ry capt +194 :: Varicella and Herpes Zoster Kenneth E. Schmader & Michael N. Oxman oi eickenpon ana herpes zoster is twee) ‘ye distinct clinical entities caused (eet eps beste virus (V2) anacute, highly contagious Yap that occurs most often in cilthood, ihe sult of primary VZV infection of « Srsepable individual, ‘s-therndh usualy begins on the face and SBipana spends apy tothe trunk, with Ace sparing ofthe extremities. Lesions are ‘Biers rather than clustered, and progress fom rve-colored macules to paptles, esces pustules, and crusts, In varicella in Sort to amallpox, lesions in all stages are Coually present on the boty at the same time, «Nariel + Innormal chikdren, systemic symptoms ane usually mild and serious complications rena. Inadults and immunologically “compromised persons of any age, varicella ismore likely tobe associated! with life- ehreatening complications. + Where use of varicella vaccine in susceptible Juldren and adults is widespread, the science of varicella is markedly reduced, though breakthrough varicella may occur. EPIDEMIOLOGY EPIDEMIOLOGY OF VARICELLA’ Nancella is distributed worldwide, but its af c jist 7 ige-specific — differs in temperate versus tropical climates, ‘ilbPepulatons that have rceived varicella wace ‘Perate climates in the absence of varicella vacei- sctavclla is endemic, with a regularly recurring, SENS prevalence in winter and spring, and Pett Perri that depend upon the accumulation of se prable persons. In Europe and North America in aqgh™%Cination era, 90% of cases occurred if chile ingunser than 10 years of age and fewer than 5% Tg viduals older than the age of 15.! From 1888 10 fens ang Ta heTE approximately 11,000 hospitaliza- te [nt 100 deaths caused by varicella each year It ited States. The risk of hospitalization and UWAAND.HEBPES ZOSTER ATA.GLANCE oo eieantssainenes * Horpes zoster is characterized by unilateral, dermatomal pain, and rash that rests from revctivation and multiplication of endogenous VZV that had persisted in latent form within serory gang fiowing an cote atch of * The erythematous, maculopapular, and vesicular lesions of herpes zoster are clustered rather ‘than scattered because virus reaches the skin via sensory nerves rather than vitemia. ‘= Herpes zoster is most common in older adults and immunosuppressed individuals. + Pains an important clinical manifestation of herpes zoster, and the most common debilitating complication is chronic pain or postherpetic ‘neuralgia (PHN). ‘© Antiviral therapy and analgesics reduce acute pin; lidocaine patch (5%), high dose capsaicin patch, gabapentin, pregabalin, opioids, and tricyclic antidepressants may reduce the pain of PHN. = Aliveattenuated zoster vaceine reduces the incidence of herpes zoster by one-half and the incidence of PHN by two-thirds. death was much higher in infants and adults than in Shildren, and most varicella-related deaths occurred in previously healthy people. In tropical and semitropi- Per countries, the mean age of varicella js higher and Susceptibility among adults to primary VZV infection ie Significantly: greater than in temperate climates High levels of susceptibility to varicella among adult immigrants from tropical climates are well docu: rented in the US military, where many recruits from Puerto Rico and the Philippines have been seronega~ live, This is important for hospitals, where susceptible fuaithcare workers may posea significant risk of noso- comial varicella. Widespread use of the varicella vaccine has mark- edly altered the epidemiology of varicella. In the United States, vaccine coverage rates among, sus- Ciptible children increased from O% in 1995, when Sericella vaccine was licensed, to 88% in 2004. This Mae esulted ina marked decline in varicella casesand varicellarelated hospitalizations. From 1995 through 2000, varicella cases reported to the Centers for Disease Control (CDC) declined by 71-84%, depending upon surveillance area; by 2005 the inci- dence of varicella had decreased by 90%, with a comparable decline in varicella-related hospitaliza- tions.” The decline was greatest among children aged 1-4 years, but cases declined in all age BroUpS, including unvaccinated infants and adults, reflect- {ing herd immunity. Varicella-related mortality has also declined substantially after introduction of the varicella vaccine, From 1990 to 1994, mortality from varicella decreased by 66% in all age groups under 50 years, with the greatest reduction (92%) among, children 1-4 years of age-* Varicella is highly contagious. Attack rates of 87% among susceptible siblings in households and nearly 70% among susceptible patients on hospital wards have been reported. More than 95% of cases of vari cella are clinically apparent, although occasionally the exanthem may be s0 sparse and transient as to pass unnoticed. A typical patient i infectious for 1-2 days (rarely, 3-4 days) before the exanthem appears, and for 4or 5 days thereafter thats, until the last crop of ves- icles has crusted. The immunocompromised patient, who may experience many successive crops of lesions for a week or more, is infectious for a longer period ‘of time. The mean incubation period of varicella is 14 (15 days, with a range of 10-23 days. It is often pro- longed in patients who develop varicella after passive immunization with varicella-zoster immune globu- lin (VZIG) or zoster immune plasma (ZIP), oF after ppostexposure immunization with live atenuated Oka strain varicella vaccine." The major route by which varicella is acquired and transmitted is thought to be the respiratory trac, but infection may also be spread by direct contact. Vari- cella crusts are not infectious, and the duration of infectivity of droplets containing virus is probably 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, VZV DNA can be detected in the oropharynx of the majority of patients using polymerase chain reaction (PCR)- based assays.” Natural varicella (1e., varicella caused by wild- type VZV) generally confers life-long immunity to the disease, Re-exposure to the virus boosts humoral and cell-mediated immune responses, but rarely leads to clinical illness. Most reported second attacks of varicella involve incorrect diagnoses; others may represent cutaneous dissemination in patients with herpes zoster (see below). With severe immunocom. promise, reinfections manifested as varicella have been observed. In addition, persons who develop modified varicella (eg,, because they are infected early in infancy in the presence of maternal antibody oor have been immunized with live attenvated var cella vaceine) may respond to exogenous exposure by developing a second, usually mild, episode of "break through” varicella. | EPIDEMIGLOGY OF HERPES oan STER Herpes zoster occurs sporadically thr without seasonal prevalence, The gece zoster is independent of the prevent land there is no convincing evidence et °" Ying tercan be agulred by contact witha ns varicella or herpes zoster. Rather, the ve pes zoster is determined by factors that yen hy host-virus relationship. uence ‘One strong risk factor is older age (Fi incidence of herpes zoster is 150 erat, yearsinall ages and 7-11 per 1,000 per yor R= over 60 yeuts of age in European and No studies." It is estimated that there are Ati, million new cases of herpes zoster inthe Ung each yeat, more than half of which occur 260 years of age, and this number wil inceaet* population ages "222 a Another major Fisk factor is cellular immune g function, Immunosuppressed patients hive so times greater risk of herpes zoster than i - petent individuals ofthe same age. Inman sive conditions associated with high rak f zoster include HIV infection, bone marrow t leukemia and lymphoma, use of cancer chemother and use of corticosteroids. Herpes zoster ss nent and early “opportunistic infection” in infected with HIV, in whom it soften the fists immune deficiency. Thus, HIV infection should kes sidered in individuals who develop herpes zester, Other factors reported to increase the risk of hers zoster include female sex.” physical trauma in te affected dermatome," IL-10 gene polymorphisss? and white race." Exposure to children and const with cases of varicella have been reported to ince levels of VZV-CMI and confer protection against pes zoster" Second episodes of herpes zoster are uncomment immunocompetent persons, and third attacks re rare, Persons suffering more than one episode my immunocompromised. Immunocompetent pater® suffering multiple episodes of zosteriibe d= ease are likely to be suffering from recurrent 20% form herpes simplex virus infections” Patients with herpes zoster are less contagious patients with varicella, The rate at which susp household contacts develop varicella ater ever herpes zoster appears to be about one-third of WEA observed following exposure to varicella.’ Virus isolated from vesicles and pustules in af herpes zoster for up to 7 days after the re the as, and for much longer periods in i, Promised individuals. Patients with wry dermatomal zoster appear to spread the in ‘means of direct contact with their lesions in transmission has also been documented.” Patt se disseminated herpes zoster may also transmit ef tion via aerosols, so tha airborne precavin as {8 contact precautions, are required fo" ¥2) Po The effect of the marked reduction it cad of varicella, due to widespread varicellaa a —— 0 4 fy PPP ee e dene 194-1 A. The epidemiology of herpes 705 mete neuralgia, The annual Incidence of herpes me p00 Dersons In a ‘general medical practice. 1 anptcentage of patients with pain persisting after Se pacyel the herpes zoster rash. These data are from adiiceba recipients In one large, double-blind treak- tc S.C. The proportion of patients with Pont Aegon 1 age rom Kn to tRogeness, treatment. 20d ecralgi: Pal "ern Ng! died 338.32 196 with Permission? children, on the epidemiology of herpes zoster is unclear Inthelong er eninge herpes znteri ike decline as the cohorts of children now receiving varicella Yercine Dome aly vaccine vrusawsciated Dees rout wal probably be es regent acd Hs severe ‘older adults than wild-type virus associated herpes 205- ter because the vaccine virus is highly attenuated. In the short term, the incidence of herpes zoster could increase ‘because a decline in the incidence of varicella will reduce the adult population’ exposure to VZV thereby rexluc- ing immune boosting, hastening the age-related decline inimmunity 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 vace rica eee te em incese in he incidence of herpes aster! 2 ETIOLOGY AND PATHOGENESIS VZV is a member of the herpesvirus family." Other members pathogenic for humans include herpes simplex Viruses type 1 (HSV-1) and type 2 (HSV-2);cytomenalor ‘Virus (CMV); Epstein-Barr virus (EBV); human herpes- virus-6 (HHV-6) and human herpesvirus:7 (HHV-7), which cause roseola; and Kaposi's sarcoma-assoxiated herpesvirus, also called human herpesvirus type & All herpesviruses are ally. indistinguishable land share a number of properties, nclusting the capacity foestablish latent infections that persist for life. ‘The VZV genome encodes about 70 unique genes, most of which have DNA sequence and functional homology to genes of the other herpesviruses." Imme- diate early (IE) gene products regulate VZV replic tion. Early gene products, such as the virus-specific thymidine kinase andthe viral DNA polymerase, sup- port viral replication. Late genes encode virus struc Pinal proteins that serve as targets for neutralizing ‘antibodies and cellular immune responses segregation at jn their nucleotide sequences al Aid type from vaccine virus strains, and to “inger- prin” viruses slated from individual patients as dymP te eticlcendothelisl system, the major ste of Tis replication during the remainder of the incubation eid to te skin where innate immune responses stay VZV replication and rash formation ey Nncubating snfection is partially contained by innate host defenses [eg interferon, natura) Kir {NK cells] and by ig VZV-specific immune (em sses In mest individuals, virus replication ven ‘ech overs these developing host defenses 50that about 2 weeks after infection, a much larger (sex ondary) viremia and associated symptoms and lesions ‘occur. Skin lesions appear in successive crops, reflect twa cyctic viremia, which in the normal host is termi- ated after about 3 days by VZV.specific humoral and cellular immune responses. Virus circulates in mono- nuclear leukocytes, primarily lymphocytes. Even in uncomplicated varicella, the secondary viremia results In the subclinical infection of many organs in addition to the skin. Effective host immune responses terminate viremia and limit the progression of varicella lesions {n the skin and other organs. Humeral immunity to VEN protects against varicella. People with detectable serum antibody resulting from wild-type VZV infec- tion do not usually become ill after exogenous expo- sure. Cell-mediated immunity to VZV also develops during the course of varicella, persists for many years, and protects against severe infections.” MATa eet 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 cent tally up the sensory fibers to the sensory ganglia. Infected T cells may also carry virus to sensory ganglia hematogenously, In the ganglia, the virus establishes 4 latent infection that persists for life. Herpes zoster ‘occurs most often in dermatomes in which the rash of varicella achieves the highest density—those inner- vated by the first (ophthalmic) division of the trigemi- nal nerve and by spinal sensory ganglia from T] to L2.” Although the latent virus in the ganglia retains its potential for full infectivity, reactivation is sporadic and infrequent, and infectious virus does not appear to be present during latency. The mechanisms involved in reactivation of latent VZV are unclear, but reactivation hasbeen associated with immunosuppression;emotional stress; irradiation of the spinal column; tumor involve- ‘ment of the cord, dorsal root ganglion, or adjacent struc- tures; local trauma; surgical manipulation of the spine; and frontal sinusitis (as a precipitant of ophthalmic z0s- ter). Most important, though, is the decline in VZV-spe- cific cellular immunity that occurs with increasing age.” VZV may also reactivate without producing overt disease. The small quantity of viral antigens released during such contained reactivations would be expected. to stimulate and sustain host immunity to VZV." When VZV-specific cellular immunity falls below some critical level, reactivated virus can no longer be contained." Virus multiplies and spreads within the ganglion, causing neuronal necrosis. and intense inflammation, a process that is often accompanied by severe neuralgia." Infectious VZV then spreads anti- dromically down the sensory nerve, causing intense neuritis, and is released from the sensory nerve end- ings in the skin, where it produces the characteristic cluster of zoster vesicles. Spread of the ganglionic infec- tion proximally along the posterior nerve root to the meninges and cord may result in local leptomeningitis, cerebrospinal fluid pleocytosis, and segmental myeli- tis. Infection of motor neurons in the anterior horn and | for ay accompany the cutanene don, at ex-ssaon ot infection within the eng sous sytem (C75) may FMA IN Fare compe oF herpes zoster , meningsencep halite tanga? tnyeliti). Viromia alo occurs during herpes age local pls PNinekds Seay nlastose ZOSTER AND POSTHERPETIC REVERSI Pain is a major symptom of herpes 20%!