Immunosuppression in Liver Transplant Recipients in the Setting of Sepsis

Abstract

Management of immunosuppression (IS) in liver transplant recipients in the setting of sepsis is an open stage for debate. The age-long practice of reduction or complete cessation of IS during sepsis has been followed by most centres across the world, although, their exact strategies are highly heterogeneous. On the other hand, the emergence of striking new evidence suggesting that there is, in fact, decreased mortality with the continuation of IS in sepsis, has raised doubts about our previously conceived intuitive notion that IS portends increased risk in sepsis. The theory postulated is that IS agents, perhaps reverse the state of dysregulated immune response in sepsis to that of an iatrogenically modulated immune response, thus dimming the inflammatory cascade and preventing its deleterious effects. Of note, none of these studies reported exaggerated rejection-related complications. These contrasting outlooks have made it rather onerous to formulate an evidence-based recommendation for liver transplant recipients afflicted with sepsis. Inclusion of transplanted patients in randomised controlled trials of sepsis-related interventions seems to be the need of the hour.

Keywords: cytokine storm; immune dysregulation; immunomodulation; immunosuppression in liver transplant; immunosuppression in sepsis.

Figure 1

Usual response to sepsis. Typically, following sepsis, a hyper-inflammatory response characterized by fever, tachycardia and hypotension occurs. This may be due to exogenous bacteria/virus/fungi releasing PAMPs or trauma, ischaemia reperfusion releasing DAMPs. PAMPs and DAMPs are recognised by PRRs like TLR which leads to pro-inflammatory cytokine release. This phase is aided by innate immune cells like neutrophils and macrophages causing phagocytosis. All these elements additionally have a down-regulatory signalling pathway as well. This is particularly seen during the controlled apoptosis of neutrophils and macrophages. Simplistically, the ‘on’ switch begins the pro-inflammatory phase while the ‘off’ switch shuts it down. IS perhaps modulate both these phases, particularly the anti-inflammatory phase. Abbreviations: DAMPS, damage associated molecular patterns; IS, immunosuppressants; PAMPs, pathogen associated molecular patterns; PRR, patterns recognition receptors; TLR, toll like receptors.

Figure 2

Hyper-inflammatory state leading to cytokine storm. In this state, the anti-inflammatory phase does not occur at all. Instead of controlled apoptosis of the innate cells there is uncontrolled apoptosis and necrosis of neutrophils and macrophages thus releasing ROS and RNS, resulting in multi-organ failure and death. Whether immunosuppressant drugs ameliorate this response and leads to better survival needs further scientific rigor. Abbreviations: ROS, reactive oxygen species; RNS, reactive nitrogen species.