible children in the household are generally more severe : C,

1894

Treatment of Herpes Zoster PATIENT GRouP Normal Neonate Child Adolescent, adult, or glucocorticoids used Pneumonia, pregnancy Immunocompromised Mild varicella or mild compromise Severe varicella or severe compromise Acyclovir resistant (advanced acquired immunodeliciency syndrome) than the index cases, and because early initiation of treatment is more readily accomplished in secondary cases, treatm ent with acyclovir seems reasonable for such secondary cases. ?1AdolasntsandAi*jits. A randomi zed, controlled trial of acyclovir treatm ent of healthy adolescents 13 to 18 years of age found that early treatment with oral acydovir (800 mg five times a day for 5 days) reduced the maximum number of lesions and time to cessation of new lesion formation compared with plac ebo?5 A randomized, placebo-controlled trial of oral acyclovir in healthy young adults with varicella showed that early treatment (within 24 hours of rash onset) with oral acyclovir (800 ing five times a day for 7 days) significantly reduced the time to crusting of lesions, the extent of disease, and duration of symptoms and fever.42 Thus, routine treatment of van- celia in adults seems reasonable. Although not tested, it is likely that Iamciclovir, 500 mg orally every 8 hours, or valacyclovir, 1000 nig orally every 8 hours, would be convenient and appropriate substitutes for acyclovir in normal adolescents and adults. Many physicians do not prescribe oral acyclovir in uncomplicated varicella during pregnancy because the risk to the fetus of treatment is unknown. Other physicians recommend oral acyclovir for infections in the third trimester when org anogenesis is complete, when there may be a heightened risk of varicella pneumon ia, and when infection can be spread to the newborn. Intravenous acyclovir is oft en considered for pregnant women with varicella who have extensive cutaneous andior systemic disease. Complications of Varicella In Norma! Pers ons. Uncontrolled trials in immunoc ompetent adults with varicella pneu

EGIMEN Acyclovir, 500 mg/rn q8h x 10 days Symptomatic treatment alone, or acyclovir, 20 mg/ kgPoqidx5days

Acydovir, 800 mg PC 5day x 7 days Acyclovir, 800 mg PC 5day x 7 days, or acyclov ir, 10 mg/kg IV q8h x 7 days Acydovir, 800 mg PC Sx/day x 710 days Acyclovir, 10 mg/kg IV q8h x 7 days or longer Foscarnet, 40 mg/kg IV q8h until healed monia suggest that early treatment (within 36 hours of hospitalization) with intravenous acyclovir (10 mg/kg every 8 hours) may reduce fever and tachypnea and improve oxygenation. Other serious complications of varicella in the immunocompetent host, such as encephalitis, meningoencephalitis, mye litis, and ocular complications, should be treated with intravenous acydovir. Immunocompromised Patients. Controlled trials in irnmunocornpromised patients with varicelia demonstrated that treatm ent with intravenous acyclovir dec reased the incidence of life-threatening visceral complications when treatment was initiated within 72 hours of rash ons et.7 Immune compromise, however, is a continuum ranging from minimal to sev ere. Intravenous acyclovir has been the standard of care for varicella in patients with substantial immunodeficiency. Alt hough oral therapy with famciclovir or valacyclovir might suffice for patients with mild degrees of immune impairm ent, there are no controlled clinical tria ls to guide the decision. Normal Age < 50 yr Age 50 yr. or with ophthalmic involvement lmmunocomixomnised Mild compromise, or human immunod eficiency virus Severe compromise Acyclovir resistant (advanced acquireJ immunodeficiency syndrome)

