Varicella and Herpes Zoster EPIDEMIOLOGY Epidemiology of Varicella Varicella is distributed worldwide, but its age-specific incidence differs

s in temperate versus tropical climates and in populations that have received varicella vaccine. In temperate climates in the absence of varicella vaccination, varicella is endemic, with a regularly recurring seasonal prevalence in winter and spring, and periodic epidemics that depend on the accumulation 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 15.1 From 1988 to 1995, there were approximately 11,000 hospitalizations and 100 deaths caused by varicella each year in the United States.2 The risk of hospitalization and death was much higher in infants and adults than in children, and most varicella-related deaths occurred in previously healthy people.3 In tropical and semi-tropical countries, the mean age of varicella is higher and susceptibility among adults to primary varicella-zoster virus (VZV) infection is significantly greater than in temperate climates. High levels of susceptibility to varicella among adult immigrants from tropical climates are well documented in the U.S. military, where up to 40 percent of recruits from Puerto Rico and the Philippines have been seronegative. This is important for hospitals, where susceptible health care workers may pose a significant 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 children increased from 0 percent in 1995, when varicella vaccine was licensed, to 88 percent in 2004.4 This has resulted in a marked decline in varicella cases and varicella-related hospitalizations. From 1995 through 2000, varicella cases reported to the Centers for Disease Control and Prevention (CDC) declined by 71 percent to 84 percent, depending on surveillance area, and by 2002 the incidence of varicella had decreased from 2.63 to 0.92 cases/1000 person years.5,6 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 decline in varicella-related hospitalization rates was greatest among 0- to 4-year-old children, but rates also declined among youths aged 5 to 19 years and adults.7 Varicella is highly contagious. Attack rates of 87 percent among susceptible siblings 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 exanthem may be so sparse and transient as to pass unnoticed. A typical patient is infectious 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 vesicles has crusted. The immunocompromised patient, who may experience many successive crops of lesions for 1 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 to 23 days. It is often prolonged in patients who develop varicella after passive immunization with varicella-zoster immune globulin (VZIG) or zoster immune plasma, or active post-exposure immunization with live attenuated Oka strain varicella vaccine.8 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 infectiousness of patients with varicella 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, it can be detected in the oropharynx of the majority of patients using polymerase chain reaction-based assays.9 Natural varicella (i.e., varicella caused by wild-type VZV) generally confers lifelong immunity to the disease. Reexposure to the virus boosts humeral 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 Epidemiology of Herpes Zoster). With severe immunocompromise, 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 antibody or have been immunized with live attenuated varicella vaccine) may respond to exogenous exposure by developing a second, usually mild, episode of breakthrough varicella. Epidemiology of Herpes Zoster Herpes zoster occurs sporadically throughout the year without seasonal prevalence. The occurrence of herpes zoster is independent of the prevalence of varicella, and there is no convincing evidence that herpes zoster can be acquired by contact with other persons with varicella or herpes zoster. Rather, the incidence of herpes zoster is determined by factors that influence the host-virus relationship. One strong risk factor is older age (Fig. 194-1A). The incidence of herpes zoster is 1.5 to 3.0 per 1000 person years in all ages and 7 to 11 per 1000 per year in persons over 60 years of age in European and North American studies.10, 11, 12, 13, 14, 15, 16, 17 It is estimated that there are more than a million new cases of herpes zoster in the United States each year, more than one-half of which occur in persons 60 years of age or older, and this number increase as the population ages.11,14 VARICELLA AND HERPES ZOSTER AT A GLANCE

Varicella (chickenpox) and herpes zoster (shingles) are distinct clinical entities caused by the varicella-zoster virus. Varicella, an acute, highly contagious exanthem that occurs most often in childhood, 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 clustered, and progress from rose-colored macules to papules, vesicles, pustules, and crusts. In varicella, lesions in all stages are usually present on the body at the same time. In normal children, serious complications are rare. In adults and in immunologically compromised persons, varicella is more likely to be associated with life-threatening complications. Where use of varicella vaccine in susceptible children and adults is widespread, the incidence of varicella is markedly reduced. Herpes zoster is characterized by unilateral, dermatomal pain and rash as the result of the reactivation of endogenous varicella-zoster virus that had persisted in latent form within sensory ganglia after an earlier attack of varicella. The erythematous, 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 and immunosuppressed individuals. Pain is the most important clinical manifestation 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 tricyclic antidepressants reduce postherpetic neuralgia. The zoster vaccine reduces the incidence of herpes zoster by one-half and the incidence of postherpetic neuralgia by two-thirds.

Another major risk factor is cellular immune dysfunction. Immunosuppressed patients have a 20 to 100 times greater risk of herpes zoster than immunocompetent individuals of the same age. Immunosuppressive conditions associated with high risk of herpes zoster include human immunodeficiency virus (HIV) infection, bone marrow transplant, leukemia and lymphoma, use of cancer chemotherapy, and use of corticosteroids. Herpes zoster is a prominent and early