€¢ I fen precedes and generally accompanies the rash, and'n frequently persists after the rash has healed ca, plication known as postherpetic neuralgia (Prin A mumber of diferent but overlapping mechinsey appear to be involved in the pathogenesis of pain i pea ested page pa 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 excn atory amino acids and neuropeptides induced by the sustained barrage of afferent impulses during the pro drome and acute phase of herpes zoster may cause tay totoxic injury and the loss of inhibitory interneuron in the spinal dorsal hom. Damage to neurons in the spinal ‘ord and ganglion, and tothe peripheral nerve, signe tant in the pathogenesis of PHN. Damaged primary afferent nerves may become spontaneously active and hypersensitive to peripheral stimuli, and alse to symm pathetic 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 unpleas ant sensations elicited by stimuli that are normally not Painful, eg, light touch) with little or no sensory ess. ‘The anatomic and functional changes responsible for PHN appear to be established early in the course of her es zoster. This would explain the correlation of init pain severity and the presence of prodromal pain with the subsequent development of PHN, and the fale of antiviral therapy to fully prevent PHN (see below) CLINICAL FINDINGS PRODROME OF VARICELLA. In young childee Prodromal symptoms are uncommon. In older chikdre” and adults, the rash is often preceded by 2-3 days of fever, chills, malaise, headache, anorexia, severe back” ache, and, in some patients, sore throat and dry coug* RASH OF VARICELLA. In unvaccinated perso the rash begins on the face and scalp and spreads 1" idly to the trunk, with relative sparingzof theextsen"™ (Fig. 194-3). New lesions appear in successive COPS ‘but their distribution remains central, The rash #7Fee 194-2 Pathway of normal pain perception. ‘nou simul activate free nerve endings in the skin to rere vgnals that are conveyed through unmyelinated Cons (nth and small AS fibers to the neuronal bodies ‘he segmental dorsal root ganglia, then proximally 0 ‘e dara’ hoen of the spinal cord, where they form syn “besweth second-order neurons. Spinal cord neurons are Noectto powertl descending inhibitory signals rom the ‘2 geen mediated by the biogenic amines serotonin {re rorepnephrine, Drugs that potentiate the central ‘tec of biogenic amines, suchas tricyclic antidepressant 2.94 ray act by enhancing these descending pathways dogercus opiates aso contribute to descending inhibi ZIERA The net resut of peripheral afferent input and Sxerénginhbtory nput's projected cephalad jiring Sx Beerng fibers in the contralateral spnetalamic range) nformation from the spinothalamic act {hx8ed seth input from brainstem and cortical areas Se perception of specific aspects of pain as well as "* General affective components of pain perception. SLE the sa ofthe hack and betwee the oe pr bledes than on the and buttocks and ty achmfsse on the medial than on the lateral aspects {tabs ts nt uncommon to have afew lesions reaps and soles, and vesicles often appear f° seh gt larger numbers in areas of inflammation, “hh dpertasho sunbu, Pact etre of varicella sions Ue ap PS” * ver shite as 12 hour ro vcore tks, vesicles 194-3), pustules, crusts. ‘halyard nd Jes and multinucleated giant cells similar to those seen in the cutaneous lesions of the disease. These chat are indistinguishable from those produced by HSV, whereas HSV rapidly spreads to infect the remaining, cells in the culture, the eytopathic effect of VZV remains focal, Cytopathicetfeetsof VZV are generally not appar cent until several days after specimen inoculation. Mod= ifications of the cell culture assay in which vesicle fie ‘or lesion scrapings are centrifuged onto cetls growing ‘on coverslips at the bottom of thin glass-walled “shell” vials followed 24-72 hours later by tivation and stai ing with Muorescein- or enzyme-labeled monoclonal antibodies to VZV proteins, can confirm the presence of VZV relatively quickly, well before cytopathic effects are evident in conventional cell cultures.” Immunofluorescent or immunoperosidase staining, ‘of cellular material from fresh vesicles or prevesicular lesions has become the diagnostic method of choice tant VZV in patients. with AIDS Herpes zoster, histopathology. A. Intraepidermal vesicle, acanthalyis, reticular degeneration: underying shows ede rab naseuae Bu Mutmucicated giant cls with chaactentc nuclear changesin many centers; it can detect VZV signaticantly more often and faster than virus culture, even relatively late in the disease when cultures ate no longer positive Enzyme immunoassays provide another rapid and sensitive method for antigen detection, Detection of VZV DNA in clinical specimens follow- ing amplifications by PCR provides the greatest assay sensitivity, very high specificity and rapid turnaround time, It has revolutionized the diagnosis of VZV infec- tions, and can distinguish among wild type and Oka vaccine strains of VZV and HSV. Serologic tests permit the retrospective diagnosis of varicella and herpes zoster when acute and convales- ‘cent sera are available for comparison.” These assays can also identify susceptible individuals who may be ‘candidates for isolation or prophylaxis. The technique most commonly used is a solid-phase enzyme-linked immunosorbent assay (ELISA). However, this assay often lacks sensitivity and specificity, failing to detect antibody in people who are immune and sometimes yielding false-positive results in susceptible indi- viduals. Several more sensitive techniques have been developed to measure humoral responses to VZV. ‘These include an immunofluorescence assay for anti- body to VZV-induced membrane antigens [fluorescent antibody to membrane antigen (FAMA)] that reliably distinguishes immune from susceptible adults and a latex agglutination test that is comparable in sensitiv- ity and specificity to FAMA assays, but is much sim- pler to perform. COMPLICATIONS ee oa ciasen. Inthe normal child, varicella is rarely complicated. The most common complication is the secondary bacterial infection of skin lesions, usually by Staphylococci ot ‘Streptococci, which may produce impetigo, furuncles, cellulitis, erysipelas, and, rarely, gangrene** These local infections often lead to scarring and, rarely, to septicemia with metastatic infection of other organs. Bullous lesions may develop when vesicles are super- infected by Staphylococci that produce exfoliative toxins. Invasive group A streptococcal infections are particularly virulent. In the absence of varicella vac- ‘ination, up to one-third of varicella is associated with invasive group A streptococcal infections; they usu- ally occur within 2 weeks of the onset of the varicella rash™ Widespread varicella vaccination appears to have markedly reduced the percentage of invasive {gr0up A streptococcal hospitalizations associated with varicella in the United States.” 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 dis- semination. adults, fever and constitutional symptoms 4, a prominent and prolonged, the rash of varia, more profuse, and complications are more frequeny High rates of complications have been reported iy adults not born in the United States (1, adults bors in Merico)” Primary varicella pneumonia is me major complication of adult varicella. Some patent, are virtually asymptomatic, but others develop severe respiratory embarrassment, with cough, dysprey, tachypnea, high fever, pleuritic chest pain, cyanosis and hemoptysis 1-6 days after onset of the rash. The severity of the symptoms usually exceeds the physica findings, but the roentgenogram typically reveals dit. fuse, peribronchial nodular densities throughout both lung fields with a tendency to concentrate in the peri. hilar regions and at the bases. The mortality in adults with frank varicella pneumonia has been estimated to be between 10% and 30%, but it is less than 10% if immunocompromised patients are excluded.” Varicella during pregnancy is a threat to both mother and fetus. Disseminated infection and varicella pneu. monia may result in maternal death, but neither the incidence nor the severity of varicella pneumonia appear tobe 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 abnor- malities.” Perinatal varicella (ie. ricella 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 mark- edly increased in immunocompromised patients. In these patients, continued virus replication and dis- semination result in a prolonged high-level viremia, 4 more extensive rash, a longer period of new vesicle formation, and clinically significant visceral dissem- rane iyi and soma ents may develop pneumonia, itis, encephali tis, and hemorrhagic. eplcedase te vantain which range in severity from mild febrile purpura to severé and often fatal purpura fulminans and “malignant” varicella. CNS complications of varicella occur in fewer than 1 in 1,000 cases; they include several distinct sy" dromes. Varicella-associated Reye syndrome (acute encephalopathy with fatty degeneration of the live!) typically occurs 2-7 days after the appearance of tht rash, In the past, from 15% to 40% of all cases of Reyt syndrome occurred in association with varicella, wit) ‘mortality