TOPICAL THERAPY During the acute phase of herpes zoster, the application of cool compresses, calamine lotion, corns tarch, or baking soda may help to allevia te local symptoms and hasten the drying of vesicular lesions. Ocdusive ointments should be avoided, and creams or lotions containing glucocormicoids should not be used. Bacterial superinfection of local les ions is uncommon and should be treated with warm soaks; bacterial cellulitis req uires systemic antibiotic therapy. Topical treatment of the herpes zoster rash with aritiviral agents is not effective. ANTIVIRAL THERAPY The major goals of therapy in patients with herpes zoster are to (1) limit the extent, duration, and severity of pain and rash in the primary derniarome; (2) prevent disease elsew here; and 3) prevent PHN. Norma!Patients. I lists the curr ent recommendations for treatment of herpes zoster. Randomized controlled trials indicate that oral acydovir (800 mg five times a day for 7 days), famciclovir (500 mg every 8 hours for 7 days), and valacydovir (1 g three times a day for 7 days) reduce time to rash healing, and the duration and severity of acute pain in older adults with herpes zoster who are treated within 72 hours of rash onset. Tn some studies, the duration of chronic pain was also reduced, but the U.S. Food and Drug Administration (FDA) has not approved these agents for the prevention of PHN.2859 Randomized controlled trials comparing acydovir with valacyc lovir, acyclovir with famciclovir, and valacyclovir with famciclovir demons trated equivalent results in rash healing, acute pain, and the duration of chronic painP2 AU three drugs are acceptable Symptomatic treatment only, or acyclovir, 800 mg/P0 5x/day x 7 days Acyclovir, 800 mg PD 5x/day x 7 days, or valacyclovir, g P0 q8h x 7 days, or farnciclovir, 500 mg P0 q8h x 7 days Acyclovir, 800 mg P0 5x/day x 710 days, or valacyc lovir or famciclovir Acyclovir, 10 mg/kg IV q8h x 710 days Foscarnet, 40 mg/kg IV q8h until healed TABLE 1942 Treatment of Vancella in the Normal and lmmunocompromised Patient

C-) I>= TABLE 194-3 Treatment of Herpes Zoster in the Normal lmmunocompromised Patient PATIENT GROUP REGIMEN

agents for older adults, with Cost and dosing schedule determining the choice of agent. However, the reduced sensitivi ty of VZV compared with HSV. and the higher and more reliable blood levels of antiviral activity achieved, make Iamcic lovir or valacyclovir preferable to acyc lovir for oral treatment of herpes zoster. Because of the lower risk of PHN, ant iviral therapy is less valuable or necess ary for treatment of uncomplicated herpes zoster in healthy people younger than 50 years of age. The use of antiviral agents is unproven if treatment is initia ted more than 72 hours after rash ons et. Nevertheless, we believe that it is prudent to initiate antiviral therapy even if more than 72 hours have elapsed after rash onset in patients who have ophthalmic zoster or who continue to have new vesicle formation.59 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 randomized, controiled trial to be effective in preventing ocular complicat ions of ophthalmic zoster. Fanicidovir and valacyclovir appear to have efficacy comparable to that of acydovir in the treatment of ophthalmic zosrer, and are preferred for the reasons cited above.6 Immunocompromised Patients. A randomi zed, double-blind, placebo-controlled trial in iminunocompromised patients with herpes zoster showed that intraven ous acyclovir (500 mg/rn2 every 8 hours for 7 days) halted progression of the dise ase, both in patients with localized herp es zoster and in patients with cutaneo us dissemination before treatment. Acyclovir accelerated the rate of cleara nce of virus from vesicles and markedly reduced the incidence of visceral and progressive cutaneous dissemination. Pain subsided faster in acyclovir recipie nts, and fewer reported PHN, but these differences were not statistically signific ant. Clinical trials comparing intraven ous acyclovir with intravenous vidarab ine for the treatment of herpes zoster in immunocompromised patients showed that acyclovir was significantly more eff ective and less toxic. In patients with mild irnmunocornpromise and loc alized herpes zoster, oral acydovir, valac yclovir, or famcidovir usually suf1 ices. A randomized, controlled trial of oral famciclovir versus oral acyclovir in patients with localized herpes zoster after bone marrow or organ transplantat ion or cancer chemotherapy showed that the two treatments were equivalent in rash healing and loss of acute pain and that both were well tolerated. ANTI-INFLAMMATORY THERAPY The poss ibility that PHN might be caused by inf lammation of the sensory ganglion and contiguous neural structures provided the rationale for the use of glucocorticoids during the acute phase of herpes zoster in an attempt to further reduce acute pain and prevent PHN. Randomized controlled trials, however, showed that the addition of glucocorricoids to acyclovir did not change the incidence of chronic pain.7 However, glucocorticoids did reduce acute pain in most trials, and in one trial of acyclovir and prednisone, the time to uninterrupted sleep, return to baseline daily activity, and cessation of analgesic therapy was reduced in patients who rec eived glucocorticoids. Consequently, some experts advocate oral glucocortic olds for otherwise healthy older adults whose rash is complicated by moderate to severe pain and who have no contraind icanons to glucocorticoids. Others bel ieve that the common adverse effects of glucocorticoids argue against their rout ine use in older patients with herpes zost er. The authors agree and do not recomm end the use of glucocorticoids in this setting. Glucocorticoids, in combination with effective antiviral therapy, may imp rove motor outcomes and acute pain in VZV-induced facial paralysis and cranial polyneuritis, where compression of aff ected nerves may contribute to disability. ANALGESICS Greater severity of acute pain is a risk factor for PHN, and acute pain may contribute