opportunistic infection in persons infected with HIV, in whom it is often the first sign of immune deficiency. Thus, HIV infection should be considered in individuals who develop herpes zoster. Other factors reported to increase the risk of herpes zoster include female sex,17 physical trauma in the affected dermatome,18 interleukin 10 gene polymorphisms,19 and black race,16,17 but confirmation is required. Exposure to children and contact with cases of varicella have been reported to confer protection against herpes zoster.17,20 Second episodes of herpes zoster are uncommon in immunocompetent persons, and third attacks are very rare. Persons suffering more than one episode may be immunocompromised. Immunocompetent patients suffering multiple episodes of herpes zoster-like disease are likely to be suffering from recurrent zosteriform herpes simplex virus (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.11 Virus can be isolated from vesicles 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 precautions, are required for such patients. The effect of the marked reduction in the incidence of varicella, due to widespread varicella vaccination of children, on the epidemiology of herpes zoster is unclear. In the long term, the incidence of herpes zoster is likely to decline as the cohorts of children now receiving the 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 zoster 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 reducing 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 vaccination have shown little or no increase in the incidence of herpes zoster.6,12,22 ETIOLOGY AND PATHOGENESIS VZV is a member of the herpesvirus family.23 Other members pathogenic for humans include HSV-1 and HSV-2; cytomegalovirus; Epstein-Barr virus; human herpesvirus-6 (HHV-6) and HHV-7, which cause roseola; and Kaposi sarcoma-associated herpesvirus, also called HHV-8. All herpesviruses are morphologically indistinguishable and share a number of properties, including the capacity to establish latent infections that persist for life. The VZV genome encodes approximately 70 unique genes, most of which have DNA sequence and functional homology to genes of the other herpesviruses. Immediate early gene products regulate VZV replication. Early gene products, such as the virus-specific thymidine kinase and the viral DNA polymerase, support viral replication. Late genes encode virus structural proteins that serve as targets of antibody and cellular immune responses. There is only one VZV serotype. Although viruses isolated from individual cases of varicella or herpes zoster worldwide are basically similar, minor variations in their nucleotide sequences allow one to distinguish wild-type from vaccine virus strains, and to fingerprint viruses isolated from individual patients. Pathogenesis of Varicella Entry of VZV is through the mucosa of the upper respiratory tract and oropharynx. 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 reticuloendothelial system, the major site of virus replication during the remainder of the incubation period.

The incubating infection is partially contained by innate host defenses (e.g., interferon, natural killer cells) and by developing VZV-specific immune responses. In most individuals, virus replication eventually overwhelms these developing host defenses, so that approximately 2 weeks after infection, a much larger (secondary) viremia and associated symptoms and lesions occur. Skin lesions appear in successive crops, reflecting a cyclic viremia, which in the normal host is terminated after approximately 3 days by VZV-specific humeral and cellular immune responses. Virus circulates in mononuclear leukocytes, primarily lymphocytes. Even in uncomplicated varicella, the secondary viremia results in the sub-clinical infection of many organs in addition to the skin. Effective host immune responses terminate viremia and limit the progression of varicella lesions in the skin and other organs. Humeral immunity to VZV protects against varicella. People with detectable serum antibody do not usually become 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 from lesions in the skin and mucosal surfaces into the contiguous endings of sensory nerves and is transported centripetally up the sensory fibers to the sensory ganglia. 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 densitythose innervated by the first (ophthalmic) division of the trigeminal nerve and by spinal sensory ganglia from T1 to L2 (Fig. 194-2). P.1888

Although the latent virus in the ganglia retains its potential for full infectivity, re-activation is sporadic and infrequent, 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 immunosuppression; emotional stress; irradiation of the spinal column; tumor involvement of the cord, dorsal root ganglion, or adjacent structures; local trauma; surgical manipulation of the spine; and frontal sinusitis (as a precipitant of ophthalmic zoster). Most important, though, is the decline in VZV-specific cellular immunity that occurs with increasing age.25 VZV may also re-activate without producing overt disease. The small quantity of viral antigens released during 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 virus can no longer be contained.11 Virus multiplies and spreads within the ganglion, causing neuronal necrosis and intense inflammation, a process that is often accompanied by severe neuralgia.27 Infectious VZV then spreads antidromically down the sensory nerve, causing intense neuritis, and is released from the sensory nerve endings in the skin, where it produces the characteristic cluster of zoster vesicles. Spread of the ganglionic infection proximally along the posterior nerve root to the meninges and cord results in local leptomeningitis, cerebrospinal fluid pleocytosis, 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 accompany the cutaneous eruption, and extension of infection within the central nervous system (CNS) may result in rare complications of herpes zoster (e.g., meningoencephalitis, transverse myelitis). Pathogenesis of Pain in Herpes Zoster and Postherpetic Neuralgia Pain is a major symptom of herpes zoster. It often precedes and generally accompanies the rash, and it frequently persists after the rash has healeda complication known as postherpetic neuralgia (PHN). A number of different but overlapping mechanisms appear to be involved in the pathogenesis of pain in herpes zoster and PHN (Fig. 194-3).28,29 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 interneurons 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 primary afferent nerves may become spontaneously active and hypersensitive to peripheral stimuli, and also to sympathetic stimulation. Excessive nociceptor activity and ectopic impulse generation may, in turn, sensitize CNS neurons, augmenting and prolonging central responses to innocuous as well as noxious stimuli. Clinically, these mechanisms result 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 established early in the course of herpes zoster. This would explain the correlation of initial pain severity and the presence of prodromal pain with the subsequent development of PHN, and the failure of antiviral therapy to fully prevent PHN (see Treatment). CLINICAL FINDINGS Clinical Findings of Varicella PRODROME OF VARICELLA In young children, prodromal symptoms are uncommon. 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 VARICELLA In unvaccinated persons, the rash begins on the face and scalp and spreads rapidly to the trunk, with relative sparing of the extremities (Fig. 194-4). New lesions appear in successive crops, but their distribution remains central. The rash tends to be denser in the small of the back and between the shoulder blades than on the scapulae and buttocks and more profuse on the medial than on the lateral aspects of the limbs. It 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 inflammation, such as diaper rash or sunburn. A striking feature of varicella lesions is their rapid progression, over as little as 12 hours, from rose-colored macules to papules, vesicles, pustules, and crusts (see Fig. 194-4). The typical vesicle of varicella 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 irregular area of erythema, which gives the lesions the appearance of a dewdrop on a rose petal. The vesicular fluid soon becomes cloudy with the influx of inflammatory cells, which convert the vesicle to a pustule (see Fig. 194-4). The lesion then dries, beginning in the center, first producing an umbilicated pustule and then a crust. Crusts fall off spontaneously in 1 to 3 weeks, leaving shallow pink depressions that gradually disappear. Scarring is rare unless the lesions were traumatized by the patient or superinfected with bacteria. Healing lesions may leave hypopigmented spots that persist for weeks to months. Vesicles also develop in the mucous membranes of the mouth, nose, pharynx, larynx, trachea, gastrointestinal tract, urinary tract, and vagina. These mucosal vesicles rupture so rapidly that the vesicular stage may be missed. Instead, 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 development. Careful prospective studies have shown that the average number of lesions in healthy children ranges from 250 to 500; secondary cases resulting from household exposure are more severe 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 (105F) in severe cases with extensive rash. Prolonged fever or recurrence of fever after defervescence

