Reply to Jorgensen, et al.

To the Editor—In response to our recent publication in Clinical Infectious Diseases, Cerda-Contreras et al present the case of a critically ill 72-year-old woman with coronavirus disease 2019 (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 severe acute respiratory syndrome coronavirus 2 (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. In addition, we also note that 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. Although 1 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. Although 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 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 hyperinflammation 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 immunomodulatory therapies in the treatment of COVID-19.