水痘

VARICELLA–ZOSTER VIRUS (HHV-3) Introduction VZV is the etiology of varicella (chickenpox) and herpes zoster (shingles). Varicella is usually symptomatic, and, before the advent of the varicella vaccine, it occurred in 90% of children in the US by the time they reached 10 years of age. Herpes zoster represents reactivation of latent varicella infection and develops in approximately 20% of healthy adults and 50% of immunocompromised persons. Due to the high morbidity and mortality of VZV in immunocompromised hosts, the clinician should remain vigilant for disease manifestations and be able to differentiate herpes zoster from other zosteriform cutaneous eruptions. Early initiation of antiviral treatment is crucial, as it can reduce or eliminate serious disease-associated sequelae. History Heberden first distinguished chickenpox from smallpox in 1767. The word ‘chickenpox’ comes either from the old French word ‘chiche-pois’ for chickpea (referring to the vesicle size) or the Old English word ‘gican’ meaning ‘to itch’[24]. Varicella and zoster were not associated clinically until 1888, when von Bokay described the development of varicella in children following exposure to those with herpes zoster infection. Kundratiz (1922) and Bruusgarrd (1932) more convincingly demonstrated the association between the two diseases by the development of varicella in susceptible children who had been inoculated with vesicle fluid from patients with herpes zoster lesions. Weller et al.[25] identified in vitro the same virus in both diseases, confirming that their etiologies were identical. Epidemiology VZV has a worldwide distribution and 98% of the adult population is seropositive. Varicella, characterized by disseminated pruritic vesicles, affects 90% of unvaccinated children less than 10 years of age. Prior to the introduction of the varicella vaccine, 3 to 4 million cases occurred annually in the US. Varicella epidemics occur seasonally (during the winter and spring) in metropolitan areas with temperate climates[26]. Although herpes zoster classically is a disease of adulthood that affects those older than 50 years of age more severely, it is common in younger persons who had primary varicella infection within the first year of life. Individuals with a history of primary varicella have a 20% lifetime chance of developing zoster. The severity and incidence of the infection increase significantly with age. The annual incidence of herpes zoster in the US and Europe is 2.5/1000 persons between ages 20 and 50 years, 5.1/1000 between ages 51 and 79 years, and 10.1/1000 in those older than 80 years of age[27]. It is likely, however, that introduction of the varicella vaccine will alter the incidence of zoster. The incidence of both varicella and herpes zoster has increased in the immunocompromised population, especially in those infected with HIV. Pathogenesis Airborne droplets are the usual route of transmission of primary varicella (chickenpox), although direct contact with vesicular fluid is another mode of spread. The incubation period ranges from 11 to 20 days. Varicella is extremely contagious, with 80-90% of susceptible household contacts developing clinical infection[26]. The affected individual has the ability to infect others until all of the vesicles have crusted. During primary varicella infection, viremia follows an initial 2 to 4 days of replication within regional lymph nodes. A secondary viremia develops after a second cycle of viral replication in the liver, spleen and other organs, and seeds the entire body. The virus travels to the epidermis by invasion of capillary endothelial cells approximately 14 to 16 days post exposure. VZV subsequently travels from cutaneous and mucosal lesions to invade dorsal root ganglion cells, where it remains until reactivation at a later date. Herpes zoster appears upon reactivation of VZV, which may occur spontaneously or may be induced by stress, fever, radiation therapy, tissue damage (i.e. trauma) or immunosuppression. During a herpes zoster infection, the virus continues to replicate in the affected dorsal root ganglion and produces a painful ganglionitis. Inflammation and neuronal necrosis can result in a severe neuralgia that intensifies as the virus spreads down the sensory nerve. A person with zoster can infect another with varicella (i.e. chickenpox) if the susceptible person comes into direct contact with vesicular fluid. Individuals with chickenpox or shingles, however, cannot directly give another person shingles, because herpes zoster is caused by the reactivation of latent VZV. Clinical FeaturesVaricella Primary varicella usually begins as a prodrome of mild fever, malaise and myalgia, followed by an eruption of pruritic, erythematous macules and papules, starting on the scalp and face then spreading to the trunk and extremities (Fig. 79.13). Lesions rapidly evolve over 12 to 14 hours into vesicles 1–3 mm in diameter with clear serous fluid surrounded by narrow red halos (‘dew drops on a rose petal’). The number of vesicles varies from only a few to several hundred and there is often involvement of the oral mucosa. Sparing of the distal or lower extremities is common. Older lesions evolve to form pustules and crusts and heal within 7 to 10 days. The presence of lesions in all stages of development is the hallmark of chickenpox. The disease course is usually self-limited and benign in healthy children. However, complications can occur in otherwise healthy children, as manifested by 11 000 hospitalizations annually in the US prior to the introduction of the varicella vaccine in 1995 (which has led to a dramatic decrease). Secondary bacterial infection of lesions with subsequent scarring is the most common complication. CNS complications, including Reye's syndrome, encephalitis and acute cerebellar ataxia, are rare, occurring in less than 1 per 1000 cases[28]. Primary