Sarah is an 8-year-old girl with a history of sJIA, managed with infliximab therapy for the past 2 years. Four days ago, Sarah returned from a class trip to Japan. Shortly after, her school informed her parents that 1 of her classmates on the trip was diagnosed with chickenpox (varicella), raising concerns about Sarah’s exposure.

Although Sarah received the 2-dose varicella vaccine in early childhood, her ongoing infliximab therapy may compromise her immune response, putting her at an increased risk for infection and complications if exposed to the virus. Exposure in a travel or school setting increases the risk due to prolonged close contact.

Sarah shows no signs of illness, such as fever, rash, or fatigue, and her general activity and appetite are normal. However, given her exposure, her parents should monitor her closely for symptoms like fever, fatigue, or rash and seek immediate medical attention if they develop.

Expert Consensus

• Children maintained on immunosuppressive therapy and exposed to VZV are at higher risk of severe varicella complications, including infections like cellulitis, sepsis, pneumonitis, encephalitis, and hepatitis (Levin MJ et al., 2019) despite prior vaccination.
• In children who have rheumatic diseases such as sJIA and are on immunosuppressive therapy, the clinical presentation of VZV infection may differ, often involving a higher rate of complications and increased need for hospitalization (Leuvenink R et al., 2016).
• Immunosuppressive and anti-TNF medications like infliximab can reduce vaccine effectiveness, and even vaccinated children may still develop varicella.
• Infliximab therapy is associated with marked suppression of cellular immunity, an effect that may be prolonged with regular, intermittent administration. When infliximab is administered during the incubation phase of primary VZV infection, this immunosuppression can facilitate viral dissemination, leading to a heightened risk of severe and potentially systemic disease (Balato N et al., 2009)​​.
• Varicella zoster immune globulin (VARIZIG) is recommended as a post-exposure prophylaxis to prevent or reduce the severity of infection in such individuals (Levin MJ et al., 2019).
• For best results, VARIZIG should be given as soon as possible after exposure, preferably within 96 hours; however, the CDC allows for administration up to 10 days after exposure (CDC, 2013).
• Current guidelines offer limited direction on using prophylactic acyclovir or valaciclovir in immunocompromised individuals. Significantly, if oral therapy proves ineffective, the window for optimal VARIZIG administration (within 96 hours) may close (Lachiewicz AM and Srinivas ML, 2020).
• Other antiviral agents, such as famciclovir, lack sufficient evidence for prophylactic use in this population and are typically reserved for alternative clinical indications.

Introduction

VZV, a highly contagious member of the Herpesviridae family, is responsible for 2 distinct clinical conditions: varicella (chickenpox) as the primary infection and herpes zoster (shingles) due to viral reactivation (CDC Yellow Book, 2024). While routine vaccination has significantly reduced the burden of varicella, specific populations remain at high risk for severe disease, particularly individuals with compromised immune systems who lack evidence of immunity (CDC Yellow Book, 2024).

Pediatric patients with sJIA undergoing immunosuppressive therapy represent a uniquely vulnerable group, facing an increased likelihood of varicella-related complications (Leuvenink R et al., 2016) even if previously vaccinated.

This review examines the interplay of these factors and highlights the critical role of PEP strategies, particularly VARIZIG, in mitigating severe outcomes in this population.

Background: sJIA and Immunosuppression

sJIA is a subtype of juvenile idiopathic arthritis characterized by systemic inflammation, intermittent fever, and potential multi-organ involvement​​. Immunosuppressive therapy in sJIA targets inflammation, remission, and complications like MAS. Biologics (e.g., canakinumab, tocilizumab) are preferred, while traditional treatments (e.g., methotrexate, glucocorticoids) are less effective and have more side effects. MAS requires urgent treatment with glucocorticoids, anakinra, and cyclosporine. A treat-to-target approach improves outcomes. (Grevich S et al., 2017)​​. However, these therapies also suppress the immune system, increasing susceptibility to infections.

Impact of Immunosuppression on Varicella Risk

• Altered immune response: Immunosuppression prevents T-cell clonal expansion, thus limiting the magnitude of the ensuing immune response. This impairs T-cell-mediated control of viral replication, increasing the risk of severe VZV infections and limiting the efficacy of live attenuated vaccines.
• Breakthrough infections: despite vaccination, immunosuppressed children may experience varicella due to inadequate seroconversion or waning immunity. Studies report breakthrough infections with milder but significant disease burden in these children (CDC Yellow Book, 2024).

Epidemiology and Transmission Dynamics in Pediatric sJIA

VZV is highly contagious, with an infection rate of ≈85% among susceptible individuals following exposure (CDC Yellow Book, 2024). Pediatric patients with sJIA are particularly vulnerable due to their immunosuppressed status​​ and frequent exposure in high-transmission settings such as households, schools, and travel environments.