to central sensitizat ion and the genesis of chronic pain. Therefore, aggressive pain control is both reasonable and humane. The severity of acute herpes zoster pain should be determ ined using simple standardized pain scales. Clinicians should prescribe non- opiate or opiate analgesics with the goal of limiting the severity of pain to less than 3 or 4 on a 0 to 10 scale, and to a level that does not interfere with sleep. The choice, dosage, and schedule of drugs are gove rned by the patients pain severity, und erlying conditions, and response to spec ific drugs. If pain control remains inadequate, regional or local anesthetic nerve blocks should be con.sidered for acute pain control.7: Although carefully managed opiates, anticonvulsants, and tn- cyclic antidepressants (fCAs) have demo ristrated efficacy in established PHN, their effectiveness when administered during the acute phase of herpes zoster in reducing the incidence, duration, or severi ty of P1-IN is not known. This needs to be evaluated in rigorous clinical trials. A rand omized controlled trial demonstrated that a single epidural infection of corticos teroids and local anesthetics in the acute phase of herpes zoster did not prevent the subsequent development of PHN.71 Treatment of Postherpetic Neuralgia Once established, PHN is difficult to treat. Fortunately, it resolves spontaneo usly in most patients, although this often requires several months (see lL Clinicians have advocated a wide range of treatments, including many oral and topic al medications, epidural injection of local anesthetic and glucocorticoids, acupunct ure, biofeedback, subcutaneous inject ions of triarncinolone, trans-epidermal electric nerve stimulation, spinal cord stimulators, and systemic administration of a variety of compounds, but most have not been validated by controlled trials. However, the topical 5 percent lidocaine patch, gabapentin. pregabalin, opioids, and TCAs have been shown in randomi zed, controlled trials to be effective in pat ients with PHN. On average, these agents provide adequate pain relief (defined as reduction of pain to below 4 on a 0 to 10 point scale or by 50 percent on a visual ana log or I.ikert scale) in 30 percent to 60 percent of patients. These modalities are now recommended as first-line, evidence- based phannacotherapy for P1-IN in pract ice management guidelines.7273 II) PICAL THERAPY Topical anesthesia del ivered by means of a 5 percent lidocaine patch has been shown in controlled clinic al trials to produce significant pain relief in patients with PHN. The 10 cmx 14cm lidocaine patch contains 5 percent lidoc aine base, adhesive, and other ingredie nts on a polyester backing. It is easy to use and is not associated with systemic lidocaine toxicity.74 Up to three patches are applied over the affected area for 12 hours a day. The disadvantages of the patch are application site reactions, such as skin redness or rash, and substantial cost. EMLA (cute ctic rnbcture of local ane sthetics) cream applied once a day over the affected area under an occlusive dressing is an alternative method of del ivering topical anesthesia. Capsaicin (sraiis-8-methyl-N-vanillyl- 6-nonenamide), an extract of hot chili peppers, is a chemical known to deplete substance P, an important cndogenous neuropeptide that acts as a chemornedia tor of nociceptive impulses from the