may signify a secondary bacterial infection or another complication. The most distressing symptom is pruritus, which is usually present throughout the vesicular stage. The varicella vaccine alters the natural history of the rash. A small percentage of vaccinees develop breakthrough varicella after exposure to people with active VZV infections. The usual breakthrough rash is predominately maculopapular 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.30 Clinical Findings of Herpes Zoster PRODROME OF HERPES ZOSTER Pain and paresthesia in the involved dermatome often precede the eruption by several days and vary from superficial itching, tingling, or burning to severe, deep, boring, or lancinating pain. The pain may be constant or intermittent, and it is often accompanied by tenderness and hyperesthesia 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, appendicitis, prolapsed intervertebral disk, or early glaucoma, and this may lead to serious misdiagnosis and misdirected interventions. Prodromal pain is uncommon in immunocompetent persons younger than 30 years of age, but it occurs in the majority of persons with herpes zoster over the age of 60 years. A few patients experience acute segmental neuralgia without ever developing a cutaneous eruptiona condition known as zoster sine herpete. RASH OF HERPES ZOSTER The most distinctive feature of herpes zoster is the localization and distribution of the rash, which is nearly always unilateral and is generally limited to the area of skin innervated by a single sensory ganglion (Fig. 194-5). The area supplied by the trigeminal nerve, particularly the ophthalmic division, 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.11,15 Although the individual lesions of herpes zoster and varicella are indistinguishable, those of herpes zoster tend to evolve more slowly and usually consist of closely grouped vesicles on an erythematous 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 erythematous 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. Vesicles form within 12 to 24 hours and evolve into pustules by the third day. These dry and crust in 7 to 10 days. The crusts generally persist for 2 to 3 weeks (see Fig. 194-5B). In normal individuals, 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 trigeminal nerve (see Fig. 194-5C).31 The rash of ophthalmic zoster may extend from the level of the eye to the vertex of the skull, but it terminates sharply at the midline of the forehead. When only the supratrochlear and supraorbital branches are involved, the eye is usually spared. Involvement 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 structures. Thus, when ophthalmic zoster involves the tip 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. Corneal sensation is generally impaired and when impairment is severe, it may lead to neurotrophic keratitis and chronic ulceration. Herpes zoster affecting the second and third divisions of the trigeminal nerve (Fig. 194-6) as well as other cranial nerves may produce symptoms and lesions in the mouth, ears, pharynx, or larynx. The so-called Ramsay Hunt syndrome (facial palsy, in combination with herpes zoster of

the external ear or tympanic membrane, with or without tinnitus, vertigo, and deafness), results from involvement of the facial and auditory nerves. PAIN OF HERPES ZOSTER Although the rash is important, pain is the cardinal problem posed by herpes zoster, especially in the elderly. Most patients experience dermatomal pain or discomfort during the acute phase (30 days from rash onset) that ranges from mild to severe. Patients describe 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 horrible or excruciating are used to describe the experience. Acute herpes zoster pain is associated with decreased physical functioning, emotional distress, and decreased social functioning.32 HERPES ZOSTER IN THE IMMUNOCOMPROMISED HOST Except for PHN, most serious complications of herpes zoster occur in immunocompromised persons. These complications include necrosis of skin and scarring (Fig. 194-7) and cutaneous dissemination with an incidence as high as 25 percent to 50 percent. Approximately 10 percent of patients with cutaneous dissemination also manifest widespread (Fig. 194-8), often fatal, visceral dissemination, particularly to the lungs, liver, and brain.33 HIV-infected patients are fairly unique in their tendency to suffer multiple recurrences of herpes zoster as their HIV infection progresses; herpes zoster may recur in the same or different dermatomes or in several contiguous or non-contiguous dermatomes. Herpes zoster in patients with acquired immunodeficiency syndrome (AIDS) may be severe, with cutaneous and visceral dissemination. Patients with AIDS may also develop chronic verrucous, hyperkeratotic (Fig. 194-9), or ecthymatous cutaneous lesions caused by acyclovir-resistant VZV. DIAGNOSIS OF VARICELLA Varicella can usually be diagnosed readily on the basis of the appearance and evolution of its characteristic rash (see Fig. 194-4), particularly when there is a history of exposure within the preceding 2 to 3 weeks. 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 not infrequent in profoundly immunosuppressed, seropositive persons (see Fig. 194-7). Disseminated HSV infections may resemble 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 Box 194-1. The character, distribution, and evolution of the lesions, together with a careful epidemiologic history, usually differentiate these diseases from varicella. When any doubt exists, the clinical impression should receive laboratory confirmation. Box 194-1 Differential Diagnosis VARICELLA HERPES ZOSTER Most Likely Most Likely Vesicular exanthems of coxsackie viruses and Zosteriform herpes simplex echoviruses Contact dermatitis Impetigo Insect bites Insect bites Burns Contact dermatitis Consider Papular urticaria Erythema multiforme Drug eruptions Consider Scabies Papular urticaria Erythema multiforme Drug eruptions Always Rule Out

