Association between cytomegalovirus infection and allograft rejection in a large contemporary cohort of heart transplant recipients

Abstract

Background: Cytomegalovirus (CMV) infection remains a common complication after heart transplantation (HTx). The association between CMV infection and allograft rejection is debated in the era of efficient prophylactic antiviral therapies.Methods: This single-center cohort study utilized a highly phenotyped database of HTx recipients (2012)(2013)(2014)(2015)(2016). The primary endpoint was the analysis of the association between CMV infection (CMV load ≥ 500 IU/mL whole blood) and the risk of allograft rejection (cellular rejection ≥ 1R1B, antibody-mediated rejection ≥ pAMR1).Secondary endpoints included the analysis of a higher CMV load threshold (≥10 000 IU/mL) and different risk periods after PCR positivity. A mixed-effect logistic regression model with a random intercept was applied. Results were adjusted for important risk factors of rejection.Results: Overall, 384 patients were included and 6388 CMV loads and 3,494 endomyocardial biopsies were analyzed. CMV infections ≥ 500 IU/mL were diagnosed on 1223 (19.2%) blood samples from 284 (72.1%) patients and allograft rejections on 246 biopsies (7%) from 149 patients (38.8%). We did not find any association between CMV infection ≥ 500 IU/mL and rejection (univariable: OR 0.94, 95% CI [0.61, 1.45], P = .78, multivariable: OR 0.86, 95% CI [0.55, 1.33], P = .85). These results were consistent when analyzing a higher CMV load threshold and different periods of risk, reinforced by internal validation procedures and a posteriori calculation of the power (primary endpoint: power = 0.82, 95% CI [0.79-0.84]) and reproducible across different clinical scenarios.Conclusions: CMV infection was not associated with an increased risk of rejection in a contemporary cohort of HTx recipients.

The Incidence and Effect of Cytomegalovirus Disease on Mortality in Transplant Recipients and General Population: Real-world Nationwide Cohort Data

“…Litjens et al recently reported that donorderived memory-like NKG2C + natural killer cells and Vδ2 neg γδ T lymphocytes could be expanded by CMV replication, and the terminally differentiated TCR αβ + T lymphocytes with poor alloimmunity, NKG2C gene expression, and resistance of the adaptive immune system driven by interferon could be enhanced during CMV infection [51]. These immunological alterations by active CMV replication may be associated with allograft acceptance in kidney, liver, or heart transplant recipients, as well as protection against post-HSCT leukemic relapse in patients with acute myeloid leukemia [27,[51][52][53][54][55][56][57]. Even though further studies are needed to explore more evidence for causal relationships, some studies suggest that CMV infection or disease after transplantation might have beneficial effects to avoid various adverse morbidities or mortality in special recipients [51,58,59].…”

“…The IR for CMV in lung transplantation may be underestimated due to the exclusion of CMV syndrome in our study. However, all previous studies presenting CMV epidemiology with percentage did not assess IR, taking into consideration the follow-up duration [21][22][23][24][25][26][27][28][29]31]. This first analysis assessing direct comparison of CMV IRs according to transplant organs in a specific cohort showed that liver or lung transplant recipients had lower IRs for CMV, and heart transplant recipients had the highest IRs.…”

“…Despite the clinical significance and impact, the precise incidence rate (IR) per person-years of CMV infection or disease in solid organ transplantation (SOT) or hematopoietic stem cell transplantation (HSCT) recipients as well as non-transplant individuals has not been evaluated [1]. Most studies assessing post-SOT CMV epidemiology presented only the frequency (percentage) of CMV infection or disease in a single institution with relatively small recipients (6.2-60%, 1-65%, 19-72.1%, and 15-33.9% in kidney, liver, heart, and pancreas transplantation, respectively) in clinical settings applying various preventive strategies against CMV [21][22][23][24][25][26][27][28][29][30][31]. Similarly, the overall incidence of CMV infection or disease after allo-HSCT was reported to range from 3% to 40% [32][33][34][35][36][37].…”

“…Similarly, the overall incidence of CMV infection or disease after allo-HSCT was reported to range from 3% to 40% [32][33][34][35][36][37]. In addition, the definition of CMV infection or disease as well as the cut-off threshold for clinically significant DNAemia were not uniform in publications [21][22][23]27,28,30,32]. Some studies defined CMV infection as asymptomatic viremia, DNAemia, or antigenemia, while others used suspected or probable end-organ disease [22,23,32,38].…”

Early Postoperative Cardiac Complications Following Heart Transplantation

“…Even more, viral infections such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection could cause acute biventricular heart failure symptoms following a post-myocarditis state in a heart transplantation recipient [67]. Fortunately, regarding viral infections, a large contemporary cohort study on heart transplant recipients demonstrated that cytomegalovirus infection was not associated with cardiac allograft rejection [68]. However, a retrospective cohort study from 2000 to 2009 on 966 patients who underwent heart transplantation depicted that renal replacement therapy and allograft rejection were related to invasive fungal and mold infections [69].…”