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Varicella-zoster virus (VZV) infections occur worldwide. In the prevaccine era, approximately 4 million cases of varicella occurred annually in the United States. Since the institution of universal varicella vaccination for healthy children, the incidence of varicella and its associated morbidity and mortality have decreased by approximately 74%-90% (951Gershon A, Seward J, Takahashi M. Varicella vaccine. In: Plotkin S, Orenstein W, Offit PA. Vaccine. 5th ed. Philadelphia, PA: Saunders;2008:915-958.). Varicella can cause greater morbidity and mortality in HIV-infected persons than among the general population (952Gershon A, Mervish N, LaRussa P, et al. Varicella-zoster virus infection in children with underlying human immunodeficiency virus infection. J Infect Dis 1997;176:1496-500., 953Derryck A, LaRussa P, Steinberg S, et al. Varicella and zoster in children with human immunodeficiency virus infection. Pediatr Infect Dis J 1998;17:931-3.).

VZV causes both varicella (a primary infection) and zoster (a secondary infection caused by reactivation of latent VZV acquired during varicella) (954Hambelton S, Gershon AA. Preventing varicella-zoster disease. Clin Microbiol Rev 2005;18:70-80.). The incubation period for varicella ranges from 10 to 21 days (average: 14 days). Before the widespread use of varicella vaccine in the United States, the annual rate of varicella infection in children aged <10 years was 9%; by adulthood >95% of persons had antibodies to VZV, indicating a history of primary infection (955LaRussa P, Steinberg SP, Seeman MD, et al. Determination of immunity to varicella-zoster virus by means of an intradermal skin test. J Infect Dis 1985;152:869-75.).

Once established, VZV latency persists for life. Reactivation, causing clinical zoster, occurs in roughly 25% of people. A decline in specific cellular immunity to VZV contributes significantly to development of zoster (954Hambelton S, Gershon AA. Preventing varicella-zoster disease. Clin Microbiol Rev 2005;18:70-80.). HIV-infected persons are at higher risk for zoster, by a factor of 15-25 times, than the general population (956Veenstra J, Krol A, van Praag RM, et al. Herpes zoster, immunological deterioration and disease progression in HIV-1 infection. AIDS 1995; 9:1153-8.). The incidence of zoster also increased with age, particularly in persons aged >50 years.

VZV is transmitted mainly from skin lesions during illness but also can be transmitted through airborne spread (957Chen JJ, Zhu Z, Gershon AA, et al. Mannose 6-phosphate receptor dependence of varicella zoster virus infection in vitro and in the epidermis during varicella and zoster. Cell 2004;119:915-26.). Varicella is highly contagious; clinical infection develops in about 80% of susceptible persons exposed in a household (958Ross AH. Modification of chicken pox in family contacts by administration of gamma globulin. N Engl J Med 1962;267:369-76.). Second attacks of varicella are uncommon (954Hambelton S, Gershon AA. Preventing varicella-zoster disease. Clin Microbiol Rev 2005;18:70-80.). Zoster is less contagious than varicella.

Mother-to-child transmission of VZV can occur; however, because most adults are immune, varicella complicating pregnancy is unusual. In one study, 13% of HIV-infected pregnant women lacked immunity to VZV (959Clark R, Wilson S, Williams T. Varicella immunity in women infected with the human immunodeficiency virus. Clin Infect Dis 1994;19:1165-6.). Whether mother-to-child VZV transmission increases among HIV-infected pregnant women who have varicella is unknown. Congenital varicella syndrome occurs in approximately 0.4% (95% CI: 0.05%-1.5%) of infants born to women who have varicella during pregnancy before 13 weeks' gestation and in approximately 2% (95% CI: 0%-5%) of infants born to women who have varicella at 13-20 weeks' gestation (960Schulze A, Dietzsch HJ. The natural history of varicella embryopathy: a 25-year follow-up. J Pediatr 2000;137:871-4.). This syndrome is not seen among women who develop herpes zoster during pregnancy. Fewer than 100 cases of congenital VZV have been reported, none so far in HIV-infected mothers. However, congenital varicella syndrome may not be recognized. Before the availability of varicella vaccine in the United States, approximately 44 cases occurred each year. Congenital varicella syndrome is characterized by cicatricial skin scarring, limb hypoplasia, and neurologic (e.g., microcephaly, cortical atrophy, seizures, and mental retardation), eye (e.g., chorioretinitis, microphthalmia, and cataracts), renal (e.g., hydroureter, and hydronephrosis) and autonomic nervous system abnormalities (neurogenic bladder, swallowing dysfunction, and aspiration pneumonia) (961Arvin AM. Varicella-zoster virus. Clin Microbiol Reb 1996:9:361-81., 962Pastuszak AL, Levy M, Schick B, et al. Outcome after maternal varicella infection in the first 20 weeks of pregnancy. N Engl J Med 1994;330:901-5., 963Ussery XT, Annunziato P, Gershon AA, et al. Congenital varicellazoster virus infection and Barrett's esophagus. J Infect Dis 1998; 178:539-43.).

