Gary is a 28-week preterm infant currently in the NICU. Two days ago, his 3-year-old sibling visited him in the NICU, and shortly afterward, he was diagnosed with chickenpox (varicella), prompting concern about Gary’s potential exposure to the virus.

Due to his extreme prematurity, Gary likely did not receive maternal antibodies against varicella, leaving him vulnerable to infection. Additionally, as a preterm infant, his immune system is not fully developed, which further increases his risk of severe complications if he contracts the virus. The close contact during his sibling’s visit may have elevated his exposure risk.

Gary shows no signs of illness, such as fever, rash, or respiratory distress, and his condition is stable. However, because of his high-risk status, close monitoring is essential. His medical team should observe him for symptoms, including fever, rash, or changes in respiratory function, and ensure prompt intervention should any signs of varicella infection arise.

Expert Consensus

• Preterm infants, particularly those born before 32 weeks gestation, have a high risk of severe complications from varicella due to insufficient maternal antibody transfer, which typically occurs later in pregnancy (Ciobanu AM et al., 2020).). This lack of passive immunity increases their vulnerability to infections like varicella, leading to serious complications such as encephalitis, pneumonia, and other life-threatening conditions (Levin MJ et al., 2019).
• In the NICU setting, strict infection control measures are essential to prevent varicella exposure, as visiting family members, including siblings, can increase the risk of transmission. Protocols like limiting visitors during outbreaks and enforcing airborne and contact precautions help minimize this risk (Johnson et al., 2021).
• Early administration of VARIZIG within 96 hours of exposure is crucial for preterm infants at risk. VARIZIG provides temporary passive immunity, reducing disease severity and preventing complications of varicella infection (Duchon JM et al., 2020)..

Introduction

VZV, a double-stranded DNA virus belonging to the subfamily alphaherpesvirinae, is the etiological agent of chickenpox in childhood and herpes zoster (shingles) later in life. Following primary infection, VZV establishes latency in the dorsal root ganglia, with potential reactivation under conditions of immunosuppression or age-related decline in immune function (CDC Yellow Book, 2024).

While varicella is typically mild in healthy individuals, preterm infants exposed to varicella or herpes zoster are at risk for severe varicella due to their immunological immaturity and limited passive antibody transfer from their mothers (Duchon JM et al., 2020).

Preterm infants, particularly those born before 32 weeks of gestation, have significantly reduced IgG levels compared to full-term neonates, making them more vulnerable to infections (Ciobanu AM et al., 2020).

Therefore, exposure to VZV poses significant risks, including severe systemic disease and complications like encephalitis and pneumonia (Levin MJ et al., 2019).

This literature review explores VZV exposure's epidemiological, immunological, and clinical aspects in preterm infants. It highlights their heightened risks, the importance of infection control in NICUs, and the role of PEP with VARIZIG in mitigating complications.

The Vulnerability of Preterm Infants to VZV

Insufficient Maternal Antibody Transfer

Maternal antibodies protect infants from infections during their first months of life. These antibodies are primarily transferred transplacentally during the third trimester, exceeding maternal levels by 37–40 weeks of gestation. Consequently, preterm infants born before 32 weeks may be deprived of this critical immune protection, leaving them with inadequate levels of maternal IgG antibodies against pathogens like VZV (Ciobanu AM et al., 2020).

The implications of this insufficient antibody transfer are profound. Without these passive antibodies, preterm infants cannot rely on maternal immune memory to neutralize VZV upon exposure, rendering them more susceptible to severe primary varicella infections (CDC, 2024). This vulnerability is further compounded by their deficient immune system (Duchon JM et al., 2020), which struggles to respond to the virus effectively.

Maternal-Fetal Transmission of Varicella

When maternal-fetal transmission occurs, the clinical presentation and severity of the neonate's condition depend on the timing of the mother's varicella infection during pregnancy.

Congenital Varicella Syndrome

Congenital varicella syndrome (CVS) occurs when a mother is infected with VZV during the first half of pregnancy. The highest risk period is between 13 and 20 weeks of gestation, with an estimated risk of 2% for fetal infection. Rare cases of CVS have been reported as late as 28 weeks of gestation . CVS can be fatal in preterm infants (Bhavsar SM and Mangat C, 2023).

CVS involves skin, limbs, eyes, and central and autonomic nervous system defects. Common features include cicatrix scarring, limb hypoplasia, ocular abnormalities (e.g., cataracts, chorioretinitis), and central nervous system issues like microcephaly and seizures (Bhavsar SM and Mangat C, 2023).

