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Pranee Sitaposa,M.D. Pediatric ID Fellow Division of Infectious Diseases Department of Pediatrics Queen Sirikit National Institute of Child Health Oct 5, 2007.
Varicella-Zoster Virus
Varicella (chickenpox) acute, highly contagious viral disease with worldwide distribution majority of annual costs* 80% to 85% of chickenpox : physician visits 85% to 90% of chickenpox : hospitalization most of which are related to productivity losses by caregivers mainly a childhood disease 5 years of age : infection rate 50% 12 years of age : infection rate 90%
Health Canada. CCDR 1999;25(S5):1-29.
Varicella-Zoster Virus
mostly a mild disorder in childhood tends to be more severe in adults It may be fatal Neonates Immunocompromised persons 4% to 13% of individuals who had previous varicella infection : recurrences of varicella-like rash* The risk factors
young age (< 12 months) at first infection a milder symptoms at first infection
*Hall S, et al. Pediatrics 2002;109:1068-73.
Varicella-Zoster Virus
Fatality rates for varicella* adults 30 deaths/100,000 cases infants 7 deaths/100,000 cases 1-19 yr of age 1-1.5 deaths/ 100,000 cases In the United States adults account for only 5% of cases but for 55% of the approximately 100 chickenpox deaths each year In Canada, from 1987 to 1996 70% of the 53 reported chickenpox deaths occurred in those > 15 years of age.
*Meyer PM, et al. J Infect Dis 2000;182:383-90.
Preblud SR. Pediatrics 1981;68:14-7.
The pathogen
a double-stranded DNA virus : human herpesvirus-3 subfamily Alphaherpersviridae only one serotype is known humans are the only reservoir VZV enters the host through the nasopharyngeal mucosa, and almost invariably produces clinical disease in susceptible individuals Following varicella, the virus persists in sensory nerve ganglia, from where it may later be reactivated to cause herpes zoster (Shingles)
Transmission
The virus is transmitted by direct contact with the rash Airborne respiratory droplets vertical transmission (mother to baby) during pregnancy can transmit the virus for up to 48 hours before rash appears and remains contagious until all spots crust over little genetic variation no animal reservoir visceral dissemination of the virus has occurred in 30% and mortality in 7% to 10% of these patients*
*Feldman S, et al. Pediatrics 1975;56:388.
In healthy children the disease is generally mild. The illness usually 1416 days after exposure Incubation period 10-21 days Prodromal symptoms : particularly in older children Low-grade fever preceding skin manifestations by 1-2 D 24-48 hr before rash Mild abdominal pain Mild cough and runny nose Mild headache
malaise or irritability
red, itchy rash appear first on the scalp, face, trunk quickly turn into clear fluid-filled vesicles 24-48 hr later, clouding and umbilication of lesions initial lesions are crusting, new crops form on trunk and then the extremities Characteristics : various stages of evolution oropharyngeal, vagina involvement : common cornial involvement and serious ocular disease : rare the average number of varicella lesion is about 300 lesions <10 to >1,500 lesions Itching may range from mild to intense
Laboratory studies
unnecessary for diagnosis, obvious clinically Immunohistochemical staining of skin lesion scrapings can confirm varicella A Tzanck smear : multinucleated giant cells useful for high-risk patients who require rapid confirmation not sufficiently sensitive or specific for varicella more specific immunohistochemical staining of such scrapings, if available Immunoglobulin M tests : not reliable, positive results indicate current or recent VZV activity
Redbook27th Ed;2006;711-725.
Immune response
Natural infection induces lifelong immunity to clinical varicella in almost all immunocompetent persons Newborn babies of immune mothers are protected by passively acquired antibodies during their first months of life Temporary protection of non-immune individuals can be obtained by injection of varicella-zoster immune globulin within 3 days of exposure The immunity acquired in the course of varicella prevents neither the establishment of a latent VZV infection, nor the possibility of subsequent reactivation as zoster.