as high as 40%, particularly when aspiti® ‘was administered for fever" Acute cerebellar ata is more common than the other neurologic complicl- tions of varicella, occurring in 1 in 4,000 cases. &s more benign’ Encephalitis is much less coma" eaanins in 1 in 33,000 cases, but it frequently causes th OF Permanent neurologic sequelae. The Benesis of cerebellar ataxia and encephalitis remaité obscure, but in many cases itis possible to detect VZV antigens, VZV antibodies, and VZV DNA in the cerseqinal fluid of patients os.cesting ditect infection ough elevated aminctransterase levels are com- si inxal hepatitis is rare except as a complication, “cessive Varicella, Other rate complications of include myocarditis, glomerulonephitis, pancreatitis, gastritis and ulcerative lesions of JLarthrtis, Henoch-Schonlein vasculitis, optic and iritis. The pathogenesis of many 0 ap teh hea rine comphications has not been delineated, but Geet parenchymal or endovascular VZV infection, Stocults induced by VZV antigen-antibody com: Sears appear tobe responsible in most cases, ecu omens ee Table 1941) ‘The sequelae of herpes zoster include cutaneous, ‘ular neurologic, and visceral complications.” Most ‘omplications of a nd are associated with spread of VZV from the initially involved senso on son, nerve, or skin, either via the bloodstream or by direct neural extension, The rash may dissemi- ‘ute alter the initial dermatomal eruption has become apparent. When immunocompetent patients are care- ‘thy examined, it is not uncommon to have at least afew vesicles in areas distant from the involved and. mediately adjacent dermatomes. The disseminated ewes usually appear within a week of the onset of te segmental eruption and, if few in number, are eas- ) overlooked. More extensive dissemination (with ‘S-Mlesions or more), producing a varicella-like erup- ton (generalized herpes zoster; Fig. 194-7), occurs in Ye10% of unselected patients with localized herpes taster, most of whom have immunologic defects a8 a ‘sult of acquired immunodeficiency, as seen with HIV siection, underlying malignancy (particularly lym- poms), or immunosuppressive therapy. If the rash ‘spreads widely from a small, painless area of herpes ‘ote, the initial dermatomal presentation may go ‘=eoted, and the ensuing disseminated eruption ‘ay be mistaken for varicell - ‘When the dermatomal rash is particularly extensive, ‘siteften is in severely immunocompromised patients, there may be superficial gangrene with delayed heal ing and subsequent scarring (Fig. 194-6). Secondary bacterial infection may also delay healing and cause scarring, The eye is involved in 20%-70% of patients with ‘ophthalmic zoster, with a wide range of possible com- plications.” VZV is also the principal cause of acute retinal necrosis (ARN), a fulminant sight-threatening, disease observed primarily in otherwise healthy indie als 88 Herpes zoster may be attended by a variety of new- rologic complications (Table 191-1), of which PHN is the most common and important. PHN has been var ably defined as any pain after rash healing or any pain 1 month, 3 months, 4 months, or 6 months after rash onset" In clinic and community studies, the overall incidence of PHN is 8%-15% depending. on the defini- tion (Fig. 194-1A)2**" Age is the most significant risk factor for PHN (Fig. 194-1C). Clinically significant pain lasting 3 months or more is rare in immunocompetent persons younger than 50 years of age, but complicates 12%-15% of cases of herpes zoster in persons 60 years of age and older” 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.” Increasing age, greater acute pain severity, presence of prodro- mal pain, and greater rash severity have each been reported to be independent predictors of PHN.” The positive predictive value of each factor alone was low, but, together, the positive predictive value was almost 50%. PHN usually remits spontaneously over several ‘months but, as with PHN itself, the risk of long-lasting, PHN 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% of patients with PHN, Patients with allodynia may suf- fer severe pain after even the lightest touch of theaffected skin by things as trivial asa breeze or a piece ‘of clothing, These subtypes of pain may produce disor dered sleep, depression, anorexia, weight loss, chronic fatigue, and social isolation, and they often interfere iy, traveling, with dressing, bathing, general act shopping, cooking, and housework. ANTIVIRAL AGENTS. (See also Chapter 231). The nucleoside analogues acyclovir, fameiclovi,valacyclo- vir,and brivudin and the pyrophosphate analog foscar- net show efficacy in treating VZV infections. Acyclovir is a guanosine analogue that is selectively phosphory- lated by VZV thymidine kinases (it is a poor substrate for cellular thymidine kinase) and thus is concentrated in infected cells. Cellular enzymes then convert acyclo- vir monophosphate to acyclovir triphosphate, which interferes with viral DNA synthesis by inhibiting viral DNA polymerase. VZV is approximately tenfold less sensitive to acyclovir than herpes virus. Two prodrugs, valacyclovir and famciclovir, are better and more reliably absorbed than acyclovir fol- lowing oral administration. Thus, they produce much higher blood levels of antiviral activity and permit less frequent dosing than acyclovir. Valacyclovir isa valine ‘ester of acyclovir that is converted enzymatically to acyclovir after absorption. Fameciclovir is a prodrug of ppenciclovir, a nucleoside analogue similar to acyclovir in mechanism of action and antiviral activity against VZV and HSV. Famciclovir is converted enzymatically to penciclovir ater absorption, Brivudin is a uracil analogue with very high activ= ity against VZV. Although effective in the treatment of herpes zoster, and licensed for stich use outside the United States, itis not licensed in the United States, in part because of a potentially lethal interaction with S-fluorouracil. Foscarnet is an analogue of inorganic pyrophosphate that inhibits the replication of all known herpesvi- ruses in vitro. Itexerts its antiviral activity by selective inhibition at the pyrophosphate-binding site of virus- specific DNA polymerases and reverse transcriptases at concentrations that do not affect cellular DNA poly- ‘erases. Foscarnet does not require phosphorylation by thymidine kinase to be activated and is therefore active against acyclovir-resistant VZV mutants that have reduced or altered thymidine kinase activity. ‘Topical antiviral therapy lacks efficacy in patients with varicella and herpes zoster and is not recom- mended. Systemic therapy, either oral or parenteral, is required, Because of their superior pharmacokinet- ics, the lower sensitivity of VZV compared to HSV, and the existence of barriers to the entry of antiviral agents into tissues that are sites of VZV replication, famciclovir or valacyclovir are preferred to acyclo- vir for oral therapy of VZV infections. Acyclovie- resistant VZV has been documented in varicella and herpes zoster in patients with advanced AIDS (Fig. 194-8). Because of the mechanism of acyclovir resis- tance (mutations in the viral thymidine kinase gene), these acyclovir-resistant mutants are cross-resistant to i aad ts caret 1 mg ee con onion mes ganciclovi ‘They usual hours; however, the treatment has ended. Medan aauuaas )PICAL THERAPY. In normal children, va TORICAL THERAPY em ti or calamine lotion locally, tepid baths with Soda or colloidal oatmeal (three cups per tub of wate, ‘and oral antihistamines may relieve itching. Creamy ‘and lotions containing glucocorticoids and occing Gintments should not be used. Antipyretics may fe needed, but salicylates must be avoided because their association with Reye syndrome. Minor back. rial infections are treated with warm soaks. Bacterial cellulitis requires systemic antimicrobial therapy tha. is effective against Staphylococcus aurews and group A Bhemolytic streptococcus. ANTIVIRAL THERAPY Normal Children, (See Table 194-2). A large ran- domized, controlled trial of acyclovir treatment of healthy children 2-12 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 cf lesions, the time to cessation of new lesion formation, and the duration of the rash, fever, and constitutional symptoms when compared to placebo.” Treatmert initiated more than 24 hours after rash onset was net effective. Because varicella is a relatively benign inlec tion in children and the clinical benefits of treatment are modest, routine antiviral treatment is not recom ‘mended in otherwise normal children”””; howevet, many have favored its use where cost is nota concer where it can be begun in time to benefit the patent (within 24 hours of rash onset), and where there is perceived need to speed resolution of the infection 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, The American Academy of Pediatrics recommend oral acyclovir for persons aged >12 years, persons wit? chronic cutaneous or pulmonary disorders, perso" receiving long-term salicylate therapy, and penor receiving short, intermittent, or aerosolized couse 0f corticosteroids because these individuals are increased risk for moderate-to-severe varicella.” Normal Adolescents and Adults. 