Following organ transplantation, cytomegalovirus (CMV) reactivation is a common and serious adverse in event in many patients, mainly due to the use of immunosuppressive drugs to prevent rejection of the transplanted organ. CMV, however, is not the only virus which can cause issues due to reactivation during this vulnerable time. Herpes Simplex Virus-1 or HSV-1, which is a common virus found in a latent form in many adults, occasionally reactivates to cause the dreaded cold-sores. Patients who have received an organ transplant, who then take immunosuppressive agents, are at risk for increased symptomatic HSV-1 reactivation. Early studies have suggested that subclinical shedding episodes may occur at least once a month in immunocompetent hosts (those not under immunosuppression), but the frequency or kinetics of these events in solid organ transplant (SOT) recipients has not been reliably investigated. Because the lack of symptoms in subclinical reactivation makes these events hard to detect, little is known about how these events might impact patient outcomes after SOT. It was with this in mind that Molly Fischer, a graduate student with Drs. Steve Pergam, Margaret Green and Christine Johnston, recently published in Transplant Infectious Disease, highlighting the importance of this type of data.
For their study, the research team enrolled 15 patients who had received an SOT at least 3 months prior to enrollment and who were seropositive for HSV-1. After an initial medical exam, the participants self-collected oral swabs 3 times daily for 6 weeks. The swabs were analyzed for the presence of HSV DNA, which would indicate that the participant had experienced a shedding episode. When combined with clinical symptom reporting, they could determine which of these reactivation events were subclinical. Of the 15 participants, 12 were observed to have had a shedding episode throughout the course of the study—3 of whom had never had clinical oral HSV symptoms. Throughout the duration of the study, the research team counted a total of 32 HSV shedding episodes, 27 of which occurred without lesions. When the research team assessed viral DNA in the swabs, they observed that longer (>24-hour) episodes had the highest median viral titer. Ms. Fischer emphasized that these results were encouraging; “our pre-formed hypotheses were that transplant (immunosuppressed) patients would shed HSV frequently, and for longer periods than those with normal immune systems – so to see that our data supported our hypotheses was important.” Yet, they were still intrigued by some of the results, as she explained that, “the frequency of brief episodes of reactivation was what surprised me.”
The research team concluded that this form of surveillance in post SOT recipients was a viable and likely important study method for looking at HSV subclinical episodes in immunosuppressed populations in the future. They observed that the participants had no issues adhering to the schedule of swabbing 3 times a day, noting that this sampling type also has precedent for being a reliable method for HSV detection. “The methods in this study may be applicable to future studies to evaluate novel antiviral agents or drug dosing strategies in immunosuppressed patients,” Ms. Fischer explained. They observed that the participants were able to adhere to the schedule of swabbing 3 times a day, noting that this sampling frequency was informed by prior studies of HSV shedding in other populations, which showed this method to be a reliable method for HSV-1 detection. They also pointed out that, because the majority of shedding episodes were over 12 hours, that twice daily swabs would likely even be good enough to capture the majority of these events. “These short episodes helped us to prepare for future studies, and to define how often we might need to sample patients to capture these short periods of shedding,” she added. While the team concedes there are considerations when comparing to previous swab-sampling studies in immunocompetent participants, their data suggests a potentially longer duration of shedding in SOT patients, possibly due to the transplant and immunosuppression. Ms. Fischer also highlighted future studies to investigate these shedding events in allogeneic hematopoietic stem cell transplant recipients (aHCT), as they have data to suggest that “HSV-1 seropositive aHCT patients had an increased risk of one-year mortality.” Because transplant patients are at high risk for many forms of reactivating or new infections, graft rejection or graft-versus-host disease, it is important to identify and reduce risk where possible. When it comes to HSV, utilizing data such as what was proposed in this study could help inform whether reactivation is associated with inflammation or other adverse events in these patients, and how to mitigate this in the future.
Fischer MD, Green ML, Selke S, Limaye AP, Wald A, Boeckh MJ, Phipps AI, Pergam SA, Johnston C. Evaluation of oral herpes simplex virus shedding among solid organ transplant recipients: A pilot study. Transpl Infect Dis. 2024 Aug;26(4):e14335. doi: 10.1111/tid.14335. Epub 2024 Jul 15. PMID: 39010324; PMCID: PMC11329158.
This spotlighted work was funded by the NIAID and the Joel Meyers Endowment Scholarship.
Fred Hutch/University of Washington/Seattle Children's Cancer Consortium members Drs. Margaret Green, Anna Wald, Michael Boekh, Amanda Phipps and Steve Pergam contributed to this work.