147: Varicella-Zoster Infections

Varicella-zoster virus (VZV) is a member of the herpesvirus family. Primary maternal VZV infection (chickenpox) can result in fetal or neonatal infection. Other rare complications include spontaneous abortion, fetal demise, and premature delivery. Reactivation infection (zoster) does not result in fetal infection. Primary maternal VZV infection during the last trimester can cause pneumonia with significant morbidity and mortality. The overall incidence of maternal and neonatal varicella has decreased over the past 10–15 years, presumably due to varicella vaccination. Active surveillance among adults has shown that the incidence of varicella declined 74% during 1995–2005, despite vaccination rates among adults of only 3%. Herd immunity is the likely explanation for this phenomenon. Varicella immunization is recommended for all nonimmune women as part of prepregnancy and postpartum care. Varicella vaccine should not be administered to pregnant women, because the possible effects on fetal development are unknown, although no cases of congenital varicella syndrome or patterns of malformation have been identified after inadvertent immunization of pregnant women. When postpubertal females are immunized, pregnancy should be avoided for at least 1 month after immunization. Reporting of instances of inadvertent immunization with a varicella-zoster–containing vaccine during pregnancy is encouraged (1-800-986-8999, www.merckpregnancyregistries.com/varivax.html).

There are three forms of varicella-zoster infections involving the neonate: fetal, congenital (early neonatal), and postnatal.

This form occurs when the mother has her first exposure to VZV during the first half of pregnancy. It is also recognized in the literature as congenital varicella syndrome (CVS).

This form is fortunately rare; only ∼5% of women of childbearing age are susceptible to VZV. The incidence of varicella during pregnancy is estimated at 1–5 cases per 10,000 pregnancies. The incidence of embryopathy and fetopathy after maternal varicella infection in the first 20 weeks is ∼1%. Recent evidence suggests that the incidence is much lower than previously estimated.

Maternal transmission of the virus probably occurs via respiratory droplets or direct contact with chickenpox or zoster lesions. The virus replicates in the oropharynx, and viremia results, before the onset of rash, with transplacental passage to the fetus. Almost all cases reported have involved exposure between the 8th and 20th weeks of pregnancy. The pathogenesis of fetal varicella syndrome (FVS) may reflect disseminated infection in utero or as a consequence of failure of virus–host interaction to result in establishment of latency, as normally occurs in postnatal VZV infection. Since VZV is a lymphotropic virus, it has the potential to spread to all fetal organs by the hematogenous route. Pathology specimens from aborted fetuses with VZV infection have shown the virus to be distributed throughout fetal tissues. Microcephaly can be attributed to VZV encephalitis and irreversible damage to growth of the developing brain. Of interest, the virus does not appear to cause intrauterine damage to the lungs or liver in infants with FVS, as it can in perinatal varicella or in other immunocompromised hosts. Fulminant infection involving these organs may result in fetal demise, rather than birth of an infant with FVS. VZV is also a neurotropic virus; many of the defects have been postulated to be a direct result of spinal cord and ganglia infection, which causes destruction of the plexi during embryogenesis, leading to denervation of the limb bud and subsequent hypoplasia. Failure of muscle development has consequences for limb bone formation. The cutaneous defects are also likely to reflect VZV infection of sensory nerves. VZV infection of cells in developing optic tracts also explains the optic atrophy and chorioretinitis. From the pattern of dermatomal distribution of the skin defects seen in FVS, particularly the scarring and limb hypoplasia, it has been suggested that FVS is the result of intrauterine herpes zoster. The extremely short latent period between fetal infection and reactivation, if latency is established at all, is the consequence of the lack of cell-mediated immunity in the fetus before 20 weeks' gestation. Infants exposed to VZV in utero also can develop unapparent varicella and subsequent zoster early in life without having had extrauterine varicella.

A pregnant woman with no history of varicella infection or vaccination who becomes exposed to VZV between the 8th and 20th weeks of gestation is at risk.

The main symptoms of FVS are:

1. Skin lesions (60–70%). Cicatricial scars and skin loss.

2. Central nervous system defects or disease (60%). Microcephaly, seizures, encephalitis, cortical atrophy and spinal cord atrophy, mental retardation, and cerebral calcifications.

3. Ocular abnormalities (60%). Microphthalmia, chorioretinitis, cataracts, optic atrophy, nystagmus, and Horner syndrome (ptosis, miosis, and enophthalmos).

4. Limb hypoplasia and other skeletal defects (50%).

5. Prematurity and intrauterine growth restriction (35%).

Alkalay et al proposed the following criteria for the diagnosis of FVS in the newborn:

1. Appearance of maternal varicella during pregnancy.

2. Presence of congenital skin lesions in dermatomal distribution and/or neurologic defects, eye disease, or limb hypoplasia.

