key: cord-251945-v077hhgk
authors: Titanji, Boghuma K; Farley, Monica M; Schinazi, Raymond F; Marconi, Vincent C
title: Response to Correspondence: Baricitinib as Treatment of COVID-19 Friend or Foe of the Pancreas? Cerda-Contreras et.al
date: 2020-08-14
journal: Clin Infect Dis
DOI: 10.1093/cid/ciaa1212
sha: 
doc_id: 251945
cord_uid: v077hhgk

nan

A c c e p t e d M a n u s c r i p t Dear Editor, In response to our recent publication in your journal, Cerda-Contreras et.al present the case of a critically ill 72-year-old woman with COVID-19 and multiple comorbidities. She was treated with baricitinib and steroids though subsequently succumbed to complications of acute pancreatitis. The authors hypothesized this complication could have been related to baricitinib. Contrary to what is stated in their correspondence, acute pancreatitis has been described in several case reports as a manifestation of COVID-19 1,2 . The ACE-2 receptor used by SARS-CoV2 to bind to target cells is highly expressed in the pancreas making it an attractive target for infection by the virus. The cytopathic effects from local virus replication and significant inflammation associated with severe disease may contribute to pancreatic tissue damage in patients with COVID-19. New onset type I diabetes mellitus and worsening type II diabetes mellitus have been linked to damage of pancreatic islet cells in patients with COVID-19 3 , further supporting the tropism of SARS-CoV2 for the pancreas and the potential damaging effects to that organ. We also note that in addition, the patient received treatment with steroids and propofol, both of which have been independently associated with acute pancreatitis 4-6 . Furthermore, the patient was obese, which may have predisposed her to acute pancreatitis and contributed to adverse outcomes 7 . The abundance of confounding factors and alternative etiologies for acute pancreatitis in this case make it difficult to attribute the patient's complications exclusively to treatment with baricitinib. While one case of pancreatitis was reported in adverse events monitoring during clinical trials of baricitinib for the treatment of rheumatoid arthritis , long-term safety monitoring of up to 8.4 years has not identified additional cases 8 , which suggests that this is a rare occurrence. It was notable that the patient received substantial immunosuppression with both baricitinib and dexamethasone for treatment of COVID-19. While plausible antiviral properties of baricitinib against coronaviruses have been hypothesized 9 and confirmed in primary lung cells, this is yet to be demonstrated in humans infected with SARS-CoV2. Although speculative, it is possible that baricitinib in combination with dexamethasone without concurrent use of a proven antiviral agent, may have produced profound immunosuppression with enhanced viral replication resulting in multi-organ damage. The immunosuppressive effects of steroids are pleiotropic and mainly mediated M a n u s c r i p t by sequestration of CD4+ T lymphocytes in the reticulo-endothelial system and inhibition of gene expression for important cytokines and chemokines. In fact, the use of corticosteroids in viral infections has been fraught with controversy given the well described association with enhanced respiratory virus replication 10 . JAK1/2 inhibitors such as baricitinib are more targeted but still highly potent immunosuppressive drugs that inhibit JAK-STAT signaling thus reducing downstream production of several important inflammatory cytokines. In targeting the hyper-inflammation that is associated with severe COVID-19, timing of immunomodulatory therapy is key, and combining potent immuno-modulators requires caution to avoid tipping the balance in favor of enhanced viral replication. Ongoing clinical trials will provide much needed clarification on the appropriate timing and choice of immune-modulatory therapies in the treatment of COVID-19.

A c c e p t e d M a n u s c r i p t

COVID-19 presenting as acute pancreatitis

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

New-Onset Diabetes in Covid-19

Acute pancreatitis associated with intravenous administration of propofol: evaluation of causality in a systematic review of the literature

Acute Pancreatitis Associated with Steroid Therapy

Acute necrotising pancreatitis derived from lowdose corticosteroid use: an important reminder of clinical management

Obesity is a definitive risk factor of severity and mortality in acute pancreatitis: An updated meta-analysis

FRI0123 Safety profile of baricitinib for the treatment of rheumatoid arthritis up to 8.4 years: an updated integrated safety analysis

COVID-19: combining antiviral and antiinflammatory treatments

Glucocorticosteroids enhance replication of respiratory viruses: effect of adjuvant interferon