Varicella-Zoster Virus Done by : Mohammed A Qazzaz

Varicella-Zoster Virus (VZV) • Causes primary, latent, and recurrent infections. • The primary infection: varicella (chickenpox)• Followed by: lifelong latent infection of sensory ganglion neurons. • Reactivation causes herpes zoster (shingles).

• Chickenpox causes morbidity and mortality which is more in: - adolescents, adults - immunocompromised• Can be treated with antiviral drugs. • Can be prevented by immunization.

ETIOLOGY VZV

• Neurotropic human α-herpesvirus

EPIDEMIOLOGY

• Vaccine started in 1995

• Most children were infected by 15 yr. • < 5% of adults remaining susceptible. • Epidemics occurred in winter and spring,

• More serious in infants, adults, and immunocompromised.

• Households transmission 65–86%; • Contagious period from 2days before rash

until vesicles are crusted, usually 3–7 days after onset of rash.

• Chicken pox can be acquired after close contact with cases having herpes zoster

PATHOGENESIS

• VZV is transmitted in respiratory secretions and in the fluid of skin lesions either by airborne spread or through direct contact.

• Primary infection (varicella) results from inoculation of the virus onto the mucosa of the upper respiratory tract and tonsillar lymphoid tissue.

• virus replicates in the local lymphoid tissue then by viremia spreads to the reticuloendothelial system.

• During viremia the mononuclear cells carry the virus to form new crops of vesicles.

• Also goes back to upper respiratory mucosa during the late incubation period, becoming infectious before rash(2d).

• Host immune responses limit viral replication. • In the immunocompromised continued viral

replication cause disseminated infection with complications in the lungs, liver, brain, and other organs.

PATHOGENESIS • Virus is transported through sensory axons to the dorsal root ganglia

throughout the spinal cord, causing latent infection in the neurons. • Subsequent reactivation of latent virus causes herpes zoster.

• The skin lesions of varicella and herpes zoster have identical histopathology, and infectious VZV is present in both.

• Varicella causes humoral and cell-mediated immunity that is highly

protective against symptomatic reinfection. • Suppression of cell-mediated immunity to VZV correlates with an

increased risk for VZV reactivation as herpes zoster

CLINICAL MANIFESTATIONS • usually self-limited.• may be associated with severe complications: bacterial superinfection Pneumonia Encephalitis bleeding disorders congenital infection life-threatening perinatal infection.• Herpes zoster, uncommon in children, causes localized

cutaneous symptoms, but may disseminate in immunocompromised patients.

Varicella (Chicken pox) • I.P: 10 to 21 days • The illness usually begins 14–16 days after exposure. • Prodromal symptoms 24–48 hr before rash: - Fever: moderate - malaise - anorexia - headache - mild abdominal pain (occasional). • symptoms persist 1st 2–4 days after rash onset.

• lesions appear first on the scalp, face, or trunk. • Initially: pruritic erythematous macules then papular

stage to form clear, fluid-filled vesicles. • umbilication of the lesions begin in 24–48 hr. • While the initial lesions are crusting, new crops form

on the trunk and then the extremities.

• presence of various stages at a time is characteristic of varicella

• The rash is predominantly centripetal. • Ulcerative lesions involving the mucosa of oropharynx,

eyelids and conjunctivae. • The average lesions is 300, but healthy children(10-1500) • The rash is more extensive with eczema.

• Hypopigmentation or hyperpigmentation of lesion sites persists for days to weeks.

• severe scarring is unusual unless the lesions were secondarily infected

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The differential diagnosis • herpes simplex virus, • enterovirus, • monkey pox, • rickettsial pox• S. aureus; • drug reactions; • contact dermatitis; • insect bites. Severe varicella was the most common illness confused with

smallpox before the eradication of smallpox.

Varicella in Vaccinated Individuals

• Vaccine is effective in; - >95% preventing severe disease - 80% preventing all disease. • 1 of every 5 vaccinated children may develop varicella in school

outbreak.• Mild disease with mild or no fever.• The rash is atypical: - maculopapular - vesicles - <50 lesions • less contagious.

Progressive Varicella

• visceral organ involvement, • coagulopathy, • severe hemorrhage, and • continued vesicular lesions, hemorrhagic

vesicles . • Severe abdominal pain, • The mortality rate is 7%; within 3 days after the

diagnosis of varicella pneumonia.

Risk factors for progressive varicella

1. congenital cellular immune deficiency.2. malignancy, particularly on chemotherapy.3. after organ transplantation4. high-dose corticosteroids

• Immunization of the following gp helps to reduce the problem:

- HIV-infected children who have a CD4 count > 15% - children with leukemia and solid organ tumors who are

stable on maintenance chemotherapy.