VZV can be transmitted to the fetus in later gestation, resulting in acute neonatal varicella. When the mother develops varicella from 4 days before to 2 days after delivery without passive antibody prophylaxis, the attack rate for infants is approximately 20% and mortality, before the availability of antiviral therapy, was approximately 30% (961Arvin AM. Varicella-zoster virus. Clin Microbiol Reb 1996:9:361-81.). In comparison, if maternal varicella precedes delivery long enough to allow transfer of VZV IgG antibodies across the placenta, infants can develop varicella in the first 5 days of life, but it is rarely severe and usually requires no medical intervention.

Zoster occurs only among persons previously infected with VZV. Zoster used to be common in HIV-infected children who had primary varicella infections when their CD4 counts were normal or mildly suppressed. Before PIs were commonly administered to children, among HIV-infected children with low CD4 percentage (i.e., CD4 <15%) at the time of primary varicella, the rate of subsequent zoster was approximately 70% (952Gershon A, Mervish N, LaRussa P, et al. Varicella-zoster virus infection in children with underlying human immunodeficiency virus infection. J Infect Dis 1997;176:1496-500., 953Derryck A, LaRussa P, Steinberg S, et al. Varicella and zoster in children with human immunodeficiency virus infection. Pediatr Infect Dis J 1998;17:931-3.). The incidence of zoster among HIV-infected children who developed primary varicella when they were immunocompromised was 467 per 1000 child-years, substantially higher than the rates for immunocompromised HIV-infected adults (98 per 1000 person-years) and for children with leukemia (25 per 1000 child-years). As in adults, the CD4 count in children correlates with the frequency of zoster recurrences (964von Seidlein L, Gillette SG, Bryson Y, et al. Frequent recurrence and persistence of varicella-zoster virus infections in children infected with human immunodeficiency virus type 1. J Pediatr 1996;128:52-7.). The incidence of zoster reportedly increases transiently after institution of PIs (22Puthanakit T, Oberdorfer P, Punjaisee S, et al. Immune reconstitution syndrome due to bacillus Calmette-Guérin after initiation of antiretroviral therapy in children with HIV infection. Clin Infect Dis 2005;41:1049-52., 965Martinez E, Gatell J, Morán Y, et al. High incidence of herpes zoster in patients with AIDS soon after therapy with protease inhibitors. Clin Infect Dis 1998;27:1510-3.). The cause of this phenomenon is not known; one hypothesis is that it results from return of regulatory T-cell function with transient immune dysregulation. Overall, however, the incidence of herpes zoster in HIV-infected children is lower during the HAART era than it was during the pre-HAART era (3Gona P, Van Dyke RB, Williams PL, et al. Incidence of opportunistic and other infections in HIV-infected children in the HAART era. JAMA 2006;296:292-300.). One reason may be immunization of many HIV-infected children with the Oka vaccine strain. The Oka vaccine strain of VZV is the licensed live attenuated varicella vaccine (marketed by Merck in the United States and by GlaxoSmithKline in other countries).

Varicella in HIV-infected children may be associated with a prodrome of malaise and fever, followed by pruritic vesiculopapular lesions that are more numerous on the face and trunk than on the extremities. Lesions evolve over 5 days through macular, papular, vesicular, pustular, and crust stages. In profoundly immunocompromised hosts, vesicles can persist for weeks and coalesce to form large lesions resembling a burn. Complications of varicella include superinfection of skin with bacterial pathogens, such as staphylococci and streptococci; neurologic manifestations, such as encephalitis, cerebellar ataxia, and transverse myelitis; and on occasion, vasculitic stroke, hepatitis, and pneumonia.