Immune response
Antibody assays : indication of previous infection or response to vaccination less reliable as correlates of immunity, particularly to zoster failure to detect antibodies against VZV does not necessarily imply susceptibility, as the corresponding cell-mediated immunity may still be intact 20% of persons aged 5565 show no measurable cell-mediated immunity to VZV in spite of persisting antibodies, and a history of previous varicella Zoster is closely correlated to a fall in the level of VZVspecific T-cells an episode of zoster will reactivate the specific T-cell response
High-risk groups
High risks of complications Newborns and infants whose mothers never had chickenpox or the vaccine Teenagers Adults Pregnant women People whose immune systems are impaired by another disease or condition People who are taking steroid medications for another disease or condition, such as asthma People with the skin inflammation eczema
Complications of Varicella
herpes zoster (shingles) lifetime risk 15%-20% mainly affecting the elderly and immunocompromised persons secondary bacterial skin and soft tissue infections otitis media bacteremia, pneumonitis osteomyelitis septic arthritis
endocarditis necrotizing fasciitis toxic shock-like syndrome hepatitis thrombocytopenia hemorrhegic varicella cerebellar ataxia encephalitis severe invasive group A streptococcal infection increases the risk 40-60 fold*
*Health Canada. CCDR 1999;25(S5):1-29. Davies HD, et al. N Eng J Med 1996;335:547-54.
Complications of Varicella
When compared with children, adults are 3 to 18 fold higher risk : admitted to hospital for varicella 11 to 20 fold higher : higher rates of complications such as pneumonia 1.1- to 2.7-fold higher : encephalitis* The risk factors identified in adults for varicella pneumonia underlying chronic lung disease Smoking** varicella pneumonia occurring in 3.4% to 9.3% of pregnant women (no higher than in nonpregnant adults)*** High mortality
*Choo PW, et al. J Infect Dis 1995;172:706-12 **Ellis ME, et al. Br Med J 1987;294:1002. ***Harger JH, et al. Obstet Gynecol 2002;100(2):260-65.
Neonatal varicella
can be a serious illness, depending upon the timing of maternal varicella and delivery If the mother develops varicella within 5 days before or 2 days after delivery acquires the virus transplacentally no protective antibodies
Prophylaxis or treatment is required with varicella-zoster immune globulin (VZIG) and acyclovir Without these drugs, mortality rates 20% - 30%*
The primary causes of death are severe pneumonia and fulminant hepatitis
*Derrick CW Jr, et al.South Med J 1998 Nov; 91(11): 1064-6.
Neonatal varicella
Onset of maternal varicella more than 5 days antepartum provides the mother sufficient time to manufacture and pass on antibodies along with the virus. Full-term neonates : usually have mild varicella Treatment with VZIG is not recommended, but acyclovir may be used, depending on individual circumstances
increase in spontaneous abortion, stillbirth, or prematurity transplacental or perinatal infection can have other serious outcomes.
0.4% of live births when maternal infection occurred from conception through the 12th week of gestation 2% when infection occurred between the 13th and 20th week of gestation* A smaller, prospective study of 347 women who had varicella during pregnancy found an overall congenital varicella syndrome rate of 0.4%**
*Enders G, et al. Lancet 1994;343:1547-50. **Harger JH, et al. Obstet Gynecol 2002;100(2):260-65.
maternal infection with chickenpox (maternal varicella zoster) early during pregnancy (i.e., up to 20 weeks gestation)
The range and severity of associated symptoms and physical findings may vary greatly from case to case depending upon when maternal varicella zoster infection occurred during fetal development
Damage to Sensory Nerves Cicatricial skin lesions Hypopigmentation Damage to Optic Stalk and Lens Vesicle
Damage to Brain/Encephalitis
Hypoplasia of an extremity Motor and sensory deficits Absent deep tendon reflexes Anisocoria Horners syndrome Anal/urinary sphincter dysfunction
Type of exposure
Household
NB : mother had onset of chickenpox within 5 days before delivery or within 2 days after delivery
Redbook27th Ed;2006;711-725.
