Lipotoxicity and Cytokine Storm in Severe Acute Pancreatitis and COVID-19

Abstract

See “Mortality from coronavirus disease 2019 increases with unsaturated fat and may be reduced by early calcium and albumin supplementation,” by El-Kurdi B, Khatua B, Rood C, et al, on page 1015. See “Mortality from coronavirus disease 2019 increases with unsaturated fat and may be reduced by early calcium and albumin supplementation,” by El-Kurdi B, Khatua B, Rood C, et al, on page 1015. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–induced coronavirus disease-2019 (COVID-19) has become a pandemic affecting >7 million people worldwide so far.1WorldometerCOVID-19 coronavirus pandemic.www.worldometers.info/coronavirus/Google Scholar The relatively high mortality of COVID-19 (around 10% of closed cases) is often linked to multiorgan failure, which supports the notion that an inappropriate host response to the viral infection might play a role in disease outcomes. In this issue of Gastroenterology, the Lipotoxicity in COVID-19 Study Group from the Mayo Clinic reports the enticing observation that progression of COVID-19 to multiorgan failure resembles lipotoxic organ failure during severe acute pancreatitis. Thus, the authors posit that, in both diseases, interstitial leakage of pancreatic lipase may occur resulting in adipose lipolysis and increased levels of unsaturated fatty acids.2El-Kurdi B. Khatua B. Rood C. et al.Mortality from coronavirus disease 2019 increases with unsaturated fat, and may be reduced by early calcium and albumin supplementation.Gastroenterology. 2020; 159: 1015-1018Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar These toxic fatty acids cause mitochondrial injury and stimulate the excessive production and release of proinflammatory immune mediators (cytokine storm) that can drive disease progression with eventual multiorgan failure, including the acute respiratory distress syndrome, the leading cause of COVID-19 related mortality (Figure 1, A).3de Oliveira C. Khatua B. Noel P. et al.Pancreatic triglyceride lipase mediates lipotoxic systemic inflammation.J Clin Invest. 2020; 130: 1931-1947Crossref PubMed Scopus (54) Google Scholar An increasing number of publications have reported that SARS-CoV-2 targets the pancreas resulting in elevation of serum lipase activity or rarely even frank pancreatitis.4McNabb-Baltar J. Jin D.X. Grover A.S. et al.Lipase elevation in patients with COVID-19.Am J Gastroenterol. 2020 Jun 3; ([Epub ahead of print])Crossref PubMed Scopus (65) Google Scholar, 5Bruno G. Fabrizio C. Santoro C.R. et al.Pancreatic injury in the course of coronavirus disease 2019 (COVID-19): a not-so-rare occurrence.J Med Virol. 2020 Jun 4; ([Epub ahead of print])Crossref Scopus (25) Google Scholar, 6Thaweerat W. Current evidence on pancreatic involvement in SARS-CoV-2 infection.Pancreatology. 2020 May 27; ([Epub ahead of print])Crossref PubMed Scopus (21) Google Scholar, 7Hadi A. Werge M. Kristiansen K.T. et al.Coronavirus disease-19 (COVID-19) associated with severe acute pancreatitis: case report on three family members.Pancreatology. 2020; 20: 665-667Crossref PubMed Scopus (131) Google Scholar Autopsy data suggest that the incidence of focal pancreatitis in COVID-19 may be higher than diagnosed clinically.8Lax S.F. Skok K. Zechner P. et al.Pulmonary arterial thrombosis in COVID-19 with fatal outcome: Results from a prospective, single-center, clinicopathologic case series.Ann Intern Med. 2020 May 14; ([Epub ahead of print])Crossref PubMed Scopus (476) Google Scholar However, it is conceivable that the virus targets not only the pancreas, but also adipocytes causing increased lipolysis through the adipose triglyceride lipase (Figure 1, A).2El-Kurdi B. Khatua B. Rood C. et al.Mortality from coronavirus disease 2019 increases with unsaturated fat, and may be reduced by early calcium and albumin supplementation.Gastroenterology. 2020; 159: 1015-1018Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar Fatty acids bind to calcium and albumin and hypocalcemia and hypoalbuminemia are often present in severe COVID-19. Therefore, the authors propose that early treatment of COVID-19 with albumin and calcium supplementation may improve disease outcomes by complexing unwanted fatty acids.2El-Kurdi B. Khatua B. Rood C. et al.Mortality from coronavirus disease 2019 increases with unsaturated fat, and may be reduced by early calcium and albumin supplementation.Gastroenterology. 