Varicella-Zoster virus: Recent therapeutic advances

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Rosalie Sagraves, Pharm D, FCCP Professor of Pharmacy Practice Assistant Dean for Academic Affairs College of Pharmacy University of Oklahoma Health Sciences Center Oklahoma City, Oklahoma

Varicella-Zoster Virus: 9 Recent Therapeutic Advances

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Yvette Morrison, PharmD, BCPS

Infection with the herpes virus known as varicella-zoster virus (VZV) is generally manifested in two different forms during two separate periods of the human life cycle. The primary infection, varicella, commonly referred to as chickenpox, usually occurs during childhood while reactivation of the latent virus typically among the elderly causes secondary zostcr, or shingles. Treatment of varicclla infections in otherwise healthy pediatric patients has traditionally been symptomatic. Acyclovir (Zovirax) is an antiviral compound with known activity against VZV, and recent studies suggest it may have a role in therapy under certain circumstances. Also, on the horizon is a vaccine against VZV infection that may soon be marketed in the United States. The purpose of this article is twofold. First, a review of the epidemiology, clinical manifestations, and complications of childhood chickcnpox will be presented. Second, the literature surrounding the use of acyclovir in otherwise healthy children and possible vaccine prevention of this common childhood disease will bc summarized. 9 EPIDEMIOLOGY Infection with V Z V is virtually a universal childhood infection that commonly occurs during late winter through early spring (Committee on Infectious Diseases, American Academy of Pediatrics, 1994). In the

Yvette Morrison, PharmD, BCPS, is a Clinical Assistant Professor in the Department of Pharmacy Practice at the College of Pharmacy of the University of Oklahoma Health Sciences Center in Oklahoma City, Oklahoma. J PEDIATRHEALTHCARE. (1995). 9, 81-86. Copyright 9 1995 by the National Association of Pediatric Nurse Associates and Practitioners. 0891-5245/95/$3.00 + 0

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United States alone, varicella develops in an estimated 3.5 million persons each year. About 90% of these cases occur in children 1 to 14 years of age. Usually a selflimiting disease in an otherwise healthy child, complications can result in at least 4000 hospitalizations and 50 to 100 deaths annually (Preblud et al., 1984; Preblud, 1986). Furthermore, in 1986 Preblud estimated the annual cost derived from varicella infection to be approximately $400 million in the United States. Comparatively, a significantly larger portion of this cost is allocated toward lost wages by parents who care for their sick children at home rather than "traditional" medical costs such as physician office visits and medications (Preblud, 1986). Because of the financial impact resulting from varicella infection, emphasis is now being focused on therapeutic options either presently available or ones that could bc developed to reduce the financial hardship of childhood chickcnpox. 9 CLINICAL MANIFESTATIONS VZV infections are highly contagious and occur in susceptible individuals exposed to the virus following intimate contact. Approximately 90% of susceptible family members with continuous exposure to an infected individual will contract the disease (Balfour et al., 1990). The time interval between exposure to the virus and the development of symptoms generally ranges between 10 to 20 days (Whitley, 1995). Otherwise healthy children are deemed most contagious during the period beginning 1 to 2 days before the onset of lesions up to 5 days after lesions appear (Committee on Infectious Diseases, American Academy of Pediatrics, 1994). In the normal child, chickenpox usually is seen as a 1- to 2-day prodromal illness consisting of a low-grade fever and malaise. The characteristic vesicular eruption 81

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often begins on the head and trunk, spreading outward to the extremities. These lesions exist in various evolutionary stages, initially appearing as red papules, then clear "dew droplike" vesicles. Within a few hours, the vesicular fluid will become cloudy in appearance and scab formation ensues. Successive "pox crops" generally appear over a 2- to 4-day period. Other constitutional symptoms that may be experienced by a child with chickenpox include pruritis, anorexia, and headache (Balfour et al., 1990; Committee on Infectious Diseases, American Academy of Pediatrics, 1994; Drwal-Klein & O'Donovan, 1993; Whitley, 1995). Immunocompetent children are generally considered to be at low risk for developing serious varicella-related complications. Of those complications reported to occur, most involve the skin, central nervous system, or respiratory system. The most common complication is bacterial superinfection of the skin secondary to normal skin flora. Central nervous system complications include encephalitis and Reye's syndrome. Respiratory complications in the form of viral or bacterial pneumonia may also occur, although the latter is more common (Preblud, 1986). 9 TREATMENT