Postexposure Immunization
Varicella vaccine Susceptible people > 12 mo of age, including adults As soon as possible within 72 hr and possibly up to 120 hr after varicella exposure To prevent or modify disease
Chemoprophylaxis
If VariZIG is not available or > 96 hr after exposure Oral Acyclovir (some experts recommend) 80 mg/kg/day divided 4 times/day for 7 days Start on day 7-10 after varicella exposure if vaccine is contraindicated Susceptible immunocompromised adults Limited data on acyclovir as postexposure prophylaxis in healthy children
Passive immunoprophylaxis
VZIG : cessation of manufacture,2005 VariZIG (Varicella-Zoster Immune Globulin) 125 U/10 kg IM, Maximum dose 625U
lessen the severity of the disease Likelihood that the exposed person is susceptible to varicella Probability that a given exposure to varicella or zoster will result in infection Likelihood that complications of varicella will develop if person is infected
Passive immunoprophylaxis
VariZIG should be administered as soon as possible, but no later than 96 hours after exposure Newborns whose mothers have chicken pox five days prior to two days after delivery Children with leukemia or lymphoma who have not been vaccinated Persons with cellular immunodeficiencies or other immune problems Persons receiving drugs, including steroids, that suppress the immune system Pregnant women
Immunocompromised children without Hx.of varicella or varicella immunization NB : mother had onset of chickenpox within 5 days before delivery or within 2 days after delivery Hospitalized preterm infants (GA 28 wks) whose mother lack Hx or serology of varicella
Treatment
Healthy children no medical treatment antihistamine to relieve itching IV Acyclovir (nucleoside analogues) < 1 yr 30 mg/kg/day in 3 divided doses for 7-10 days > 1 yr 1500 mg/m2/day divided q 8 h for 7-10 days Immunocompromised patients Patients being treated with chronic corticosteroids
medications to shorten the duration of the infection help reduce the risk of complications
Treatment
80 mg/kg/day divided in 4 doses for 5 days, Max dose 3200 mg/day (* some experts recommend) Healthy people at increased risk of moderate to severe varicella
> 12 yr of age Chronic cutaneous or pulmpnary disorders Receiving long-term salicylate therapy Receiving short, intermittent, or aerosonized courses of corticosteroids *Secondary household cases (disease usually is more severe than in primary case) *Pregnancy, especially during the second and third trimesters *HIV-infected patients with relatively normal CD4+ T-lymphocytes *Leukemia in whom careful follow-up
Treatment
Complicated cases Hospitalization skin infections and pneumonia : antibiotics encephalitis : antiviral drugs Don't give Aspirin : Reye's syndrome.
Identify those who are susceptible: both personel and patients immunocompromised patient immunocompetent patient who: < 6 month old without maternal history of chickenpox > 6 month old with unimmunized/unvaccinated All exposed susceptible patients should be discharged as soon as possible. All susceptible patients who cannot be discharged should be placed in airborne and contact precaution from day 10-21 after exposure.(28 day who received VariZIG)
Redbook27th Ed;2006;711-725.
All susceptible exposed staff should be furloughed from day 8-21 post exposure to an infectious patient. (28 day who received VariZIG) Serologic testing for immunity is not necessary for personel who have been immunized Immunizaed health care personel who develop breakthough infection should be considered infectious Varicella immunization is recommended for susceptible personnel if there are no contraindications to vaccine use
Redbook27th Ed;2006;711-725.