 Disseminated herpes simplex Scabies

Always Rule Out Secondary syphilis Disseminated herpes zoster Dermatitis herpetiformis Smallpox and other poxviruses DIAGNOSIS OF HERPES ZOSTER In the pre-eruptive stage, the prodromal pain of herpes zoster is often confused with other causes of localized pain. Once the eruption appears, the character and dermatomal location of the rash, coupled with dermatomal pain or discomfort, usually makes the diagnosis obvious (see Figs. 194-5 and 194-6). A cluster of vesicles, particularly near the mouth or genitals, may represent herpes zoster, but it may also be a recurrent HSV infection.12 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 but does not occur in herpes zoster in the absence of profound and clinically obvious immune deficiency. Box 194-1 lists other considerations in the differential diagnosis of herpes zoster. LABORATORY TESTS The lesions of varicella and herpes zoster are indistinguishable by histopathology (Fig. 194-10). The presence of multinucleated giant cells and epithelial cells containing acidophilic intranuclear inclusion bodies (see Fig. 194-10B) distinguishes the cutaneous lesions produced by VZV from all other vesicular eruptions (e.g., those caused by variola and other poxviruses, and by coxsackie viruses and echoviruses) except those produced by HSV (see Fig. 193-9 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 hematoxylin-eosin, Giemsa, Papanicolaou, or Paragon 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 lesions produced by acyclovir-resistant VZV in patients with AIDS (see Fig. 194-9). The definitive diagnosis of VZV infection, as well as the differentiation of VZV from HSV, is accomplished by the isolation of virus in cell cultures inoculated with vesicle fluid, blood, cerebrospinal 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 analysis, such as determination of its sensitivity 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 virus recovery, specimens should be inoculated into cell culture immediately. It is important to select new vesicles containing clear 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 cytopathic effects induced by the replicating virus in such cell cultures are characterized by the formation of acidophilic intranuclear inclusion bodies and multinucleated 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 remaining cells in the culture, the cytopathic effect of VZV remains focal. Cytopathic effects of VZV are generally not apparent until several days after specimen inoculation. Modifications of the cell culture assay in which vesicle fluid or lesion scrapings are centrifuged onto cells growing on coverslips at the bottom of thin glasswalled shell vials followed 24 to 72 hours later by fixation and staining with fluorescein- or enzyme-labeled monoclonal antibodies

Bullous pemphigoid Pemphigus vulgaris Dermatitis herpetiformis Epidermolysis bullosa herpetiformis

to VZV proteins, can confirm the presence of VZV relatively quickly, well before cytopathic effects are evident in conventional cell cultures.34 Immunofluorescent or immunoperoxidase 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.34 Enzyme immunoassays provide another rapid and sensitive method for antigen detection. Detection of VZV DNA in clinical specimens after amplifications by polymerase chain reaction provides the greatest assay sensitivity, very high specificity, and rapid turn-around time. It has revolutionized the diagnosis of VZV infections.34,35 Serologic tests permit the retrospective diagnosis of varicella and herpes zoster when acute and convalescent sera are available for comparison.34 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. This assay, however, often lacks sensitivity and specificity and does not detect antibody in people who are immune, and sometimes yield false-positive results in susceptible individuals. Several more sensitive techniques have been developed to measure humoral responses to VZV. These include an immunofluorescence assay for antibody to VZV-induced membrane antigens (fluorescent antibody to membrane antigen) that reliably distinguishes 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 COMPLICATIONS Complications of Varicella In the normal child, varicella is 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.37 These local infections often lead to scarring and, rarely, to septicemia with metastatic infection of other organs. Bullous lesions may develop when vesicles are superinfected by staphylococci that produce exfoliative toxins. Invasive group A streptococcal infections are particularly virulent. In the absence of varicella vaccination, up to one-third of invasive group A streptococcal infections are associated with varicella; they usually occur within 2 weeks of the onset of the varicella rash.38 Widespread varicella vaccination appears to have markedly reduced the percentage of invasive group A streptococcal hospitalizations associated with varicella in the United States.39 Secondary bacterial pneumonia, otitis media, and suppurative meningitis are rare complications and typically respond to appropriate antibiotic therapy. However, bacterial superinfection is common and potentially life-threatening in leukopenic patients. Other complications reflect a basic defect in the capacity of the host to limit VZV replication and dissemination.40 In adults, fever and constitutional symptoms are more prominent and prolonged, the rash of varicella is more profuse, and complications are more frequent.40 High rates of complications have been reported in adults not born in the United States (i.e., adults born in Mexico).41 Primary varicella pneumonia is the major complication of adult varicella. Some patients are virtually asymptomatic, but others develop severe respiratory embarrassment, with cough, dyspnea, tachypnea, high fever, pleuritic chest pain, cyanosis, and hemoptysis 1 to 6 days after onset of the rash. The severity 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 perihilar regions and at the bases. The mortality in adults with frank varicella pneumonia has been estimated to be between 10 percent and 30 percent, but it is less than 10 percent if immunocompromised patients are excluded.42 TABLE 194-1 Complications of Herpes Zoster CUTANEOUS VISCERAL NEUROLOGIC Bacterial Pneumonitis Postherpetic neuralgia superinfection Hepatitis Meningoencephalitis

Scarring Zoster gangrenosum Cutaneous dissemination

Esophagitis Gastritis Pericarditis Cystitis Arthritis

Transverse myelitis Peripheral nerve palsies Motor Autonomic Cranial nerve palsies Sensory loss Deafness Ocular complications Granulomatous angiitis (causing contralateral hemiparesis)

Varicella during pregnancy is a threat to both mother and fetus.43 Disseminated infection and varicella pneumonia may result in maternal death, but neither the incidence nor the severity of varicella pneumonia appear to be significantly increased by pregnancy. The fetus may die as a consequence of premature labor or maternal death caused by severe varicella pneumonia, but varicella during pregnancy does not, otherwise, substantially increase fetal mortality. Nevertheless, even in uncomplicated varicella, maternal viremia can result in intrauterine (congenital) VZV infection, and a characteristic constellation of congenital abnormalities.43 Perinatal varicella (i.e., varicella occurring within 10 days of birth) is more serious than varicella in infants infected even a few weeks later. The morbidity and mortality of varicella are markedly increased in immunocompromised patients. In these patients, continued virus replication and dissemination result in a prolonged high-level viremia, a more extensive rash, a longer period of new vesicle formation, and clinically significant visceral dissemination. Immunosuppressed and glucocorticoidtreated patients may develop pneumonia, hepatitis, encephalitis, and hemorrhagic complications of varicella, which range in severity from mild febrile purpura to severe and often fatal purpura fulminans and malignant varicella. CNS complications of varicella occur in fewer than 1 in 1000 cases; they include several distinct syndromes. Varicella-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 Reye syndrome occurred in association with varicella, particularly when aspirin was administered for fever, with mortality as high as 40 percent.44 Acute cerebellar ataxia is more common than the other neurologic complications of varicella, occurring in 1 in 4000 cases, and is more benign.45 Encephalitis is much less common, occurring in 1 in 33,000 cases, but it frequently causes death or permanent neurologic sequelae. The pathogenesis of cerebellar ataxia and encephalitis remains obscure, but in many cases it is possible to detect VZV antigens, VZV antibodies, and VZV DNA in the cerebrospinal 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 progressive varicella. Other rare complications of varicella include myocarditis, glomerulonephritis, orchitis, pancreatitis, gastritis and ulcerative lesions of the bowel, arthritis, Henoch-Schnlein vasculitis, optic neuritis, keratitis, and iritis. The pathogenesis of many of these complications has not been delineated, but direct parenchymal or endovascular VZV infection, or vasculitis induced by VZV antigen-antibody complexes, appear to be responsible in most cases. Complications of Herpes Zoster (Table 194-1) The sequelae of herpes zoster include cutaneous, 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 after the initial dermatomal eruption has become apparent. When immunocompetent patients are carefully examined, it is not uncommon to have at least a few vesicles in areas distant from the involved and immediately adjacent dermatomes. The