Therapeutic interventions in the otherwise healthy child are typically symptomatic and targeted toward the reduction of complications, namely the development of secondary skin infections. Close attention to hygiene is of the utmost importance. The child's fingernails should be trimmed, and the child should be bathed with an antibacterial soap to decrease the risk of infection. Frequent lukewarm soaks may help reduce pruritis, and the use of commercial products, like (colloidal oatmeal (Aveeno; Rydelle Laboratories, Racine, Wis.), may provide soothing relief (Edwards, 1993). Over-the-counter medications are often relied on for their palliative effects. Because of the association between aspirin use and Reye's syndrome, acetaminophen (Tylenol; McNeil Consumer Products Co., Washington, Pa.) is considered the antipyretic of choice when indicated for a child with varicella (Committee on Infectious Diseases, American Academy of Pediatrics, 1994). Topical products such as calamine lotion (8% calamine, 8% zinc oxide, 2% glycerin) may exacerbate the development of skin infections especially when used on weeping lesions because caking of the lotion may prompt a child to pick at the lesions (Drwal-Klein & O'Donovan, 1993; Edwards, 1993). Diphenhydramine (Benadryl; ParkeDavis Pharm. Research, Morris Plains, N.J.) is another over-the-counter item frequently utilized in the treatment of chickenpox and is available both orally and topically. Although effective at relieving the troublesome pruritis, it should be administered with extreme caution. Chan and Wallander (1991) reported three

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cases of diphenhydramine toxicity in children with VZV infection. These children displayed acute mental status changes and had serum diphenhydramine concentrations approximately 15 to 20 times higher than what is considered potentially toxic. Two of the three children received oral diphenhydramine concomitantly with topical administration; however, the remaining case resulted from topical use only. Because patients with chickenpox have disrupted skin barriers in conjunction with potentially extensive surface area involvement, significant diphenhydramine absorption can be expected. Consequently, if diphenhydramine is used, oral administration alone is preferred (Drwal-Klein & O'Donovan, 1993). In 1992, oral acyclovir received approval from the Food and Drug Administration for the treatment of varicella infections in otherwise healthy children, representing another therapeutic modality (Committee on Infectious Diseases, American Academy of Pediatrics, 1993). Acyclovir is an acyclic analogue of guanosine. To exert its antiviral activity, it must be phosphorylated first by viral thymidine kinase and then subsequently by host cell enzymes. In its triphosphate form, acyclovir inhibits viral DNA polymerase thus terminating viral replication. Based on this mechanism of action, prompt initiation of therapy seems logical so that its maximal effect on an active, replicating virus can be exerted. Acyclovir displays selective uptake into infected cells, thereby reducing the potential toxic effect to the host (Balfour & Englund, 1989; Whitley & Gnann, 1992). Three randomized, double-blind, placebo-controlled studies have been designed to evaluate the safety and efficacy of acyclovir therapy for varicella in otherwise healthy children and adolescents. Balfour et al. (1990) enrolled 105 children (5 to 16 years of age) with laboratory-confirmed varicella. Fifty-two were given placebo, and 50 received acyclovir suspension in an ageadjusted dose of 10 to 20 mg/kg/dose four times daily for a minimum of 5 days. The administration of acyclovir within 24 hours of the rash onset shortened the median number of days from enrollment to certain defined events: (a) number of days until the maximum number of lesions was observed (1 vs 2 days, p -- 0.02); and (b) number of days until a decrease in the quantity of lesions was noted (3 vs 4 days, p = 0.001). A significant difference existed between acyclovir and placebo in the maximum number of lesions (336 vs 500, p = 0.02) and the median number of days to defervescence post-enrollment (1 vs 2 days,p = 0.001). Acyclovir use had no significant effect on the frequency of pruritis, complication rate, number of missed school days, or intrafamilial transmission ofchickenpox. A subset analysis of placebo patients revealed adolescent patients were sicker than subjects 2 to 12 years of age. VZV antibody titers were unaffected by acyclovir therapy when titers were obtained 1 year after treatment.

