Acute-on-chronic liver failure (ACLF) is a severe form of acutely decompensated cirrhosis (ADC) defined by failure of one or more of six major organ systems (liver, kidney, brain, coagulation, circulation, respiration) per the CLIF-C OF scoring system and is associated with high short-term (28-day) mortality [
1]. Common precipitants include proven bacterial infection, alcohol-related hepatitis, gastrointestinal hemorrhage with hemodynamic instability, and viral flares, but up to a third of patients have no clinically apparent precipitant after the systematic workup recommended by EASL [
1]. This gap raises the possibility that uncommon precipitants—notably opportunistic viruses—are being overlooked in routine care. Clinically, opportunistic viral infections are plausible culprits: human cytomegalovirus (HCMV; the prototypical beta herpesvirus and the largest member of the
Herpesviridae family), herpes simplex virus, and Epstein– Barr virus can all mediate organ injury in vulnerable hosts [
1].
An earlier study by Hong and colleagues used plasma metagenomic next-generation sequencing to interrogate this “gray zone” in ADC [
2]. They identified a non-hepatotropic viral signal—with HCMV most frequently detected—associated with poor response to empirical antibiotics, progression from ADC without ACLF to ACLF, and higher 90-day mortality. These data positioned HCMV reactivation as an under-recognized signal of risk during AD and flagged opportunistic viruses as potential precipitants when standard microbiology is unrevealing [
2]. Writing in CMH, Hong and colleagues now report the results of a large, prospective, multicenter study whose objective was to assess HCMV reactivation in a total of 1,013 patients with ADC (2 cohorts) who were positive for IgG anti-HCMV antibodies [
3]. HCMV reactivation was sought with the use of real-time quantitative polymerase chain reaction (qPCR) [
3]. Several relevant messages are provided by this study: 1) Reactivation of HCMV is not rare with ~5% of all ADC patients; 2) Bacterial infection and liver failure were independently associated with HCMV reactivation; 3) Increasing HCMV loads were associated with higher risk of 90-day mortality; 4) Among patients with bacterial infection, those with concomitant HCMV reactivation had higher incidence of poor outcomes (ACLF, death by 90 days) relative to those without reactivation; 5) In a small subset of patients treated with ganciclovir (n=8), mortality was lower. These observations support recommendations made in the EASL Clinical Practice Guidelines on ACLF [
1]. Thus, these guidelines recommend a systematic work-up for common precipitants in every ACLF patient and acknowledged that a substantial fraction remain “indeterminate,” for whom uncommon precipitants (including HCMV) should be considered case-by-case. HCMV is listed as a rare precipitant of ACLF-associated hepatitis (diagnostic cues being AST and ALT >3× ULN IU/mL, IgG anti-HCMV antibody positivity, and positive on quantitative HCMV PCR). The current study by Hong and colleagues confirms that HCMV reactivation occurs in ADC and is associated with ACLF development, but it did not adjudicate how many cases met stricter criteria for HCMV hepatitis-a gap to be filled by future research.
Host immune response against acute HCMV infection involves cells of the innate and adaptive classes. NK cells (which are group 1 innate lymphoid cells [ILC]) together with ILC1) are rapid responders against herpesviruses; they are pre-armed via constitutive transcription of the type 1 cytokine interferon-γ (IFN-γ) and cytotoxic granules (perforin/granzymes), enabling immediate effector activity upon target engagement. Individuals with impaired NK function are notably susceptible to herpesvirus infections, underscoring the front-line role of innate immunity. Within the adaptive arm, CD8
+ T cells are indispensable for limiting HCMV reactivation-haematopoietic stem-cell transplant recipients recover from HCMV disease as the CD8
+ T cells pool reconstitutes-and IFN-γ–secreting CD4
+ T cells contribute to durable protection [
4]. Maximal restraint depends on DC-NK and NK-T-cell crosstalk; nonetheless, sterilizing clearance rarely occurs because HCMV deploys broad immunoevasins [
5]. In clinical settings (e.g., hematopoietic transplantation), recovery of CD8
+ (and IFN-γ
+ CD4
+) responses tracks with protection against reactivation [
5]. Liver-resident NK cells (lrNK) exhibit an adaptive NKG2C
+ CD2
+ phenotype that constrains hepatic HCMV replication; donor livers with “strong” lrNK control were less likely to develop posttransplant viraemia, and CD2 blockade abrogated controlpointing to a tissue-resident checkpoint for HCMV [
6]. Yet, even with this orchestration, HCMV establishes lifelong latency, notably in bone-marrow hematopoietic progenitors and tissue endothelial cells [
4].