disseminated lesions usually appear within a week of the onset of the segmental eruption and, if few in number, are easily overlooked. More extensive dissemination (with 25 to 50 lesions or more), producing a varicella-like eruption (generalized herpes zoster; see Fig. 194-7), occurs in 2 percent to 10 percent of unselected patients with localized zoster, most of whom have immunologic defects as a result of acquired immunodeficiency, as seen with HIV infection, underlying malignancy (particularly lymphomas), or immunosuppressive therapy. 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 particularly extensive, as it often is in severely immunocompromised patients, there may be superficial gangrene with delayed healing and subsequent scarring (see Fig. 194-7B). Secondary bacterial infection may also delay healing and cause scarring. The eye is involved in 20 percent to 70 percent of patients with ophthalmic zoster, with a wide range of possible complications.31 VZV is also the principle cause of acute retinal necrosis, a fulminant sight-threatening disease observed primarily in otherwise healthy individuals.46 Herpes zoster may be attended by a variety of neurologic complications (see Table 194-1), of which PHN is the most common and important.47 PHN has been variably defined as any pain after rash healing or any pain 1 month, 3 months, 4 months, or 6 months after rash onset, with most recent definitions focusing on 90 to 120 days after rash onset.48,49 In clinic and community studies, the overall incidence of PHN is 8 percent to 15 percent, depending on the definition (see Fig. 194-1).28,50,51 Age is the most significant risk factor for PHN (see Fig. 194-1). 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.14 Other risk factors for PHN include the presence of prodromal pain, severe pain during the acute phase of herpes zoster, greater rash severity, more extensive sensory abnormalities in the affected dermatome and, possibly, ophthalmic (as opposed to thoracic or abdominal) herpes zoster.52 Increasing age, greater acute pain severity, presence of prodromal pain, and greater rash severity have each been reported to be independent predictors of PHN.49 The positive predictive value of each factor alone was low, but, together, the positive predictive value was almost 50 percent. Conversely, 90 percent to 95 percent of patients with herpes zoster who had none of these risk factors developed PHN. PHN usually remits spontaneously over several months but, as with PHN itself, the risk of long-lasting PHN also increases with increasing age. Patients with PHN may suffer from constant pain (described as burning, aching, throbbing), intermittent pain (stabbing, shooting), and/or stimulus-evoked pain, including allodynia (tender, burning, stabbing). Allodynia (pain elicited by stimuli that are normally not painful) is a particularly disabling component of the disease that is present in approximately 90 percent of patients with PHN. Patients with allodynia may suffer severe pain after even the lightest touch of the affected skin by things as trivial as a breeze or a piece of clothing. These sub-types of pain may produce disordered sleep, depression, anorexia, weight loss, chronic fatigue, and social isolation, and they often interfere with dressing, bathing, general activity, traveling, shopping, cooking, and housework. TREATMENT Antiviral Agents The nucleoside analogues acyclovir, famciclovir, valacyclovir, and brivudin and the pyrophosphate analog foscarnet show efficacy in treating VZV infections. Acyclovir is a guanosine analog that is selectively phosphorylated by VZV thymidine kinases (it is a poor substrate for cellular thymidine kinase) and thus is concentrated in infected cells. Cellular enzymes then convert acyclovir monophosphate to acyclovir triphosphate, which interferes with viral DNA synthesis by inhibiting viral DNA polymerase. VZV is approximately 10-fold less sensitive to acyclovir than HSV (see Chap. 232).

Two prodrugs, valacyclovir and famciclovir, are better and more reliably absorbed than acyclovir after oral administration. Thus, they produce much higher blood levels of antiviral activity and permit less frequent dosing than acyclovir. Because of their superior pharmacokinetics and the lower sensitivity of VZV compared with HSV, famciclovir, or valacyclovir are preferred to acyclovir for oral therapy of VZV infections. Acyclovir-resistant varicella and herpes zoster have been documented in patients with advanced AIDS (see Fig. 194-9). Because of the mechanism of acyclovir resistance in VZV (mutations in the viral thymidine kinase gene), these infections are cross-resistant to ganciclovir, valacyclovir, famciclovir, and penciclovir. They usually respond to foscarnet, 40 mg intravenously every 8 hours; however, the infections commonly recur after 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 colloidal oatmeal (3 cups per tub of water) may relieve itching. Creams and lotions containing glucocorticoids and occlusive ointments should not be used. Antipyretics may be needed, but salicylates must be avoided because of their association with Reye syndrome.44 Minor bacterial infections are treated with warm soaks. Bacterial cellulitis requires systemic antimicrobial therapy that is effective against Staphylococcus aureus and group A -hemolytic streptococcus. ANTIVIRAL THERAPY Normal Children. (Table 194-2) A large randomized, controlled 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 compared with placebo.53 Treatment initiated 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 are modest, it does not require routine acyclovir treatment.54 However, many have favored its use when cost is not a concern, when it can be begun in time to benefit the patient (within 24 hours of rash onset), and when there is a perceived need to speed resolution of the infection so that parents can comfortably return to work. Because secondary cases among susceptible children in the household are generally more severe than the index cases, and because early initiation of treatment is more readily accomplished in secondary cases, treatment with acyclovir seems reasonable for such secondary cases. TABLE 194-2 Treatment of Varicella in the Normal and Immunocompromised Patient PATIENT GROUP REGIMEN Normal Neonate Acyclovir, 500 mg/m2 q8h 10 days Child Symptomatic treatment alone, or acyclovir, 20 mg/kg PO qid 5 days Adolescent, adult, or glucocorticoids used Acyclovir, 800 mg PO 5/day 7 days Pneumonia, pregnancy Acyclovir, 800 mg PO 5/day 7 days, or acyclovir, 10 mg/kg IV q8h 7 days Immunocompromised Mild varicella or mild compromise Acyclovir, 800 mg PO 5/day 7-10 days Severe varicella or severe compromise Acyclovir, 10 mg/kg IV q8h 7 days or longer Acyclovir resistant (advanced acquired Foscarnet, 40 mg/kg IV q8h until healed immunodeficiency syndrome) Normal Adolescents and Adults. A randomized, controlled trial of acyclovir treatment of healthy adolescents 13 to 18 years of age found that early treatment with oral acyclovir (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

