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(Pediatrics in Review. 2008;29:5-11.)
© 2008 American Academy of Pediatrics
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Objectives |
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 Top Objectives The PathogenEpidemiologyThe DiseasesDiagnosisTreatmentPreventionSummaryReferences |
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The Pathogen |
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TopObjectivesThe PathogenEpidemiologyThe DiseasesDiagnosisTreatmentPreventionSummaryReferences |
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Epidemiology |
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TopObjectivesThe PathogenEpidemiologyThe DiseasesDiagnosisTreatmentPreventionSummaryReferences |
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VZV spreads primarily from the skin vesicles of persons who have varicella or zoster to the respiratory tract of susceptible persons, who then become infected. Electron microscopic studies have shown a high concentration of well-formed, cell-free VZV in skin vesicles. (1) Respiratory spread is difficult to rule out entirely, but during disease, it is rare to isolate the virus from the throat, although it is common to isolate it from skin vesicles. VZV spreads as cell-free enveloped viral particles, or virions, which are present in skin vesicles and are small enough (approximately 200 nm in diameter) to be aerosolized. (2) The virus spreads by the airborne route and requires direct exposure to an infected individual for transmission.
Evidence for spread of VZV from skin is as follows. A 14% transmission rate of the vaccine (Oka) strain of VZV occurred when susceptible siblings were exposed to a recently immunized child who had leukemia and had a vaccine-associated rash. No transmission occurred if the vaccinee had no rash, and VZV could not be isolated from the throats of any of vaccinees, whether or not they had a vaccine-associated rash. Transmission rates were directly proportional to the number of skin lesions. Recent observations in otherwise healthy children who contracted wild-type breakthrough varicella after immunization also have indicated that VZV spreads from skin. (3) Another recent study indicated that children who had active varicella and were not excluded from school on day 1 after rash onset played a major role in spreading the virus in their classrooms. (4) Finally, spread of VZV to observers during an autopsy indicates that transmission by other means than the respiratory tract must occur. (5)
VZV is highly communicable, and subclinical infection is unusual; clinical infection develops in about 80% of susceptibles after family exposure. In contrast, in healthy vaccinees, the Oka strain very rarely spreads to others, even if a rash is present.
Patients who have zoster can transmit varicella to others because the vesicular lesions contain infectious VZV. About 100 years ago, during early attempts to develop a VZV vaccine, children were inoculated with vesicular fluid from zoster patients, and they developed mild chickenpox. Zoster, however, is less contagious than varicella.
The incubation period of varicella ranges from 10 to 23 days (average, 14 days). During the incubation period, VZV multiplies, spreads to regional lymph nodes, and causes viremia. Wild-type VZV has been isolated from blood cultures just before and during very early chickenpox in immunocompetent children. An attractive, recently proposed pathogenetic mechanism is that VZV reaches keratinocytes soon after infection by way of VZV-infected CD4 memory T cells from infected tonsillar cells. These lymphocytes normally circulate through the skin, engaged in immune surveillance; some also become infected with VZV as they circulate, spreading the virus in the body. In this model, overcoming innate immunity in skin accounts for the 2- to 3-week incubation period following infection, as reviewed by Gershon and associates. (6)
Second attacks of varicella are uncommon but may occur. Asymptomatic immunologic boosting of VZV immunity occurs after re-exposure to VZV in varicella-immune individuals and may play a role in long-term maintenance of immunity to VZV.
Patients who develop zoster usually have a history of previous varicella. Zoster can occur in childhood; the incidence is increased by a factor of as much as 20 in those who had varicella in utero or before age 2 years, possibly because the immune response to VZV in young infants is immature. Infants afflicted with the congenital varicella syndrome are at even greater risk for developing zoster.
The incidence of zoster is age-related and begins to increase sharply at 50 years of age. (7) Loss of VZV CMI, which occurs during normal aging, is related to development of zoster. In keeping with this observation, zoster can be prevented by immunization. Zoster also develops commonly in patients treated for cancer and after organ transplantation. Spinal trauma, irradiation, and corticosteroid therapy are other precipitating factors for zoster. Children infected with human immunodeficiency virus (HIV) are at increased risk for developing zoster. Children who develop zoster should be screened (usually by history) for possible risk factors such as HIV infection and underlying immunodeficiency; most often, however, no predisposing factors are identified.