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Adverse effects caused by acyclovir were not reported during this trial. In a subsequent trial, Dunkle et al. (1991) administered acyclovir suspension 20 mg/kg/dose or placebo to 724 healthy children 2 to 12 years of age in whom a varicella rash developed during the previous 24 hours. Therapy was given four times a day for 5 days. The children who received acyclovir (n = 367) had significandy fewer lesions than those in the placebo group (294 vs 347, p < 0.001) and had a smaller percentage of patients with more than 500 lesions (21% vs 38%, p < 0.001). By day 3, more than 95% of the children in the acyclovir group had formed all cutaneous lesions compared to less than 80% in the placebo group. Cutaneous improvement as defined by the investigators was noted by day 2 in 80% of the acyclovir patients as compared to 45% of the placebo patients. Children receiving acyclovir had fewer residual lesions at day 28 compared to those in the placebo group (13 vs 33, p < 0.001). Defervescence by day 3 was noted in nearly all acyclovir recipients, compared to approximately 25% of placebo recipients (p < 0.001). Disease-related complications were reported in this study; however, their occurrence was not statistically correlated with either treatment group. O f the complications noted, secondary bacterial skin infections were the most commonly identiffed. The use of acyclovir did not affect antibody titers when evaluated at day 28. As a follow-up to their previous work, Balfour et al. (1992) conducted a trial involving 62 adolescents (13 to 18 years of age) with varicella. The premise of the study was to determine the efficacy of acyclovir in this particular age group, given that their disease might be more severe than in younger children. Placebo or an acyclovir 800-mg tablet was administered four times daily for 5 days, beginning within 24 hours of rash onset. Those receiving acyclovir required fewer days to cessation of new lesion formation (2.7 vs 3.2, respectively; p < 0.001), less time to the maximum number of lesions (1.9 vs 3.5 days, respectively; p = 0.020), and fewer days to achieve a 5% decrease in the maximum number of lesions (2.9 vs 4.1, respectively; p = 0.004). Compared to placebo, acyclovir recipients also had fewer residual lesions at day 28 (22.7 vs 92.7, p = 0.018). A significantly smaller proportion of acyclovir patients were febrile at day 3 than were their placebo counterparts (4% vs 37%, p = 0.006), despite a higher percentage of acetaminophen use by the placebo group. As was seen in previous studies, no significant difference was noted in V Z V antibody titers when evaluated after treatment (day 28 in the present study). No adverse events or complications occurred in the acyclovir recipients. Collectively, these trials point to the safety and efficacy of acyclovir as a treatment modality for varicella in

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otherwise healthy children and adolescents. Before widespread use of acyclovir can be recommended in all cases of childhood varicella, several factors must be taken into consideration. First, it remains debatable whether the benefits seen with acyclovir use justify the cost of therapy in otherwise healthy children. For a 20-kg child, the recommended 5-day course of therapy at 20 mg/kg/dose four times daily (maximum dose, 800 mg) would cost approximately $40 based on the average wholesale price of acyclovir suspension (Red Book, 1994). Assuming 3.5 million cases annually, an estimated $140 million would be spent annually for acyclovir therapy, a figure that would be further compounded by the cost of a physician visit to obtain the prescription. Intuitively, if the use of acyclovir could return sick children to school sooner and likewise, their parents to work earlier, then the cost might be justified. Thus far, treatment with acyclovir has not been shown to decrease the number of days missed from school by the infected child nor has it been proved to significantly decrease the occurrence of varicella-related complications. Because complications infrequently occur in this population, a sizable study would be required to show a significant effect attributable to acyclovir (Drwal-Klein & O'Donovan, 1993). A second consideration surrounds the possible perpetuation o f resistance through widespread acyclovir use. Evidence exists in the literature to support viral resistance to acyclovir; therefore there is similar concern specifically regarding varicella-zoster virus. Proposed mechanisms for resistance include altered thyrnidine kinase that prevents phosphorylation of acyclovir to its active form and/or an alteration in DNA polymerase (Balfour & Englund, 1989; Whitley & Gnann, 1992). Cole and Balfour (1986) showed that short-term use (5 to 10 days) of acyclovir for zoster did not result in resistant V Z V strains in a small study of 20 patients. Since that study, a case of VZV in an immunocomproraised child in whom resistance to acyclovir developed has appeared in the literature (Pahwa et al., 1988). The third point regarding acyclovir use for varicella is a logistic problem. The aforementioned studies limited enrollments to subjects whose varicella rash had appeared no more than 24 hours earlier. A physician is rarely consulted within this initial time period. However, families with more than one susceptible child could be alerted to watch for the subsequent onset ofvaricella infection in their other youngsters, who could possibly be treated in a timely fashion. This is especially noteworthy because children who contract varicella through household contact have been shown to be sicker than their index-case siblings (Balfour et al., 1990; Balfour et al., 1992; Dunkle et al., 1991). On the basis of existing data, the Committee on Infectious Diseases of the American Academy of Pediatrics