placebo.55 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 mg 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 varicella in adults seems reasonable. Although not tested, it is likely that famciclovir, 500 mg orally every 8 hours, or valacyclovir, 1000 mg 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 organogenesis is complete, when there may be a heightened risk of varicella pneumonia, and when infection can be spread to the newborn. Intravenous acyclovir is often considered for pregnant women with varicella who have extensive cutaneous and/or systemic disease. Complications of Varicella in Normal Persons. Uncontrolled trials in immunocompetent adults with varicella pneumonia 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.56 Other serious complications of varicella in the immunocompetent host, such as encephalitis, meningoencephalitis, myelitis, and ocular complications, should be treated with intravenous acyclovir. Immunocompromised Patients. Controlled trials in immunocompromised patients with varicella demonstrated that treatment with intravenous acyclovir decreased the incidence of life-threatening visceral complications when treatment was initiated within 72 hours of rash onset.57 Immune compromise, however, is a continuum ranging from minimal to severe. Intravenous acyclovir has been the standard of care for varicella in patients with substantial immunodeficiency. Although oral therapy with famciclovir or valacyclovir might suffice for patients with mild degrees of immune impairment, there are no controlled clinical trials to guide the decision. TABLE 194-3 Treatment of Herpes Zoster in the Normal Immunocompromised Patient PATIENT GROUP REGIMEN Normal Age < 50 yr Symptomatic treatment only, or acyclovir, 800 mg/PO 5/day 7 days Age 50 yr, or with ophthalmic Acyclovir, 800 mg PO 5/day 7 days, or involvement valacyclovir, 1 g PO q8h 7 days, or famciclovir, 500 mg PO q8h 7 days Immunocompromised Mild compromise, or human Acyclovir, 800 mg PO 5/day 7-10 days, or immunodeficiency virus valacyclovir or famciclovir Severe compromise Acyclovir, 10 mg/kg IV q8h 7-10 days Acyclovir resistant (advanced acquired Foscarnet, 40 mg/kg IV q8h until healed immunodeficiency syndrome) Treatment of Herpes Zoster TOPICAL THERAPY During the acute phase of herpes zoster, the application of cool compresses, calamine lotion, cornstarch, or baking soda may help to alleviate local symptoms and hasten the drying of vesicular lesions. Occlusive ointments should be avoided, and creams or lotions containing glucocorticoids should not be used. Bacterial superinfection of local lesions is uncommon and should be treated with warm soaks; bacterial cellulitis requires systemic antibiotic therapy. Topical treatment of the herpes zoster rash with antiviral 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 dermatome; (2) prevent disease elsewhere; and (3) prevent PHN.

Normal Patients. Table 194-3 lists the current recommendations for treatment of herpes zoster. Randomized controlled trials indicate that oral acyclovir (800 mg five times a day for 7 days), famciclovir (500 mg every 8 hours for 7 days), and valacyclovir (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. In 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.28,58,59 Randomized controlled trials comparing acyclovir with valacyclovir, acyclovir with famciclovir, and valacyclovir with famciclovir demonstrated equivalent results in rash healing, acute pain, and the duration of chronic pain.60-62 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, and the higher and more reliable blood levels of antiviral activity achieved, make famciclovir or valacyclovir preferable to acyclovir for oral treatment of herpes zoster. Because of the lower risk of PHN, antiviral therapy is less valuable or necessary 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 initiated more than 72 hours after rash onset. 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, controlled trial to be effective in preventing ocular complications of ophthalmic zoster.63 Famciclovir and valacyclovir appear to have efficacy comparable to that of acyclovir in the treatment of ophthalmic zoster, and are preferred for the reasons cited above.64,65 Immunocompromised Patients. A randomized, double-blind, placebo-controlled trial in immunocompromised patients with herpes zoster showed that intravenous acyclovir (500 mg/m2 every 8 hours for 7 days) halted progression of the disease, both in patients with localized herpes zoster and in patients with cutaneous dissemination before treatment.66 Acyclovir accelerated the rate of clearance of virus from vesicles and markedly reduced the incidence of visceral and progressive cutaneous dissemination. Pain subsided faster in acyclovir recipients, and fewer reported PHN, but these differences were not statistically significant. Clinical trials comparing intravenous acyclovir with intravenous vidarabine for the treatment of herpes zoster in immunocompromised patients showed that acyclovir was significantly more effective and less toxic.33,66 In patients with mild immunocompromise and localized herpes zoster, oral acyclovir, valacyclovir, or famciclovir usually suffices.67,68 A randomized, controlled trial of oral famciclovir versus oral acyclovir in patients with localized herpes zoster after bone marrow or organ transplantation or cancer chemotherapy showed that the two treatments were equivalent in rash healing and loss of acute pain and that both were well tolerated.68 ANTI-INFLAMMATORY THERAPY The possibility that PHN might be caused by inflammation 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 glucocorticoids to acyclovir did not change the incidence of chronic pain.69,70 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 received glucocorticoids.70 Consequently, some experts advocate oral glucocorticoids for otherwise healthy older adults whose rash is complicated by moderate to severe pain and who have no contraindications to glucocorticoids. Others believe that the common adverse effects of

