INTRODUCTION

VZV, a member of the Herpesviridae family, is a ubiquitous pathogen responsible for causing 2 clinically distinct conditions: varicella (chickenpox) as the primary infection and herpes zoster (shingles) due to reactivation of latent virus in sensory ganglia (CDC Yellow Book, 2024). Despite the widespread availability of vaccines, VZV remains a significant public health concern due to breakthrough infections, under-vaccinated populations (Newman AM and Jhaveri R, 2019), and its severe manifestations in high-risk groups, including immunocompromised individuals, adults, and neonates (CDC Yellow Book, 2024).

The CDC advises providing the varicella vaccine to unvaccinated, healthy individuals aged 12 months or older who lack evidence of immunity to prevent or mitigate the disease (CDC Yellow Book, 2024). Various strategies, including passive immunization with VARIZIG, active immunization with the varicella vaccine, and antiviral medications, are employed based on the patient's immune status and exposure context (Lachiewicz AM and Srinivas ML, 2019).

EPIDEMIOLOGY
Varicella is a global disease with epidemiological differences based on climate. In temperate regions, it predominantly affects preschool and school-aged children, with peak incidence in late winter and early spring. Fewer than 5% of adults are susceptible (CDC Yellow Book, 2024).

In tropical climates, infection occurs later in childhood, with higher susceptibility among adults, particularly in less populated areas, and peaks during the driest, coolest months (CDC Yellow Book, 2024). Since the introduction of routine childhood varicella vaccination in the United States in 1996, there has been a substantial decline in disease incidence. However, breakthrough varicella can occur in vaccinated individuals, although it is typically mild (CDC Yellow Book, 2024).

Certain Populations Remain Disproportionately Affected by VZV, and they include:

Immunocompromised patients: higher risk of disseminated infection and complications such as encephalitis.
Pregnant women: increased risk of varicella pneumonia and vertical transmission, potentially leading to congenital varicella syndrome or neonatal varicella.
Neonates: susceptible to severe varicella due to immature immune systems, especially if born to mothers with active infection near delivery (CDC Yellow Book, 2024).

SYMPTOMS AND CLINICAL PRESENTATION
Varicella is typically a mild illness in pediatric populations, with most affected individuals recovering without significant complications. The disease has an average incubation period of 14 to 16 days, though it can range from 10 to 21 days (CDC Yellow Book, 2024). The clinical manifestations of VZV vary based on the stage of infection and the host's immune status:

Primary Infection (Varicella)

⁠Prodromal symptoms include fever, malaise, and anorexia.

The hallmark vesicular rash typically begins on the face and trunk and progresses to the extremities. Lesions evolve from macules to papules, vesicles, and crusts over 7–10 days.
Complications include secondary bacterial infections, pneumonia, hemorrhagic conditions, and encephalitis, with increased severity in adults (CDC Yellow Book, 2024).

Reactivation (Herpes Zoster)

Characterized by a painful dermatomal rash preceded by tingling or burning sensations.
Herpes zoster is ≈20% as infectious as varicella; in susceptible people, contact with herpes zoster rash causes varicella, not herpes zoster (CDC Yellow Book, 2024).

PROGNOSIS
The prognosis of VZV infection varies based on the host's immune status and timely initiation of treatment:

Healthy individuals: varicella is typically self-limited, with full recovery expected.
Immunocompromised patients: risk of severe disease and complications, such as disseminated infection, requires aggressive treatment and monitoring.
Pregnant women: increased maternal morbidity from varicella pneumonia; potential teratogenic effects include limb hypoplasia, skin scarring, and neurologic deficits in the fetus.
Neonates: high mortality rates without PEP. Prompt VARIZIG and antiviral therapy administration can significantly improve outcomes.

Risk of Symptomatic Disease by Contact Setting
Household contact significantly increases the risk of symptomatic VZV infection compared to classroom or casual exposures. This elevated risk arises from prolonged and close interactions within a family setting, facilitating higher viral transmission (Newman & Jhaveri, 2019).