Initial reports of varicella among HIV-infected children suggested severe disease manifestations (966Jura E, Chadwick EG, Josephs SH, et al. Varicella-zoster virus infections in children infected with human immunodeficiency virus. Pediatr Infect Dis J 1989;8:586-90.), but more recent studies support less complicated courses, particularly in children receiving antiretroviral therapy or having higher CD4 counts at the time of infection (952Gershon A, Mervish N, LaRussa P, et al. Varicella-zoster virus infection in children with underlying human immunodeficiency virus infection. J Infect Dis 1997;176:1496-500., 953Derryck A, LaRussa P, Steinberg S, et al. Varicella and zoster in children with human immunodeficiency virus infection. Pediatr Infect Dis J 1998;17:931-3., 967Kelley R, Mancao M, Lee F, et al. Varicella in children with perinatally acquired human immunodeficiency virus infection. J Pediatr 1994;124:271-3., 968Leibovitz E, Cooper D, Giurgiutiu D, et al. Varicella-zoster virus infection in Romanian children infected with the human immunodeficiency virus. Pediatrics 1993;92:838-42.). However, the disease may last longer than normal, and the rate of complications is higher than in otherwise healthy children with varicella (968Leibovitz E, Cooper D, Giurgiutiu D, et al. Varicella-zoster virus infection in Romanian children infected with the human immunodeficiency virus. Pediatrics 1993;92:838-42.).

Uncommonly, HIV-infected children can have persistent chronic infection, with continued appearance of new VZV lesions for >1 month after primary or recurrent infection (969Leibovitz E, Kaul A, Rigaud M, et al. Chronic varicella zoster in a child infected with human immunodeficiency virus: case report and review of the literature. Cutis 1992;49:27-31. 126 MMWR September 4, 2009). The lesions are characteristically varicelliform at onset but evolve into nonhealing ulcers that become necrotic, crusted, and hyperkeratotic. Persistent lesions may be atypical and lack a vesicular component. Chronic VZV was reported in 14% of HIV-infected children with VZV, usually in children with low CD4 counts (964von Seidlein L, Gillette SG, Bryson Y, et al. Frequent recurrence and persistence of varicella-zoster virus infections in children infected with human immunodeficiency virus type 1. J Pediatr 1996;128:52-7.). The virus may become resistant to acyclovir during prolonged therapy (970Pahwa S, Biron K, Lim W, et al. Continuous varicella-zoster infection associated with acyclovir resistance in a child with AIDS. JAMA 1988;260:2879-82.).

The classical presentation of zoster is a painful or pruritic unilateral vesicular eruption with a dermatomal distribution. Less typical rashes, however, including those that extend beyond dermatomal boundaries or are bilaterally distributed or generalized, also can represent zoster in HIV-infected children. HIV-infected children can have recurrent episodes of reactivated VZV infection that present with a disseminated rash more similar to varicella than zoster but without visceral dissemination; they also can have multiple episodes of recurrent dermatomal disease (964von Seidlein L, Gillette SG, Bryson Y, et al. Frequent recurrence and persistence of varicella-zoster virus infections in children infected with human immunodeficiency virus type 1. J Pediatr 1996;128:52-7.). Encephalitis without rash resulting from zoster also has been reported (971Silliman CC, Tedder D, Ogle JW, et al. Unsuspected varicella-zoster virus encephalitis in a child with acquired immunodeficiency syndrome. J Pediatr 1993;123:418-22.). Diagnostic laboratory studies are useful if children or adolescents present with unusual clinical manifestations suspected to be caused by zoster. Ruling out HSV infection, which can be confused with VZV skin manifestations, also is important (972Gershon A, Chen J, LaRussa P, et al. Varicella-zoster virus. In: Murray PR, Baron EJ, Jorgenson JH, Pfaller MA, Yolken RH, eds. Manual of clinical microbiology. 8th ed. Washington, DC: ASM Press: 2007;1319-30.).