45 yrs-old, Thai woman, admitted to Thammasart Hospital ICU because of CAP Day 11, she develop chicken pox
Healthcare workers Hx of Varicella + Hx of Varicella IgG + IgG 23 30 0 47
Sereprevalence >90% adults seropositive (in general) History of Varicella 97-99% predictive of antibodies Negative or uncertain history 79-93% seropositive
Apisarnthanarak A, et al. Infect Control Hosp Epidemio,2007
Recommended for patients with varicella for a minimum of 5 days after onset of rash and until all lesions are crusted Airborne and contact precautions from 10-21 days after exposure to index patient (28 days for those who received VariZIG or IGIV)
For neonates born to mothers with varicella and, if still hospitalized, should be continued until 21 or 28 days of age if they received VariZIG or IGIV
Redbook27th Ed;2006;711-725.
all susceptible children and adults A second dose catch-up varicella vaccination is recommended for
children, adolescents, and adults who previously had received only one dose
exposed to chickenpox may receive varicella vaccine within 3 days (72 hours) to 5 days (120 hours) prevent or diminish the severity of illness
special consideration in Adults not received the vaccine not already had chickenpox higher risk for exposure/transmission College students Household contacts of immunocompromised persons Residents and staff in institutional settings Inmates and staff of correctional institutions International travelers Military personnel Nonpregnant women of childbearing age Teachers and day care workers Non-immune persons
National Foundation for Infectious Diseases.USA. August 2006
Prevention
The attack rate in unvaccinated susceptible children was 88% The varicella vaccine is the best way to prevention CDC estimate complete protection from the virus for nearly 90% Unvaccinated older children 7-13 yr receive two catch-up doses of the varicella vaccine at least 3 mo apart > 13 yr receive two catch-up doses of the varicella vaccine at least 4 wks apart
CDC. MMWR 2005 Jul 29; 54(29): 717-21.
Prevention
Unvaccinated adults who've never had chickenpox but are at high risk of exposure
If you don't remember whether you've had chickenpox or the vaccine, a serum antibody test If you've had chickenpox, you don't need the vaccine
Varicella vaccine
Oka strain of VZV since 1974 a single dose of vaccine : seroconversion 95% optimal age for varicella vaccination is 1224 months In Japan and several other countries one dose of the vaccine : sufficient, regardless of age In the United States two doses, four to eight weeks apart Recommendation for adolescents and adults after the first dose : seroconversion 78% after the second dose : seroconversion 99%
Varicella vaccine
Varicella outbreak in a day-care center efficacy 100% in preventing severe disease 86% in preventing all disease From the Japanese experience immunity to varicella following vaccination lasts for at least 1020 years
In the United States : routine vaccination Since 1995 70%90% protection against infection > 95% protection against severe disease 710 years after immunization*
*Clements DA, et al. Pediatr Infect Dis J 1999;18:1047-50. Vasquez M, et al. N Eng J Med 2001;344:955-60. Izurieta H, et al. JAMA 1997;279:1495-99.
Varicella vaccine
In immunocompromised persons, including patients with advanced HIV infection contraindication : fear of disseminated vaccine-induced disease Vaccine safety asymptomatic HIV-infected children with CD4 counts of more than 1,000 cell/L patients with leukaemia in remission or solid tumours before chemotherapy uremic patients waiting for transplantation a killed varicella vaccine has been studied in VZV-positive bone marrow transplant patients where a multiple-dose schedule has been reduce the severity of zoster
Randomized, double-blind, placebo-controlled trial of an investigational live attenuated Oka/Merck VZV vaccine enrolled 38,546 adults 60 years of age or older
burden of illness due to herpes zoster, a measure affected by the incidence, severity, and duration of the associated pain and discomfort secondary end point was the incidence of postherpetic neuralgia > 95 % of the subjects continued in the study to its completion a median of 3.12 years of surveillance for herpes zoster. A total of 957 confirmed cases of herpes zoster (315 among vaccine recipients and 642 among placebo recipients)
Results
NEJM2005;352:2271-2284.