• Household exposure: close and prolonged interactions within households result in a higher degree of virus exposure, amplifying the likelihood of symptomatic disease (Newman AM and Jhaveri R, 2019)​​.
• School and travel settings: School outbreaks or travel-related exposures pose additional risks due to sustained close contact in enclosed spaces. These environments often exacerbate exposure and delay diagnosis and intervention.

Clinical Course and Complications in Pediatric sJIA

Children with sJIA on immunosuppressive therapy face distinct challenges when exposed to VZV. While healthy children typically experience a self-limiting course of varicella, immunosuppressed patients are predisposed to severe complications due to impaired immune function (Levin MJ et al., 2019).

Severe Complications

Severe complications are most frequently observed in infants, adults, and individuals with weakened immune systems. These may include cerebellar ataxia, encephalitis, bleeding disorders, pneumonia, and secondary bacterial infections of skin lesions, which can occasionally lead to bacteremia or sepsis. In rare instances (approximately 1 in 40,000 varicella cases), such complications can be fatal (CDC Yellow Book, 2024).

Breakthrough Disease in Vaccinated Children

Vaccination significantly reduces disease severity but may not fully protect immunosuppressed children. Breakthrough Varicella, or modified varicella,is characterized by milder symptoms, although is still contagious (CDC Yellow Book, 2024).

Vaccine Efficacy and Limitations in sJIA

The live attenuated varicella vaccine has demonstrated remarkable efficacy in reducing the incidence and severity of varicella. However, it is contraindicated in immunocompromising conditions or treatments, making it unsuitable for sJIA (CDC Yellow Book, 2024).

PEP: Strategies and Considerations

PEP is critical for preventing or mitigating severe VZV infections in high-risk populations. Current guidelines recommend VARIZIG as the first-line prophylactic intervention for immunosuppressed children following significant exposure (Levin MJ et al., 2019).

Role of VARIZIG

VARIZIG provides passive immunity by supplying pre-formed antibodies that neutralize VZV, preventing systemic spread and severe complications (Levin MJ et al., 2019).

• Timing of administration:
• Optimal efficacy is achieved when VARIZIG is administered within 96 hours of exposure.
• It remains effective up to 10 days post-exposure, allowing for delayed recognition or logistical challenges (Levin MJ et al., 2019).
• Efficacy:
• Clinical studies have shown that VARIZIG reduces the risk of severe disease and secondary complications in immunocompromised patients (Levin MJ et al., 2019)

Antiviral Prophylaxis

Antiviral agents, such as acyclovir or valacyclovir, are recommended for children who cannot receive VARIZIG or when VARIZIG is unavailable (AAP Red Book, 2024)​​. While not as effective as VARIZIG, these agents can reduce viral replication and the risk of systemic complications.

Combination Approaches

Combination approaches are increasingly utilized in the management of varicella, particularly in immunocompromised individuals at heightened risk for severe disease. Preemptive oral acyclovir, in conjunction with varicella-zoster immune globulin (VZIG) or intravenous immunoglobulin (IVIG), has been recommended as a strategy to reduce disease severity and complications (Lachiewicz & Srinivas, 2019).

Clinical Management of Exposed Pediatric Patients

Effective management of VZV exposure in pediatric patients with sJIA requires a multidisciplinary approach involving pediatricians, rheumatologists, and infectious disease specialists.

Initial Evaluation

• Risk stratification: assess exposure type (household, school, travel) and proximity to index case (Lachiewicz & Srinivas, 2019).
• Immune status: Review vaccination history to obtain evidence of immunity and current immunosuppressive therapy to determine susceptibility (Lachiewicz & Srinivas, 2019).

Prophylactic Intervention

• Administer VARIZIG: Prioritise early administration for household exposures and immunosuppressed children (Lachiewicz & Srinivas, 2019)
• Initiate antivirals: begin antiviral therapy promptly for patients beyond the 10-day window or those contraindicated for VARIZIG (Lachiewicz & Srinivas, 2019)

Monitoring and Follow-Up

• Symptom surveillance: monitor for fever, rash, and systemic symptoms indicative of progression (CDC: Varicella, 2024).

Logistical Considerations

Managing VZV exposure in pediatric sJIA patients involves navigating logistical challenges, including access to PEP, ensuring timely intervention, and balancing the risks of immunosuppression against infection risks.

Access to VARIZIG

• Expedited ordering for VARIZIG is available to meet the optimal therapeutic window. In the United States, VariZIG can be obtained from specialty distributors (Newman AM and Jhaveri R, 2019)​​.

Educational Outreach

Educating caregivers and school personnel about the risks of VZV exposure and the importance of timely PEP can improve outcomes and reduce intervention delays (Lachiewicz & Srinivas, 2019).

Summary and Recommendations

Pediatric patients with sJIA represent a high-risk group for severe VZV-related complications due to their immunosuppressive treatment regimens. This vulnerability underscores the importance of proactive management strategies, including early recognition of exposure, prioritization of VARIZIG administration, and integration of antiviral therapies when necessary.