4 randoo ized, controlled trial of acyclovir treatment of healthY adolescents 13-18 years of age found that early ‘Pent with oral acyclovir (800 mg five times @ re * days) reduced the maximum number of lesion® time to cessation of new lesion formation compete! © Placebo" A randomized, placeborcontoled iTreatment of Varicella in the Normal and immuno. ae ‘patient Group owt ‘ete Qu itto<18 years of age) Agokscent (240 kg or aut especialy with mild immune conpreene (09. se of inhaled glucacorticards) Preven Regimen ‘Aeyclovi 10 mg/kg or 500 mg/m every Bh for 10 days Symptomatic treatment alone, oF MaRaelows 20mg/g every Shor sda" nottowaceed 39/ ‘Acyclovir 20 mg/kg po four times aday «5 days (not to exceed 3200 mg/day) one Valacyclovir 9 po every 8h for? days or Fameck ovr $00 mg po every 8 hfor 7 days ot ‘Acyclovir £00 mg po five times a day for 7 days ‘Acyclovi 10 maykg W every 8h 7-10 days Routine use of acyclovit isnot recommended. {there are complication (9. pneumonia) teat pneumonia as ‘ber recommendation above ‘Valacyclovir 1g po every 8h for 7-10 days or Fameiclowir $00 mq po every 8h for 7-10 days or ‘Acyclovir 800 mg po five times a day for 7-10 days ‘Aayctovir 10mg/hg IV every Sh for 7-10.days, Foscamet 40 mg/kg IV every 8 hunt healed "Oy nycowr or preferably famciclovir or valacyclovir, shouldbe considered for ethers healthy persons at increased isk for moderate to- sere arc eg, persons aged >12 years, persons with chronic cutaneous ot pulmonary disorders, persons recevng log term saleylate ‘Deux. and persons receiving shor, intermittent, of aerosolized courses cf corticosteroids (From Matin M etal Prevention of varicella Recomm ‘encatons of the Advisory Commattee on lrymunization Practices (ACI. MMWR Recomm Rep $6140, 2007) ‘Yat prepare suspension by grinding 500-mg valacyclowr capets and suspending in cherry favored Suspension Structural Veical USP NE S97 #25 mg md oF 59 mg/mL in lots of 100 mL at time of dispensing, ‘onl acyclovir in healthy young adults with varicella ‘owed that early treatment (within 24 hours of rash “Sset) with oral acyclovir (800 mg five times a day for 7 days) significantly reduced the time to crusting of the extent of disease, and duration of symp- ‘Ges and fever.” Thus, routine treatment of varicella ‘S.duls seems reasonable. Although not tested, it is ely that famciclovir 500 mg PO qh or valacyclovir LN mg PO g8h would be convenient and appropri- ‘substitutes for acyclovir in normal adolescents and. ‘ists Many physicians do not prescribe oral acyclovir se implicated varicella during pregnancy because ‘isk to the fetus of treatment is unknown. Other as ecommend oral antiviral therapy oF ine ind trimester when organogenesis is com- ‘et when there may be a heightened risk — ia, and when infection can be sp! ‘eho. Intravenous acyclovir is often considered for Fount women with varicella who have extensive ‘sareous and oe systemic disease. Fomlications of Varicella in Normal Mlajy ns Uncontrolled trials in immunocompetent tmaepgith varicella preumonia suggest that carly Sent (within 36 hours of hospitalization) with pron (WO mg/kg gh) may reduce fever ane tachy esa improve oxygenation.” Other senous ewer sy OF ice in the inn 1 host, SM ocuigr Phat, meningoencep! “Vdovie complications, should Immunocompromised Patients. Controlled trials in immunocompromised patients with v cella demonstrated that treatment with IV acyclovir decreased the incidence of life-threatening, visceral complications when treatment was initiated within 72 hours of rash onset” Immune compromise, how- ever isa continuum ranging from minimal to severe. Intravenous acyclovir has been the standard of care for varicella in patients with substantial immunodefi ciency. Although oral therapy with famciclovir or vala- ir might suffice for patients with mild degrees june impairment, there are no controlled clinical trials to guide the decision. TREATMENT OF HERPES ZOSTER TOPICAL THERAPY. During the acute phase of her- ‘zoster, the application of cool compresses, calamine fotion, comstarch, or baking soda may help to allevi- ate local symptoms and hasten the drying of vesicular esions. Occlusive ointments should be avoided, and creams of lotions containing glucocorticoids should thot be used. Bacterial superinfection of local lesions is e ‘and should be treated with warm soaks; bacterial cellulitis requires systemic antibiotic therapy. Topical treatment with antiviral agents isnot effective. ANTIVIRAL THERAPY. The major goals of therapy in patients with herpes zoster are to (1) limit the extent, uration, and severity of pain and rash in the primaryar sacra tices es. | Patient Group Normal ‘Age <50 years ‘Age 250 years and patients of any age with cranial nerve Involvement (eg. ophthalmic zoster) |Immunacompromised ‘Mild compromise, including HV infection Severe compromise ‘Aeycovirresistant eg, advanced ADS) Regimen ‘Symptomatic treatment alone, or Fameiclovr 500mg PO every 8h for 7 days or Valacyclovir 1g PO every 8 for 7 days or ‘Acyclovir 800 mg POS times a day for 7 days* Fameiclovie $00 mg PO every 8 for 7 days or Valacyclovir 1 g PO every Bh for? days of ‘Acyclovie 800 -mg PO'S times a day for 7 days Famciclovr $00.9 PO every 8 for 7-10 days or Valacyclove 1 g PO every Bh for 7-10 days or ‘Acyclovir 800 mg FO S times a day for 7-10 days? ‘Acyclovir 10 mg/kg every Bh for 7-10 days Foscarnet 40 mg/hy V every 8 huntl healed “Fameiclovir ot valacyclovir ar prefered because thie greater and mee reliable oa boavalabihty result in higher bod level fant _2cthty. the lower suscepiilty of VZV (compared 1 HSV) ad the existence of barre tothe entyof antiviral agents nto tssoes hate aan ‘of VZV replication, dermatome; (2) prevent disease elsewhere; and (3) pre- vent PHN, Normal Patients. Table 194-3 lists the current recommendations for treatment of herpes zoster. Randomized controlled trials indicate that oral acyclo- vir (800 mg five times a day for 7 days), famciclovir {500 mg q 8 hours for 7 days), and valacyclovir (1 g three times a day for 7 days) reduce time to rash heal ing, and the duration and severity of acute pain in ‘older adults with herpes zoster who are treated within 72 hours of rash onset.” In some studies, the duration of chronic pain was also reduced, but the FDA has not approved these agents for the prevention of PHN.” Randomized controlled trials comparing acyclovir to valacyclovir, acyclovir to famciclovir, and valacyclo- ‘ir to lameicovi demonetrted equivalent rea rash healing, acute pain, and the duration of chronic pain." All three drugs are acceptable agents for older adults, with cost and dosing schedule determining the choice of agent. However, the reduced sensitivity of VZV compared with HSV, the existence of barriers to the entry of antiviral agents into tissues that are sites ‘of VZV replication, and the higher and more reliable blood levels of antiviral activity achieved, make fam- Ciclovir or valacyclovir preferable to acyclovir for oral treatment of herpes zoster. Because of the lower risk of PHN, antiviral therapy is less valuable 0 for treatment of uncom plicated herpes zoster in healthy people younger than ‘SOyears of age. The utility of antiviral agents isunproven if treatment is initiated more than 72 hours after rash ‘onset. Nevertheless, we