Joe is a 14-year-old boy who underwent a kidney transplant 5 months ago and is on a maintenance immunosuppressive regimen of tacrolimus, mycophenolate mofetil, and prednisone. Three months post-transplant, he experienced an episode of acute rejection, which was successfully treated with Thymoglobulin and corticosteroids.

Recently, Joe was exposed to VZV through a friend. Although Joe received the varicella vaccine during childhood and had documented immunity to VZV before his transplant, his immunosuppressed state places him at increased risk of developing severe or disseminated VZV infection.

Joe remains asymptomatic, showing no signs of fever, rash, or fatigue, and continues his normal activities without complaint. However, given his immunocompromised status, his parents should closely monitor for symptoms of VZV infection, such as fever, rash, or fatigue.

Expert Consensus

• Immunosuppressive therapy following kidney transplantation significantly increases the risk of severe varicella infections, even in patients who were vaccinated before transplantation. This is due to waning immunity and the inability of a suppressed immune system to mount an effective response to the VZV (Gans H, Chemaly RF, 2021).
• Close household contact with individuals actively infected with VZV, such as those with shingles, represents a high transmission risk for immunocompromised patients. Such exposures necessitate immediate evaluation and intervention to mitigate the potential for severe or disseminated disease (Pergam & Limaye, 2019).
• Immunosuppressive regimens, commonly used to manage autoimmune diseases and transplant recipients, significantly increase the risk of varicella-zoster virus (VZV) reactivation (Ishihara et al., 2024).
• The suppression of T-cell-mediated immunity, which is critical for viral clearance, places transplant recipients on these therapies at an elevated risk of severe and potentially life-threatening varicella infections (Tayyar R and Ho D, 2023)​​.
• VARIZIG is recommended as the first-line prophylactic measure for high-risk patients exposed to VZV. Optimal efficacy is achieved when administered within 96 hours of exposure. However, it remains effective for up to 10 days post-exposure (Levin MJ et al., 2019).
• VARIZIG has demonstrated the ability to reduce the severity and complications of VZV infections, making it an essential component of care for immunocompromised individuals following exposure (Levin MJ et al., 2019).

INTRODUCTION

According to US Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines, kidney transplantation remains the definitive treatment for kidney failure, significantly improving patient survival and quality of life compared to dialysis (KDIGO, 2009). However, its success is contingent on immunosuppressive therapies to prevent transplanted kidney rejection. These therapies, particularly those that deplete or suppress T-cell function, heighten the risk of infections, including the reactivation of latent viruses such as VZV (Tayyar R and Ho D, 2023)​​.

VZV, a member of the Herpesviridae family, causes primary infection (varicella, or chickenpox) and subsequent reactivation (herpes zoster, or shingles) from its latent state in sensory ganglia. CDC identifies VZV as a highly contagious viral disease (CDC Yellow Book, 2024). In immunocompetent individuals, these infections are typically self-limited. However, according to the US KDOQI, primary VZ infection is potentially life-threatening in kidney transplant patients. Furthermore, disseminated varicella-zoster virus (VZV) infection can occur in individuals with weakened immune systems, potentially affecting the lungs, liver, central nervous system, and other internal organs. (KDIGO, 2009).

MECHANISMS OF IMMUNOSUPPRESSION AND VZV REACTIVATION

The Role of T-Cell Immunity in VZV Control

T-cell-mediated immunity is crucial for controlling VZV infections, as it regulates the severity and spread of the virus and reduces reactivations. While humoral responses provide some protection, the presence of VZV-specific CD8+ T cells is the strongest predictor of reactivation risk. Immunocompromised patients, particularly those undergoing T-cell-depleting therapies or HCT, are at higher risk of severe VZV reactivation and require prophylactic measures (Tayyar R, Ho D, 2023).

Impact of Immunosuppressive Regimens

Immunosuppressive regimens, commonly used to manage autoimmune diseases and transplant recipients, significantly increase the risk of varicella-zoster virus (VZV) reactivation, particularly as herpes zoster (HZ). Glucocorticoids (GCs), a cornerstone in the treatment of autoimmune diseases, induce lymphocyte apoptosis and suppress both innate and adaptive immunity. This dose-dependent immunosuppression elevates the risk of HZ, with higher cumulative doses linked to greater hazard ratios for reactivation. Even a single systemic GC prescription can increase the likelihood of HZ, and doses of 10 mg or more of prednisolone equivalents nearly double the risk (Ishihara et al., 2024).

Disease-modifying antirheumatic drugs (DMARDs), including conventional synthetic (csDMARDs), biologic (bDMARDs), and targeted synthetic DMARDs (tsDMARDs), also contribute to heightened susceptibility to VZV. While some csDMARDs like methotrexate and leflunomide show limited risk, drugs like hydroxychloroquine and azathioprine are associated with a higher HZ incidence. Mycophenolate mofetil (MMF) and cyclophosphamide present clear risks, with MMF nearly doubling the HZ risk in transplant and autoimmune patients. Similarly, bDMARDs, particularly TNF inhibitors and rituximab, and tsDMARDs like JAK inhibitors, show an elevated risk for VZV reactivation. By disrupting cytokine pathways essential for viral immunity, JAK inhibitors exhibit a class-wide increased risk of HZ, with dose-dependent severity. Physicians prescribing these immunosuppressive agents should remain vigilant about the risk of VZV reactivation and implement appropriate preventive strategies (Ishihara et al., 2024).