C, ci =1 C) 1896

penpheiy to the CNS. A small clinical trial of topical capsaicin for 4 weeks in patients with PHN demonstrated signifi cant effects of this therapy on pain, with 75 percent of patients experiencing substantial pain relief75 Unfortunately, the ointment bums too much to be tole rated by many patients. In the authors experience, capsaicin is rarely effective in patients with PHN. ORAL AGENTS Gabapentin has been shown to produce moderate or greater pain relief in 41 percent to 43 percent of patients with PHN compared to 12 percent to 23 percent in patients receiving

placeho.7 Frequent adverse effects of gahapcntin in- dude somnolence, dizziness, and periphe ral edema. Pregabalin has been shown to produce 50 percent or greater pain relief in 50 percent of patients with PHN comp ared to 20 percent in placebo recipie nts7a Dizziness, somnolence, and per ipheral edema were the most common adverse effects reported with this medicat ion737 Pregabahn has a less complicated dose titration schedule and a faster onset of action than gabapentin. TCAs have been shown to produce moderate to good pain relief in 44 perc ent to 67 percent of elderly patients with PHN in several randomized, cont rolled trials.7273 Nortriptyline and des ipramine are preferred alternatives to amitriptyline because they cause fewer cardiac adverse effects, sedation, cognit ive impairment, orthostacic hypotens ion, and constipation in the elderly.3 Treatment with scheduled opioids may also reduce P1-LI. In a randomized, plac ebo-controlled crossover trial of sust ained-release oxycodone in patients with PHN, patients reported significant pain rel ief when treated with opioid compared to placebo.8 In a crossover study in patients with PHN, both controlled-release morp hine and TCAs provided significant pain relief compared to placebo. In this trial, patients preferred treatment with opioid analgesics to either TCAs or placebo des pite a greater incidence of adverse effects and more dmp-outs during opioid treatm ent. In a randomized controlled trial, combination therapy with morphine and gabapencm produced greater pain relief than each agent alone and placebo but with greater adverse effects. PREVENTION Prevention of Varicella VARICELLA VACCINE Several studies cond ucted in Europe, Japan, and the United States from the early 1970s through the early 1990s demonstrated that live attenu ated (Oka strain) VZV vaccines were immunogenic and efficacious in protecti ng susceptible children against varicella. Although breakthrough cases of vanc elIa were observed after subsequent exp osure to wild-type VZV, they were relat ively mild.i Similar results were obtained in adults when two doses were given 4 to 8 weeks apart. Vaccinated child ren and adults developed breakthrough varicella caused by wildtype VZV at a rate of 1 percent to 3 percent per year compared to an attack rate of 8 percent to 13 percent per year in unvaccinated children. On the basis of these data, the FDA licensed the Oka/Merck varicella vaccine in the United States in 1995. The Advisoiy Committee on Immuniz ation Practices ACIP) and the American Academy of Pediatrics recommend vanc elIa vaccine for 1) routine childhood imm unization, one dose at 12 to 18 months of age, (2) susceptible, immunocompet ent children older than 13 years of age, adolescents, and adults, using two doses, 4 to 8 weeks apart; (3) susceptible indiv iduals at high risk for exposure or transm ission, including susceptible health care workers, family of immunosuppressed individuals, teachers of children, day care workers, residents and staff in institut ional settings, nonpregnant women of childbearing age, and college students; (4) post-exposure prevention and outbreak control; and (5) day care and school ent ty. The A1P issued expanded recomm endations for varicella vaccine in 2005 to promote wider use for adolescents and adults, in HIV-infected children, and a seco nd dose for outbreak control. These reco mmendations are under review by the CDC and Department of Health and Human Services chttp://www.cdc.gov/ vaccines/vpd-vacivaricellaJdefaulLhtm). The immunity to varicella induced by varicella vaccine is not as solid as that ind uced by wild-type VZV infection, and the duration of vaccine-induced immun ity is not yet known. However, a high percentage of children followed long-term have remained seropositive86 Recent exp erience in clinical practice indicates that vaccine efficacy in children is modestly lower than that reported in clinical trials, and outbreaks of breakthrough varicella in schools and day care centers do occur.87 In a prospective, population-based study, vaccine effectiveness for prevention of all disease was 78.9 percent (95 percent conf idence interval; 69.7 percent to 85.3 perc ent); for prevention of moderate disease, it was 92 percent (50 to 500 lesions); and for prevention of severe disease and phys ician visits, it was 100 percent59 Interesti ngly, cases of breakthrough varicella in household settings were half as contag ious as cases of varicella in