Proximity and duration of exposure: household members often share living spaces for extended periods, providing greater opportunity for virus-laden respiratory droplets or vesicle fluid to spread.
Physical contact: in family settings, frequent physical interactions, such as hugging or sharing personal items, amplify the risk of direct exposure to VZV.
Viral load: household exposure is associated with a higher inoculum of the virus due to repeated contact with an infected individual over time, increasing the likelihood of symptomatic infection (Newman & Jhaveri, 2019).

DIAGNOSIS

Diagnosis in the Context of PEP
Identifying susceptibility to VZV infection guides whether to initiate PEP, especially in high-risk individuals such as immunocompromised patients, pregnant women, and neonates.

In high-risk groups, such as immunocompromised individuals, pregnant women, or neonates, PEP (e.g., VARIZIG or antiviral prophylaxis) is recommended immediately if there is any doubt about immunity (CDC Yellow Book, 2024).
Testing may delay intervention, which is particularly detrimental for groups at risk of severe disease. Furthermore testing isn’t necessary to decide on post-exposure prophylaxis (PEP) because the presence of antibodies doesn’t guarantee protection (AAP Red Book, 2024).

RISK OF VARICELLA-ZOSTER VIRUS IN ONCOLOGY PATIENTS
Oncology patients are at heightened risk for severe VZV infection due to compromised immunity from their disease and its treatment (Tayyar R and Ho D, 2023). This vulnerability is exacerbated by the lack of pre-transplant vaccination, incomplete vaccination schedules, or waning immunity over time. The introduction of T-cell-targeting therapies in cancer treatment, such as CAR-T cell therapy or immune checkpoint inhibitors, further undermines the immune system's ability to respond effectively to VZV, leaving patients unprotected despite prior vaccination (American Cancer Society, 2022).

Mechanisms of Increased Susceptibility in Oncology Patients
Impact of T-cell-Targeting Therapies

Many anti-cancer therapies suppress T-cell function directly (e.g., T-cell depleting agents) or indirectly by altering cytokine signaling pathways critical for immune defense against viral infections (Tayyar R and Ho D, 2023).
This suppression can weaken immune responses and impair the host’s ability to respond robustly to latent or newly acquired VZV infections (American Cancer Society, 2022).

Role of VZV in T-lymphocyte Infection and Dissemination

VZV infects T-lymphocytes, epithelial cells, and sensory ganglia.
Upon entering the bloodstream, infected T-cells act as vectors, rapidly disseminating VZV to target tissues, including the skin, where characteristic lesions form (Arvin AM et al., 2010).
This mechanism contributes to the quick progression of symptoms in immunocompromised patients (Arvin AM et al., 2010).

Waning Immunity in the Oncology Population
HSV and VZV are highly prevalent viruses that can cause a wide spectrum of infections in cancer patients. Immunocompromised individuals are at increased risk of such HSV and VZV infections and their complications due to their deficient immune responses (Tayyar R and Ho D, 2023).

Pre-transplant vaccination is often missed due to the contraindication of live vaccines in immunosuppressed individuals (CDC Yellow Book, 2024).

Clinical Implications
Given the rapidity with which VZV can disseminate and the severe complications associated with infection in this population, prophylactic measures are critical. Post-exposure prophylaxis with VARIZIG or antivirals should be prioritized in oncology patients after significant exposure to VZV. Timely intervention can mitigate the risk of widespread disease, particularly in those undergoing T-cell-targeting treatments (Tayyar R and Ho D, 2023).

This underscores the importance of preventative strategies, including vaccination before immunosuppressive therapy when feasible, and heightened vigilance for VZV symptoms in oncology patients.