glucocorticoids argue against their routine use in older patients with herpes zoster. The authors agree and do not recommend the use of glucocorticoids in this setting. Glucocorticoids, in combination with effective antiviral therapy, may improve motor outcomes and acute pain in VZV-induced facial paralysis and cranial polyneuritis, where compression of affected nerves may contribute to disability. ANALGESICS Greater severity of acute pain is a risk factor for PHN, and acute pain may contribute to central 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 scales. Clinicians should prescribe nonopiate 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 governed by the patient's pain severity, underlying conditions, and response to specific drugs. If pain control remains inadequate, regional or local anesthetic nerve blocks should be considered for acute pain control.71 Although carefully managed opiates, anticonvulsants, and tricyclic antidepressants (TCAs) have demonstrated efficacy in established PHN, their effectiveness when administered during the acute phase of herpes zoster in reducing the incidence, duration, or severity of PHN is not known. This needs to be evaluated in rigorous clinical trials. A randomized controlled trial demonstrated that a single epidural injection of corticosteroids 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.28 Fortunately, it resolves spontaneously in most patients, although this often requires several months (see Fig. 194-1). Clinicians have advocated a wide range of treatments, including many oral and topical medications, epidural injection of local anesthetic and glucocorticoids, acupuncture, biofeedback, subcutaneous injections of triamcinolone, 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 randomized, controlled trials to be effective in patients 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 analog or Likert scale) in 30 percent to 60 percent of patients. These modalities are now recommended as first-line, evidence-based pharmacotherapy for PHN in practice management guidelines.72,73 TOPICAL THERAPY Topical anesthesia delivered by means of a 5 percent lidocaine patch has been shown in controlled clinical trials to produce significant pain relief in patients with PHN. The 10 cm 14 cm lidocaine patch contains 5 percent lidocaine base, adhesive, and other ingredients 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 (eutectic mixture of local anesthetics) cream applied once a day over the affected area under an occlusive dressing is an alternative method of delivering topical anesthesia. Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide), an extract of hot chili peppers, is a chemical known to deplete substance P, an important endogenous neuropeptide that acts as a chemomediator of nociceptive impulses from the periphery to the CNS. A small clinical trial of topical capsaicin for 4 weeks in patients with PHN demonstrated significant effects of this therapy on pain, with 75 percent of patients experiencing substantial pain relief.75 Unfortunately, the ointment burns too much to be tolerated 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

placebo.76,77 Frequent adverse effects of gabapentin include somnolence, dizziness, and peripheral edema. Pregabalin has been shown to produce 50 percent or greater pain relief in 50 percent of patients with PHN compared to 20 percent in placebo recipients.78 Dizziness, somnolence, and peripheral edema were the most common adverse effects reported with this medication.78,79 Pregabalin 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 percent to 67 percent of elderly patients with PHN in several randomized, controlled trials.72,73 Nortriptyline and desipramine are preferred alternatives to amitriptyline because they cause fewer cardiac adverse effects, sedation, cognitive impairment, orthostatic hypotension, and constipation in the elderly.80 Treatment with scheduled opioids may also reduce PHN. In a randomized, placebo-controlled crossover trial of sustained-release oxycodone in patients with PHN, patients reported significant pain relief when treated with opioid compared to placebo.81 In a crossover study in patients with PHN, both controlled-release morphine and TCAs provided significant pain relief compared to placebo.82 In this trial, patients preferred treatment with opioid analgesics to either TCAs or placebo despite a greater incidence of adverse effects and more drop-outs during opioid treatment. In a randomized controlled trial, combination therapy with morphine and gabapentin produced greater pain relief than each agent alone and placebo but with greater adverse effects.83 PREVENTION Prevention of Varicella 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 immunogenic and efficacious in protecting susceptible children against varicella. Although breakthrough cases of varicella were observed after subsequent exposure to wild-type VZV, they were relatively mild.84 Similar results were obtained in adults when two doses were given 4 to 8 weeks apart. Vaccinated children and adults developed breakthrough varicella caused by wild-type 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 Advisory Committee on Immunization Practices (ACIP) and the American Academy of Pediatrics recommend varicella vaccine for (1) routine childhood immunization, one dose at 12 to 18 months of age; (2) susceptible, immunocompetent children older than 13 years of age, adolescents, and adults, using two doses, 4 to 8 weeks apart; (3) susceptible individuals at high risk for exposure or transmission, including susceptible health care workers, family of immunosuppressed individuals, teachers of children, day care workers, residents and staff in institutional settings, nonpregnant women of childbearing age, and college students; (4) postexposure prevention and outbreak control; and (5) day care and school entry.85 The ACIP issued expanded recommendations for varicella vaccine in 2005 to promote wider use for adolescents and adults, in HIV-infected children, and a second dose for outbreak control. These recommendations are under review by the CDC and Department of Health and Human Services (http://www.cdc.gov/vaccines/vpd-vac/varicella/default.htm). The immunity to varicella induced by varicella vaccine is not as solid as that induced by wildtype VZV infection, and the duration of vaccine-induced immunity is not yet known. However, a high percentage of children followed long-term have remained seropositive.86 Recent experience 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.87-90 In a prospective, population-based study, vaccine effectiveness for prevention of all disease was 78.9 percent (95 percent confidence interval; 69.7 percent to 85.3 percent); for prevention of moderate disease, it was 92 percent (50 to 500 lesions); and for prevention of severe disease and physician visits, it was 100 percent.89 Interestingly, cases of breakthrough varicella in household settings were half as contagious as cases of varicella in unvaccinated