2020; 159: 1015-1018Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar However, once a cytokine storm has been triggered by the toxic effects of unsaturated fatty acids, calcium/albumin supplementation is not expected to be effective any longer as the host immune response drives further organ damage, resulting in high mortality. Similar to COVID-19, a fraction of cases of acute pancreatitis also progresses to severe disease with multiorgan failure as the leading cause of mortality.9Schepers N.J. Bakker O.J. Besselink M.G. et al.Impact of characteristics of organ failure and infected necrosis on mortality in necrotising pancreatitis.Gut. 2019; 68: 1044-1051Crossref PubMed Scopus (139) Google Scholar,10Párniczky A. Lantos T. Tóth E.M. et al.Antibiotic therapy in acute pancreatitis: From global overuse to evidence based recommendations.Pancreatology. 2019; 19: 488-499Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar Although fatty acid-induced damage may be involved in the early stages of both diseases, the primary cause of organ failure is more likely the ensuing cytokine storm. To compare the relationship of serum cytokines and severity, we performed a meta-analysis of cytokine patterns in the early stages of the 2 diseases. After careful selection, 12 studies on acute pancreatitis and 9 studies on COVID-19 were eligible for inclusion in the meta-analysis. Details of the systematic search, the selection process, the analysis, the characteristics and quality of the studies are described in the Supplementary Methods, Supplementary Figure 1, and Supplementary Tables 1–3. The results show that the pattern of altered cytokine levels is very similar in severe acute pancreatitis and COVID-19. Thus, IL-6, IL-8, and IL-10 levels were higher in severe versus nonsevere cases of the two diseases (Figure 1, B). A similar tendency was observed for tumor necrosis factor-α, whereas interferon-γ levels showed no difference as a function of severity. Lower levels of IL-1β were apparent in severe versus nonsevere acute pancreatitis, but this difference was absent in COVID-19 (Supplementary Figure 2). The remarkable similarity of cytokine elevations in severe acute pancreatitis and severe COVID-19 suggests that therapeutic removal of cytokines may improve outcomes in both diseases. In this regard, extracorporeal cytokine adsorption has been beneficial in septic shock.11Friesecke S. Stecher S.-S. Gross S. et al.Extracorporeal cytokine elimination as rescue therapy in refractory septic shock: a prospective single-center study.J Artif Organs. 2017; 20: 252-259Crossref PubMed Scopus (104) Google Scholar,12Hawchar F. László I. Öveges N. et al.Extracorporeal cytokine adsorption in septic shock: a proof of concept randomized, controlled pilot study.J Crit Care. 2019; 49: 172-178Crossref PubMed Scopus (78) Google Scholar Furthermore, it was recently suggested that hemoadsorption with CytoSorb may decrease 28-day all-cause mortality in patients treated in intensive care units.13Brouwer W.P. Duran S. Kuijper M. et al.Hemoadsorption with CytoSorb shows a decreased observed versus expected 28-day all-cause mortality in ICU patients with septic shock: a propensity-score-weighted retrospective study.Crit Care. 2019; 23: 317Crossref PubMed Scopus (88) Google Scholar Huber et al14Huber W. Algül H. Lahmer T. et al.Pancreatitis cytosorbents (CytoSorb) inflammatory cytokine removal: a prospective study (PACIFIC).Medicine (Baltimore). 2019; 98e13044Crossref PubMed Scopus (11) Google Scholar have initiated the PACIFIC trial in which the investigators will evaluate the effectiveness of 2 consecutive 24-hour treatments with CytoSorb on the hemodynamics of patients with early severe acute pancreatitis. The recently registered CYTOAID-COVID-19 (NCT04422626) international, multicenter clinical trial aims to collect systematic, high-quality data on COVID-19 patients admitted to the intensive care unit with acute respiratory failure and treated with CytoSorb. Taken together, the new observations from the Lipotoxicity in COVID-19 Study Group and the ongoing clinical trials suggest a convincing pathophysiologic rationale for a 2-pronged strategy to prevent progression of acute pancreatitis and COVID-19 to severe, potentially fatal disease. Early supplementation with calcium and albumin to decrease fatty acid toxicity and subsequent quelling of the cytokine storm by extracorporeal cytokine adsorption may prevent dismal disease outcomes. Download .pdf (.44 MB) Help with pdf files Supplementary Material Mortality From Coronavirus Disease 2019 Increases With Unsaturated Fat and May Be Reduced by Early Calcium and Albumin SupplementationGastroenterologyVol. 159Issue 3PreviewAlthough most coronavirus disease 2019 (COVID-19) infections are self-limited, some develop into sepsis and multisystem organ failure (MSOF),1 resembling lipotoxic acute pancreatitis.2,3 Understanding underlying mechanisms may guide supportive care while clinical trials are ongoing. Unsaturated fatty acids (UFAs) generated by adipose lipolysis2,3 cause MSOF, including acute lung injury.2 Severe acute pancreatitis and severe COVID-19 share obesity as a risk factor,4 along with lipase elevation,5 hypoalbuminemia,1 and hypocalcemia. Full-Text PDF Open Access