TREATMENT
Management of VZV depends on the infection type, severity, and patient population:
PEP should be initiated promptly after a significant exposure to VZV, defined as:

Household: residing in the same household.
Playmate: face-to-face indoor play for ≥5 minutes (some experts suggest >1 hour).
Newborn infant.
Hospital: Being in the same 2- to 4-bed room or adjacent beds in a large ward, face-to-face contact with an infectious staff member or patient, or a visit by a contagious person (AAP Red Book, 2024).

Post-Exposure Prophylaxis

VARIZIG: passive immunization indicated for high-risk individuals (e.g., immunocompromised, pregnant women, and neonates) within 10 days of exposure. It reduces disease severity and complications (Levin et al., 2019).

Varicella vaccine: active immunization within 3–5 days of exposure is effective for susceptible individuals without contraindications, such as immunocompromised states.

Antiviral prophylaxis is recommended for patients exposed to VZV when VARIZIG is unavailable (AAP Red Book, 2024).

Urgency of Action in Immunocompromised Patients
The window for effective intervention following VZV exposure is limited in immunocompromised patients. The CDC recommends no later than 10 days after exposure, thus, necessitating swift action. These patients are at heightened risk for severe complications, including disseminated VZV infection, pneumonia, and encephalitis (Levin MJ et al, 2022). Prompt administration of PEP can significantly reduce morbidity and mortality.

VARIZIG: First-Line PEP for High-Risk Patients
VARIZIG is the primary prophylactic intervention recommended for high-risk patients, including:

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 (CDC, 2013).

Key Aspects of VARIZIG Use

Timing of administration:
a. Optimal efficacy is achieved when VARIZIG is administered within 96 hours of exposure (Levin et al., 2019).
b. It remains effective up to 10 days after exposure, making it an important option even when exposure recognition is delayed (Levin et al., 2019).
Mechanism of action:
a. VARIZIG provides passive immunity by supplying pre-formed antibodies that neutralize the virus before it establishes a systemic infection.
b. This intervention is particularly critical for patients who cannot mount an adequate immune response due to their compromised condition (Levin et al., 2019).
Rapid accessibility:
a. The CDC reports that VARIZIG is widely available through a broad network of specialty distributors across the United States. For high-risk patients following exposure to the VZV, it can be readily obtained within 24 hours (Newman AM and Jhaveri R, 2019).

Clinical Importance of the Prophylactic Window
The effectiveness of VARIZIG hinges on prompt delivery within the therapeutic window. Beyond this timeframe, the virus may have disseminated, reducing the efficacy of passive antibodies. Therefore, healthcare providers must act decisively to initiate prophylaxis without waiting for confirmatory diagnostic results in high-risk cases (AAP Red Book, 2024).

By ensuring the timely availability and administration of VARIZIG, healthcare providers can mitigate severe outcomes and offer significant protection to vulnerable patients.

Considerations for Prophylactic Use of Antivirals
Prophylactic antiviral therapy, such as acyclovir, valacyclovir, or famciclovir, is an alternative to VARIZIG for PEP in certain situations (AAP Red Book, 2024). However, using these agents must be carefully considered, as it can complicate subsequent treatment options if the patient develops symptomatic VZV infection.

1. Potential Drawbacks of Antiviral Prophylaxis

Missed opportunity for VARIZIG:
- The use of antivirals, which are given 7 - 10 days after exposure, could obscure the chance of administering VARIZIG, which must be given within 10 days of exposure to offer protective passive immunity (CDC Yellow Book, 2024).
- VARIZIG, when administered within 96 hours of exposure, reduces the risk of clinical varicella and lowers disease severity in immunocompromised individuals (CDC, 2013).
Reduced treatment efficacy:
- If prophylactic antivirals are administered but the patient progresses to symptomatic illness, subsequent antiviral therapy may be less effective. Prolonged or inappropriate dosing could contribute to drug resistance or diminished efficacy when the disease requires treatment (Piret & Boivin, 2016).