varicella in adults often produces a more severe clinical syndrome, with more complications and an increased number of skin lesions, than in children. Pneumonia may develop in affected adults and has a 10-30% mortality rate if untreated[29]. Rare complications include glomerulonephritis, optic neuritis or keratitis, arthritis, myocarditis, pancreatitis, orchitis, hepatitis and vasculitis. Congenital varicella infection can be associated with a wide array of fetal abnormalities, especially if the maternal infection occurs during the first trimester. This infection carries a 2% risk of embryopathy. Congenital defects include low birthweight, cicatricial skin lesions, ocular abnormalities, cortical atrophy, psychomotor retardation and hypoplastic limbs. In immunocompromised individuals, varicella can lead to significant morbidity and mortality. These patients frequently have a more extensive and atypical cutaneous eruption, often with hemorrhagic or purpuric lesions. Visceral involvement of the lung, liver and CNS is common. Herpes zoster Reactivation of VZV may occur at any time after the primary varicella infection. Herpes zoster often begins with a prodrome of intense pain, and, in more than 90% of patients, it is associated with pruritus, tingling, tenderness or hyperesthesia. If severe enough, the pain can be misdiagnosed as a myocardial infarction, pleurisy or surgical abdomen. Rarely, the pain is not followed by the cutaneous eruption of herpes zoster, and this clinical presentation is known as ‘zoster sine herpete’ (i.e. zoster without rash). However, in most patients, a painful eruption of grouped vesicles on an erythematous base develops within a sensory dermatome (Fig. 79.14), usually on the trunk. In some cases, the face, neck, scalp or an extremity may be involved (Fig. 79.15). The cutaneous eruption typically involves a single dermatome and rarely crosses the midline. Zoster usually resolves without sequelae in children and young adults with intact immune systems. However, the pain, cutaneous eruption and complications of zoster become more severe with increasing age and immune compromise. Complications of zoster include postherpetic neuralgia, secondary bacterial infection, scarring, ophthalmic zoster, Ramsay–Hunt syndrome, meningoencephalitis, motor paralysis, pneumonitis and hepatitis. Both the severity and the incidence of postherpetic neuralgia increase with age, with 10-15% of all zoster patients developing this complication[30]. Ophthalmic zoster occurs in 7% of zoster patients (see Fig. 79.15B), with 20-70% developing associated ocular disease, including blindness[31]. Ramsay-Hunt syndrome is due to reactivation of VZV infection of the geniculate ganglion, and in addition to vesicles of the ear canal, tongue and/or hard palate, patients may have acute facial nerve paralysis, pain in the ear, taste loss of the anterior two-thirds of the tongue, and a dry mouth and eyes. If the vestibulocochlear nerve is also affected, then tinnitus, hearing loss and/or vertigo can develop. In immunocompromised hosts, herpes zoster may be quite severe and can have unusual clinical presentations, e.g. persistent, crusted, verrucous lesions in HIV-infected patients (Fig. 79.16) or postherpetic hyperhidrosis[32]. Disseminated cutaneous disease (defined as more than 20 vesicles outside the area of primary or adjacent dermatomes) and/or visceral involvement occurs in approximately 10% of immunocompromised persons (Fig. 79.17)[33]. Diagnosis and Pathology A clinical diagnosis, based upon both the history (e.g. initial episode versus multiple recurrences; previous history of varicella or receipt of the varicella vaccine) and the physical examination, is very important because a decision regarding instituting antiviral therapy is critical. If further laboratory tests are warranted to aid in the diagnosis, a Tzanck smear and/or a DFA are initially performed, given their rapid turnaround times. In the former, characteristic multinucleated epithelial giant cells are visualized by light microscopy, but cannot be differentiated from those due to HSV infection. DFA, on the other hand, allows distinction. Likewise, a lesional biopsy will demonstrate the same histopathologic features for both HSV and VZV, but immunohistochemical staining can differentiate between the two viral infections. Additional laboratory tests include viral culture, serology and PCR. Viral culture is a very specific test; however, it is not very sensitive and results may not be available for at least 1 week. Serologic assays are diagnostic of VZV if the convalescent serum has at least a fourfold increase in the VZV titer relative to the acute serum. As a result, serology is only useful retrospectively (i.e. after it is too late to initiate antiviral therapy). PCR is a highly sensitive molecular technique and its use as a diagnostic test of choice is increasing[26]. Differential Diagnosis The differential diagnosis of varicella includes HSV, vesicular viral exanthems (Coxsackie, ECHO), pityriasis lichenoides et varioliformis acuta (PLEVA), rickettsialpox, a drug eruption, contact dermatitis, and, occasionally, insect bites or even scabies. HSV typically has more localized lesions at the site of primary infection; however, disseminated disease can sometimes mimic varicella. PLEVA is a chronic inflammatory disorder; hand, foot and mouth disease also involves the oral mucosa but favors the distal extremities; and the initial lesion in rickettsialpox is the site of the mite bite. Insect bites are associated with an underlying wheal and can occur singly or multiply. Scabies tends to occur within body folds and is associated with linear burrows and a more prolonged period for lesion development. Contact dermatitis is not associated with the clinical prodrome of VZV infection and it more commonly involves the extremities. Although no longer naturally occurring, smallpox