unvaccinated persons, although the minority of breakt hrough cases with 50 lesions or more were as contagious as cases in unvaccin ated persons. In adults, approximately 20 percent of vaccinees lose detectable ant ibodies to VZV over time, but continue to be partially protectedbreakthrough varicella is characterized by mild disease rather than severe varicella.0 In 2006, the ACIP recommended rout ine administration of a second booster dose of the varicella vaccine to increase the proportion of the population prot ected and the duration of inununity.9 The second dose may be especially imp ortant because of the approval by the FDA in 2005 of a combined measles, mumps, rubella and vancella vaccine for routine immunization of children 12 months to 12 years of age. More than 15,000 adverse events aft er varicella vaccination were reported to the FDAs Vaccine Adverse Event Rep orting System and the CDC from March 1995 through December 2001, over 95 percent of which were non-serio us events, mainly minor rashes and inj ection site reactions.92 Serious adverse events were rare and, in the majority, a causal relationship between the rep orted serious adverse event and vanc elIa vaccine could not be established. Herpes zoster has been reported in vaccinees, but it occurred at a signific antly lower frequency than herpes zost er in persons of similar age following varicella caused by wild-type VZV. Cases of laboratory-confirmed herpes zoster in vaccinees from several studies included some cases caused by re-activ ation of the vaccine virus and others caused by re-activation of wild-type vir us acquired before vaccination as a consequence of unrecognized varicella, POST-EXPOSURE PROPIIYLAXIS AND INFECT ION CONTROL Patients with varicella and herpes zoster may transmit VZV to susceptible individuals. No preventive measures are recommended for a norm al child who has been exposed to vanc elIa or herpes zoster. On the other hand, it is desirable to prevent or modi fy varicella in high-risk immunocomp romised individuals. Passive immunization with VZIG was an effective preventive strategy hut the production of VZIG has been disc ontinued in the United States. An in-

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TABLE 194-4 Criteria for the Use of Investigational Varicella-Zoster Immune Globulin for the Prophylads of Varicella lmrnunocompromised patients. Neonates whose mothers have signs and symptoms of varicella around the time of delivery (i.e., 5 days before to 2 days after). Premature infants born at 28 wk of gest ation who are exposed (luring the neonatal period and whose mothers do not have evid ence of immunity. Premature infants born at < 28 wk of gest ation or who weigh 1000 g at birth and were exposed during the neonatal peod, regardless of maternal history ol varicella disease, x vaccination. Pregnant women. vestigational VZIG, VariZiG, is availa bLe under an investigational new drug application submitted to the FDA. The investigational VariZIG is a purified hum an immune globulin preparation made from plasma containing high leve ls of anti-varicella antibodies (immunog lobulin class G). This product can be requested for patients who have been exposed to varicella and who are at inc reased risk for severe disease and cornp licationsYa The patient groups recomm ended by AC1P to receive VariZIG are listed in Iab 1 4-4. Active immunization with the live att enuated varicella vaccine is also effective in preventing illness or modifying vancella severity in children if used within 3 days after exposure. \Vhereas protection aff orded by zoster immune globulin is tranc i sient, vancella vaccine induces long-lasti ng (active) immunity to VZV and protection against subsequent exposures. Chemoprophylaxis with acyclovir also has been studied in susceptible children after household exposure to varicella. Children who received post-exposure treatment with acyclovir experienced fewer and less severe cases of varicella than children in the control group.9 However, appropriate