Neonatal Varicella

Neonatal varicella occurs when a mother develops a varicella infection close to the delivery time. Mother-to-child transmission of VZV can happen through 3 primary routes:

• Transplacental viremia: the virus crosses the placenta during maternal infection.
• Direct contact: the neonate comes into contact with infectious vesicles or maternal blood during delivery.
• Postnatal exposure: respiratory droplets or direct skin contact with vesicles from an infected person expose the infant (Bhavsar SM and Mangat C, 2023).

Neonates are at the highest risk for severe varicella infections when maternal varicella develops between 5 days before and 2 days after delivery. Infants born to mothers with varicella during the high-risk period for neonatal infection often appear healthy at birth but may later develop vesicular skin lesions. In severe cases, they can present with disseminated disease, including pneumonia, hepatitis, meningoencephalitis, and coagulopathy due to liver failure and thrombocytopenia (Bhavsar SM and Mangat C, 2023).

Immunological Immaturity

In addition to limited maternal antibody transfer, preterm infants have underdeveloped immune systems. This leads to an age-related impairment in cellular response, putting preterm infants at a greater risk of invasive disease and varicella complications (Duchon JM et al., 2020).

VZV in the NICU Environment

Risks and Vulnerabilities in NICUs

NICUs present a heightened risk for infection due to several factors (Johnson et al., 2021):

• Healthcare-Associated Infections (HAI)s: High risk of infections like bloodstream and surgical site infections due to invasive devices and prolonged stays.
• Antimicrobial Resistance: Increased infections from MDROs like Staphylococcus aureus and carbapenem-resistant pathogens.
• Environmental Contamination: Risks from unclean equipment, surfaces, and plumbing systems.
• Prematurity: Immature skin and immune systems in preterm infants increase infection risks.
• Resource Limitations: PPE shortages and overcrowding in low-resource settings raise infection rates.
• Inadequate Hand Hygiene: Poor compliance with hand hygiene protocols contributes to infection spread.
• Outbreaks: Pathogens like Candida auris and Acinetobacter baumannii can cause outbreaks in NICUs.
• Visitor-Related Risks: Ill or unvaccinated visitors may introduce infections to neonates.
• Central Line Risks: Improper insertion or maintenance of CVCs increases bloodstream infection risks.
• Ventilation-Associated Risks: Poor ventilation protocols may lead to respiratory infections and complications.

Clinical Manifestations and Complications in Preterm Infants

Disease Severity

When preterm infants contract varicella, their clinical course tends to be more severe than that of term infants or older children. Common complications include (Levin MJ et al., 2019):

• Encephalitis: Brain inflammation can lead to seizures, cognitive impairments, and long-term neurological sequelae.
• Pneumonia: VZV-associated pneumonia is a leading cause of mortality in infected neonates, characterized by respiratory distress, hypoxemia, and a high need for ventilatory support.
• Hepatitis and coagulopathy: disseminated infection can cause liver dysfunction, coagulopathies, and multi-organ failure.
• Secondary bacterial infections: impaired skin barrier repair increases the risk of cellulitis, necrotizing fasciitis, and sepsis.

Mortality Risk

The mortality rate of varicella in newborns exposed to the virus around the time of birth has historically ranged between 14% and 31%, with severe cases often involving complications such as pneumonia and visceral dissemination. However, the introduction of VARIZIG as post-exposure prophylaxis has significantly improved outcomes in high-risk neonates (Levin MJ et al., 2019).

Long-Term Outcomes and Quality of Life

While varicella is often considered a mild illness, severe cases with complications such as bone and joint infections or neurological conditions can lead to substantial long-term impacts. Hospitalized children experience significantly greater Quality-Adjusted Life Year (QALY) losses compared to those managed in the community, highlighting the burden of severe cases. Common complications include dermatologic, neurologic, and respiratory issues, which contribute to prolonged recovery and greater healthcare demands (F. Rodrigues et al., 2022).

Impact on Quality of Life for Families

Varicella significantly affects the quality of life (QoL) of both children and their caregivers, with hospitalized cases having the greatest impact. Caregivers, especially primary ones, report high levels of anxiety and disruption of daily life, while children experience increased pain, anxiety, and limitations in activities. Community-managed cases have a smaller individual impact, but the overall burden is substantial due to the high incidence of the disease, underscoring its broad societal effects (F. Rodrigues et al., 2022).

Implications for Public Health and Policy

The significant QoL impact of varicella, particularly in severe cases, emphasizes its public health burden. Including caregiver QoL and productivity losses in cost-effectiveness evaluations is essential to accurately assess the true impact of the disease. These findings support the consideration of vaccination programs to reduce the overall burden of varicella and its complications, improving outcomes for affected children and their families (F. Rodrigues et al., 2022).

