Dear Editor,
We would like to thank Dr. Cao et al. for their interest in our study entitled “Human cytomegalovirus reactivation in cirrhosis patients with acute decompensation” and for their insightful comments [
1,
2]. This editorial further elaborates on the multiple clinical implications of human cytomegalovirus (HCMV) reactivation: 1) could be an indicator of immunosuppression among patients with acute decompensation (AD) and sometimes aggravate immune dysfunction in the clinical course; 2) could be a promoter of disease progression, leading to some HCMV-related end organ diseases. We would like to take the opportunity to provide additional information about the potential links in cirrhosis-associated immune dysfunction and pathogenesis of HCMV reactivation based on previous studies.
Cirrhosis-associated immune dysfunction consists of systemic inflammation and immune deficiency, and its severity varies across different stages of cirrhosis and specific precipitating complications [
3]. The landmark CANONIC study introduced the concept of acutely decompensated cirrhosis (ADC) and defined the distinct entity of acute-on-chronic liver failure (ACLF) as ADC, characterized by the development of organ failure and high short-term mortality [
4]. The subsequent study, the PREDICT study, portrayed three clinical trajectories of patients with ADC: development of ACLF (pre-ACLF), re-hospitalization without developing ACLF (unstable decompensated cirrhosis) and without rehospitalization (stable decompensated cirrhosis) [
5]. Cirrhosis-associated immune dysfunction begins in compensated cirrhosis, increases through different decompensated stages, varies between clinical trajectories of ADC and peaks in ACLF [
6]. In our studies, we found that the incidence of HCMV reactivation closely paralleled the severity of cirrhosis: highest in ACLF, followed by ADC patients and compensated cirrhosis [
1,
7], which provides evidence of a correlation between HCMV reactivation and cirrhosis-associated immune dysfunction.
HCMV is a ubiquitous pathogen that infects most individuals early in life, and approximately 90% of Chinese adults are carriers of the virus [
1]. Like other herpesviruses, HCMV establishes lifelong latency following primary infection, which is generally asymptomatic in immunocompetent hosts. Mechanistically, HCMV could infect various cell types, resulting in either productive or latent infection depending on the cellular context. Hematopoietic progenitor cells (HPCs) in the bone marrow and monocytes in the circulation play an important role in maintaining lifelong latent infection and serve as major reservoirs for latent HCMV, but they do not support lytic viral replication [
8]. Major immediate early gene (MIE) expression, pivotal for HCMV reactivation, is controlled by differential regulation of the MIE promoter (MIEP) through epigenetic reprogramming [
9]. In vitro models of CD34+ HPC and CD14+ monocyte, several of the transcription factor families binding to the MIEP could be activated by various stimuli, including inflammatory signalling, DNA damage response pathways or oxidative stress, and lead to activating the MIEP [
9]. In murine models of mouse cytomegalovirus latency, viral reactivation is associated with the expression of inflammatory cytokines (TNF-a, IL-1, and IFN-g) and activation of transcription factors such as NF-kB and AP-1 [
10].
Similarly, in patients undergoing allogeneic hematopoietic stem cell transplantation, an elevated inflammatory cytokine/chemokine profile (e.g., TNF, IL-18, IP-10, MIG) correlates with the progression of HCMV reactivation and the magnitude of viral load [
11]. Elevated plasma levels of inflammatory cytokines (TNF, IL-6) and markers of leukocyte activation (e.g., soluble CD163) have also been observed in cirrhotic patients with AD and are particularly marked in those with ACLF [
12]. The heightened systemic inflammation in ADC patients may contribute to frequent HCMV reactivation. Furthermore, patients with bacterial infections in our study had a higher incidence of HCMV reactivation, could be linked to the increased inflammation associated with bacterial infection complications [
1]. Thus inflammation-associated signalling might be a key driver of HCMV reactivation among cirrhotic patients, but further studies are still required to validate this hypothesis.
Immunosuppression due to several reasons, like administration of immunosuppressive agents, is also well- recognized as an important factor for HCMV infection and endorgan diseases [
13]. Lymphopenia, HCMV-specific T-cell immunodeficiency and immunosuppression intensity are associated with higher risk of HCMV reactivation in transplant recipients [
14]. The main assessment method of HCMV-specific T cell immunity was to measure the production of interferon gamma (IFN-g) in response to HCMV-antigen stimulation of adaptive immune cells, including CD4+ and CD8+ T cells. In patients with AD, decreased levels of IFNg in blood was associated with disease progression independently of the presence of HBV flare [
15]. The potential relationship between immune cell dysfunction and HCMV reactivation in cirrhosis remains an area requiring further investigation.
We appreciate the comprehensive analysis of our work as well as the insightful ideas proposed for further research presented in the editorial. It highlights the mechanisms underlying HCMV reactivation among patients with cirrhosis, which is an aspect not fully explored in our study. Previous research suggests that HCMV reactivation may serve as a significant indicator of immune dysfunction including both systemic inflammation and immune deficiency. We hope our research contributes to a broader interest in the pathogenesis of latent viral reactivation among patients with cirrhosis.
FOOTNOTES
-
Authors’ contribution
Manuscript drafting and revision: H.C., C.J.
-
Conflicts of Interest
The authors have no conflicts to disclose.
Abbreviations
acute-on-chronic liver failure
acutely decompensated cirrhosis
allogeneic hematopoietic stem cell transplantation
interferon gamma-induced protein
major immediate early gene
major immediate early gene promoter
monokine induced by interferon gamma
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