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•

BOX

R E C O M M E N D A T I O N S FOR ACYCLOVIR*

Not routine use • Uncomplicated varicella in otherwise healthy children Consider use in the following high-risk groups • Otherwise healthy, nonpregnant individuals -> 13 years of age • ->12 months of age with a chronic cutaneous or pulmonary disorder • ---12 months of age receiving long-term salicylate therapy • Pediatric patients receiving short, intermittent, or aerosolized courses of corticosteroids Dosing • 20 mg/kg/dose (maximum dose, 800 mg) four times daily for 5 days • Initiate therapy within the first 24 hours of rash onset *Committee on Infectious Diseases,American Academy of Pediatrics, 1993

(1993) does not recommend the routine use ofacyclovir for uncomplicated varicella in otherwise healthy children. However, depending on individual family circumstances, such as financial hardship that might result from the loss of work by a single parent, therapy initiated within the first 24 hours of rash onset may justify the marginal clinical benefit. Other instances in which acyclovir use should be considered include children at high risk for severe varicella and/or those prone to the development of complications (Box). •

PREVENTION

VZV immunization is imminently on the horizon in the United States. In Japan, Takahashi and colleagues (1974) developed the Oka strain of live attenuated varicella vaccine through the cultivation of virus from a 3year-old boy with chickenpox. Currently, the vaccine is licensed for use in Korea, parts of Europe, and Japan (Drwal-Klein & O'Donovan, 1993). In the United States, initial interest was limited, but studies showing efficacy in such high-risk groups as children with leukemia paved the way for trials in healthy children. The efficacy of VZV vaccine was initially seen in the United States in a placebo-controlled study by Weibei et al. (1984) in which approximately 1000 healthy children between the ages of 1 and 14 years were enrolled. The seroconversion rate of those vaccinated was 94% eight weeks after the vaccination. During the 9-month observation period, 39 cases of chickenpox were clinically diagnosed, all in unvaccinated children. This translated into a vaccine protection rate of 100%. Adverse effects attributable to the vaccine were minimal in this