3. Proof of intrauterine VZV infection by detection of viral DNA in the infant by polymerase chain reaction (PCR), presence of VZV-specific immunoglobulin (Ig)M, persistence of VZV IgG beyond 7 months of age, or appearance of zoster during early infancy. VZV DNA PCR (both from fetal blood or amniotic fluid) appears to be sensitive and accurate in detecting fetal infection; however, most of the “infected” fetuses are morphologically normal (ie, not affected by FVS). Prenatal diagnosis is most often done by detailed ultrasound, searching for typical anomalies and VZV-specific PCR in amniotic fluid. At least a 5-week interval is advised between onset of maternal rash and obtaining of the ultrasound. An initial ultrasound is recommended at 17–21 weeks' gestation with a follow-up study done 4–6 weeks later. The role of prenatal magnetic resonance imaging for assessment of the fetus after maternal varicella is only beginning to be delineated, but it may provide improved specificity, particularly for central nervous system damage.

Isolation precautions for all infectious diseases, including maternal and neonatal precautions, breast-feeding, and visiting issues, can be found in Appendix F.

1. Mother. If the mother is exposed to VZV infection in the first or second trimester, treat the mother with varicella-zoster immune globulin (VZIG) if her past history of varicella infection or vaccination is negative or uncertain. For dosage, see Chapter 148. VZIG should be given within 72–96 hours and appears to protect both mother and fetus. In 2012, the U.S. Food and Drug Administration (FDA) extended the period for administration of VZIG from 96 hours to 10 days after exposure. The only U.S.-licensed VZIG was discontinued by the manufacturer in 2004. Since February 2006, an investigational (not licensed) VZIG called VariZIG has become available under an investigational new drug (IND) protocol and can be requested by calling FFF Enterprises, 24-hour toll-free, at 800-843-7477. If VariZIG is not available, intravenous immunoglobulin (IVIG) can be used. If chickenpox is diagnosed during pregnancy, antiviral therapy with acyclovir should be strongly considered. Acyclovir therapy during pregnancy appears to be safe; it has not been associated with increased congenital abnormalities compared with the general population.

2. Infant. Supportive care of the infant is required because there is usually profound neurologic impairment. Acyclovir therapy may be helpful to stop the progression of eye disease or to treat recurrent zoster (shingles), which is common in the first 2 years of life.

3. Isolation. Isolation is not necessary.

Approximately 30% of these infants die in the first months of life, often because of intractable gastroesophageal reflux, severe recurrent aspiration pneumonia, and respiratory failure. Survivors usually suffer profound mental retardation and major neurologic disabilities. These infants are also at risk for developing zoster (shingles) in the first 2 years of life.

This is the form of the disease that occurs when a pregnant woman suffers chickenpox during the last 3 weeks of pregnancy or within the first few days postpartum. Disease begins in the neonate just before delivery or within the first 10–12 days of life.

Although the congenital form is more common than the teratogenic form, it is still rare, with recent estimates of 0.7 per 100,000 live births per annum. The introduction of varicella vaccination in 1995 greatly reduced the incidence of varicella infection in all age groups (herd immunity).

Maternal chickenpox near term or soon after delivery may cause severe or fatal illness in the newborn. Maternal varicella can affect the baby through transplacental viremia, ascending infection during birth, or respiratory droplet/direct contact with infectious lesions after birth. Neonatal chickenpox occurring in the first 10–12 days of life is typically caused by intrauterine transmission of VZV (incubation period 10–21 days). Chickenpox after the 10th to 12th day of the neonatal period is most likely acquired by postnatal VZV infection. If the onset of maternal disease is between 5 days before delivery or 2 days postpartum, there is a high attack rate (up to 50%) with significant associated mortality (up to 30%). Those babies present with the classic skin lesions, but can disseminate with pneumonia, hepatitis, meningoencephalitis, and severe coagulopathy (disseminated intravascular coagulation [DIC]) resulting from liver failure and thrombocytopenia. If the maternal rash happens >5 days before delivery, there is enough maternal anti-VZV IgG production with subsequent transplacental transfer that protects the newborn and results in a milder case of chickenpox.

Primarily a mother with chickenpox during the last 3 weeks of pregnancy or within the first few days postpartum. There is a higher risk of mortality if the onset of maternal disease is 5 days before delivery or 2 days postpartum. Premature infants, especially those <28 weeks, are extremely susceptible.

Clinical presentation is variable. There may be only mild involvement of the infant, with vesicles on the skin, or the following may be seen:

1. Skin. A centripetal rash (beginning on the trunk and spreading to the face and scalp, sparing the extremities) begins as red macules and progresses to vesicles and encrustation. Lesions are more common in the diaper area and skin folds. There may be 2 or 3 lesions or thousands of them. The differential diagnosis includes herpes simplex virus and enterovirus. The main complication is staphylococcal and streptococcal secondary skin infections.

2. Lungs. Lung involvement is seen in all fatal cases. It usually appears 2–4 days after the onset of the rash but may be seen up to 10 days after. Signs include fever, cyanosis, rales, and hemoptysis. Chest radiograph shows a diffuse nodular-miliary pattern, especially in the perihilar region.

3. Other organs. Focal necrosis may be seen in the liver, adrenals, intestines, kidneys, and thymus. Glomerulonephritis, myocarditis, encephalitis, and cerebellar ataxia are sometimes seen.