timing is critical, but poorly defined immunity to varicella may not be achieved, especially with early post-exposure treatment, and there arc always fears that resistant strains will he selected by promiscuous application of this approach. Hence, post-exposure antiviral chemotherapy is not recomm ended for routine use in children. Infection control practices for VZV inc rease in importance with the age and compromised immune status of the exp osed, susceptible individual. There is no need to prevent exposure of suscep1 898 tible normal children to VZV, but careful isolation procedures should be enforced to prevent infection of susceptible irnr nunocompromised patients, newborn infants, and adults, particularly women of childbearing age. Exposure of suscept ible immunocompromised patients to VZV warrants reduction in the dosage of glucocorticoids and other immunos uppressive drugs, and administration of investigational VariZIG. Hospital and long-term care facility personnel witho ut a clear history of varicella or herpes zoster should be tested for antibody to VZV so that appropriate leave from work can he instituted after VZV expos ure. In hospitals, airborne and contact precautions are recommended until all lesions are crusted for patients with vari cella, immunocompromised patients with localized herpes zoster, and any patient with disseminated herpes zost er.96 Contact precautions are recomm ended for immunocompetent pat ients with localized herpes zoster. Prevention of Herpes Zoster: Zoster Vaccine Until universal varicella vaccination greatly reduces the number of people lat ently infected with wild-type VZV, prev ention of herpes zoster must be aimed at preventing re-activation and spread of the latent virus. Long-term suppress ive acyclovir treatment is only practic al in immunocompromised patients at proven risk of developing herpes zoster within a defined time period, for examp le, in the year after bone marrow or solid organ transplantation. Other strate gies must be devised for the general population. One approach to the prevention of herp es zoster is the stimulation of immunity toVZ which wanes in the elderly and in other high-risk individuals. Studies of healthy adults older than 55 years of age with a history of varicella have demons trated an increase in \ZV.specific T lymp hocytes and humoral immunity after vaccination with live attenuated WV vacc ine that is similar to the increase obs erved after an episode of herpes zosterY7 These findings suggest that vaccination of older persons may be useful in preventing herpes zosrer and its complications. A rec ent Veterans Affairs Cooperative Study tested the hypothesis that vaccination against VZV would decrease the incid ence andlor severity of herpes zoster and PHN among older adults.14 The study enr olled 38,546 adults 60 years of age or older in a randomized, double-blind, plac ebo-controlled trial of a live attenuated (OkalMerck) VZV vaccine of much greater potency than the currently lic ensed varicella vaccine. A total of 957 confirmed eases of herpes zoster (315 among vaccine recipients and 642 among plac ebo recipients) and 107 cases of P1-IN (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 herp es zoster by 61.1 percent (p < 0.001), red uced the incidence of PHN by 66.5 perc ent p < 0.001), and reduced the incidence of herpes zoster by 51.3 percent (p < 0.001). Reactions at the injection site were more frequent among vaccine recipi ents but were generally mild. This landm ark study showed that the zoster vacc ine markedly reduced morbidity from herpes zoster and PHN among older adults. The FDA licensed the zoster vacc ine for the prevention of herpes zoster in adults 60 years of age and older in 2006. With the development of the varicella and zoster vaccines, antiviral therapy, and neuropathic pain treatments, clinicians now have multiple effective tools to markedly reduce human suffering from varicella and herpes zoster. KEY REFERENCES The full reference list for all chapters is available at www.digm7.com. 5. Seward JF et al: Variella disease after introduction of varicdlla vaccine in the United States, 19952000.j.4AL4 287:6416, 2002 11. Hope-Simpson RE: The nature of herpes zoster: A long-tenn study and a new hypothesis. ProcRSocAkd58:9, 1965

14. Oxman MN et al: A vaccine to prevent herpes zoster and postherpetic neuralg n in older adults. N big! J Med 352:2271, 2005 21. Kalman CM, 1.askin CL: Herpes zoster and zosteriform herpes simplex infect ions in immunocompetent adults. Am] Mcd 81:775, 1936 23. Cohen JI, Straus SE: Varicella-zoster virus and its replication, in Fields Vir,logy, edited by Knipe DM ct al. Philadelphia, lippinc ott -Williams & Williams, 2001, p 2707 28. Kost RG, Straus SE: Postherpetic neuralg ia: Pathogenesis, treatment, and prev ention. NEt.glJMed 335:32, 1996 54. Klassen TP et al: Acyclovir for treating varicella in otherwise healthy children and adolescents. C.,ditane Dazabasc of SVsFmaIi Rev,ce 4:CD002980, 2005 59. Gnann JW Jr, Whitley RJ: Herpes zoster. N big!] Mcd 347340, 2002 71. van Wijck AJ ct al: The PINE study of epidural steroids and local anaesthencs to prevent postherpetic neuralgia: A randorniscd controlled trial. Laucci 367:2 19, 2006 72. Dubinsky KM et al. Practice parameter: Treatment of postherpetic neuralgia. \euro!oy 63:959, 2004 C,