Reactivation occurs when latent HCMV is tipped back into lytic replication by signals that converge on the major immediate-early locus-most prominently myeloid differentiation (progenitors towards macrophages or dendritic cells) and inflammation-associated cytokines such as TNF and IL-6. This cytokine–myeloid axis was first demonstrated when allo-stimulated T-cell supernatants triggered reactivation in vitro, is amplified in posttransplants, and extends to critical illness, where sepsis is accompanied by frequent HCMV reactivation [
4]. HCMV reactivation associates with loss of CD8
+ functions (and exhaustion markers), consistent with a permissive T-cell landscape [
7]. Cirrhosis is characterized by cirrhosis-associated immune dysfunction-a status of systemic inflammation coupled with innate and adaptive immunosuppression [
8]. The disease trajectory of ADC without ACLF to ACLF is characterized by a progressive intensification of immunosuppression—independently of clinically apparent precipitants—evidenced by lymphopenia (falling CD3
+/CD4
+ with the most pronounced CD8
+ reductions in ACLF), declining IFN-γ, and rising anti-inflammatory mediators (IL-10, soluble CD163) [
9]. These evolving signatures together mark a steadily deepening immunosuppressive state with high risk of spontaneous bacterial infections and opportunistic fungal infection [
10], and activation of lifelong infected virus as was clearly shown in the current study [
3]. Of note, peripheral blood mononuclear cells from patients with decompensated cirrhosis exhibit a decrease in the constitutive expression and inducibility of genes induced by type-1 interferons (IFNs; e.g., IFN-β) [
11]. Because of the central role of type-1 IFNs and their target genes in immune responses against virus [
12], a defect in IFN-mediated response immune response against HCMV may contribute to reactivation of this virus. Another permissive mechanism might be the surge of immature, T-cell–suppressive neutrophils released during emergency granulopoiesis—first characterized in sepsis (in patients without cirrhosis) [
13] and also observed in ACLF [
9,
14]—which typifies an “extreme-response” endotype that favors HCMV reactivation. This is consistent with the results from immunocompetent ICU cohorts, showing common reactivation of HCMV (30–40%) with a viral-load-outcome gradient that independently tracks morbidity (longer ventilation and ICU stay) and, in some series, mortality-establishing HCMV DNAemia as a clinically meaningful risk signal [
15-
17].
The relationship between HCMV DNAemia and ACLF may be bidirectional. On one hand, reactivation can serve as a signal of underlying immune failure, highlighting patients at highest risk. On the other hand, reactivation may itself exacerbate injury through direct cytopathic effects (hepatitis, pneumonitis, retinitis) or by fueling systemic inflammation and immunopathology, especially when superimposed on bacterial infection. The net result is an infection– inflammation–reactivation vicious cycle that propels cirrhosis toward multi-organ damage and ACLF. In Hong’s study, although there are links with higher viral loads of HCMV and higher mortality in contrast to those who have received antiviral therapies against HCMV. However, direct causality for organ injury remains insufficiently proven due to the lack of tissue histology and organ-specific virologic confirmation, and confounding effects by illness severity are hard to be eliminated fully in observational cohorts.
From a clinical perspective, these insights raise critical questions. Should HCMV screening be incorporated into the standard diagnostic workup of ACLF, particularly when no obvious precipitant is found? Could HCMV reactivation serve as a prognostic biomarker to identify high-risk patients? Should antiviral therapy be considered selectively, particularly in patients with bacterial infection and detectable HCMV viremia? Hong’s findings suggest potential benefit, but robust randomized trials are needed to confirm efficacy and clarify patient selection.
In summary, HCMV reactivation in ADC and ACLF exemplifies the complexity of host–pathogen interactions in immunocompromised states. Hong’s studies provide compelling clinical evidence that HCMV is not merely an incidental finding but a clinically relevant event with prognostic significance. Mechanistic insights from transplantation, sepsis, and cirrhosis immunology converge to support a model in which HCMV reactivation both reflects and reinforces immune collapse. Future research must determine whether routine HCMV monitoring, risk stratification, and targeted antiviral therapy can improve outcomes in this vulnerable population. Until then, clinicians should remain vigilant for the silent presence of opportunistic viruses in ACLF-a hidden layer of risk that may hold the key to better management and prognosis.
FOOTNOTES
-
Authors’ contributions
Zhujun Cao drafted the editorial. Richard Moreau revised the editorial.
-
Conflicts of Interest
The authors declare no conflict of interest for this article.
Abbreviations
acute-on-chronic liver failure
acutely decompensated cirrhosis
quantitative polymerase chain reaction
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Citations
Citations to this article as recorded by
- Correspondence to editorial on “Human cytomegalovirus reactivation in cirrhosis patients with acute decompensation”
Changze Hong, Jinjun Chen
Clinical and Molecular Hepatology.2026; 32(3): e336. CrossRef