2. Clinical Implications

Prophylactic antivirals should be reserved for cases where VARIZIG is contraindicated or outrightly unavailable. (Lachiewicz AM and Srinivas ML, 2019).
In high-risk patients, particularly immunocompromised individuals, prioritizing VARIZIG within the appropriate time frame ensures maximum preventive benefit and leaves antivirals as a secondary option for treating symptomatic illness.

3. Striking the Right Balance
Healthcare providers must weigh the benefits and limitations of antiviral prophylaxis against the potential loss of the opportunity to administer VARIZIG. In cases of significant exposure and high-risk conditions, initiating VARIZIG first and reserving antivirals for subsequent symptomatic treatment remains the optimal strategy for maximizing patient outcomes.

SUMMARY AND RECOMMENDATIONS
VZV poses significant risks, particularly for immunocompromised patients, oncology patients undergoing T-cell-targeting therapies, pregnant women, and neonates. Despite advances in vaccination, breakthrough infections and waning immunity leave certain populations vulnerable.
PEP is important in mitigating the risk of severe disease and complications, but timely and strategic intervention is critical. (Levin et al., 2019)

Key Points

Elevated risk in specific populations:
- Oncology patients are highly susceptible due to waning immunity or lack of pre-transplant vaccination and the effects of T-cell-targeting therapies (Tayyar & Ho, 2023).
- VZV’s ability to infect T-lymphocytes and rapidly disseminate underscores the urgency of prophylaxis in these patients (Tayyar & Ho, 2023).
- Household contacts carry a greater risk of symptomatic disease due to prolonged and frequent exposure than in classroom settings (Newman & Jhaveri, 2019).
Post-exposure prophylaxis options:
- VARIZIG is the first-line option for high-risk individuals. It offers passive immunity when administered within 96 hours of exposure and has efficacy for up to 10 days (CDC, 2013). Expedited delivery ensures timely availability.
- Antivirals like acyclovir can be used prophylactically, but prolonged use may lead to resistance, which may interfere with later treatment efficacy (Piret & Boivin, 2016). It should not preempt the use of VARIZIG during its therapeutic window.
Diagnostic and prophylaxis timing:
- Rapid assessment of VZV susceptibility is acceptable, but prophylaxis should not be delayed for diagnostic confirmation in high-risk individuals.
- Acting within the narrow window for effective intervention is essential to prevent severe outcomes, particularly in immunocompromised patients.

Recommendations

Prioritize VARIZIG for high-risk populations:
- These include immunocompromised individuals without evidence of immunity, as well as newborns whose mothers develop varicella symptoms from five days before to two days after delivery. It is also advised for hospitalized premature infants: those born at 28 weeks gestation or later if their mothers lack immunity, and all infants born before 28 weeks or weighing 1,000 grams or less at birth, regardless of maternal immunity. Additionally, pregnant women without evidence of varicella immunity are considered candidates for VZIG (CDC, 2013).
- Ensure rapid access through expedited ordering to meet the 10-day post-exposure window (Newman AM and Jhaveri R, 2019).

2. Use antivirals strategically:

Reserve prophylactic antivirals for scenarios where VARIZIG is unavailable or contraindicated CDC Yellow Book, 2024).
Avoid overusing antivirals in the PEP setting to preserve their efficacy and prevent the development of resistance. (Piret & Boivin, 2016).

Act quickly in household exposure:
- Prolonged exposure in household settings increases the risk of symptomatic disease (Newman & Jhaveri, 2019). Initiate PEP promptly in these cases.
Strengthen preventative measures:
- Ensure at-risk patients, such as those undergoing immunosuppressive therapy, receive prophylaxis vaccination when feasible.
- Raise awareness among healthcare providers and patients about the urgency of timely PEP and the risks of delayed intervention (Lachiewicz & Srinivas, 2019).

By following these recommendations, healthcare providers can reduce the incidence of severe VZV complications, particularly in the most vulnerable populations, ensuring better outcomes through timely and appropriate prophylactic interventions.