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trial. No significant difference in the incidence of fever was reported between vaccine and placebo recipients. Pain and redness at the injection site were significantly (p < 0.05) more common among children in the vaccine group compared to those in the placebo group (pain, 26.4% vs 17.5%, and redness 5% vs 2.5%, respectively). The authors attributed the relatively high incidence of injection site pain in both groups to the volume of the injection (1 ml) that was administered subcutaneously. Varicella-like rashes developed in 4% of the initially seronegative vaccine recipients compared with 2% of placebo recipients (p < 0.054). All rashes reported were mild, non-vesicular, and well tolerated. Contagion of the virus vaccine was evaluated in this study; however, no clinical evidence of viral spread was reported. The findings of other studies evaluating the efficacy of a varicella vaccine have been similar. Overall, the seroconversion rate as a result of the vaccine ranges between 94% to 100%, affords a protection rate between 88% and 100%, and displays a relatively benign adverse effect profile with the incidence of rash and injection site reactions 5% to 10% each (Arbeter et al., 1984; Arbeter et al., 1986; Asano et al., 1985; Johnson et al., 1988; Weibel et al., 1985; White et al., 1991). Johnson et al. (1988) described three patients in their study who did not sero-convert after vaccination. Varicella that was unusually mild subsequently developed in these children. None of the cases were febrile, and they all had less than 20 vesicles each. From this, the authors suggested that the vaccine may modify the severity of clinical disease when it occurs, despite the lack of documented seroconversion. In most studies conducted in healthy children, vaccination was performed before varicella exposure, but the efficacy of varicella vaccine given immediately after exposure has been shown by Arbeter, et al. (1986). Of 13 susceptible siblings vaccinated within 5 days of exposure, clinical evidence of mild disease developed in only four (no more than 50 lesions each) compared to 12 of 13 placebo recipients (having 60 to 600 lesions). Because reactivation of latent VZV in adults can be potentially severe, the hope is that vaccination will provide long-lasting protection. Duration of immunity in conjunction with the varicella vaccine is another critical issue in addition to seroconversion and protectio n rates. This concern has been addressed by measuring the persistence of V Z V antibody after vaccination. Thus far, evidence shows the persistence of detectable VZV antibodies in children 7 to 10 years after vaccination (Asano et al., 1985). Clinical reinfection has been documented in children exposed to variceUa within 3 years of vaccination as evidenced by a fourfold or greater increase in their antibody titers. It has been postulated

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that asymptomatic or mild cases o f reinfection may be a critical component for the preservation o f lifelong immunity (Johnson et al., 1989). In early studies, no cases o f reactivated zoster infection had been reported in healthy children; however, Plotldn et al. (1989) reported two cases o f zoster occurring approximately 4 years after vaccination. Both cases were mild; neither child had any long-term sequelae. Studies with the Oka strain vaccine have shown its immunogenicity, protection from natural infection, and persistence o f response in otherwise healthy children. T o facilitate the universal acceptance o f a varicella vaccination program, the hope is that this vaccine can be administered in conjunction with the measles, mumps, and rubella (MMR) vaccine when a child is approximately 15 months o f age. Data have been generated to assess the immunogenic response to all four vaccine components when administered concurrently (Arbeter et al., 1986a; Brunell et al., 1988; Enghmd et al., 1989). From these trials, it has been proved that a " M M R V " combination vaccine would be as effective as individual M M R and varicella vaccines with no increase in adverse effects. Additionally, the combination product would not require an additional injection for the child to endure and would be cost-effective by negating the need for an additional physician visit (Arbeter et al., 1986b). In 1985, Preblud et al. designed a model to evaluate the cost benefit o f instituting a childhood varicella vaccination program. The model was designed with the following assumptions: (a) 90% o f a cohort o f 3.5 million children would be vaccinated at 15 months o f age with a combination " M M R V " vaccination; (b) vaccine efficacy o f 90%; (c) vaccine cost o f $15; and (d) lifelong vaccine-induced immunity. Under these conditions, the prediction was that a vaccination program would result in a 66% reduction in disease-related costs, most o f which represented savings o f home care costs.

9 SUMMARY

Chickenpox is a common childhood problem. In otherwise healthy children, the disease is usually benign, although secondary complications can occur. Symptomatic therapy has long been the mainstay o f treatment. Acyclovir use in such cases remains controversial secondary to the marginal benefit in relation to the additional cost incurred by an already costly disease. Advancements in the form o f prevention have been made in an attempt to decrease the current hardship o f V Z V infection. The Oka strain o f varicella vaccine should soon be available in the United States. Varicella vaccine has been shown to be immunogenic and well tolerated in healthy children. Lifetime follow-up is needed to determine the true duration o f immunity and any effect on the epidemiology o f adult varicella or recurrent zos-

