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

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.¹ 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.² 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).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 1, A).²

Figure 1.

A, Role of fatty acid toxicity and cytokine storm in acute pancreatitis and coronavirus disease-19 (COVID-19). Factors inducing pancreatitis and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection damage the pancreas and cause lipase leakage resulting in increased lipolysis in visceral adipocytes in both conditions. SARS-CoV-2 may directly affect adipocytes as well. Lipolysis increases levels of unsaturated fatty acids (UFA), causing organ damage and inducing the cytokine storm, which drives disease progression and determines the ultimate severity. B, Early IL-6, -8, and -10 levels are strongly associated with severity in acute pancreatitis and COVID-19. Standardized mean differences (squares) with 95% confidence intervals (CI; horizontal lines) were calculated for each study in this meta-analysis. The “Total” column gives the number of patients in the analysis. Results of individual studies were pooled with the random effects model; the pooled point estimates with CI is represented by diamonds in the figure. If the CI does not cross the line of no effect (vertical black line at the 0 value on the horizontal axis), the difference should be considered statistically significant. Studies including patients with acute pancreatitis and those with COVID-19 were pooled separately (top and bottom panels for each cytokine, respectively). Severity of acute pancreatitis was defined as per the 2012 Atlanta Classification in all studies, the nonsevere group consists of cases without persistent organ failure including mild and moderately severe cases. The severity of COVID-19 was defined as per the definitions used in the individual studies: all but one adhered to the Guidelines for the Diagnosis and Treatment of New Coronavirus Pneumonia by the National Health Commission of the People’s Republic of China. Further technical details are provided in the Supplementary Methods. The meta-analysis shows that IL-6, -8, and -10 levels were significantly higher in severe versus nonsevere disease in both acute pancreatitis and COVID-19, with considerable statistical heterogeneity across the studies. SD, standard deviation.

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.

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.^{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 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.^{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.¹³ Huber et al¹⁴ 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.