Prolonged viral prophylaxis helps limit reactivation events after cord blood transplantation

From the Hill Group, Vaccine and Infectious Disease and Clinical Research Divisions

Reactivation of viral infection is a common worry for patients who receive hematopoietic cell transplant (HCT) due to prolonged immune suppression during and after treatment. HCT patients who receive cells from adult donors can have some protective viral immunity from their graft, as adult donors have often experienced similar viral infections to the patients. When a perfectly matched HCT donor is not found, HCT patients can receive a cord blood transplant (CBT); however, these cells will have no viral memory as they originate from the umbilical cord. Additionally, immune reconstitution from the graft generally takes longer after CBT than adult donor HCT, leaving patients at prolonged risk for viral reactivation. In 2009, guidelines were set for viral prophylaxis following CBT of at least one year from date of CBT and at least eight months from the time the patient stops receiving any immune suppressive drugs. Varicella zoster virus (VZV) is the virus that causes chickenpox with initial infection and herpes zoster with reactivation later in life, commonly known as shingles. VZV remains dormant in the body for life after infection, making it especially prone to reactivation. The Hill Group (Clinical Research and Vaccine and Infectious Disease Divisions) wanted to better understand the risk of VZV reactivation in CBT patients after the adoption of the guidelines for prolonged viral prophylaxis. Their results were recently published in Clinical Infectious Diseases.

The authors analyzed 227 CBT patients treated at Fred Hutch from 2006-2016. All patients were VZV seropositive, meaning they had experienced a VZV infection in the past and would be at risk for reactivation. The authors analyzed records for each patient for up to five years post-CBT, including the duration of viral prophylaxis and any viral reactivation events. During this time, there were 44 cases of VZV reactivation. Five patients had disseminated disease, and 11 patients were hospitalized for disease management. 32% of patients with reactivation experienced postherpetic neuralgia, the persistent burning sensation commonly associated with shingles. By one-year post-transplant, the reactivation rate was only 1.8%; however, this jumped to 26% by five years post-CBT. 91% of patients who survived one-year post-CBT were still on prophylaxis at the one-year mark. Increased CD4 T cell count, one measurement of immune reconstitution, was not associated with reduced risk of reactivation, which had been proposed by other studies. However, as expected, prophylaxis was associated with a lower risk of reactivation.

Varicella zoster virus causes chickenpox and shingles
Varicella zoster virus causes chickenpox and shingles From Wiki Commons

To better understand how prophylaxis influenced reactivation, the authors analyzed if and how long patients had been off prophylactic drugs at the time of reactivation. Of the 44 patients who experienced VZV reactivation, 31 were not on any prophylaxis at the time of reactivation. The median time from weaning of prophylactic drugs to reactivation was approximately four and a half months. Of the 13 breakthrough cases (reactivation during presumed prophylaxis), six patients were documented to be on prophylactic drugs, while the other seven were estimated from medical records. Five of the 13 breakthrough events occurred while patients were on immunosuppressive drugs. The authors analyzed adherence to the 2009 guidelines for prophylaxis and, of the 101 patients evaluated, only 43 patients received the recommended length of prophylaxis. Rates of VZV reactivation were 23.3% in patients who received prophylaxis in adherence to current guidelines, and 34.5% in patients who did not receive the recommended length of prophylaxis, indicating significant risk in both groups. These data indicate that adherence to longer prophylaxis is associated with a lower risk of VZV reactivation, though current guidelines may not be adequate to sufficiently limit risk. Patient adherence to guidelines of prolonged daily prophylactic medication may limit their effectiveness. One potential alternative the authors proposed is vaccination with inactivated VZV post-transplant to boost immunity, which may help prevent reactivation. Dr. Hill explained: “Although antiviral prophylaxis effectively mitigates the risk for zoster, taking a medication twice a day for years is challenging, as demonstrated in our study. A number of highly immunogenic herpes zoster vaccines with good safety profiles in immunocompromised patients are currently or will soon be available. Dedicated studies in allogeneic transplant recipients will be important to demonstrate safety but will likely be a successful intervention to improve the lives of our patients.”

This study was supported by the National Institutes of Health.

UW/Fred Hutch Cancer Consortium members Rachel Salit, Colleen Delaney, Steven Pergam, Michael Boeckh, Filippo Milano, and Joshua Hill contributed to this work.

Xue E, Xie H, Leisenring WM, Kimball LE, Goyal S, Chung L, Blazevic R, Maltez B, Edwards A, Dahlberg AE, Salit RB, Delaney C, Pergam SA, Boeckh M, Milano F, Hill JA. 2020. High incidence of herpes zoster after cord blood hematopoietic cell transplant despite longer duration of antiviral prophylaxis. Clin Infect Dis. doi: 10.1093/cid/ciaa222.