Potential novel approaches to prevent the risk of infection in patients with variceal bleeding

We read with great interest the paper by Martinez et al.[1]Martínez J. Hernández-Gea V. Rodríguez-de-Santiago E. Téllez L. Procopet B. Giráldez Á. et al.International Variceal Bleeding Observational Study Group and Baveno Cooperation. Bacterial infections in patients with acute variceal bleeding in the era of antibiotic prophylaxis.J Hepatol. 2021 Aug; 75 (PMID: 33845059): 342-350Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar published recently in the Journal of Hepatology. The article made the important observation that the prevalence of infections is high (almost 20%) in patients with acute variceal bleeding (AVB) despite antibiotic prophylaxis and pointed to severe hepatic encephalopathy (HE grade III & IV) as independently associated with bacterial infections. Although several previous studies have described the risk of infection as being related to the severity of liver disease, we would like to highlight the possible mechanisms underlying the development of infection following a variceal bleed and point to potential novel approaches to reduce the risk of infection. Isoleucine hypothesis: Haemoglobin is the only protein known to man that is deficient in a single essential amino acid, isoleucine, making it a very poor-quality protein. Ingestion of haemoglobin, as occurs during AVB causes severe hypoisoleucinemia due to a mechanism referred to as branched-chain amino acid antagonism as it is also very rich in leucine and valine.[2]Olde Damink S.W. Jalan R. Deutz N.E. Hayes P.C. Soeters P.B. Protein synthesis is severely diminished following a simulated upper GI bleed in patients with cirrhosis.J Hepatol. 2008 Nov; 49 (PMID: 18602715): 726-731Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar,[3]Olde Damink S.W. Jalan R. Deutz N.E. Dejong C.H. Redhead D.N. Hynd P. et al.Isoleucine infusion during "simulated" upper gastrointestinal bleeding improves liver and muscle protein synthesis in cirrhotic patients.Hepatology. 2007 Mar; 45 (PMID: 17326149): 560-568Crossref PubMed Scopus (41) Google Scholar This hypoisoleucinemia eventually results in diminished protein synthesis, DNA synthesis, cell proliferation, and subsequently impaired immune function.[2]Olde Damink S.W. Jalan R. Deutz N.E. Hayes P.C. Soeters P.B. Protein synthesis is severely diminished following a simulated upper GI bleed in patients with cirrhosis.J Hepatol. 2008 Nov; 49 (PMID: 18602715): 726-731Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar,[3]Olde Damink S.W. Jalan R. Deutz N.E. Dejong C.H. Redhead D.N. Hynd P. et al.Isoleucine infusion during "simulated" upper gastrointestinal bleeding improves liver and muscle protein synthesis in cirrhotic patients.Hepatology. 2007 Mar; 45 (PMID: 17326149): 560-568Crossref PubMed Scopus (41) Google Scholar In cirrhosis, administration of an amino acid mixture mimicking haemoglobin results in impairment of neutrophil function. It was shown that infusion of isoleucine during a simulated gastrointestinal bleed restores impaired protein synthesis by the liver, which is critical for immunity.[3]Olde Damink S.W. Jalan R. Deutz N.E. Dejong C.H. Redhead D.N. Hynd P. et al.Isoleucine infusion during "simulated" upper gastrointestinal bleeding improves liver and muscle protein synthesis in cirrhotic patients.Hepatology. 2007 Mar; 45 (PMID: 17326149): 560-568Crossref PubMed Scopus (41) Google Scholar Taken together, the existing data suggest that isoleucine administration during an AVB may reduce the risk of bacterial infection and its concentrations may be a potential biomarker to guide intervention. Role of ammonia: Given the peculiar amino-acid composition of haemoglobin, it is also one of the most ammoniagenic substances known.[4]Bessman A.N. Mirick G.S. Blood ammonia levels following the ingestion of casein and whole blood.J Clin Invest. 1958; 37 (PMCID: PMC1062760): 990-998Crossref PubMed Scopus (35) Google Scholar In addition to the known neurotoxic role of ammonia, it also impairs neutrophil function – with the production of excess reactive oxygen species, systemic inflammation, oxidative stress, high spontaneous oxidative burst, and decreased phagocytosis – leading to a significantly greater risk of infection.[5]Shawcross D.L. Wright G.A. Stadlbauer V. Hodges S.J. Davies N.A. Wheeler-Jones C. et al.Ammonia impairs neutrophil phagocytic function in liver disease.Hepatology. 