Editorial: Dysfunctional Neutrophils in Cirrhosis With Acute Decompensation: Why It Matters

Infections have traditionally been labelled a complication of cirrhosis, but increasing evidence supports viewing them as a pivotal turning point in the disease trajectory, marking the shift from stable compensated cirrhosis to a phase dominated by organ dysfunction, hospitalisation and excess mortality [1]. A documented infection in cirrhosis is associated with roughly a four-fold increase in the risk of death, and approximately one in three patients die within about 1 month of the infectious episode [2]. As cirrhosis-associated immune dysfunction advances, functional defects in neutrophils develop affecting the innate and adaptive immunity, increasing the vulnerability to bacterial and fungal infections [3]. Clinically, the point at which this immunological failure becomes manifest can be regarded as a crucial turning stage in the course of cirrhosis because it coincides with a marked escalation in the risk of acute decompensation (AD), acute-on-chronic liver failure (ACLF) and death over the following months. Identifying the point in the evolution of cirrhosis at which neutrophils start to lose their effectiveness is important because it signals a shift to a phase in which infections are far more likely to occur and to be life-threatening. If this turning point can be recognised at or near the time it occurs, clinicians can escalate infection-centered management by intensifying clinical observation and lowering the threshold for microbiological investigations. Targeted prophylactic measures for prevention of neutrophil dysfunction may even push the patients back toward the stable state in order to lower the likelihood of infection-driven AD or progression to ACLF. In sepsis, systemic inflammation alters the plasma milieu, driving complement activation, cytokinaemia, and accumulation of damage- and pathogen-associated molecular patterns, which together induce a dysregulated neutrophil phenotype, delayed apoptosis and reduced pathogen clearance, thereby predisposing to secondary infections and organ dysfunction [4, 5]. In cirrhosis and acute-on-chronic liver failure, circulating neutrophils develop a characteristic functional failure with blunted phagocytosis and microbial killing which, in addition to an impairment in the production of reactive oxygen species (ROS), correlates with the severity of markers of systemic inflammation as well as bacterial translocation and mortality risk [6]. In a well-designed and clinically relevant study, Sriphoosanaphan and colleagues show that plasma from patients with AD appears to push otherwise healthy neutrophils into a state of chronic low-grade activation in which baseline activity is high but the capacity to provide sufficient effector responses is blunted [7]. A subgroup of patients with AD without ACLF already showed markedly increased short-term mortality, suggesting that this neutrophil profile characterises individuals who may soon develop clinical deterioration. These observations support a model in which ongoing plasma-driven stimulation gradually exhausts neutrophil function, diminishing pathogen control and helping to explain why an initial infection in cirrhosis so often precedes further infectious episodes and decompensation. Clinically, recognising this biology highlights the period after a first infection as a critical window in which intensified infection surveillance, rapid diagnostic work-up and carefully targeted preventive strategies may have the greatest potential to alter outcomes. Future clinical research in both neutrophil function in cirrhosis and exploration of the plasma components triggering neutrophil dysfunction may foster risk prediction models of progression in cirrhosis and even molecular targets for reversing neutrophil dysfunction in cirrhosis. L. L. Gluud: conceptualization, writing – original draft, writing – review and editing. N. Kimer: writing – review and editing. The authors have nothing to report. This article is linked to Sriphoosanaphan et al. papers. To view these articles, visit https://doi.org/10.1111/apt.70480 and https://doi.org/10.1111/apt.70512. The data that support the findings of this study are available from the corresponding author upon reasonable request.