Editorial: Dysfunctional Neutrophils in Cirrhosis With Acute Decompensation—Why It Matters. Authors' Reply

We thank Professor Gluud and Dr. Kimer for their insightful editorial [1] regarding our recent study [2]. We greatly appreciate their perspective that the onset of neutrophil dysfunction represents a pivotal turning point in the trajectory of cirrhosis, marking the critical shift from a stable state to one dominated by infection susceptibility and organ failure. In addition to their excellent comments, we would like to highlight the novel perspective of our paper, which indicates that humoral factors in the circulation are enough to rapidly change the function of normal cells, a phenomenon we refer to as plasma-induced neutrophil dysfunction (PIND). We agree with their assessment that this plasma-induced functional neutrophil phenotype, which we characterise as ‘primed but exhausted’, provides a mechanistic explanation for why an initial infection so often precipitates a downward spiral of further infectious episodes and acute-on-chronic liver failure (ACLF). Recognising this critical window after a first infection offers a unique opportunity for clinical intervention. A central finding of our study is the speed and transferability of this neutrophil phenotype. By exposing healthy donor neutrophils to patient plasma for only 90 min, we demonstrated that the circulating milieu in acute decompensation can rapidly induce a reproducible pattern of neutrophil dysfunction. This rapid induction is consistent with our group's previous validation of this ex vivo approach [3, 4], supporting that the defect is driven primarily by the humoral environment rather than being solely attributable to intrinsic cellular failure. Together, these findings strengthen the rationale to focus on circulating mediators as mechanistic drivers and potential therapeutic targets. Our model is therefore intentionally positioned to facilitate discovery of soluble contributors (e.g., pathogen- and damage-associated molecular patterns, complement activation products, cytokine networks, and metabolic mediators) that may be amenable to intervention. Indeed, we recognised the importance of endotoxin as a key mediator [4], leading to the discovery of DIALIVE [5], a novel liver assist device that has the ability to remove DAMPs and PAMPs. Furthermore, this observation also provides the rationale for the use of Toll-like 4 receptor blockers for patients with ACLF [6]. We also share the editorial's emphasis on clinical actionability. In patients with acute decompensation without ACLF, PIND identified individuals at increased risk of subsequent infection, an endpoint for which conventional severity scores (including MELD and CLIF-C AD) were not predictive in our cohort. We would frame this not as replacing established prognostic scores, but as capturing a complementary dimension of risk: functional immune competence, which is not directly measured by organ-failure metrics. Future therapeutic strategies could therefore focus on modifying the pathogenic circulating milieu. Interventions that remove inhibitory plasma factors, such as the DIALIVE device which was shown in a randomised clinical trial to reduce the risk of bacterial infection [5], provide proof of concept for the clinical importance of PIND. A further unmet need is to develop this assay so that it can be translated into clinical practice. Supachaya Sriphoosanaphan: conceptualization, writing – original draft, writing – review and editing, visualization. Rajiv Jalan: conceptualization, writing – review and editing, supervision. 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.70502. The data that support the findings of this study are available from the corresponding author upon reasonable request.