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ter compared to natural infection. With the development o f immunization, it is hoped that the varicella vaccine will become the next addition to the childhood vaccination schedule, possibly as a "quadrivalent" product with measles, mumps, and rubella. Widescale use o f the varicella vaccine may render this once common childhood disease obsolete. REFERENCES

Arbeter, A.M., Baker, L., Starr, S.E., Levine, B.L., Books, E., & Plotkin, S.A. (1986a). Combinationmeasles,mumps, rubella, and varicella vaccine. Pediatrics, 78, 742-747. Arbeter, A.M., Starr, S.E., & Plotkin, S.A. (1986b). Varicellavaccine studies in healthy children and adults. Pediatrics, 78, 748-756. Arbeter, A.M., Starr, S.E., Preblud, S.R., Ihara, T., Paciorek, P.M., Miller, D.S., Zelson,C.M., Proctor, E.A., & Plotkin, S.A. (1984). Varicella vaccine trials in healthy children: A summary of comparative and follow-upstudies.AmericanJ0urnalofDiseasesofChildren, 138, 434-438. Asano, Y., Nagai, T., Miyata, T., Yazaki, T., Ito, S., Yamanishi, K., & Takahashi, M. (1985). Long-term protectiveimmunity of recipients of the OKA strain of live varicellavaccine.Pediatrics, 75, 667-671. Balfour, H.H., & Englund, J.A. (1989). Antiviraldrugs in pediatrics. American Journal of Diseases of Children, 143, 1307-1316. Balfour, H.H., Kelly,J.M., Suarez, C.S., Heussner, R.C., Englund, J.A., Crane, D.D., McGuitt, P.V., Clemmer, A.F., & Aeppli, D.M. (1990). Acyclovirtreatmentofvaticellain otherwisehealthy children.Journal of Pediatwics, 116, 633-639. Balfour, H.H., Rotbart, H.A., Feldman, S., Dtmkle, L.M., Feder, H.M., Prober, C.G., Hayden, G.F., Steinberg, S., Whitley, R.J., Goldberg, L., McGuirt, P.V., & the CollaborativeAcyclovirVaricella Study Group. (1992). Acyclovirtreatment of varicella in otherwise healthy adolescents.Journal of Pediatrics, 120, 627-633. Brunell, P.A., Novelli, V.M., Lipton, S.V., & Pollock, B. (1988). Combined vaccineagainst measles, mumps, rubella, and varicella. Pediatrics, 81, 779-784. Chan, C.Y.J., & Wallander, K.A. (1991). Diphenhydraminetoxicity in three children with varicella-zosterinfection.Drug Intelligence in Clinical PharmacyAnnals of Pharmacotherapy, 25, 130-132. Cole, N.L., & Balfour, H.H. (1986). Varicella-zostervirus does not become more resistant to acyclovirduring therapy.Journal ofInfectious Diseases, 153, 605-608. Committee on InfectiousDiseases, AmericanAcademyof Pediatrics. (1993). The use of oral acyclovirin otherwise healthy children with varicella.Pediatrics, 91, 674-676. Committee on InfectiousDiseases, AmericanAcademyof Pediatrics. (1994). Varicella-zosterinfections. In: Report of the committee on infectious diseases(pp. 510-517). Elk GroveVillage, IL: American Academy of Pediatrics. Drwal-Klein,L.A., & O'Donovan, C.A. (1993). Varicellain pediatric patients. Annals of Pharmacotherapy 27, 938-949. Dunkle, L.M., Arvin, A.M., Whitley, R.]., Rotbart, H.A., Feder, H.M., Feldrnan, S., Gershon, A.A., Levy, M.L., Hayden, G.F., McGuirt, P.V., Harris, J., & Balfour, H.H. (1991). A controlled trial of acyclovirfor chickenpoxin normal children.New England Journal ofMedicine, 325, 1539-1544. Edwards, D.L. (1993). So your child has chicken pox: Pharmacists can help parents recognize when medical attention is needed. American Pharmacy, NS33, 52-53, 66. Englund, J.A., Suarez, C.S., Kelly,J., Tate, D.Y., & Balfour, H.H. (1989). Placebo-controlledtrial of varicellavaccinegiven with or aftermeasles-mumps-rubellavaccine.Journal ofPediatrics, 114, 3744.

