Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Jul 3:14:1183703.
doi: 10.3389/fimmu.2023.1183703. eCollection 2023.

Prediction of herpes virus infections after solid organ transplantation: a prospective study of immune function

Dina Leth Møller  1 , Søren Schwartz Sørensen  2   3 , Omid Rezahosseini  1 , Daniel Bräuner Rasmussen  1 , Nicoline Stender Arentoft  1 , Josefine Amalie Loft  1 , Michael Perch  3   4 , Finn Gustafsson  3   5 , Jens Lundgren  3   6 , Thomas Scheike  7 , Jenny Dahl Knudsen  8 , Sisse Rye Ostrowski  3   9 , Allan Rasmussen  10 , Susanne Dam Nielsen  1   3   10
Affiliations

Prediction of herpes virus infections after solid organ transplantation: a prospective study of immune function

Dina Leth Møller et al. Front Immunol. .

Abstract

Introduction: Herpes virus infections are a major concern after solid organ transplantation and linked to the immune function of the recipient. We aimed to determine the incidence of positive herpes virus (cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex virus type 1/2 (HSV-1/2), and varicella zoster virus (VZV)) PCR tests during the first year post-transplantation and assess whether a model including immune function pre-transplantation and three months post-transplantation could predict a subsequent positive herpes virus PCR.

Methods: All participants were preemptively screened for CMV, and EBV IgG-negative participants were screened for EBV during the first year post-transplantation. Herpes virus PCR tests for all included herpes viruses (CMV, EBV, HSV-1/2, and VZV) were retrieved from the Danish Microbiology database containing nationwide PCR results from both hospitals and outpatient clinics. Immune function was assessed by whole blood stimulation with A) LPS, B) R848, C) Poly I:C, and D) a blank control. Cytokine concentrations (TNF-α, IL-1β, IL-6, IL-8, IL-10, IL-12p40, IL-17A, IFN-α, and IFN-γ) were measured using Luminex.

Results: We included 123 liver (54%), kidney (26%), and lung (20%) transplant recipients. The cumulative incidence of positive herpes virus PCR tests was 36.6% (95% CI: 28.1-45.1) during the first year post-transplantation. The final prediction model included recipient age, type of transplantation, CMV serostatus, and change in Poly I:C-induced IL-12p40 from pre-transplantation to three months post-transplantation. The prediction model had an AUC of 77% (95% CI: 61-92). Risk scores were extracted from the prediction model, and the participants were divided into three risk groups. Participants with a risk score <5 (28% of the cohort), 5-10 (45% of the cohort), and >10 (27% of the cohort) had a cumulative incidence of having a positive herpes virus PCR test at 5.8%, 25%, and 73%, respectively (p < 0.001).

Conclusion: In conclusion, the incidence of positive herpes virus PCR tests was high, and a risk model including immune function allowed the prediction of positive herpes virus PCR and may be used to identify recipients at higher risk.

Keywords: TruCulture®; cytomegalovirus; herpes virus; immune functional assay; prediction; solid organ transplantation.

PubMed Disclaimer

Conflict of interest statement

OR received a grant from the Research Foundation of Rigshospitalet related to this work, and a grant from AP Møller Fonden not related to this work. MP has participated in advisory boards for Takeda, and PulmonX, served as a research consultant for AMBU, received an unlimited institutional research grant from Roche and travel grants from Boeringer-Ingelheim, received lecturing honorary from AstraZeneca, GSK, Therakos and PulmonX but declares no conflict of interest directly related to the study; FG reports consulting fees from Pfizer, Alnylam, Ionis, and Abbott and lecture fees from Novartis, not related to this work; SN received unrestricted research grants from Novo Nordisk Foundation and Independent Research Fund FSS. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Cumulative incidence of first positive herpes virus PCR test during the first year post-transplantation.
Figure 2
Figure 2
Induced cytokine concentration at three months post-transplantation in participants with (boxplots in red/purple/green/grey) or without (blue boxplots) subsequent positive herpes PCR tests for (A) LPS-induced cytokines, (B) R848-induced cytokines, (C) Poly I:C-induced cytokines, and (D) Unstimulated (Blank) cytokines. All cytokine concentrations are reported in pg/mL. The light grey boxplots in the background indicate the 5-95% reference interval based on healthy individuals. No p-values were significant after the Benjamini-Hochberg correction for multiple comparisons.
Figure 3
Figure 3
Median change in induced cytokine concentration pre- and post-transplantation in participants with or without subsequent positive herpes PCR tests. All cytokine concentrations are reported in pg/mL. No p-values were significant after the Benjamini-Hochberg correction for multiple comparisons.
Figure 4
Figure 4
Screening for associations between subsequent positive herpes virus PCR tests and induced cytokine concentrations using Cox proportional hazards regressions adjusted for age, type of transplantation, and CMV serostatus for (A) absolute cytokine concentrations at three months post-transplantation and (B) changes in cytokine concentration from pre-transplantation to post-transplantation. P-values are represented as: * <0.05 and ** <0.01.
Figure 5
Figure 5
Receiver operating characteristics (ROC) curve for the best performing model consisted of age, type of transplantation, CMV serostatus, and Δ Poly I:C-induced IL-12.
Figure 6
Figure 6
Cumulative incidence of first positive herpes virus PCR test during the first year post-transplantation in participants divided according to risk score using cut-off values of 5 and 10.
See this image and copyright information in PMC

Similar articles

See all similar articles

References

    1. Kotton CN, Kumar D, Caliendo AM, Huprikar S, Chou S, Danziger-Isakov L, et al. . The third international consensus guidelines on the management of cytomegalovirus in solid-organ transplantation. Transplantation (2018) 102:900–31. doi: 10.1097/TP.0000000000002191 - DOI - PubMed
    1. Fishman JA, Emery V, Freeman R, Pascual M, Rostaing L, Schlitt HJ, et al. . Cytomegalovirus in transplantation - challenging the status quo. Clin Transplant (2007) 21:149–58. doi: 10.1111/j.1399-0012.2006.00618.x - DOI - PubMed
    1. Fishman JA. Infection in organ transplantation. Am J Transplant (2017) 17:856–79. doi: 10.1111/ajt.14208 - DOI - PubMed
    1. Green M, Michaels MG. Epstein-Barr Virus infection and posttransplant lymphoproliferative disorder. Am J Transplant (2013) 13 Suppl 3:41–54. doi: 10.1111/ajt.12004 - DOI - PubMed
    1. Wilck MB, Zuckerman RA. Herpes simplex virus in solid organ transplantation. Am J Transplant (2013) 13 Suppl 4:121–7. doi: 10.1111/ajt.12105 - DOI - PubMed

Publication types

Grants and funding

This work was supported by the Novo Nordic Foundation, the Independent Research Fund (FSS), the Danish National Research Foundation (DNRF) grant no. 126, and the Research Foundation of Rigshospitalet. The funding sources were not involved in any part of the study design, data collection, data analysis, and interpretation of the data or the writing of this manuscript.