Neonatal Chickenpox

• Newborns have high mortality in susceptible mother contracting varicella around the time of delivery.

• Infants whose mothers develop varicella in the period from 5 days prior to delivery to 2 days afterward are at high risk for severe varicella.

• The infant acquires the infection transplacentally as a result of maternal viremia, which may occur up to 48 hr prior to the maternal rash.

• Rash appears at the end of the 1st week.

Neonatal Chickenpox • Because the mother has not yet developed a significant

antibody response, the infant receives a large dose of virus without the moderating effect of maternal anti-VZV antibody.

• If the mother develops varicella > 5 days prior to delivery, she still may pass virus to the soon-to-be-born child, but infection is attenuated due to transmission of maternal antibody across the placenta.

Neonatal Chickenpox ttt • human varicella-zoster immune globulin (VariZIG) is indicated. • Newborns whose mothers develop varicella 5 days before to 2 days after

delivery should receive 1 vial. • Although neonatal varicella may occur in about half of these infants

despite administration of VariZIG, it is usually mild.

Congenital Varicella Syndrome

• up to 2% of fetuses whose mothers had varicella in the 1st 20 wk of pregnancy may have a VZV embryopathy.

• Fetuses infected at 6–12 wk of gestation appear to have maximal interruption with limb development;

• fetuses infected at 16–20 wk may have eye and brain involvement.

• The organs involved mainly the skin, extremities, eyes, and brain

• The characteristic cutaneous lesion has been called a cicatrix, a zigzag scarring, in a dermatomal distribution, often associated with atrophy of the affected limb.

Stigmata of Varicella-Zoster Virus Fetopathy

DAMAGE TO SENSORY NERVES

• Cicatricial skin lesions • Hypopigmentation

DAMAGE TO OPTIC STALK AND LENS VESICLE

• Microphthalmia • Cataracts • Chorioretinitis • Optic atrophy

DAMAGE TO BRAIN/ENCEPHALITIS • Microcephaly • Hydrocephaly • Calcifications • Aplasia of brain

DAMAGE TO CERVICAL OR LUMBOSACRAL CORD • Hypoplasia of an extremity • Motor and sensory deficits • Absent deep tendon reflexes • Anisocoria (difference in pupil size) • Horner syndrome • Anal/urinary sphincter dysfunction

Diagnosis of VZV embryopathy

• The history.• chickenpox stigmata seen in the fetus. • Viral DNA may be detected in tissue samples by

(PCR). • VZV-specific IgM antibody in the cord blood. • Chorionic villus sampling

• Although varicella immune globulin to exposed mother may not modify infection in the fetus.

• Similarly, acyclovir treatment may be given to the mother with severe varicella.

• Acyclovir when the benefit to the mother outweighs the potential risk to the fetus (effect is uncertain).

• antiviral treatment of infants with congenital VZV syndrome is not indicated because it is not progressive.

Herpes Zoster • vesicular lesions clustered within 1 or less commonly

2 adjacent dermatomes In the elderly:• begins with burning pain, with clusters of skin lesions

in a dermatomal pattern. • Almost half of the elderly with herpes zoster develop

complications;• the most frequent complication is postherpetic

neuralgia, a painful condition that affects the nerves despite resolution of the shingles skin lesions.

In children:• rash is mild• lesions appearing for a few days• symptoms of acute neuritis are minimal• complete resolution usually occurs within 1–2 wk. • postherpetic neuralgia is very unusual in children. • Approximately 4% of patients suffer a 2nd episode of herpes

zoster. ( 3 or more episodes are rare ) • Transverse myelitis with transient paralysis is a rare. Risk factors:• children who acquire varicella in the 1st year of life• whose mothers have a varicella infection in the 3rd trimester

of pregnancy

Herpes Zosterin immunocompromised children

• more severe, similar to adults, including postherpetic neuralgia. • disseminated cutaneous disease like chicken pox.• visceral dissemination with pneumonia, hepatitis, encephalitis, and

disseminated intravascular coagulopathy. Patients with HIV:• chronic or relapsing cutaneous disease• Retinitis• CNS disease without rash. • A lower risk for herpes zoster in vaccinated children with leukemia.

DIAGNOSIS of Chicken pox

DIAGNOSIS of Chicken pox • Leukopenia is typical during the 1st 72 hr; it is

followed by• lymphocytosis. • liver function tests usually (75%) mildly elevated.• CSF: in CNS complications: - lymphocytic pleocytosis - increase in protein - glucose concentration is usually normal.

• Quick direct fluorescence assay of cells from cutaneous lesions,

• PCR.• tissue culture.• VZV IgG antibodies: 4-fold rise • VZV-specific IgM assays

TREATMENT

• Antiviral modifies the course of both varicella and herpes zoster (acyclovir).