Retinitis is a complication of VZV infection among HIV-infected patients that occurs in children and adolescents (973Purdy KW, Heckenlively JR, Church JA, et al. Progressive outer retinal necrosis caused by varicella-zoster virus in children with acquired immunodeficiency syndrome. Pediatr Infect Dis J 2003;22:384-6.). VZV-associated retinitis may be confused with CMV retinitis (974Hellinger WC, Bolling JP, Smith TF, et al. Varicella-zoster virus retinitis in a patient with AIDS-related complex: case report and brief review of the acute retinal necrosis syndrome. Clin Infect Dis 1993;16:208-12.). Progressive outer retinal necrosis is a VZV-associated entity that typically occurs among HIV-infected persons with CD4 counts <50 cells/mm³. This rapidly progressive necrotizing herpetic retinopathy often is associated with dermatomal zoster and is characterized by multifocal retinal opacification with little or no ocular inflammation (975Engstrom RE, Jr, Holland GN, Margolis TP, et al. The progressive outer retinal necrosis syndrome. A variant of necrotizing herpetic retinopathy in patients with AIDS. Ophthalmology 1994;101:1488-502., 976Franco-Paredes C, Bellehemeur T, Merchant A, et al. Aseptic meningitis and optic neuritis preceding varicella-zoster progressive outer retinal necrosis in a patient with AIDS. AIDS 2002;16:1045-9.) and rapid visual loss. Acute retinal necrosis occurs as a peripheral necrotizing retinitis with yellowish thumbprint lesions, retinal vascular sheathing, and vitritis, with a high rate of visual loss often caused by retinal detachment. This latter syndrome can occur in both immunologically normal and deficient persons. Among patients with HIV infection, acute retinal necrosis can occur at any CD4 count, but more often occurs at higher CD4 counts, and progressive outer retinal necrosis more often occurs at lower CD4 counts.

VZV infection should be suspected in children with unilateral vesicular rashes. Retinitis as a complication of VZV should be suspected when CMV cannot be implicated or with progressive and otherwise unexplained encephalitis and a history of varicella or varicella vaccination.

Varicella and zoster are diagnosed clinically by the typical appearance of generalized pruritic vesicular rash and fever in the former and a frequently painful or pruritic unilateral vesicular rash in a dermatomal pattern in the latter. Direct immunofluorescence for VZV antigen can be performed on cells collected from skin, conjunctiva, or mucosal lesion scrapings for diagnosis (972Gershon A, Chen J, LaRussa P, et al. Varicella-zoster virus. In: Murray PR, Baron EJ, Jorgenson JH, Pfaller MA, Yolken RH, eds. Manual of clinical microbiology. 8th ed. Washington, DC: ASM Press: 2007;1319-30.). The optimal sensitivity of this method requires obtaining cells from the base of a lesion after unroofing a fresh vesicle. Direct and indirect immunofluorescence or immunoperoxidase methods also can be used to detect VZV-infected cells in tissue sections of lung, liver, brain, or other organs. Giemsa-staining (Tzanck preparation) of scrapings from lesions is nonspecific; detection of multinucleated giant cells does not distinguish between VZV and HSV infection.

VZV can be isolated in cell culture from vesicular fluid or ulcer swabs, but the virus is labile. The specimen must be processed rapidly or kept on dry ice or frozen at -70C (-94F) if storage is required for more than a few hours (961Arvin AM. Varicella-zoster virus. Clin Microbiol Reb 1996:9:361-81.). Typical cytopathic effects usually can be detected 5-7 days after inoculation; confirmation by staining with virus-specific antiserum is then needed. Shell vial cultures combine centrifugation and staining with fluorescein-conjugated monoclonal antibodies to detect synthesis of VZV proteins in infected cells. This allows results 1-3 days after inoculation, before cytopathic effect is visible. Standard culture usually is necessary when testing the virus for antiviral susceptibility is anticipated, although PCR also can be used (972Gershon A, Chen J, LaRussa P, et al. Varicella-zoster virus. In: Murray PR, Baron EJ, Jorgenson JH, Pfaller MA, Yolken RH, eds. Manual of clinical microbiology. 8th ed. Washington, DC: ASM Press: 2007;1319-30., 977Levin MJ, Dahl KM, Weinberg A, et al. Development of resistance to acyclovir during chronic infection with the Oka vaccine strain of varicella-zoster virus, in an immunosuppressed child. J Infect Dis 2003;188:954-9.).

PCR can be used to detect VZV in samples, is extremely sensitive and specific, can differentiate between wild-type and vaccine VZV, and is becoming increasingly available and used. In some laboratories, PCR has replaced culture as the “gold standard” (972Gershon A, Chen J, LaRussa P, et al. Varicella-zoster virus. In: Murray PR, Baron EJ, Jorgenson JH, Pfaller MA, Yolken RH, eds. Manual of clinical microbiology. 8th ed. Washington, DC: ASM Press: 2007;1319-30.). Serologic tests can be used to diagnose VZV infection, noting a substantial increase in antibody titer during convalescence (e.g., 2-3 weeks after illness onset) or VZV IgM antibody. VZV reactivation also can induce VZV-IgM antibodies so their presence does not differentiate primary from recurrent VZV infections (961Arvin AM. Varicella-zoster virus. Clin Microbiol Reb 1996:9:361-81., 972Gershon A, Chen J, LaRussa P, et al. Varicella-zoster virus. In: Murray PR, Baron EJ, Jorgenson JH, Pfaller MA, Yolken RH, eds. Manual of clinical microbiology. 8th ed. Washington, DC: ASM Press: 2007;1319-30.).