WANING IMMUNITY TO VZV AFTER KIDNEY TRANSPLANTATION

Challenges in maintaining VZV immunity: Pre-transplant immunity to VZV, whether acquired through vaccination or natural infection, may not be durable in the face of aggressive immunosuppressive regimens. Vaccinated patients, in particular, may experience a significant decline in VZV-specific antibodies and T-cell memory after transplantation​​ (Gans H, Chemaly RF, 2021).

Implications of Serostatus

• Seropositive patients: while these individuals theoretically possess residual immunity, immunosuppression may diminish its efficacy, leading to an increased risk of reactivation.
• Seronegative patients: these individuals are at the highest risk for primary VZV infection, which can have severe manifestations in the immunocompromised​.

RISK OF VZV TRANSMISSION FROM CLOSE CONTACTS

Household Exposure

Seronegative transplant recipients are at high risk of severe VZV infection after prolonged face-to-face contact with infectious household members. VZV spreads through direct contact or airborne routes, including from patients with localized herpes zoster (HZ). Even seropositive recipients may be vulnerable due to impaired T-cell function and should be closely monitored for symptoms following exposure (Pergam & Limaye, 2019).

Nosocomial and Community-Acquired Infections

In hospital settings, significant exposure includes sharing a room with an infectious patient or face-to-face contact with contagious staff or visitors. VZV transmission is amplified in confined spaces via direct or airborne routes. Immunosuppressed recipients exposed in healthcare or community environments require close monitoring due to their increased risk of severe disease (Pergam & Limaye, 2019).

POST-EXPOSURE PROPHYLAXIS: THE ROLE OF VARIZIG

Mechanism and indications

VARIZIG provides passive immunity by delivering high titers of anti-VZV antibodies. It is recommended for post-exposure prophylaxis in high-risk individuals, including kidney transplant recipients, to mitigate disease severity and prevent complications ​​(Lachiewicz AM, Srinivas ML, 2019).

Efficacy and Administration

• US guidelines recommend that administering VARIZIG within 96 hours of exposure is optimal, but efficacy persists up to 10 days post-exposure (Levin MJ et al., 2019)​.
• In clinical practice, VARIZIG has been shown to reduce the incidence of severe disease and complications such as pneumonia and disseminated VZV in immunocompromised hosts​ (Levin MJ et al., 2019)​.

Combination with Antiviral Therapy

Combination strategies are increasingly employed to manage varicella in immunocompromised individuals at high risk for severe disease. Preemptive oral acyclovir, paired with prophylactic varicella-zoster immune globulin (VZIG) or intravenous immunoglobulin (IVIG), is recommended to mitigate disease severity and reduce complications (Lachiewicz & Srinivas, 2019).

STRATEGIES FOR PREVENTION AND MANAGEMENT

Vaccination before transplantation

Pre-transplant varicella vaccination is recommended for seronegative transplant candidates using the live-attenuated Oka vaccine (Varivax®), which is safe and effective in end-stage organ disease patients when administered prior to immunosuppression. A two-dose regimen with a 4–6 week interval is advised to improve immune response, given reduced vaccine efficacy (~60%) in these populations.

Administration of the vaccine should ideally be completed four weeks before transplantation, particularly when combined with MMR vaccination. Current IDSA guidelines stress the importance of completing vaccination prior to starting immunosuppressive therapy to minimize the risk of severe varicella infections post-transplant (Pergam & Limaye, 2019).

Monitoring and Prophylaxis Post-Transplant

Post-transplant patients who are seronegative for varicella-zoster virus (VZV) are at high risk of severe primary infections after significant exposure, which includes close, prolonged contact with infectious individuals in household or hospital settings. VZV can spread through direct, airborne, or contact routes, including from localized herpes zoster (HZ). Seropositive patients with impaired T-cell function due to immunosuppression are also vulnerable and require close monitoring for symptoms after exposure (Pergam & Limaye, 2019).

Post-exposure prophylaxis (PEP) includes passive immunoprophylaxis with VARIZIG, administered within 10 days of exposure to reduce disease severity, or non-specific IVIG when VARIZIG is unavailable. Antiviral agents such as valacyclovir, preferred for its improved bioavailability, or acyclovir are recommended for a 7-day course beginning 7–10 days post-exposure. For highly immunosuppressed individuals, extended antiviral prophylaxis (up to 22–28 days) may be necessary, particularly in combination with immunoglobulin therapy. These measures aim to prevent or mitigate severe VZV infections in this vulnerable population (Pergam & Limaye, 2019).

Management of Active VZV Infections

Prompt initiation of high-dose intravenous acyclovir is recommended for transplant recipients with suspected or confirmed VZV infection. Hospitalization may be necessary for disseminated infections or severe complications (Tayyar R, Ho D, 2023).

Durability of Immune Responses

The extent to which kidney transplant recipients can maintain or restore VZV-specific immunity remains an area of active investigation.

CONCLUSION

Kidney-transplant recipients face a significantly heightened risk of severe VZV infections due to the immunosuppressive therapies required for allograft maintenance. Strategies for mitigating this risk include pre-transplant vaccination, vigilant post-transplant monitoring, and timely administration of VARIZIG and antiviral agents according to guidelines following exposure. Ongoing research is essential to optimize immune protection and improve outcomes for this vulnerable population​​.