The diagnosis of varicella usually is made clinically based on the characteristic appearance of skin lesions.

1. Polymerase chain reaction (PCR). The most sensitive and specific method for detection of VZV DNA in clinical specimens. This is the diagnostic method of choice for investigation of vesicular fluid or scabs, biopsies, and amniotic fluid. This testing also can be used to distinguish between wild-type and vaccine-strain VZV (genotyping). Viral culture and direct fluorescent antibody (DFA) assay are less sensitive than PCR and are not usually recommended.

2. Serum testing of VZV antibody. Serologic tests may help to document acute infection in confusing cases. IgM antibody may be detected as soon as 3 days after the appearance of VZV symptoms, but the test may not be reliable.

1. VariZIG

   1. Perinatal infection. Infants of mothers who develop VZV infection (rash) within 5 days before or 2 days after delivery should receive 125 U of VariZIG as soon as possible and not later than 10 days. Intravenous immunoglobulin (IVIG) (400 mg/kg) should be used if VariZIG is not available. Infants treated with immune globulins should be placed in strict respiratory isolation for 28 days because immunoglobulin treatment may prolong the incubation period. VariZIG is not expected to reduce the clinical attack rate in treated newborns; however, these infants tend to develop milder infections than the untreated neonates. Prophylactic administration of oral acyclovir beginning 7 days after exposure also may prevent or attenuate varicella disease in exposed infants.

   2. Maternal rash occurring >7 days before delivery. These infants do not need VZIG. It is believed that infants will have received antibodies via the placenta.

2. Acyclovir therapy 15 mg/kg/dose every 8 hours for 7 days should be considered for postexposure prophylaxis as well as a treatment in symptomatic neonates.

3. Antibiotics. Use antibiotics if secondary bacterial skin infections occur.

Prognosis is good if the onset of maternal varicella occurs >5 days before delivery, because the mother has enough time to develop antibodies and pass these to the infant. In these cases, the infant has a mild case of varicella with excellent prognosis. If the mother has onset of disease within 5 days before delivery or 2 days after, the infant is exposed with no antibodies. In these cases the disease is usually severe with dissemination. Overwhelming sepsis and multiple organ failure can lead to a mortality rate as high as 30%. The usual causes of death are pneumonia, fulminant hepatitis, and DIC. With the use of VZIG, the mortality rate is reduced to 7%. There is an increased risk of developing zoster (shingles) in the first 2 years of life.

This form of the disease presents on days 12–28 of life. It does not represent transplacental infection from the mother.

There has been a significant decline in the incidence since the introduction of the vaccine in 1995 (by 85–90%). The incidence of neonatal varicella in the vaccine era is ∼0.7 per 100,000 live births.

Postnatal VZV infection occurs by droplet transmission. This disease is usually mild because of passive protection from maternal antibodies. Placental antibody transfer is lower in preterm infants, which makes them more susceptible compared with term infants. Horizontal transmission in Neonatal Intensive Care Units has been well documented. Neonatal vaccine-strain VZV infection after maternal postpartum vaccination has been reported.

Seronegative mother, delivery before 28 weeks, birthweight <1.5 kg, postnatal age >2 months (maternal transplacental immunity has waned), immunocompromised neonates (sepsis, steroids, etc.).

The typical chickenpox rash is seen with centripetal spread, beginning on the trunk and spreading to the face and scalp and sparing the extremities. All stages of the rash may appear at the same time, from red macules to clear vesicles to crusting lesions. Complications of this form of the disease are rare but may include secondary infections and varicella pneumonia. In older children, necrotizing fasciitis secondary to group A streptococcal infections is particularly worrisome and may be associated with ibuprofen use (Plate 13).

Same as for congenital varicella (see the previous section). Diagnosis is usually made based on clinical grounds.

For the full-term infant in community setting, the disease is usually mild. Therefore, acyclovir therapy is controversial. For nosocomial chickenpox in the intensive care nursery (exposure):

1. VariZIG. Recommended for all exposed infants of <28 weeks' gestational age or weighing ≤1000 g regardless of the maternal history. It is also recommended in premature infants whose mothers do not have a history of chickenpox or varicella vaccination (seronegative).

2. Infants >28 weeks' gestation. These infants should have sufficient transplacental antibodies, if the mother is immune to protect them from the risk of complications.

3. Isolation. Exposed infants should be placed in strict isolation for 10–21 days after the onset of the rash in the index case. Exposed infants who receive VariZIG should be in strict respiratory isolation for 28 days.

4. Acyclovir. Recommended for infants who develop breakthrough lesions or prophylactically beginning 7 days after exposure. Therapy should be continued for 7 days (if used prophylactically) or for 48 hours after the last new lesions have appeared.

This form of the disease is mild, and death is extremely rare. Normal-term infants who develop postnatal chickenpox have the same risk of complications of chickenpox as older children. Premature infants are at increased risk for nosocomial acquisition of VZV. The risk of complications for infants <28 weeks who develop postnatal chickenpox is unknown.