believe that iti prudent to ini- tiate antiviral therapy even if more than 72 hours have elapsed after rash onset in patients who have zoster involving cranial nerves (e.g, ophthalmic zoster) (or who continue to have new vesicle formation.” ‘Ophthalmic zoster represents a special therapeutic challenge because of the risk of ocular complications. Examination by an ophthalmologist should be sought in most cases. Oral acyclovir has been shown ina ta domized, controlled trial to be effective in preventing ‘ocular complications of ophthalmic zoster” Famciclo- vir and valacyclovir appear to have efficacy compare ble to that of acyclovir in the treatment of ophthalmic Zoster, and are preferred for the reasons cited above." Immunocompromised Patients. random: ized, double-blind, placebo-controlled trial in immu: nocompromised patients with herpes zoster showed that IV acyclovir (500 mg/m’ qsh for 7 days) halted Progression of the disease, both in patients with local: zed herpes zoster and in patients with cutaneous di semination prior to treatment Acyclovir accelerated the rate of clearance of virus from vesicles and mark: cally reduced the incidence of visceral and progressive cutaneous dissemination. Pain subsided faster in 2° clovit recipients, and fewer reported PHN, but these differences were not statistically significant. Clinical trials comparing IV acyclovir to IV vidarabine for the treatment of herpes zoster in immunocompromised Patients showed that acyclovie was significantly more effective and less toxic" In patients with mld imo nocompromise and localized herpes zoster, otal acyl vir, valacyclovir, or famciclovir will usualy sufice ‘Aanulomied, controlled ta of oral facili vr sus oral acyclovir in patients with localized herpes 70°" tee following bone marrow or organ rareplonatn or cancer apy showed that the two treaties were equivalent in rash healing and loss of acute Pa and that both were well tolerated.” ANTI-INFLAMMATORY THERAPY, The por sibility that PHN might be caused by inflamaatioe Of the sensory ganglion and contiguous neural st te cet it ialenate Sor he une wi gcse Is during the acute phase of zoster temp to further reduce acute pain ae ponent PHNJocwsest controlled trials, however, showed that fa aion of ghueorticotds 10 eyglovie ai ot ee Uw’ nefence of chronic pain! Howe ghrwtcokts cl rece atte pain in mont tras, fury one tal of acyclovir and prednisone, the time aunterupte sleep, return to baseline daily ativ= Wiad cessation of analgeste therapy duced tn ants who received glucocorticoids.” Consequently, meeaperts advocate oral glucocorticokds for other: wit healthy older adults whose rash is complicated fy madecatotorsevere palin and who have no contra Pjcations 40 glucocorticoids.” Others believe that fre eanmon adverse effects of glucocorticolds argue st theit routine use in older patients with herpes peer We agree and do not recommend the use of glu- fevortcoids In this setting, Glucacorticolds, tn combi ation with effective antiviral therapy, may Improve trator outcomes and acute pain in VZV-induced facial purlyss and cranial polyneutitis, where compression Malfected nerves may contribute to disability. ANALGESICS. Greater severity of acute pain is a tak factor for PHN, and acute pain may contribute to ‘tentral 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 ‘xales, Clinicians should prescribe nonopiate or opi- ate analgesics with the goal of limiting the severity of pain to less than 3or4 ona ‘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 rain severity, underlying conditions, and response to specific drugs. A randomized controlled trial of oxy codone, gabapentin, or placebo in older adults with herpes zoster showed that oxycodone, but not gaba- Fentin, provided significantly greater pain relief than Placebo in patients with moderate-to-severe pain” This trial was not powered to analyze PHN, and there seo oer controled tal of the effect of Soto with opioids or gabapentin during the acute phase o herpes zoster on the eee development of PHN, Actossover study of a single dose of 900 mg of gabap- fntin during the acute phase of herpes zoster showed ‘eater pain relief than placebo.” If pain control ‘emains inadequate, regional or local anesthetic nerys Noeks should be considered for acute pain control.” ‘Arandomized controlled trial demonstrated that 4 Single epidural injection of corticosteroids and local in the acute phase of herpes zoster did not Prevent the subsequent development of PHN: MNT POSTHERPETIC NEURALGIA QX*esbished, tel | PHN is difficult to treat. Fortunately, fiselves ‘spontaneously in most patients, although often requires several months (Fig, 194-18). Cl Tits have advocated a wide range of treatments, {xling many oral and topical medications epidural ‘of local anesthetic and glucocorticolds, acu Purtute biofeedback, subcutaneous injections of tr and systernic actin inraton tl variety of compounds, Put mon hav not been validated by controlled trials. The revults of randomized controlled trials demonstrated etficacy hs pain rele in PHAN to ving rug al sgabalin, trieyelic antidepressants (TCAs) analgesics, tramadol, lidocaine patch 5%, and high concentration capsaicin patch." Th medications should be guided by th profiles, potential for drug, interactions, and patie ‘comorbidities and treatment preferences. On average, these agents provide adequate pain relief (defined as reduction of pain to below 4 on a 0-10 point scale or by 50% on a visual analog, or Likert scale) in 30% 4A? of patients, These modalities are noww recommended ay evidence-based pharmacotherapy lor PHN in practice management guidelines." TOPICAL THERAPY. Topical anesthesia delivered y means of a 5% lidocaine patch has been shown in controlled clinical trials to produce significant pain relief in patients with PHN, The 10 « Hem lidocaine patch contains 5% lidocaine base, adhesive, and other ingredients on a polyester backing. [lis easy to use al Is not associated with systemic lidocaine toxicity Up to three patches are applied over the affected a for 12 hours a day. The disadvantages of the pate application site reactions, such as skin redness oF rash ‘and substantial cost, Eutectic mixture of local anesthet ics (EMLA) cream applied once a day over the affected farea under an occlusive dressing, is an alternative method of delivering topical anesthesia, ‘A single I-hour application of a high-concentrati capsaicin patch (6%) compared with « low-concen- tration control patch significantly reduced pain from PHN from the second week after the capsaicin appli- cation throughout a subsequent 12-week period.” The hhigh-concentration patch was generally well tolerated ‘Adverse events include increases in pain associated ‘sith patch application (usually transtent) and appli tationste reactions (€, erythema). The role of the high-concentration capsaicin patch in the treatment DEPHIN is yet to be clearly established, partly because fis long-term benefits are not yet known. However, this intervention has promise because a single 1-hour pplication may yield several weeks of pain reduction, ane RAL AGENTS. Gabapentin has been shown to aes moderate or greater pain relief in 41%-43% of patients with PHN compare! to 12 “e-23' in patients Paniving placebo."™*" Frequent adverse efits 0 gab apentin include somnolence, dso en pergbra pared 10 20% in Placebo omnolence, and perp’ Fomnmnan adverse effect reportedPHN in several randomized, controlled trials. !""* Nortriptyline and desipramine are preferred alterna tives to amitriptyline because they cause fewe adverse effects, sedation, cognitive impairment, ortho- static hypotension, and constipation in the elderly." ‘Treatment with scheduled opioids may also reduce PHN. In a randomized, placebo-controlled crossover trial of sustained-telease oxycodone in patients with PHN, patients reported significant pain relief when treated with opioid compared to placebo." In a cross- ‘over study in patients with PHN, both controlled- release morphine and TCAs provided significant pain Compared to placebo." In this trial, patients pre- ferred treatment with opioid analgesics to either TCAs or placebo, despite a greater incidence of adverse effects and more dropouts during opioid treatment. The use of combinations of these drugs for PHN is common in clinical practice and undergoing, increas- ing investigation. In a crossover trial, patients with diabetic polyneuropathy or PHN were randomized to dail placebo (lorazepam), sustained-release morphine, gabapentin, and a combination of gaba- pentin and morphine."