Cytomegalovirus (CMV), also known as human herpesvirus 5, is a member of the Betaherpesvirinae subfamily of the Herpesviridae family. It is the largest human herpesvirus with a double-stranded DNA genome of approximately 235 kbp and a diameter of approximately 180 nm [
1]. The transcription, translation, and protein synthesis processes of CMV genes take more than 48 hours, making the replication cycle significantly slower than that of the herpes simplex virus, which is completed in approximately 6–9 hours. Additionally, unlike the herpes simplex virus and varicella-zoster virus, CMV does not encode the virus-specific enzyme thymidine kinase, a characteristic that has important implications for antiviral treatment strategies [
2]. CMV is strictly species-specific and establishes lifelong latency following primary infection, which typically occurs asymptomatically in early childhood through contact with secretions, such as saliva and urine. When acquired later in life, it may present with mononucleosis symptoms, making its differentiation from Epstein-Barr virus infection challenging without serological testing. Secondary symptomatic CMV disease later in life may result from either reactivation of the latent virus or reinfection with a new exogenous strain [
3].
Although CMV infections are usually self-limiting in immunocompetent individuals, they can cause serious complications in certain high-risk populations. In pregnant women, primary infection can lead to congenital transmission, resulting in miscarriage, stillbirth, neonatal death, or long-term sequelae such as hearing loss and microcephaly [
4].
CMV reactivation is thought to occur when a latent infection is disrupted under immunosuppressive conditions. The key factors implicated in this process include tumor necrosis factor-alpha and cyclic adenosine monophosphate [
5]. CMV reactivation is frequently observed in critically ill patients and is associated with prolonged hospitalization, extended intensive care unit stay, and increased mortality [
6]. A meta-analysis reported CMV infection in 27% of these patients and identified CMV viremia as an independent risk factor for death [
6].
CMV reactivation is well documented in immunosuppressed individuals, such as organ transplant recipients, patients undergoing chemotherapy, and those with acquired immunodeficiency syndrome. In these settings, reactivation can result in significant morbidities, including pneumonia, colitis, hepatitis, retinitis, and encephalitis [
7].
Cirrhosis, the final stage of chronic liver disease, is associated with portal hypertension, hepatic decompensation, hepatocellular carcinoma, and high mortality rates. According to a 2019 global report, cirrhosis accounted for 2.4% of all deaths, and its incidence is projected to increase. Although viral hepatitis remains the predominant cause of cirrhosis worldwide, the incidence of cirrhosis due to metabolic dysfunction-associated steatotic liver disease and alcohol-associated liver disease is increasing [
8]. Cirrhosis disrupts multiple physiological systems, particularly the immune system. Cirrhosis-associated immune dysfunction is characterized by impaired pathogen defence and persistent systemic inflammation. Consequently, cirrhosis is considered an immunocompromised state [
9]. However, limited data are available regarding CMV reactivation in this patient population, and its clinical implications remain unclear [
10,
11].
In this issue of CMH, Hong and colleagues report the results of two prospective multicenter studies evaluating CMV reactivation in patients with cirrhosis hospitalized for acute decompensation (overt ascites, overt hepatic encephalopathy, and variceal bleeding) [
12]. The investigators identified CMV reactivation in 4.8% of the enrolled patients, highlighting a previously under-recognized complication in this setting. Furthermore, CMV reactivation was more frequently observed in patients with concurrent bacterial infections or liver failure, indicating a potential link between systemic immune stress and viral reactivation in patients with advanced cirrhosis.
CMV seroprevalence in adults varies widely, from 40% to nearly 100%, depending on the geographic region, age, and ethnicity. Higher rates are commonly observed in Asia and Africa [
13-
15]. The current study was conducted in China, where the seroprevalence among the cohorts ranged from 97.7% to 100%. This high baseline seropositivity may limit the generalizability of the findings to regions with lower CMV prevalence, highlighting the need for population-specific data when interpreting these findings.
