DISCUSSION
Leukopenia, decompensation, cirrhosis, decompensated cirrhosis, MELD-plus, acute-on-chronic liver failure, dyscoordination
SYSTEMIC INFLAMMATORY RESPONSE, DECOMPENSATED CIRRHOSIS, LEUKOPENIA, DISEASE, CIRRHOSIS, PATHOPHYSIOLOGY, EVENTS, COMPLICATIONS, INFLAMMATORY RESPONSE
Our parenclitic network analyses using baseline clinical data accurately predict outcome in patients with decompensated cirrhosis hospitalized for acute complications, based on disruption of organ system coupling. These analyses also identified that patients with preserved organ system coupling had significantly poorer outcomes after increased albumin treatment.Reduced organ system correlation was associated with poorer prognosis in hospitalized patients with cirrhosis independent of the severity of disease and age. The dyscoordination in the crosstalk between the key markers of systemic inflammatory response, CRP and WCC, provides a novel pathophysiological insight into the dysregulated inflammatory response in decompensated cirrhosis not captured by the MELD severity scoring system. Specifically, we found that reduced coordination between CRP and WCC predicted poorer 6-month outcomes in patients receiving standard clinical treatment. This was in line with our previous validation study in decompensated cirrhosis (Prognostic modeling in cirrhosis from Child-Pugh to MELD-plus and acute-on-chronic liver failure continues to move toward greater recognition of the impact on survival of the extrahepatic involvements of cirrhosis (Leukopenia is associated with a significantly higher risk of decompensation and mortality in patients with cirrhosis (Unexpectedly, patients with lower parenclitic deviation and by extension higher organ system connectivity showed significantly lower survival after targeted albumin therapy for a maximum of 2 weeks that persisted over the 6-month follow-up. We hypothesize that patients with preserved organ system connectivity may achieve this by the diversion of energies/resources needed for normal physiological functions toward maintaining an effective inflammatory response (The main limitation of this study includes the inherent inability of the parenclitic network to capture the time course of organ system connectivity because of the cross-sectional static feature of the data analyzed. For instance, our analysis is not robust to immediate and temporal changes to the network of organ systems that may follow albumin infusion or result from major clinical events that occur after the baseline data were gathered. Finally, although this study is multicenter in design, it applies to patients with decompensated cirrhosis admitted into hospitals in the United Kingdom where standard care may differ in definition from other countries and regions of the world. Thus, interpretation of our findings should be contextualized. However, the clinical management of patients is still strongly informed by baseline clinical variables, and the ATTIRE study represents one of the largest clinical trials of hospitalized patients with cirrhosis who were prospectively recruited and carefully followed up. The calculation of parenclitic deviation along the WCC-CRP axis is feasible at the bedside. However, further validation of the WCC-CRP axis is required in a larger, globally representative reference group to allow clinical incorporation as a bedside scoring system.In summary, network analysis using routine clinical data collected at baseline provides novel insights into the pathophysiology of cirrhosis independent of the MELD score and significantly improved MELD's prognostic value. Furthermore, we showed that an unsupervised network analysis has potential value and may predict a poor response to targeted albumin therapy, which was not observed in conventional analyses. Future studies should further investigate the value of WCC-CRP and network mapping to predict outcome in decompensated cirrhosis and improving selection of patients for further trials of albumin or other immune-/inflammation-modulating therapies.