Risk Factors for Infection
Pathogen-associated molecular patterns (PAMPs) are microbial byproducts recognized by pattern recognition receptors (PRRs) in humans and ultimately lead to complement and T-cell activation, release of cytokines and chemokines, and coagulation activation, which provides the host a means to fight infection. An imbalanced host response to infection leads to excess inflammation, damage, or even necrosis and organ failure. The damaged host tissue releases damage-associated molecular patterns (DAMPs), which also activates PRRs and further propagates the inflammatory response.
The hallmark of ACLF is a state of chronic inflammation, wherein bacteria are killed in the intestinal lumen but PAMPs enter the systemic circulation, leading to a chronic host inflammatory response. Additionally, a precipitating event may lead to the release of DAMPs, which further aggravates the cycle of inflammation. Patients with ACLF have significantly higher baseline levels of inflammatory markers as well as more pronounced responses to an ACLF-defining event; furthermore, the degree of inflammatory marker elevation parallels the severity of ACLF, particularly with a greater number of organ failures, and mortality rate.[3,16]
In patients with severe sepsis, there is a postulated initial phase of systemic inflammation followed by a later phase during which there is a further increased risk of worsening or secondary infection. The cause for this secondary immunosuppressed state occurs as a result of the body's shift to anti-inflammatory cytokines, apoptosis of immune cells, and anergy of the lymphocytes. This concept has been applied to patients with ACLF, wherein patients may have a baseline state of severe inflammation even in the absence of infection; thus, these patients are highly susceptible to infectious complications.
Bacterial translocation refers to the migration of enteric bacteria and its byproducts from the intestinal lumen to the mesenteric lymph nodes and subsequently to the bloodstream and other organs in the body. Bacterial translocation is increasingly frequent as liver disease advances (3.4% in Child's A cirrhosis vs. 30.8% in Child's C cirrhosis). In decompensated cirrhosis and ACLF, further promotion of bacterial translocation occurs because of small intestinal bacterial overgrowth (SIBO), altered mechanical barrier function leading to increased permeability, and relative immune dysfunction of the gut-associated lymphatic tissue that leads to impaired phagocytic function.
A disproportionate growth of pathogenic bacteria alongside relatively decreased populations of autochthonous bacteria, also termed gut dysbiosis, occurs in chronic liver disease and worsens with progression or decompensation. Moreover, specific taxa have been associated with the development of ACLF and increased mortality. The pathogenesis of gut dysbiosis is likely multifactorial, including small bowel dysmotility, SIBO, alteration in the bile acid pool, and recurrent or chronic exposure to antibiotics.
Small Intestinal Bacterial Overgrowth
SIBO occurs with increasing prevalence in patients with chronic liver disease and contributes further to gut dysbiosis and endotoxemia.[24,25] Cirrhotic patients are at a greater risk of numerous gastrointestinal (GI) motility disorders including prolonged small bowel transit time, which further increases the risk of developing SIBO. Furthermore, the frequency of small bowel dysmotility and SIBO is greater in patients with at least one episode of spontaneous bacterial peritonitis (SBP).
Altered Bile Acid Pool
Cirrhotic patients have a lower bile acid pool and decreased conversion of primary to secondary bile acids, which typically have important bactericidal properties. As a result, dysbiosis occurs, particularly due to the overgrowth of Enterobacteriaceae, which are well-known common pathogenic organisms. Alteration in the bile acid composition is associated with downstream effects including increased rates of endotoxemia and complications of cirrhosis including SBP and hepatic encephalopathy.
Proton Pump Inhibitor use
Long-term use of proton pump inhibitors (PPIs) in the general population has been associated with SIBO, pneumonia, bacterial enteric infections, and Clostridioides difficile infection (CDI). The cause for this increased prevalence may be due to exacerbation of SIBO as a result of hypochlorhydria with the use of acid-suppressive therapy. PPI use in cirrhotic patients is even higher than in the general population due to its prophylactic use for the prolonged risk of GI bleeding. Studies looking specifically at PPI use in cirrhotic patients showed an increased risk of recurrent infections (odds ratio [OR]: 2.7), SBP (OR: 2.1), and CDI (OR: 2.4).
Semin Respir Crit Care Med. 2018;39(5):578-587. © 2018 Thieme Medical Publishers