Acyclovir is excreted primarily by the kidney, and dose adjustment (based on creatinine clearance) is needed for patients with renal insufficiency or renal failure. Primary toxicities of acyclovir are phlebitis, renal toxicity, nausea, vomiting, and rash. Toxicities are similar for valacyclovir. Among infants receiving high-dose acyclovir for neonatal HSV disease, the major toxicity was neutropenia (absolute neutrophil count <1000/ mm³), which was observed in 21% of children (857Kimberlin DW, Lin CY, Jacobs RF, et al. Safety and efficacy of high-dose intravenous acyclovir in the management of neonatal herpes simplex virus infections. Pediatrics 2001;108:230-8.). Grade 3 or higher nephrotoxicity was observed in 6% of children. For children receiving high-dose IV acyclovir, monitoring of renal function is recommended at initiation of treatment, and once or twice weekly for the duration of treatment, particularly for those with underlying renal dysfunction or those receiving prolonged therapy.

In HIV-infected adults, immune reconstitution after initiation of HAART may be associated with increased VZV reactivation (965Martinez E, Gatell J, Morán Y, et al. High incidence of herpes zoster in patients with AIDS soon after therapy with protease inhibitors. Clin Infect Dis 1998;27:1510-3., 992Domingo P, Torres OH, Ris J, et al. Herpes zoster as an immune reconstitution disease after initiation of combination antiretroviral therapy in patients with human immunodeficiency virus type-1 infection. Am J Med 2001;110:605-9.). VZV-associated IRIS after HAART also has been described in HIV-infected children (20Tangsinmankong N, Kamchaisatian W, Lujan-Zilbermann J, et al. Varicella zoster as a manifestation of immune restoration disease in HIV-infected children. J Allergy Clin Immunol 2004;113:742-6., 24Puthanakit T, Oberdorfer P, Akarathum N, et al. Immune reconstitution syndrome after highly active antiretroviral therapy in human immunodeficiency virus-infected thai children. Pediatr Infect Dis J 2006;25:53-8.). In a study of 153 HAART-treated children in Thailand, 19% of children starting HAART experienced IRIS; 22% of IRIS cases were secondary to VZV. In the reported cases, manifestations were typically mild and cutaneous, had a typical dermatomal distribution of vesicular lesions as seen in VZV reactivation, and responded well to treatment with oral acyclovir. Most cases presented in the first 4 months of HAART; the median time from initiation of HAART to onset of clinical symptoms was 6 weeks (range: 2-21 weeks) (24Puthanakit T, Oberdorfer P, Akarathum N, et al. Immune reconstitution syndrome after highly active antiretroviral therapy in human immunodeficiency virus-infected thai children. Pediatr Infect Dis J 2006;25:53-8.).

Children who continue to develop lesions or whose lesions fail to heal after 10 days of treatment may be infected with acyclovir-resistant VZV. If possible, a culture should be obtained to analyze the virus for drug resistance. HIV-infected children with acyclovir-resistant VZV can be treated with IV foscarnet for 7 days or until no new lesions have appeared for 48 hours (AII) (990Dworkin RH, Johnson RW, Breuer J, et al. Recommendations for the management of herpes zoster. Clin Infect Dis 2007;44(Suppl 1): S1-26., 993Heininger U, Seward JF. Varicella. Lancet 2006;368:1365-76., 994Enright A, Prober C. Antiviral therapy in children with varicella zoster virus and herpes simplex virus infections. Herpes 2003;10:32-7.). The dose of foscarnet should be administered slowly over the course of 2 hours (i.e., no faster than 1 mg/kg/minute). Infusing foscarnet with saline fluid loading can minimize renal toxicity. Doses should be modified among patients with renal insufficiency.

The main toxicity of foscarnet is decreased renal function; in ≤30% of patients, serum creatinine levels increase. Renal toxicity and foscarnet binding to divalent metal ions (e.g., calcium) leads to metabolic abnormalities in approximately one third of patients. In addition, serious electrolyte imbalances (including abnormalities in calcium, phosphorus, magnesium, and potassium levels), secondary seizures, cardiac dysrhythmias, abnormal liver transaminases, and CNS symptoms can occur.

Not applicable.