? Combination therapy with morphine and gabapentin produced greater pain relief than either agent alone or placebo, but with an increase in adverse effects (constipation, sedation, and dry mouth).Ina crossover trial, patients with diabetic poly- neuropathy or PHN were randomized to receive one of tree sequences of daily oral gabapentin, nortrip- tyline, and a combination of the two." Combination therapy with gabapentin and nortriptyline produced greater pain relief than either agent alone. The most common adverse event was dry mouth secondary to nortriptyline. These results suggest that combination therapy may benefit some individuals with PHN who have responded to one of the agents chosen, but at the risk of increased adverse effects than with either drug alone. ardiac PREVENTION PREVENTION OF VARICELLA VARICELLA VACCINE, Several studies conducted in Europe, Japan, and the United States from the early 1970s through the early 19903 demonstrated that live attenuated (Oka strain) VZV vaccines were immuno- genic and efficacious in protecting susceptible children ‘against varicella, Although breakthrough cases of vari- cella were observed following subsequent exposure to wild-type VZV, they were relatively mild.” Similar results were obtained in adults when two doses were given 4-8 weeks apart. Vaccinated children and adults breakthrough varicella caused by wild-type VZV ata rate of 1%-3% per year compared to an attack rate of 8%-13% 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. In 2005, the FDA approved a combined measles, mumps, rubella, and varicella vaccine (MMRV) for routine immunization of children 12 months to 12 years of age. Because of tne mstency of breakthrough yy caused by wild-type VZV, the Advisory Comm Immunization Practices (ACIP) now recomme OS. doses of varicella vaccine fot healthy ge aged 212 months, adolescents, and adults wien dence of immunity.” For children aged 12 moa 12 years, the recommended minimum intervalteres the two doses is 3 months, although the seconds” may be administered as soon as 28 days after hee For persons aged >13 years, the recommended set mum interval is 4 weeks. Single-antigen varies ve cine is approved for use among healthy persone a. 212 months, Combination MMRV vaccine isapp for use among healthy children aged 12 month, » 12 years. Because of the increased severity of varuen, in adults, susceptible adults should be identifod wg vaccinated. High priority should be given to vaccina ingadults whomay be at increased risk foreaposuney transmission and who do not have evidence of imma nity, including (1) health care providers, (2) househis contacts of immunocompromised persons, incising susceptible pregnant women, (3) persons who Ine work in environments in which transmission of VZV is likely (e.g, teachers, day care employees, resides, and staff in institutional settings), (4) persons who live or work in environments in which transmission has been reported (e.,, college students, inmates and staff members of correctional institutions, and military personnel), (5) nonpregnant women of childbearing age, (6) adolescents anc adults living in househols with children, and (7) international travelers. Send dose catch-up varicella vaccination is recommended for children, adolescents, and adults who previously received only one dose. The immunity to varicella induced by varicella va cine is not as soli as that induced by wild-type VZV infection, and the duration of vaceine-induced imi nity is not yet known. However, a high percentage o en followed long-term have remained serop tive." Recent experience in clinical practice indicat that vaccine efficacy in children is modestly lower than that reported in clinical trials, and outbreaks of bra through varicella in schools and day care centers occur." Ina prospective, population-based tu vaccine effectiveness for prevention ofall disease "8 789% (95% Cl, 69.7%,-85.3%); for prevention of moder ate disease was 92% (50-500 lesions) and for prev”, tion of severe disease and physician visits was 10% A CDC analysis of 10 years of surveillance dats foe Varicella (1995-2004) showed that the annual rate f breakthrough varicella significantly increased with time since vaccination, from 1.6 cases per 1,000 pers Years (95°C 1.2-2.0) within 1 year after vaccinatio® 9.0 pet 1,000 person-years (95% Cl, 69-11.7) at 5 yea" and 582 per 1,000 person-years (95% Cl, 360-40) at 9 years." Although most breakthrough anc! in children are characterized by mild disease. Fecent reports indicate that 25%-20"% of breakthrou” ‘eases are not mild and are clinically similar t ¥¥ cella in unvaccinated children.” Interesting!y: Petkthrough varicella in household settings half as contagious as cases of varicella in unvoe< Persons, although the minority of breakthrough = Ah reg| él wns oF more Were as contagious as cases in <{ persons. In adults, approximately 20% of ‘e detectable antibodies to VZV over time, “to be partially protected." Of the 48 os of varicella vaccine distributed between su) 2005, there were 25306 adverse events { (52.7/100,000 doses distributed) to the FDA's ‘Adverse Event Reporting System and the for Disease Control and Prevention (CDC)"" cel which were nonserious events, mainly minor and injection site reactions." Serious adverse cents were rare (2.6/100,000 doses distributed) and, the majesty, a causal relationship between the seri- aygverse event and varicella vaccine could not be wih Herpes zoster has been reported in vaccinees, totit occurs ata significantly lower frequency than foes zoster in persons of similar age following emrella caused by wild-type VZV. Cases f laboratory herpes zoster in vaccinees from several Staies included some cases caused by reactivation of thevaceine virus and others caused by reactivation of triutype virus acquired prior to vaccination as a con- Sequence of unrecognized varicella, POSTEXPOSURE __ PROPHYLAXIS = AND INFECTION CONTROL. Patients with varicella and herpes zoster may transmit VZV to susceptible individuals. Preventive measures include the varicella vvaxine, investigational high-titer zoster immune glob- ulin (VariZIG), and postexposure chemoprophylaxis with acyelovi Active immunization with the live attenuated vari- cela vaccine is effective in preventing illness or modi- fying varicella severity in children if used within 3 days after exposure." Whereas protection afforded by zester immune globulin is transient, varicella vaccine induces long-lasting (active) immunity to VZV and Poiection against subsequent exposures. Therefore, ‘be ACIP recommends varicella vaccine for postexpo- Sure prophylaxis in unvaccinated persons without evi- ‘of immunity.” Passive immunization with VZIG was an effec: Re Beeventive strategy, but the production of VZIG ten discontinued in the United States. An ‘cvestigational VZIG, VariZIG, is available under an ezational new drug. application (IND). The saigational VariZIG isa purified human immune (Putin prepared from plasma containing high levels ated to VZV (immunoglobulin class G [IgG))- been uct can be requested for patients who have {°©-Posed to varicella and who are at increased risk Severe disease and complications." posh beet ylaxis with acyclovir also we susceptible children following household sage Wt t0 varicella, Children who received postexpo- ‘treatment with acyclovir experi fewer and try hYet® cases of varicella than children in the con- any SYP. However, appropriate timing, is eritical, cay ™Munlty to varicella may not be achieved, espe- thay ith early postexposure treatment: In addition, seg ence that eesistant strains of VZV may Pe by promiscuous application of this approach. Hence, postexposure antiviral chemotherapy is not Fecommended for routine use in children. Infection control practices for VZV increase in impor- tance with the age and compromised! immune status of the exposed, susceptible individual. There is no need to prevent exposure of