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The Diseases |
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Zoster usually appears as a unilateral vesicular skin eruption involving one to three dermatomes. Skin vesicles may be painful or pruritic, especially in adults. Zoster generally is a milder disease in children than in adults. From 25% to 50% of persons older than 50 years of age and the same proportion of immunocompromised patients who acquire zoster experience serious pain, termed post-herpetic neuralgia (PHN), after the rash has healed. The cause of PHN is unknown.
Complications
The most common complication of varicella is bacterial superinfection of the skin, lungs, or bones, most often by Staphylococcus aureus or group A beta-hemolytic streptococci (GAS). Such infections may be severe and even fatal. Whether treatment with ibuprofen is associated with increased severity of GAS after varicella remains unresolved. Therefore, this drug is not recommended for treatment of fever accompanying varicella.
Central nervous system (CNS) complications, which may precede or follow varicella, include transient cerebellar ataxia, encephalitis, aseptic meningitis, and transverse myelitis. Most CNS complications are self-limited, except for encephalitis, which frequently is associated with severe sequelae if the patient survives. Other less frequent complications of chickenpox include arthritis, glomerulonephritis, myocarditis, and purpura fulminans.
Immunocompromised Patients
Varicella may be severe and even fatal in immunocompromised patients, particularly those who have malignancy or congenital deficits in CMI, as well as in those who have undergone organ transplantation, have underlying HIV infection, or are receiving high doses of corticosteroids. Immunocompromised children who have severe varicella tend to have high fevers, extensive rashes lasting for more than 1 week, hepatitis, and primary viral pneumonia, which may be fatal despite antiviral therapy. Children who have leukemia have a 30% rate of disseminated varicella, with a 7% mortality rate. Severe varicella may occur in HIV-infected children, especially in those who have acquired immunodeficiency syndrome (AIDS). In most of these children, however, mild-to-moderate varicella occurs, although the illness often is more severe than occurs in healthy hosts.
Congenital and Neonatal Varicella
After maternal VZV infection in the first or second trimester of pregnancy, approximately 2% of infants develop the congenital varicella syndrome. (8) Approximately 100 affected infants have been described since 1947; more than 95% of cases occurred after maternal varicella and the remainder after possible maternal zoster. In the prevaccine era, an estimated 40 affected infants were born annually in the United States. Cicatricial skin scars (in >60% of cases) are the most prominent abnormalities. Other common manifestations include hypoplastic limbs, chorioretinitis, microphthalmos, Horner syndrome, cataract, nystagmus, cortical atrophy or mental retardation, zoster, and early death.
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Diagnosis |
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Diagnosis also may be made by isolating the virus from skin lesions, but this technique is more complicated and expensive, is less sensitive, and takes longer than DFA or PCR. VZV rarely can be isolated from cerebrospinal fluid (CSF) and respiratory secretions. The presence of VZV or antigens in secretions or tissues is diagnostic of acute VZV infection because this virus is not shed by asymptomatic persons. The Tzanck test is not recommended by this author because it lacks sensitivity and specificity.
Testing of skin scrapings, vesicular fluid, respiratory secretions, and CSF by PCR is useful for diagnosing VZV, and PCR is replacing culture in many laboratories. PCR is available widely in commercial laboratories and can distinguish between vaccine and wild-type VZV.
Many serologic tests measure antibodies to VZV, including fluorescent antibody to membrane antigen, latex agglutination, and enzyme-linked immunosorbent assay (ELISA). Antibody to VZV develops rapidly after the onset of varicella and persists indefinitely. Peak antibody concentrations occur after 4 to 8 weeks. VZV infections may be proven by a fourfold or greater rise in VZV antibody titer in acute and convalescent serum specimens. Specific immunoglobulin M in one serum specimen suggests recent VZV infection. Persistence of VZV antibody in infants older than 8 months of age suggests intrauterine varicella. Immunity to varicella is highly likely if there is a positive antibody titer to VZV in a single serum sample in a healthy patient. Commercial ELISAs, however, usually are not sufficiently sensitive to identify the level of immunity that develops in vaccinees. After active immunization against VZV, antibody titers are significantly lower than after natural infection.
