key: cord-0734185-ozlphnbm
authors: Pandanaboyana, S
title: Exploring Koch’s postulate for SARS-CoV-2-induced acute pancreatitis: is it all about the ACE?
date: 2021-07-06
journal: Br J Surg
DOI: 10.1093/bjs/znab178
sha: 4033b44473028ee8cbd486f6a5af66e77d8df1a1
doc_id: 734185
cord_uid: ozlphnbm

The pathogenesis of SARS-CoV-2 infection depends on the ability of the virus to bind to the angiotensin-converting enzyme 2 (ACE2) receptor-primed cellular transmembrane serine protease 2 (TMPRSS2) receptor to facilitate entry into cells.

pancreatic ductal cells (Fig. 1) to enable viral entry 6 , and infection of human organoid pluripotent stem cell-derived pancreatic cultures containing endocrine and exocrine cells by SARS-CoV-2 has confirmed infectivity and raised levels of CXCL12, a key inflammatory cytokine known to cause ribosomal damage and pancreatic dysfunction 7 . In cultured human b-cells that do not co-express ACE2 and TMPRSS2, but do express viral entry proteins (neuropilin 1), SARS-CoV-2 has been shown to replicate and cause morphological, transcriptional, and functional changes to the cells as well as impaired glucose-stimulated insulin secretion 6 . In addition, autopsy examination of pancreases from four patients with SARS-CoV-2 infection detected SARS-CoV-2 nucleocapsid protein in pancreatic exocrine cells and b-cells, and in close proximity to islets in all four patients. One patient presented with a raised serum lipase level, raising the possibility of asymptomatic acute pancreatitis 6 .

The available data currently fulfil two of the four Koch postulates, the first being that SARS-CoV-2 was identified in the pancreas of infected patients, and second that SARS-CoV-2 can infect exocrine and endocrine cells ex vivo and in vivo. However, the remaining two of Koch's postulates, including the inoculation of samples of SARS-CoV-2 obtained from pure culture into animal or human subjects to reproduce the disease, and isolation of virus from those inoculated subjects, may not be fulfilled for ethical reasons. There is not yet absolute proof of a causal it is important to remember that many bacteria and viruses fail to fulfil Koch's postulates, yet the agents are widely accepted as the cause of disease (such as Dengue virus) with which they are associated.

The COVID PAN study 5 suggested that acute pancreatitis was more severe when associated with SARS-CoV-2 infection, and patients were at greater risk of persistent organ failure, local pancreatic complications, and death. In a recent series of patients under intensive care with SARS-CoV-2 infection, acute pancreatitis was detected in 12.6 per cent of patients in the ICU, and one-third of critically ill patients with SARS-CoV-2 infection developed concomitant acute pancreatitis 8 . Hyperlipasaemia (over the 3 times upper normal limit) often with a raised D-dimer level appear to be frequent in patients with SARS-CoV-2, and predict the need for mechanical ventilation and death 9 Needle Point is possible that SARS-CoV-2 infection directly increases the risk of organ failure and mortality independent of acute pancreatitis, endothelitis and the prothrombotic state seen with SARS-CoV-2 infection and splanchnic vasoconstriction, often seen in severe acute pancreatitis, may have contributed to a spectrum ranging from subclinical pancreatitis with hyperlipasaemia to severe acute pancreatitis. Although clinical evidence indicates that acute pancreatitis is more severe when associated with SARS-CoV-2 infection, experimental evidence of more severe pancreatic injury is lacking.

The Adaptive COVID-19 Treatment Trial of remdesivir and the UK RECOVERY study of dexamethasone showed decreased recovery time and mortality in hospitalized adults with SARS-CoV-2 infection. As yet, there is no evidence that such drugs decrease the severity of acute pancreatitis or improve outcomes. In the laboratory setting, remdesivir treatment of pancreatic islets infected with SARS-CoV-2 resulted in suppression of SARS-CoV-2 replication and no detectable virus in the supernatant of islets 6 . Dexamethasone reduces oedema and apoptosis in animal models of severe acute pancreatitis. Camostat mesylate, a serine protease inhibitor used to treat acute pancreatitis in Japan, is active against TMPRSS2, inhibits SARS-CoV-2 infection in human lung cells, and is currently being evaluated in a clinical trial to see if it reduces SARS-CoV-2 disease severity 10 . These drugs have the potential to treat both SARS-CoV-2 infection and acute pancreatitis, but clinical evidence is awaited.

The COVID PAN study and laboratory investigations have increased understanding of acute pancreatitis associated with SARS-CoV-2 infection. Koch's postulates would need to be fulfilled to provide definitive proof that SARS-CoV-2 causes acute pancreatitis, but the accumulating data appear to support this. The low prevalence of acute pancreatitis (0.27 per cent) means that large population studies will be required to confirm the COVID PAN findings, and demonstrate a plausible temporal relationship between acute pancreatitis and SARS-CoV-2 infection. Future studies will need to demonstrate the replication cycle of SARS-CoV-2 in acinar cells, and the development of pancreatic inflammation and injury, but this will require human pancreas samples.

Conflict of interest. The author declares no conflict of interest.

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