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Johnson, C., Rome, L.P., Stancin, T., & Kumar, M.L. (1989). Humoral immunity and Clinical reinfections following varicella vaccine in healthy children. Pediatrics, 84, 418-421. Johnson, C.E., Shurin, P.A., Fattlar, D., Rome, L.P., & Kumar, M.L. (1988). Live attenuated varicella vaccine in healthy 12- to 24month-old children. Pediatrics, 81, 512-518. Pahwa, S., Biron, K., Lira, W., Swenson, P., Kaplan, M.H., Sadick, N., & Pahwa, R. (1988). Continuous variceUa-zoster infection associated with acyclovir resistance in a child with AIDS. Journal of the American Medical Association, 260, 2879-2882. Plotikin, S.A., Starr, S.E., Connor, K., & Morton, D. (1989). Zoster in normal children after varicella vaccine. Journal of Infectious Diseases, 159, 1000. Preblud, S.R. (1986). Varicella: Complications and costs. Pediatrics, 78, 728-735. Preblud, S.R., Orenstein, W.A., & Bart, K.J. (1984). Varicella: Clinical manifestations, epidemiology and health impact in children. Pediatric Infectious Disease, 3, 505-509. Preblud, S.R., Orenstein, W.A., Koplan, J.P., Bart, K.J., & Hinman, A.R. (1985). A benefit-cost analysis of a childhood varicella vaccination programme. PostgraduateMedical Journal, 61, 17-22. Red Book. (1994). Montvale, NJ: Medical Economics Data, p. 416. Takahashi, M., Otsuka, T., Okuno, Y., Asano, Y., Yazaki, T., &

Isomura, S. (1974). Live vaccine used to prevent the spread of varicella in children in hospital. Lancet, 2, 1288-1290. Weibel, R.E., Kuter, B.J., Neff, B.J., Rothenberger, C.A., Fitzgerald, A.J., Connor, K.A., Morton, D., McLean, A.A., & Scolnick, E.M. (1985). Live Oka/Merck varicella vaccine in healthy children: Fmx_herclinical and laboratory assessment.Journal of the American Medical Association, 254, 2435-2439. Weibel, R.E., Neff, B.J., Kuter, B.J., Guess, H.A., Rothenberger, C.A., Fitzgerald, A.J., Connor, K.A., McLean, A.A., Hilleman, M.R., Buynak, E.B., & Scolnick, E.M. (1984). Live attenuated varicella virus vaccine: efficacy trial in healthy children. New England Journal ofMedicine, 310, 1409-1415. White, C.J., Kuter, B.J., Hildebrand, C.S., Isganitis, K.L., Matthews, H., Miller, W.J., Provost, P.J., Ellis, R.W., Gerety, R.j'., & Calandra, G.B. (1991). Varicella vaccine (VARIVAX) in healthy children and adolescents: Results from clinical trials, 1987 to 1989. Pediatrics, 87, 604-610. Whitley, R.J. (1995). Varicella-zoster virus. In: G.L Mandell, J.E. Bennett, R. Dolin, eds. Principlesand practice of infectious diseases, 4th ed (pp. 1345-1351). New York: Churchill Livingstone. Whitley, R.J., & Gnann J.W. (1992). Acyclovir: a decade later. New England Journal ofMedicine, 327, 782-789.

CERTIFICATION FOR PEDIATRIC NURSE PRACTITIONERS The National Certification Board o f Pediatric Nurse Practitioners and Nurses will administer the National Qualifying Examination for Pediatric Nurse Practitioner Certification on October 13, 1995 at sites throughout the United States. Certification provides:

.Recognition for professional competency to employer, consumers and others in the health care system .Appropriate credentials to state licensing boards. .Enhancement of professional mobility and financial gain. Registration begins May 1, 1995 and ends A u g u s t 10, 1995. Contact the National Certification Board today for further information. The National Certification Board o f Pediatric Nurse Practitioners and Nurses 416 Hungerford Drive, Suite 222 Rockville, Maryland 20850 (301) 340-8213