2008 Oct; 48 (PMID: 18697192): 1202-1212Crossref PubMed Scopus (119) Google Scholar Data regarding ammonia concentrations from patients had who developed an infection in the Martinez et al. study would be interesting. Aggressive attempts to reduce ammonia concentrations rapidly may reduce the risk of infection. Hepatic encephalopathy and sympathetic nervous system: There is an increasing literature base showing that brain dysfunction due to wide-ranging causes such as traumatic brain injury, stroke, and spinal cord injury6Meisel C. Schwab J.M. Prass K. Meisel A. Dirnagl U. Central nervous system injury-induced immune deficiency syndrome.Nat Rev Neurosci. 2005 Oct; 6 (PMID: 16163382): 775-786Crossref PubMed Scopus (627) Google Scholar, 7Dantzer R. Neuroimmune interactions: from the brain to the immune system and vice versa.Physiol Rev. 2018 Jan 1; 98 (PMID: 29351513; PMCID: PMC5866360): 477-504Crossref PubMed Scopus (315) Google Scholar, 8Dirnagl U. Klehmet J. Braun J.S. Harms H. Meisel C. Ziemssen T. et al.Stroke-induced immunodepression: experimental evidence and clinical relevance.Stroke. 2007 Feb; 38 (PMID: 17261736): 770-773Crossref PubMed Scopus (356) Google Scholar even with silent infarcts leads to immune dysfunction, a condition described as CNS injury-induced immunodepression (CIDS).[9]Nakagawa T. Sekizawa K. Nakajoh K. Tanji H. Arai H. Sasaki H. Silent cerebral infarction : a potential risk for pneumonia in the elderly.. 2000 Feb; 247 (PMID: 10692089): 255-259Google Scholar The proposed underlying mechanism is that the pro-inflammatory cytokines produced by injured brain tissue can directly activate the hypothalamic-pituitary-adrenal axis, activate the sympathetic nervous system, leading to immune dysfunction and thereby increasing the risk of infection. Therefore, the observations of Martinez et al. that HE is an independent predictor of infection is important and it is possible that the mechanisms underlying CIDS also apply to HE. To reduce the risk of infection, HE should be treated with a high degree of urgency and antibiotics initiated or modified if it is present. In summary, targeting known mechanisms, as well as improving our understanding of the interaction between variceal bleeding, hyperammonaemia, HE, and the risk of infection, will further the development of novel therapeutic approaches. The authors received no financial support to produce this manuscript. RJ, EA and DrS contributed equally to this letter and all have provided intelellectual input into the drafting and writing of this manuscript. Rajiv Jalan has research collaborations with Takeda, and Yaqrit, and consults for Yaqrit. Rajiv Jalan is the founder of Yaqrit Limited, which is developing UCL inventions for treatment of patients with cirrhosis. Rajiv Jalan is an inventor of ornithine phenylacetate, which was licensed by UCL to Mallinckrodt. He is also the inventor of Yaq-001, DIALIVE and Yaq-005, the patents for which have been licensed by his University into a UCL spinout company, Yaqrit Ltd. Please refer to the accompanying ICMJE disclosure forms for further details. The following is the supplementary data to this article: Download .pdf (.24 MB) Help with pdf files Multimedia component 1 Bacterial infections in patients with acute variceal bleeding in the era of antibiotic prophylaxisJournal of HepatologyVol. 75Issue 2PreviewAntibiotic prophylaxis reduces the risk of infection and mortality in patients with cirrhosis and acute variceal bleeding (AVB). This study examines the incidence of, and risk factors for, bacterial infections during hospitalization in patients with AVB on antibiotic prophylaxis. Full-Text PDF Reply to: “Potential novel approaches to prevent the risk of infection in patients with variceal bleeding”Journal of HepatologyVol. 76Issue 3PreviewWe read with interest the letter by E. Alabsawy et al. in which they underscore the clinical relevance of hepatic encephalopathy (HE) in patients with cirrhosis and acute variceal bleeding (AVB), and suggest alternative pathophysiological mechanisms of bacterial infection.1 In our study, bacterial infection was mainly respiratory and occurred despite antibiotic prophylaxis.2 Aspiration of gastric contents to the respiratory tract shortly after admission was the most likely mechanism underlying many of the episodes of respiratory infection that occurred. Full-Text PDF