Role of PEP with VARIZIG

Mechanism of Action

VARIZIG is a hyperimmune globulin preparation containing high titers of anti-VZV antibodies (Levin MJ et al., 2019). Administered intramuscularly, VARIZIG provides passive immunity to neutralize the virus and prevent systemic infection. It is particularly effective within 96 hours of exposure but retains efficacy up to 10 days post-exposure, making it a critical intervention in NICU outbreaks (Duchon JM et al., 2020).

Evidence of Efficacy

Studies have demonstrated the efficacy of VARIZIG in reducing the severity of VZV infections in high-risk populations, including preterm infants and immunocompromised patients (Levin MJ et al., 2019) In a study of 43 newborns exposed to VZV in utero and 80 preterm infants exposed to VZV, >80% received VARIZIG within 96 hours of reported exposure. When varicella outcomes were available (Duchon JM et al., 2020):

• Among 43 newborns exposed to VZV in utero, just 18% (7 of 38) developed varicella.
• None of the 65 preterm infants exposed to VZV developed the disease. Over 80% of these infants received VARIZIG prophylaxis within 96 hours of exposure
• Varicella outcome was not available for 5 in utero–exposed infants and 15 preterm infants

Administration Guidelines

The CDC recommends the following for the Use of VARIZIG (Marin et al, 2013):

Timing: Administer within 10 days of varicella exposure.

Dosage: 125 IU/10 kg (max 625 IU); minimum dose varies by weight.

Monitoring: Observe for varicella symptoms for 28 days; start antivirals if symptoms occur. Common side effects include injection site pain and headache.

Recommended Groups

Patient groups recommended by the CDC (CDC, 2013)​ to receive VARIZIG include the following:

• Immunocompromised patients without evidence of immunity.
• Newborn infants whose mothers have signs and symptoms of varicella around the time of delivery (i.e., 5 days before to 2 days after).
• Hospitalized premature infants born at ≥28 weeks of gestation whose mothers do not have evidence of immunity to varicella.
• Hospitalized premature infants born at <28 weeks of gestation or who weigh ≤1,000 g at birth, regardless of their mothers' evidence of immunity to varicella.
• Pregnant women without evidence of immunity.

Infection Control in the NICU

The following steps are useful in controlling infection in the NICU (Johnson et al., 2021):

• Isolation of Exposed or Infected Patients: Implement airborne and contact precautions for neonates exposed to or infected with varicella-zoster virus (VZV). Place them in an airborne infection isolation room (AIIR) to prevent transmission to other patients and staff.
• Visitor Screening and Restrictions: Screen visitors for any symptoms of varicella or recent exposure and restrict access for those not fully vaccinated or symptomatic. Sibling visits should require proof of immunity to prevent transmission risks.
• Hand Hygiene Compliance: Ensure strict adherence to hand hygiene protocols among healthcare workers and visitors, using alcohol-based hand rubs or soap and water, particularly before and after patient contact.
• Vaccination Policies for Staff and Caregivers: Verify and maintain healthcare worker vaccination records for varicella. Staff who recently received live-attenuated vaccines should avoid patient contact if vesicular lesions develop.
• Administration of Immune Globulin: Administer varicella-zoster immune globulin (VARIZIG) to non-immune neonates exposed to VZV, as recommended, to mitigate the risk of severe infection.
• Environmental Cleaning: Enhance environmental cleaning protocols, focusing on high-touch surfaces and shared equipment, to minimize the risk of indirect transmission within the NICU.
• Monitoring and Education: Regularly monitor staff compliance with infection control measures and provide ongoing education about the risks of varicella transmission and the importance of preventive practices.

These measures are critical in safeguarding the vulnerable neonatal population from the potentially severe consequences of varicella infection in the NICU setting.

Conclusion

Preterm infants, particularly those born before 32 weeks gestation, face disproportionate risks from VZV exposure due to their immunological immaturity and lack of maternal antibody transfer (Ciobanu AM et al., 2020).

The NICU setting, with its unique challenges for infection control, necessitates heightened vigilance and robust preventive measures to minimize exposure risks (Johnson et al., 2021)

VARIZIG represents a cornerstone of PEP, offering passive immunity to reduce the severity of varicella infections and prevent life-threatening complications (Levin MJ et al., 2019). Early exposure identification, prompt administration of VARIZIG, and adherence to infection control protocols are critical for safeguarding the health of preterm infants in the NICU.