is in the differential diagnosis of varicella. The distinguishing features of smallpox versus chickenpox are reviewed in Chapter 80. HSV, localized contact dermatitis, and bacterial skin infections (e.g. bullous impetigo, cellulitis) are in the differential diagnosis of herpes zoster infection. HSV, especially the zosteriform variant, can simulate zoster but is associated with recurrent lesions at the same site. In contact dermatitis and bacterial skin infections, the DFA is negative and no multinucleated epithelial giant cells are seen by Tzanck smear. Treatment and Prevention Varicella in children with normal immune systems can be treated symptomatically with antipyretics, antihistamines, calamine lotion and tepid baths. If started within 24 to 72 hours after the onset of the cutaneous eruption, acyclovir has been shown to decrease the duration and severity of varicella infection. Oral acyclovir is FDA-approved for the treatment of varicella in adults and children over 2 years of age, and the intravenous form is indicated for immunocompromised patients (see Table 79.2). Acyclovir is clearly recommended for varicella in the adult population due to the increased risk of more severe disease and complications[34]. Due to their three-times-daily dosing, valacyclovir and famciclovir are frequently used (at dosages indicated for zoster) to treat primary varicella in teenagers and adults, but neither drug is specifically FDA-approved for this purpose. Prevention of primary varicella infection has become a major focus for clinicians. Varicella zoster immunoglobulin (VIG) is available as passive VZV prophylaxis for all susceptible immunocompromised individuals with a first-time exposure to varicella (recommended dose is 125 U/kg) and is to be administered within 96 hours of exposure[35]. It is also recommended for all susceptible pregnant women, as well as neonates whose mothers became infected shortly before birth. Protection usually lasts for 3 weeks. Approved by the FDA in March 1995, the live attenuated VZV vaccine (Oka strain; Varivax®) is highly efficacious, with a 96% seroconversion rate in healthy children. Two doses of the vaccine are now recommended for all children, at ages 12 months and 4-6 years, in order to improve protection and hopefully counteract waning vaccine-induced immunity (see below). Studies indicate that the vaccine is 70-90% effective in preventing all disease and 95-100% effective in preventing severe disease. Not only is the severity of the primary varicella infection less in vaccinated children who subsequently become infected, but there is a decreased incidence of zoster in vaccinated children compared to that seen in naturally infected children[36]. The CDC has also noted significantly reduced rates of varicella in areas with high rates of vaccination[37]. In a recent report based on surveillance of 350 000 subjects, loss of vaccine-induced immunity over time was observed, e.g. within 1 year of vaccination, there were 1.6 cases of varicella per 1000 person-years versus 58.2 per 1000 person-years at 9 years post-vaccination[38]. Although the Oka strain can occasionally reactivate and lead to herpes zoster (usually mild), most cases of varicella following vaccination are thought to be due to wild-type virus. For herpes zoster, early treatment with antiviral agents, i.e. within 72 hours of the onset of the first vesicle, is optimal, but initiation of antiviral therapy after 72 hours but within 7 days also appears to be beneficial[39]. Acyclovir, famciclovir and valacyclovir are all FDA-approved for the treatment of zoster in immunocompetent individuals and result in decreased disease duration and pain. Intravenous acyclovir is indicated for the treatment of zoster in immunocompromised patients as well as those with serious complications[26]. Multiple treatments are available for postherpetic neuralgia. In controlled studies, famciclovir and valacyclovir were equally effective at reducing the duration and pain of postherpetic neuralgia in immunocompetent persons over 50 years of age[40]. Other treatments include analgesics, EMLA cream, lidocaine patches, topical capsaicin, narcotics, nerve blocks, biofeedback, tricyclic antidepressants, gabapentin and pregabalin[41]. Low-dose tricyclic antidepressants have demonstrated considerable efficacy and appear to act by a mechanism of action independent from their antidepressant effects. In a randomized, controlled, multicenter trial, gabapentin (in doses ranging up to 3600 mg/day) was found to be effective in the treatment of pain and sleep interference associated with postherpetic neuralgia[42]. Additionally, combination therapy has been examined, e.g. acyclovir plus prednisone was shown to decrease pain in some individuals, but in a controlled trial there was no statistically significant difference when the combination was compared to acyclovir monotherapy[43]. In an open trial, valacyclovir plus gabapentin appeared to be very effective in preventing postherpetic neuralgia, if used acutely[44]. Because reactivation of VZV is linked with states of decreased cell-mediated immunity, the varicella vaccine has also been studied as prophylaxis for herpes zoster. Two initial investigations showed that the vaccine increased immunity against VZV in elderly patients[45], while a third study demonstrated enhanced immunity for only 1 year after vaccine administration, with 10-15% of vaccinees failing to develop any enhanced immunity[46]. However, the latest data from a large-scale trial utilizing a more concentrated (14-fold) version of the varicella vaccine in almost 40 000 patients showed a 67% decrease in the incidence of postherpetic neuralgia in vaccine recipients and a reduction of 51% in the development of zoster[47]. These results led to FDA approval of this vaccine (Zostavax®) for persons at least 60 years of age without a history of herpes zoster.