persons, although the minority of breakthrough cases with 50 lesions or more were as contagious as cases in unvaccinated persons. In adults, approximately 20 percent of vaccinees lose detectable antibodies to VZV over time, but continue to be partially protectedbreakthrough varicella is characterized by mild disease rather than severe varicella.87-90 In 2006, the ACIP recommended routine administration of a second booster dose of the varicella vaccine to increase the proportion of the population protected and the duration of immunity.91 The second dose may be especially important because of the approval by the FDA in 2005 of a combined measles, mumps, rubella and varicella vaccine for routine immunization of children 12 months to 12 years of age. More than 15,000 adverse events after varicella vaccination were reported to the FDA's Vaccine Adverse Event Reporting System and the CDC from March 1995 through December 2001, over 95 percent of which were non-serious events, mainly minor rashes and injection site reactions.92 Serious adverse events were rare and, in the majority, a causal relationship between the reported serious adverse event and varicella vaccine could not be established. Herpes zoster has been reported in vaccinees, but it occurred at a significantly lower frequency than herpes zoster 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-activation of the vaccine virus and others caused by re-activation of wild-type virus acquired before vaccination as a consequence of unrecognized varicella. POST-EXPOSURE PROPHYLAXIS AND INFECTION CONTROL Patients with varicella and herpes zoster may transmit VZV to susceptible individuals. No preventive measures are recommended for a normal child who has been exposed to varicella or herpes zoster. On the other hand, it is desirable to prevent or modify varicella in high-risk immunocompromised individuals. Passive immunization with VZIG was an effective preventive strategy but the production of VZIG has been discontinued in the United States. An investigational VZIG, VariZIG, is available under an investigational new drug application submitted to the FDA. The investigational VariZIG is a purified human immune globulin preparation made from plasma containing high levels of anti-varicella antibodies (immunoglobulin class G). This product can be requested for patients who have been exposed to varicella and who are at increased risk for severe disease and complications.93 The patient groups recommended by ACIP to receive VariZIG are listed in Table 194-4. TABLE 194-4 Criteria for the Use of Investigational Varicella-Zoster Immune Globulin for the Prophylaxis of Varicella Immunocompromised 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 gestation who are exposed during the neonatal period and whose mothers do not have evidence of immunity. Premature infants born at < 28 wk of gestation or who weigh 1000 g at birth and were exposed during the neonatal period, regardless of maternal history of varicella disease, or vaccination. Pregnant women. Active immunization with the live attenuated varicella vaccine is also effective in preventing illness or modifying varicella severity in children if used within 3 days after exposure.94 Whereas protection afforded by zoster immune globulin is transient, varicella vaccine induces long-lasting (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.95 However, appropriate timing is critical, but poorly defined immunity to varicella may not be achieved, especially with early post-exposure treatment, and there are always fears that resistant strains

will be selected by promiscuous application of this approach. Hence, post-exposure antiviral chemotherapy is not recommended for routine use in children. Infection control practices for VZV increase in importance 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 immunocompromised 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 administration 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 so that appropriate leave from work can be instituted after VZV exposure. In hospitals, airborne and contact precautions are recommended until all lesions are crusted for patients with varicella, immunocompromised patients with localized herpes zoster, and any patient with disseminated herpes zoster.96 Contact precautions are recommended for immunocompetent patients with localized herpes zoster. Prevention of Herpes Zoster: Zoster Vaccine Until universal varicella vaccination greatly reduces the number of people latently infected with wild-type VZV, prevention of herpes zoster must be aimed at preventing re-activation and spread of the latent virus. Long-term suppressive acyclovir treatment is only practical in immunocompromised patients at proven risk of developing herpes zoster within a defined time period, for example, in the year after 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.25 Studies of healthy adults older than 55 years of age with a history of varicella have demonstrated an increase in VZV-specific T lymphocytes and humoral immunity after vaccination with live attenuated VZV vaccine that is similar to the increase observed after an episode of herpes zoster.97 These findings suggest that vaccination of older persons may be useful in preventing herpes zoster and its complications. A recent Veterans Affairs Cooperative Study tested the hypothesis that vaccination against VZV would decrease the incidence and/or severity of herpes zoster and PHN among older adults.14 The study enrolled 38,546 adults 60 years of age or older in a randomized, double-blind, placebo-controlled trial of a live attenuated (Oka/Merck) VZV vaccine of much greater potency than the currently licensed varicella vaccine. A total of 957 confirmed cases of herpes zoster (315 among vaccine recipients and 642 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 percent (p < 0.001), reduced the incidence of PHN by 66.5 percent (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 recipients but were generally mild. This landmark study showed that the zoster vaccine markedly reduced morbidity from herpes zoster and PHN among older adults. The FDA licensed the zoster vaccine 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: Varicella disease after introduction of varicella vaccine in the United States, 1995-2000. JAMA 287:606, 2002 11. Hope-Simpson RE: The nature of herpes zoster: A long-term study and a new hypothesis. Proc R Soc Med 58:9, 1965 14. Oxman MN et al: A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med 352:2271, 2005

21. Kalman CM, Laskin OL: Herpes zoster and zosteriform herpes simplex infections in immunocompetent adults. Am J Med 81:775, 1986 23. Cohen JI, Straus SE: Varicella-zoster virus and its replication, in Fields Virology, edited by Knipe DM et al. Philadelphia, Lippincott-Williams & Williams, 2001, p 2707 28. Kost RG, Straus SE: Postherpetic neuralgia: Pathogenesis, treatment, and prevention. N Engl J Med 335:32, 1996 54. Klassen TP et al: Acyclovir for treating varicella in otherwise healthy children and adolescents. Cochrane Database of Systematic Reviews 4:CD002980, 2005 59. Gnann JW Jr, Whitley RJ: Herpes zoster. N Engl J Med 347:340, 2002 71. van Wijck AJ et al: The PINE study of epidural steroids and local anaesthetics to prevent postherpetic neuralgia: A randomised controlled trial. Lancet 367:219, 2006 72. Dubinsky RM et al. Practice parameter: Treatment of postherpetic neuralgia. Neurology 63:959, 2004