Several diagnostic tools are available for CMV detection [
16]. Serological assays for IgM and IgG antibodies are widely used to determine prior exposure and risk of reactivation. Quantitative PCR (qPCR) assays allow for the precise measurement of viral load, aiding in both diagnosis and treatment monitoring [
17]. The antigenemia assay detects CMV-positive leukocytes using antibodies against the pp65 antigen, and correlates well with viremia. In cases of suspected tissue-invasive diseases, such as colitis, histopathological evaluation remains the gold standard.
In the study by Hong et al., patients seropositive for CMV IgG at admission were screened for reactivation using a real-time qPCR assay (S3014E, Sansure Biotech Inc.), with reactivation defined as CMV DNA ≥100 copies/mL in blood. Notably, qPCR performed on whole blood has been shown to have superior sensitivity compared to that of plasma, which is an important consideration for clinical applications. Various commercial CMV qPCR assays are available, each with distinct detection thresholds that may affect assay selection and interpretation [
18].
Antiviral strategies for CMV in high-risk settings include prophylactic therapy, which is administered irrespective of viral detection and preemptive therapy, which is initiated based on laboratory evidence of reactivation in asymptomatic patients [
19]. Both strategies are well-established in posttransplant populations. Ganciclovir, an intravenous antiviral that inhibits viral DNA polymerase, and its oral prodrug valganciclovir are the most commonly used agents [
20,
21]. Both drugs carry the risks of bone marrow suppression and nephrotoxicity, necessitating careful monitoring during treatment.
A key clinical message from a study by Hong et al. was that preemptive ganciclovir therapy in patients with cirrhosis and CMV reactivation is associated with significantly improved clinical outcomes. These findings support the view that CMV reactivation is a modifiable contributor to morbidity in this population.
This study also raises several important clinical questions: 1) What viral load threshold best predicts adverse outcomes and warrants antiviral treatment in patients with cirrhosis and CMV viremia? 2) What are the immunological and virological mechanisms by which CMV reactivation exacerbates the clinical deterioration in cirrhosis? 3) What is the safety profile and optimal duration of antiviral therapy in this patient population, particularly considering baseline cytopenia and renal vulnerability?
By addressing the gap in our understanding of CMV reactivation in cirrhosis, this study provides a strong rationale for developing more structured diagnostic and therapeutic approaches. Based on their findings, a stepwise strategy can be proposed: a) All patients with cirrhosis hospitalized with acute decompensation should undergo CMV IgG testing upon admission. b) In seropositive patients, screening for viremia using qPCR or antigenemia assays should be considered. c) If viremia is detected, preemptive antiviral therapy should be initiated. d) In the absence of viremia, weekly monitoring akin to transplant protocols may be warranted to detect delayed reactivation (
Fig. 1).
In conclusion, Hong et al. significantly advanced our understanding of CMV reactivation in the context of acute decompensation in cirrhosis. Their findings not only identified a subset of patients at risk for adverse outcomes but also offered a potential interventional pathway through preemptive therapy. As further research refines the diagnostic thresholds and treatment algorithms, CMV may emerge as a clinically actionable target in the management of decompensated cirrhosis.
FOOTNOTES
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Conflicts of Interest
The author has no conflicts to disclose.
Figure 1.Proposed Preemptive Treatment Strategy for Cytomegalovirus Reactivation. Based on the findings of Hong et al., a stepwise clinical approach was proposed. First, all patients with cirrhosis admitted with acute decompensation should undergo CMV IgG serological testing at the time of admission. For seropositive patients, further screening for viremia using quantitative PCR or antigenemia assays is recommended. If viremia is detected, preemptive antiviral therapy should be initiated promptly. In the absence of detectable viremia, weekly surveillance similar to the protocols used for transplant recipients may be appropriate for monitoring delayed reactivation. CMV, cytomegalovirus.
Abbreviations
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Citations
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- Correspondence to editorial on “Human cytomegalovirus reactivation in cirrhosis patients with acute decompensation”
Changze Hong, Jinjun Chen
Clinical and Molecular Hepatology.2026; 32(2): e227. CrossRef