Serologic procedures for diagnosing zoster are limited because of the nonspecific increases in antibody titer against VZV in some patients who have active HSV infection. These viruses also share minor antigens, which can lead to an increase in VZV titer with HSV infection. Zoster occurs in the presence of serum VZV antibodies; elevations in titer, therefore, can be missed.
CMI responses play the major role in host defense against the virus. CMI to VZV can be demonstrated in vitro most practically by stimulation of lymphocytes with VZV antigens and by an interferon-gamma enzyme-linked immunosorbent spot (ELISPOT) assay. CMI reactions remain positive for years, although CMI often wanes in individuals older than 50 years of age.
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Treatment |
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Indications for Specific Treatment
Because most varicella infections are not serious and the illness usually is self-limited in otherwise healthy children, oral acyclovir (ACV) is not administered routinely. Further, the drug is not well absorbed from the gastrointestinal tract. Specific therapy is reserved for those at higher risk for developing severe varicella or those who already have severe disease. Because controlled studies in children and adolescents given oral ACV for 5 days, starting within 24 hours of the rash of varicella, have shown a modest benefit, prompt oral ACV therapy usually is recommended for adolescents and young adults, who are at moderately high risk for developing severe illness. (10)(11)(12) The oral dose is 20 mg/kg qid for children and 1 g qid for adolescents. The antiviral activity of ACV depends on its phosphorylation by virus-induced thymidine kinases.
Patients at serious risk for or who have severe or potentially severe VZV infections should be treated with intravenous (IV) ACV (10 mg/kg per dose tid for adults and adolescents and 500 mg/m2 per dose tid for children). Patients whose creatinine clearance is less than 50 mL/min per 1.73 m2 are given one half to one third of this dosage, with slow infusion, making sure that hydration is adequate. ACV usually is tolerated very well, but adverse effects include phlebitis, rash, nausea, and neurologic symptoms. Children who are relatively immunocompromised, such as those who have early, seemingly mild varicella and those who have early HIV infection (not AIDS), may be given a closely monitored treatment trial of oral ACV and switched to IV ACV if clinically necessary. In those who have zoster, IV or oral ACV heals skin lesions rapidly and resolves pain.
Development of drug resistance to ACV is of potential concern. Resistance of VZV has been less of a problem than with HSV; VZV resistant to ACV has been reported only rarely. A vaccinated child who had neuroblastoma and developed zoster due to the Oka strain that was resistant to ACV after prolonged treatment has been described.
Because data are few regarding the effectiveness of ACV for preventing chickenpox in susceptible healthy children, its use for this purpose is discouraged.
Famciclovir, an orally administered prodrug of ACV, is converted to ACV in the body, with resulting higher drug concentrations than oral ACV itself. Famciclovir is administered three times a day for zoster (1,500 mg/d) for adults but is not approved either for children or for treatment of varicella. Another oral prodrug of ACV, valacyclovir, achieves higher concentrations of ACV than does famciclovir, but also is not licensed in the United States for use in children or for varicella.
Foscarnet is used to treat VZV infections that are resistant to ACV; the drug inhibits synthesis of VZV DNA polymerase. The dose of IV foscarnet is 180 mg/kg per day divided into two doses, adjusted if necessary for renal function. Toxicities include renal damage and electrolyte imbalance.
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Prevention |
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Children who have chickenpox should be excluded from school or child care from the time the diagnosis is made until the lesions are crusted. Those who have zoster may attend school if the lesions can be covered or when they are crusted. The Table
lists facts that can be helpful in advising parents whose children are exposed to chickenpox. Patients who have active VZV infection and are hospitalized should be isolated, preferably in a room that has negative pressure ventilation, to minimize viral transmission.
Table. Information for Parents Who Ask What to Do If Their Child Is Exposed to Chickenpox
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Vaccination of individuals is particularly important if there are family members who cannot be vaccinated, such as a pregnant woman or immunocompromised children. Transmission of the Oka strain from vaccinated individuals, even if they develop a rash, is extremely rare and has been reported after approximately 1 in 10 million vaccinations.
