We discuss how obesity may contribute to increasing acute pancreatitis incidence, the role of lipolytic unsaturated fatty acid release in worsening acute pancreatitis, and potential approaches, including appropriate fluid management and lipase inhibition in improving acute pancreatitis outcomes.

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A lthough 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 lipolysis 2,3 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. 6 The latter 2 may progress undetected because calcium-albumin correction calculations (eg, https:// www.mdcalc.com/calcium-correction-hypoalbuminemia) can pseudonormalize calcium values (eg, uncorrected calcium of 5.9 mg/dL and albumin of 0.1 g/dL to corrected calcium of 9.0 mg/dL). Notably, calcium ameliorates MSOF, 7 and UFAs cause nonendocrine hypocalcemia. 7 The ACE2 receptor resides on adipocytes 8 containing triglycerides and adipocyte triglyceride lipase (ATGL) and on pancreatic acini expressing pancreatic triglyceride lipase (PNLIP). 2 Both oleic acid (C18:1) administration and adipose lipolysis 3 by PNLIP can cause acute lung injury and MSOF. These, and previous data showing that UFAs depolarize mitochondria, 2 inhibit complexes I and V, 3 decrease adenosine triphosphate, release intracellular calcium, 3 and increase inflammatory mediators, 3 made us explore lipotoxicity during severe COVID-19. This approach, culminating in clinical advice to keep calcium and albumin levels normal from early on in the disease, is summarized in Figure 1A and explained diagrammatically in supplementary figure 1. Methods See Supplementary Materials. Results Hypocalcemia and Hypoalbuminemia Occur Early During Severe Coronavirus Disease 2019 Seven of 15 hospitalized patients were discharged home by 3. 4 ±1.6 days. One died of hypoxemic failure after *Authors share co-first authorship.

PA is an opportunistic pathogen that is commonly associated with severe infection in immunocompromised hosts. Siglec-9 binds with Sias by cis interaction on the neutrophil surface, thereby reducing immunological activity. However, neutrophils bind with pathogens through trans interactions of siglec-9 with Sias. Neutrophils kill invading pathogens by NETs, along with extracellular phagocytosis. Here, we report the mode of the adsorption of Sias by PA from host serum, the interaction of PA(+Sias) with human neutrophils, and the resulting neutrophil immunological activity. The α2-3-linked sialoglycoproteins adsorbed by PA exhibited potent binding with the soluble siglec-9-Fc chimeras, CHO-siglec-9 and siglec-9 on neutrophils. The binding between PA(+Sias) and neutrophils was blocked by the synthetic sialoglycan Neu5Acα2-3Galβ1-4GlcNAc, confirming the linkage-specific, Sias-siglec-9 interaction. The PA(+Sias) and siglec-9 interaction on neutrophils reduced the level of ROS and the release of elastase, resulting in a reduction of NETs formation, demonstrating the role of the sialoglycoproteins adsorbed by PA in the weakening of neutrophil activity. The resistance of PA(+Sias) to NETs was made evident by the increased survival of PA(+Sias). Moreover, the decrease in PA(-Sias) survival demonstrated the involvement of NETs formation in the absence of the Sias-siglec-9 interaction. N-actylcysteine or sivelestat-pretreated neutrophils enhanced the survival of PA(-Sias). DNAse-pretreated neutrophils did not exhibit any NETs formation, resulting in the enhanced escape of PA(-Sias). Taken together, one of the survival mechanisms of PA(+Sias) is the diminution of innate immunity via its adsorption of sialoglycoproteins by its engagement of the inhibitory molecule siglec-9. This is possibly a general mechanism for pathogens that cannot synthesize Sias to subvert immunity.