107 cases of postherpetic neuralgia (27 among vaccine recipients and 80 among placebo recipients) were included in the efficacy analysis. zoster vaccine reduced the burden of illness due to herpes zoster by 61.1% (P<0.001) reduced the incidence of postherpetic neuralgia by 66.5% (P<0.001), and reduced the incidence of herpes zoster by 51.3% (P<0.001) Reactions at the injection site were more frequent among vaccine recipients but were generally mild
Conclusions The zoster vaccine markedly reduced morbidity from herpes zoster and postherpetic neuralgia among older adults
NEJM2005;352:2271-2284.
Breakthrough Varicella
Varicella in persons who have received the vaccine less severe than the disease in unvaccinated individuals 3% to 4% per year after varicella vaccination 5% to 20% after household exposure to wild-type virus. The risk that vaccinated individuals with breakthrough disease will infect others appears to correlate with the number of lesions that develop. > 50 lesions were equally as likely to transmit the infection to household contacts < 50 lesions were only half as likely to transmit the infection (J. Seward, Centers for Disease Control and Prevention, Atlanta: personal communication)
NEJM 2001;344:955-60. JAMA 1997;279:1495-99. Pediatrics 1999;104:561-63.
Comparison of severity of varicella symptoms in naturally infected children and varicella vaccine recipients
local
pain, redness and the first and second doses swelling 11% - 22% local symptoms Varicella-like rash 1% 12% and 16% other rash types 10% fever 29% and 20% Reactions at the injection varicella-like rash site tended to be mild and 0.9% and 1.3% transient Fever 11%
In healthy children 27% : local swelling and redness at the site of injection < 5% : a mild varicella-like disease with rash within 4 wks rare occasions of mild zoster following vaccination Since licensure and distribution of more than 10 million doses of vaccine in the United States, the Vaccine Adverse Event Reporting System (VAERS) reports of encephalitis, ataxia pneumonia thrombocytopenia arthropathy and erythema multiforme These events may not be causally related and they occur at much lower rates than following natural disease
99.4%
98.9%
1.Kuter B, et al. Pediatr Infect Dis J 2004;23:1327. 2.Shinefield H, et al. Pediatr Infect Dis J 2005;24:6659. 3.Reisinger KS, et al. Pediatrics 2006;117:26572.
a history of anaphylactic reactions to any component of the vaccine including neomycin pregnancy due to theoretical risk to the fetus pregnancy should be avoided for 4 wks following vaccination ongoing severe illness, and advanced immune disorders of any type except for patients with acute lymphatic leukaemia in stable remission ongoing treatment with systemic steroids for adults more than 20 mg/day for children more than 1mg/kg/day
American Hospital Formulary Service (AHFS) Drug Information 1997, p.2653-2655.
A history of congenital immune disorders in close family members is a relative contraindication both varicella-zoster immune globulin (VZIG) and antiviral drugs are available should persons in the immunocompromised categories receive the vaccine by mistake Administration of blood, plasma or immunoglobulin < 5 mo before immunization or 3 wks afterwards reduce the efficacy of the vaccine use of salicylates is discouraged for 6 wks following varicella vaccination : risk of Reye syndrome
American Hospital Formulary Service (AHFS) Drug Information 1997, p.2653-2655.
Between 1995 and 2004 : Researchers from the Centers for Disease Control and Prevention (CDC) and the Los Angeles Department of Health Services looked at data on 350,000 Californians > 11,000 people who developed chickenpox, almost 1,100 had been vaccinated The study also found that 8- to 12-year-olds who contracted chickenpox after being vaccinated at least 5 years earlier were twice as likely to have "moderate or severe" cases than those who had gotten the vaccine less than 5 years before. early on with just one dose may still develop chickenpox at an older age, when the illness may be more severe
Randomized clinical trial : compared the efficacy of 1 dose of vaccine with that of 2 doses the cumulative rate of breakthrough varicella during a 10-year observation period was 3.3-fold lower among children who received 2 doses than that among children who received 1 dose (2.2% and 7.3,respectively; p<0.001)
Breakthrough cases occurred occasionally in 0.8% of 2-dose vaccine recipients.