• foscarnet is the only drug available for the

treatment of acyclovir-resistant VZV infections (in HIV)

Acyclovir Therapy

• acyclovir therapy is not recommended routinely for treatment of uncomplicated varicella in healthy child

• Oral therapy with acyclovir (20 mg/kg/dose, maximum 800 mg/dose) given as 4 doses/day for 5 days should be used to treat uncomplicated varicella in:

(Indication of oral therapy) : - nonpregnant individuals >13 yr - children >12 mo with chronic skin or pulmonary disorders - on steroids: short-term, intermittent, or aerosolized - children receiving long-term salicylate therapy - 2nd cases in household contacts.

Acyclovir Therapy

• To be most effective, treatment should be initiated as early as possible, preferably within 24 hr of the onset of the exanthem.

• There is clinical benefit if initiation of treatment is delayed more than 72 hr after onset of the exanthem.

• Acyclovir does not interfere with VZV immunity. • Intravenous therapy is indicated for severe disease and

for varicella in immunocompromised patients (even after 72 hr duration of rash).

Acyclovir Therapy

Herpes Zoster ttt

• Antiviral drugs are effective for treatment of herpes zoster.

COMPLICATIONS of Chicken pox

• mild varicella hepatitis is relatively common but rarely clinically symptomatic.

• Mild thrombocytopenia occurs in 1–2% of children with varicella and may be associated with transient petechiae.

• Purpura, hemorrhagic vesicles, hematuria, and gastrointestinal bleeding .

• Cerebellar ataxia occurs in 1 in every 4,000 cases.• Other: include encephalitis, pneumonia, nephritis, nephrotic

syndrome, hemolytic-uremic syndrome, arthritis, myocarditis, pericarditis, pancreatitis, and orchitis

Bacterial Infections • 2ry group A streptococci and S. aureus, in up to 5%. • serious invasive infections caused by group A streptococcus, which can

have a fatal outcome • The more invasive infections, such as varicella gangrenosa, bacterial

sepsis, pneumonia, arthritis,

• toxic shock syndrome.

Encephalitis and Cerebellar Ataxia

• Encephalitis: 1/50,000 • acute cerebellar ataxia: 1/4000 • morbidity more in < 5 yr or > 20 yr • meningoencephalitis Encephalitis: neck rigidity,

altered consciousness, and seizures characterize. • cerebellar ataxia: gradual gait disturbance,

nystagmus, and slurred speech. • Neurologic symptoms usually begin 2–6 days after

onset of rash.

Encephalitis and Cerebellar Ataxia

• Clinical recovery is typically rapid, occurring within 24–72 hr, and is usually complete.

• severe hemorrhagic encephalitis is very rare.

• Reye syndrome of encephalopathy and hepatic dysfunction associated with varicella has become rare since salicylates are no longer routinely used as antipyretics

PROGNOSIS of Chicken pox

• mortality rate of 3 per 100,000 cases.• lowest fatality 1–9 yr. • infants have a 4 times greater risk of dying• adults have a 25 times greater high risk of dying.• the most common complications among people who

died from varicella were pneumonia, CNS complications, secondary infections, and hemorrhagic conditions.

• mortality in immunocompromised children: 7–14%,• mortality in immunocompromised adults: 50%

PREVENTION

• VZV transmission is difficult to prevent because the infection is contagious for 24–48 hr before the rash appears.

• All health care workers should have

documented VZV immunization.

Vaccine

• Live virus varicella vaccine: alone or combined with MMR (MMRV).

• Administration of varicella vaccine within 4 wk of

MMR vaccine has been associated with a higher risk for severe disease;

• therefore, it is recommended that the vaccines either be administered simultaneously at different sites or be given at least 4 wk apart.

Vaccine

• Varicella vaccine is recommended for routine administration to children at 12–18 mo and at

4–6 yr of age. • Vaccination with 2 doses, separated by at least 4 wk,

Vaccine contraindication

• Varicella vaccine is contraindicated in children with cell-mediated immune deficiencies,

• Can be given to children with acute lymphoblastic leukemia who are in remission, and for HIV-infected children with specific guidelines.

• Children with isolated humoral immune deficiencies may receive VZV vaccine.

Post-exposure Prophylaxis

• Vaccine given to normal children within 3–5 days after exposure is effective in preventing or modifying varicella.

• Oral acyclovir administered late in the incubation period may modify varicella.

• High-titer anti-VZV immune globulin as postexposure prophylaxis is recommended for:

- immunocompromised children, - pregnant women, and - newborns exposed to maternal varicella.

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