Author(s): Christine Bernsmeier aff1 , Arjuna Singanayagam aff1 , Vishal C Patel aff1 , Julia Wendon aff1 , Charalambos G Antoniades [*] aff1 aff2
ACLF; chronic liver disease; cirrhosis; glucocorticoids; immune dysfunction; immunomodulation; infection; liver failure; MERTK; plasma exchange
Infection related mortality in acute-on-chronic liver failure
Acute-on-chronic liver failure (ACLF) is a condition previously defined as acutely decompensated cirrhosis with development of multiple organ failure [ 1 ] and is hallmarked by its excessive in-hospital mortality of 45-65% [ 1-7 ]. Acute decompensation of cirrhosis (AD) without development of organ failure is referred to a lower mortality and higher chance of recovery [ 1 ], but might progress to ACLF. The main precipitant for decompensation of cirrhosis with and without organ failure is infection, which accounts for up to a third of hospital admissions [7-9 ]. Furthermore, infectious complications in patients with cirrhosis, AD and ACLF are associated with the development of organ failure, prolonged hospital stay and poor survival [9-13 ]. Failure of the immune system to eliminate infectious agents, termed immuneparesis in patients with decompensated cirrhosis and ACLF is believed to account for this high prevalence of infection and its associated mortality [11,14 ].
In patients presenting with AD or ACLF, it is crucial to treat and reverse the precipitant that triggers hepatic decompensation, and also avoid attendant complications such as secondary infections. This approach aims to provide time for the liver function to recover sufficiently and to reverse infection and organ dysfunction in order to provide a more definitive therapy such as transplantation. To date transplantation is contraindicated in the acute decompensated phase with infection, organ dysfunction and organ support.
Current treatment guidelines [15,16 ] recommend prophylactic and targeted antibiotic agents for selected patient groups, nonetheless secondary infections occur frequently despite these preemptive measures. Future adjuvant immunotherapeutic strategies that aim to boost the patient's immune responses to infectious challenge, may prevent irreversible hepatic decompensation, promote regenerative responses and provide reversibility of complications as a bridge to transplantation.
In this perspective review, the underlying pathophysiologic considerations will be outlined, and candidate drugs and other treatment modalities with immunomodulatory potential will be discussed.
Pathophysiology of immune dysfunction in ACLF
Immune dysfunction in patients with cirrhosis, otherwise termed cirrhosis-associated immune dysfunction (CAID), has been postulated to account for infectious complications and their deleterious impact on survival detailed above [14,17 ].
Pathophysiologically, this process is a dynamic, multisystem disorder involving cellular and soluble components in multiple compartments that impair the host's ability to combat bacterial challenge.
First, cellular components involve functionally re-orientated monocytes, macrophages, neutrophils and lymphocytes; soluble endocrine and paracrine components involve albumin, the complement system, coagulation factors, hormones, cytokines and administered drugs [14 ].
Second, the complexity of this is further highlighted by the fact that distinct immune defects are present in different tissue compartments. Relevant compartments are the circulation, gut, gut-associated lymphatic tissue (GALT), peritoneum, liver and the reticuloendothelial system (RES). Development of portal hypertension involves structural and hemodynamic changes in diverse departments and secondary consequences such as increased bacterial translocation [18 ].