The majority of cases of breakthrough disease occurred 25 years after vaccination; no cases were reported 710 years after vaccination Of 16 children with breakthrough cases, three (19%) had >50 lesions. The proportion of children with >50 lesions did not differ between the 1-dose and 2-dose regimens (p = 0.5).
In 2006, the CDC recommended First dose at 12 - 15 mo of age a booster dose at 4 - 6 yr old
Kuter B, et al. Pediatr Infect Dis J 2004;23:1327.
Category
Routine childhood schedules
1996 recommendations
1 dose recommended at age 1218months
1999 recommendations
No change
2007 recommendations
2 doses recommended 1st dose at age 12 15 months 2nd dose at age 46 years
2 doses, 48 weeks apart Recommended for all adolescents and adults without evidence of immunity
Catch-up vaccination
1 dose recommended for all susceptible children aged 19 months12 years (i.e., those with no history of varicella or vaccination)
No change
2nd dose recommended for all persons who received 1 dose previously
Recommendations of the Advisory Committee on Immunization Practices (ACIP):MMWR,June 22, 2007 / Vol. 56 / No. RR-4
Category
HIV-infected persons
1996 recommendations
Contraindicated
1999 recommendations
2 doses, 3 months apart Considered for asymptomatic or CDC N1 or A1 or CD4+ >25%
2007 recommendations
2 doses, 3 months apart Considered for CD4+ >15%
None
Should be considered Recommended within 35 days Recommended for children without evidence of immunity attending child care centers and entering elementary school
Recommended 2 dose vaccination policy No change Recommended for children attending child care centers, students in all grade levels and persons attending college
None None
Recommendations of the Advisory Committee on Immunization Practices (ACIP):MMWR,June 22, 2007 / Vol. 56 / No. RR-4
Herpes Zoster
rash usually resolves within 14-21 days Postherpetic neuralgia pain persisting at least 1 month after the rash has healed incidence increases dramatically with age
Immunocompetent host all ages : same as Varicella in imunocompromised host > 12 yr : Acyclovir 4,000 mg/day in 5 divided doses for 5-7 days Immunocompromised children < 12 yr : Acyclovir 60 mg/kg/day IV q 8 hr, for 7-10 days > 12 yr : Acyclovir 30 mg/kg/day IV q 8 hr, for 7 days
Redbook27th Ed;2006;711-725.
Herpes Zoster
the boosting of cell-mediated immunity by exposure to wild-type varicella infection reduces the risk of zoster in adults* The adults with the most contact with children had roughly one-fifth the zoster risk of those with the least contact with children**
*Solomon BA, et al. J Am Acad Dermatol 1998;38:763-65. Thomas SL, et al. Lancet. URL: 2 July, 2002. **Levine MJ, Vaccine 2000;18(25):2915-20.
Infantile zoster
The cause is maternal varicella infection after the 20th week of gestation
commonly involves the thoracic dermatomes
Postherpetic neuralgia Ocular involvement with facial zoster Meningoencephalitis Cutaneous dissemination Superinfection of skin lesions Hepatitis/pneumonitis Peripheral motor weakness/segmental myelitis Cranial nerve syndromes, particularly ophthalmic and facial (Ramsay Hunt syndrome) Corneal ulceration Guillain-Barr syndrome
Ann Neurol 1994; 35 Suppl: S4-8.
Immunocompromised patient who have zoster (localized or disseminated) and immunocompetent patients with disseminated zoster Airborne and contact precautions for the duration of illness For immunocompetent patients with localized zoster Contact precautions until all lesions are crusted
Redbook27th Ed;2006;711-725.
Immunoglobulin
Interval (months)
3 4
5 6 5 0 3 5 6 7 8 8 10 11 11
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