Passive Immunization
Passive immunization is used to protect exposed high-risk persons from developing severe VZV. Treatment is given to persons who have no history of previous VZV disease, are at high risk for developing severe varicella, and have had an intimate exposure to VZV within the preceding 5 days. Formerly, passive immunization was accomplished by injection of varicella-zoster immune globulin (VZIG). VZIG is no longer being produced, however, because there was little demand for it after 1995. A similar product is available from Canada (VariZIGTM, Cangene Corporation, Winnipeg, Canada) and is recommended for neonates whose mothers have active varicella at or soon after delivery and for exposed susceptible high-risk patients. (13) The product is available in the United States under an investigational new drug application expanded access protocol, with central institutional review board approval. IV immune globulin 400 mg/kg is an alternative should neither VZIG nor VariZIGTM be available. (13)(14)
Active Immunization
Live attenuated varicella vaccine was developed in Japan in 1974. (15) Since 1995, universal immunization of healthy children and adults in the United States who are susceptible to varicella has been recommended by the Centers for Disease Control and Prevention (CDC). This vaccine is extremely safe and well-tolerated. About 5% of healthy children develop a mild rash approximately 4 to 6 weeks after immunization. Serious neurologic events have not been related causally to varicella vaccine. Vaccinees who develop VZV rash within 2 to 3 weeks after immunization are likely to have wild-type infection and should be regarded so.
Live attenuated varicella vaccine is highly effective in healthy children and adults. Universal vaccination has decreased the incidence, complications, morbidity, and mortality of varicella by roughly 80% in the United States.
Although varicella vaccine is highly effective, approximately 20% of children develop mild chickenpox after exposure to wild VZV if they have received only one dose of vaccine. Severe varicella occurs only in about 3% of those who develop breakthrough varicella after vaccination. The vaccine is also 80% effective in adults after two doses. Severe wild-type varicella in vaccinated adults is rare. (6)(14)(16)(17)
It is unclear whether breakthrough varicella is the result more from primary or secondary vaccine failure, but primary vaccine failure seems to be the major factor. Loss of VZV antibodies occurs rarely in healthy vaccinated children, even after a follow-up for as long as 20 years. Between years 1 and 8 after immunization, there has not been a decrease in protection of healthy children. There have been, however, numerous recent reports of outbreaks of varicella among immunized children in child care facilities and schools. Most investigations of outbreaks have shown 80% to 85% vaccine effectiveness, but some show effectiveness as low as 45% to 55%. (6) (14) The children included in these studies had, for the most part, received only one dose of vaccine.
A recent investigation indicated a significant degree of primary vaccine failure (24%) in young children who received only one dose of vaccine. (18) To decrease virus transmission, improve vaccine effectiveness, and prevent accumulation of susceptible young adults, two doses of vaccine—previously recommended only for those older than 13 years of age—were recommended for all children by the CDC in June 2006. Catch-up varicella vaccination also is recommended for all children who received only one dose of varicella vaccine in the past. After a second dose of varicella vaccine, there is a marked boost in both humoral and cellular immunity, and the second dose is tolerated very well without significant complications. One small study indicated improved protection after two doses compared with one dose over 10 years of follow-up. (19)
Another important recent advance for varicella immunization was the development of the combined measles-mumps-rubella-varicella (MMRV) vaccine, which was approved by the United States Food and Drug Administration in 2005. MMRV contains about 10 times the amount of VZV as the monovalent formulation and is licensed only for children younger than 14 years of age. Currently, most infants and children will be immunized with two doses of MMRV after the shortage of this vaccine is corrected. (20) Varicella vaccine also is recommended for susceptible adults, especially for health-care workers and persons whose varicella-susceptible family members are immunocompromised or pregnant. Varicella vaccine is recommended only for healthy persons. Zoster appears to be less of a problem after immunization than after natural infection. The CDC now recommends postexposure vaccination for healthy varicella-susceptible exposed individuals.
