key: cord-0767853-5u90oin9
authors: Hegyi, Péter; Szakács, Zsolt; Sahin-Tóth, Miklós
title: Lipotoxicity and cytokine storm in severe acute pancreatitis and COVID-19
date: 2020-07-17
journal: Gastroenterology
DOI: 10.1053/j.gastro.2020.07.014
sha: 37eb12e77385e87bde29433b01c3fbcc04ec7fb4
doc_id: 767853
cord_uid: 5u90oin9

nan

SARS-CoV-2-induced coronavirus disease-2019 (COVID-19) has become a pandemic affecting over 7 million people worldwide so far [1] . The relatively high mortality of COVID-19 (around 10% of closed cases) is often linked to multi-organ 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 multi-organ 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 [2] . These toxic fatty acids cause mitochondrial injury and stimulate the excessive production and release of proinflammatory immune mediators (cytokine storm), which can drive disease progression with eventual multi-organ failure, including the acute respiratory distress syndrome, the leading cause of COVID-19 related mortality ( Figure   1A ) [3] . 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 [4] [5] [6] [7] .

Autopsy data suggest that the incidence of focal pancreatitis in COVID-19 may be higher than diagnosed clinically [8] . However, it is conceivable that the virus targets not only the pancreas but also adipocytes causing increased lipolysis through the adipose triglyceride lipase ( Figure   1A ) [2] .

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 [2] . 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.

Similarly to COVID-19, a fraction of cases of acute pancreatitis also progresses to severe disease with multi-organ failure as the leading cause of mortality [9, 10] . 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 two diseases. After careful selection, 12 studies on acute pancreatitis and 9 studies on 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 non-severe cases of the two diseases ( Figure 1B) . A similar tendency was observed for TNF-α, whereas IFNγ levels showed no difference as a function of severity. Lower levels of IL-1β were apparent in severe versus non-severe 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 [11, 12] . Furthermore, it was recently suggested that hemoadsorption with CytoSorb may decrease 28-day all-cause mortality in patients treated in intensive care units shows that interleukin-6, -8 and -10 levels were significantly higher in severe versus non-severe disease in both acute pancreatitis and COVID-19, with considerable statistical heterogeneity across the studies. CI, confidence interval; SD, standard deviation.

Mortality from COVID-19 increases with unsaturated fat, and may be reduced by early calcium and albumin supplementation

Pancreatic triglyceride lipase mediates lipotoxic systemic inflammation

Lipase elevation in patients with COVID-19

Pancreatic injury in the course of coronavirus disease 2019 (COVID-19): a not-so-rare occurrence

Current evidence on pancreatic involvement in SARS-CoV-2 infection Pancreatology

Coronavirus disease-19 (COVID-19) associated with severe acute pancreatitis: Case report on three family members

Pulmonary arterial thrombosis in COVID-19 with fatal outcome: Results from a prospective, single-center, clinicopathologic case series

Impact of characteristics of organ failure and infected necrosis on mortality in necrotising pancreatitis

Antibiotic therapy in acute pancreatitis: From global overuse to evidence based recommendations

Extracorporeal cytokine elimination as rescue therapy in refractory septic shock: a prospective single-center study

Extracorporeal cytokine adsorption in septic shock: a proof of concept randomized, controlled pilot study

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

Pancreatitis cytosorbents (CytoSorb) inflammatory cytokine removal: A prospective study (PACIFIC)