susceptible normal children to VZV, but careful isolation procedures should be enforced to prevent infection of susceptible immuno- compromised patients, newborn infants, and adults, particularly women of childbearing age. Exposure of susceptible immunocompromised ‘patients to VZV warrants reduction in the dosage of glucocorticoids and other immunosuppressive drugs, and adminis- tration of investigational VariZIG. Hospital and long term care facility personnel without a clear history of varicella or herpes zoster should be tested for antibody to VZY, and susceptible personnel vaccinated against varicella, Appropriate leave from work should be insti- tuted following VZV exposure of any susceptible per- sonnel who are not vaccinated. In hospitals, airborne and contact precautions are recommended until all lesions are crusted for patients with varicella, immu nocompromised patients with localized herpes zoster, and any patient with disseminated herpes zoster." Contact precautions are recommended for immuno- competent patients with localized herpes zoster, Ae mai Aee dt ail ZOSTER VACCINE. Until universal varicella vacel- nation greatly reduces the number of people latently infected with wildtype VZV, prevention of herpes zoster must be aimed at preventing reactivation and spread of the latent wildstype VZV. Long-term sup- pressive acyclovir treatment is only practical in immu- nocompromised patients at proven risk of developing, herpes zoster within a defined time period, for exam ple, in the year following bone marrow oF solid organ transplantation. Other strategies must be devised for the general population. ‘One approach to the prevention of herpes zoster is the stimulation of immunity to VZV, which wanes in the elderly and in other high-risk individuals.* Studies of healthy adults over 55 years of age with a history of varicella have demonstrated an increase in VZV-specific T lymphocytes and humoral immu- nity after vaccination with live attenuated VZV vac- Cine that is similar to the increase observed after an episode of herpes zoster These findings suggested that vaccination of older persons may be useful in preventing herpes zoster and its complications." A Pecent VA Cooperative Study (the Shingles Prevention Study) tested the hypothesis that vaccination against VZV would decrease the incidence and/or severity of herpes zoster and PHN among older adults." The Study enrolled 38,546 adults 60 years of age or older in a randomized, double-blind, placebo-controlled tal of a live attenuated Oka /Merck VZV vaccine of much greater potency than the currently licensed var- Itella raccine. A total of 957 confirmed cases of herpes Joster (15 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% (P <0.001), reduced the incidence of PHN by 66.5% (P <0.001) ), and reduced the incidence of herpes zoster by 51.3% (P <0.001). Reactions at the injection site were more frequent among vaccine recipients but were generally mild. The proportion of ‘subjects reporting serious adverse ‘events, and rates ‘of hospitalization and death were comparable in vac- cine and placebo recipients." Furthermore, the z03- ter vaccine neither caused nor induced herpes zoster in recipients. This landmark study showed that the zoster vaccine markedly reduced morbidity from her- Pes zoster and PHN among older adults. The FDA licensed the zoster vaccine for the prevention of her- Pes zoster in adults 60 years of age and older in 2006. The ACIP of the CDC unanimously recommended the vaccine for the prevention of herpes zoster and its complications, including PHN, in immunocompetent adults 60 years of age and older, irrespective of a his- tory of herpes zoster.” Zoster vaccine has now been added to the US schedule of routinely recommended adult immunizations.” The zoster vaccine may be administered without screening for a history of varicella or herpes zoster, nor should one conduct serologic testing for varicella immunity before vaccination.” Persons known to be VZN seronegative should be vaccinated against vari- cella according to current recommendations.” Older adults who have PHN or who have a current episode of herpes zoster may ask to be vaccinated, but zoster vaccination is not indicated to treat acute herpes 20s- ter or PHN. Some patients may want to receive 20s- ter vaccine after a recent episode of herpes zoster has resolved. The optimal time to immunize an individual after a recent episode of herpes zoster is unknown, and the clinical diagnosis of herpes zoster is not always cor- rect. The authors believe that an interval of 3-5 years after the onset of a well-documented case of herpes zoster is reasonable. A history of anaphylactic reaction to any of the vac- cine components is a contraindication to the vaccine? Neomycin is a vaccine component but contact derma- titis due to neomycin does not represent anaphylaxis and therefore is not a contraindication to zoster vacci- nation. The zoster vaccine should not be given to per sons who have severe acute illness, including active untreated tuberculosis, until the illness has subsided, Persons with leukemia, lymphomas, or other malig. nant neoplasm affecting the bone marrow or lymphatic ‘system, or with AIDS or other clinical manifestations of HIV infection, including those with COS" T-lympho. cyte counts $200 per mm’ and/or <15% of total lyme phocytes should not receive zoster vaccine.” Persons ‘on immunosuppressive therapy, including high-dose corticosteroid therapy, should not receive the vaccine. The ACIP defines high-dose corticosteroids as 20 mg or more per day of oral prednisone or equivalent fee 14 days or more” Low doses of methotrexate {204 mg/kg/week), azathioprine (53.0 mg/kg/day), or 6-mercaptopurine (S1.5 mg/kg/day) are not con. sidered to have significant immunosuppression ON When considering the zoster vaccing may express concems about transmit Aa, cine virus to other individuals. Tranam ne requires the development ofa vesiculgr nat Ve, ing vaccine virus after vaccination. If the fe there is no transmission. Zoster vacqyn° ts, vesicular rashes are very unusual, In the sti! Prevention Study, vesicular lesions at the site were observed in 20 of 19,270 vaccine, & median of 3-4 days after vaccination ang oP 19,276 placebo recipients. Neither vaccine n° wild-type VZV were detected by DNA Toye in the few specimens that were available for sO Transmission of vaccine virus from recipients vaccine to susceptible household contacts has rote documented. Thus, immunocompetent oljer in contact with immunosuppressed patiens dua receive zoster vaccine to reduce the risk tht they ns develop herpes zoster and transmit wildtype Vy their susceptible immunosuppressed contats fo the same reasons, adult contacts of susceptiie pt nant women and infants should receive roster vanes Zoster vaccine recipients with susceptible przns or immune compromised contacts need not tke special precautions following, vaccination, ec the rare situation that a vesicular rash develqy ¢ Which case standard contact precautions are adore Eligible residents and personnel in nursing homes ax! other facilities housing older adults should alo vaccinated against herpes zoster. However, VZVse- Negative persons (e.,, health care workers fom top cal countries who have not had varicella) shold © vaccinated against varicella. These recommendats are consistent with those of the ACIP Inthe unl event that an immunocompromised contact deve! significant illness caused by vaccine virus he/she) be treated with standard anti-VZV agents (accor valacyclovir, or famciclovir). With the development of the varicella and 2s ‘vaccines, antiviral therapy, and neuropathic pain" ments, clinicians now have multiple effective to reduce human suffering from varicella and bef zoster. ACKNOWLEDGMENT Dedicated to the memory of Stephen E. Stray thor of this chapter in previous editions. him Full reference lst available at wnrweDIGMSo™ ODVD contains references and additions ones! a 4 Nguyen HQ. Jurmaan AO, Seward JF Decne Spy ity due te «after implementabar of 430, sed States, Engl] Mal 3S 7 Seward J¥ et si Varicella disease afte Jy Varicella vaccine in the United States. | wet ” 8, Jumaan AO et al: Incidence of herpes 20867 in after varicellacvaceintion associated 8 co