Recently, a successful vaccine has been developed to prevent zoster in older adults; this vaccine is the Oka strain of VZV, given at a dose roughly 14 times greater than that in the monovalent formulation. One dose of this vaccine is recommended for healthy individuals older than age 60 years who have had varicella but not zoster. This vaccine is 50% to 60% protective against zoster and its major complication, PHN. (7)
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Summary |
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TopObjectivesThe PathogenEpidemiologyThe DiseasesDiagnosisTreatmentPreventionSummaryReferences |
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Footnotes |
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Dr Gershon has disclosed that she occasionally is a consultant and lecturer for Merck and Company, Inc, and GlaxoSmithKline.
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References |
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2. Hambleton S, Gershon AA. Preventing varicella-zoster disease.
Clin Microbiol Rev. 2005;18
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3. Seward JF, Zhang JX, Maupin TJ, Mascola L, Jumaan AO. Contagiousness of varicella in vaccinated cases: a household contact study.
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4. Ma H, Fontaine R. Varicella outbreak among primary school students–Beijing, China, 2004. MMWR Morbid Mortal Wkly Rep. 2006;55(suppl 1) :39 –43
5. Paul N, Jacob ME. An outbreak of cadaver-acquired chickenpox in a health care setting. Clin Infect Dis. 2006;43 :599 –601[CrossRef][Medline]
6. Gershon A, Takahashi M, Seward J. Varicella vaccine. In: Plotkin S, Orenstein W, eds. Vaccines. 5th ed. Philadelphia, Pa: Saunders; 2008; in press
7. Oxman MN, Levin MJ, Johnson GR, et al. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults.
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8. Gershon A. Chickenpox, Measles, and Mumps. 6th ed. Philadelphia, Pa: Saunders; 2006
9. Gershon A, Chen J, LaRussa P, Steinberg S. Varicella-zoster virus. In: Murray PR, Baron E, Jorgensen J, Landry M, Pfaller M, eds. Manual of Clinical Microbiology. 9th ed. Washington, DC: ASM Press; 2007:1537 –1548
10. Whitley RJ, Middlebrooks M, Gnann JW. Acyclovir: the past ten years. Adv Exp Med Biol. 1990;278 :243 –253[Medline]
11. Balfour HH, Rotbart H, Feldman S, et al. Acyclovir treatment of varicella in otherwise healthy adolescents. J Pediatr. 1992;120 :627 –633[CrossRef][Medline]
12. Dunkel L, Arvin A, Whitley R, et al. A controlled trial of oral acyclovir for chickenpox in normal children. N Engl J Med. 1991;325 :1539 –1544[Abstract]
13. Centers for Disease Control. A new product (VariZIG) for postexposure prophylaxis of varicella available under an investigational new drug application expanded access protocol. MMWR Morbid Mortal Wkly Rep. 2006;55 :209 –210[Medline]
14. Centers for Disease Control. Prevention of varicella. MMWR Morbid Mortal Wkly Rep. 2007;56 :1 –40[Medline]
15. Takahashi M, Otsuka T, Okuno Y, Asano Y, Yazaki T, Isomura S. Live vaccine used to prevent the spread of varicella in children in hospital. Lancet. 1974;2 :1288 –1290[Medline]
16. Vazquez M, LaRussa P, Gershon A, Steinberg S, Freudigman K, Shapiro E. The effectiveness of the varicella vaccine in clinical practice.
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17. Vazquez M, LaRussa PS, Gershon AA, et al. Effectiveness over time of varicella vaccine.
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18. Michalik D, La Russa P, Steinberg S, Wright P, Edwards KM, Gershon A. Primary immune failure after 1 dose of varicella vaccine may be the main cause of breakthrough infections in healthy vaccinated children. J Infect Dis. 2008; in press
19. Kuter B, Matthews H, Shinefield H, et al. Ten year follow-up of healthy children who received one or two injections of varicella vaccine. Pediatr Infect Dis J. 2004;23 :132 –137[Medline]
20. Centers for Disease Control. Supply of vaccines containing varicella-zoster virus. MMWR Morbid Mortal Wkly Rep. 2007;56 :146 –147
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