key: cord-1003568-be2eeki7
authors: Huang, Brian Z.; Sidell, Margo A.; Wu, Bechien U.; Setiawan, V. Wendy; Chen, Zhanghua; Xiang, Anny H.
title: Pre-existing pancreatitis and elevated risks of COVID-19 severity and mortality
date: 2022-02-08
journal: Gastroenterology
DOI: 10.1053/j.gastro.2022.02.005
sha: 2b1c44934895a8008d498319080441efca171b06
doc_id: 1003568
cord_uid: be2eeki7

nan

Over the COVID-19 pandemic, there have been several case reports and studies describing acute pancreatitis as a presenting symptom or manifestation of COVID-19 disease [1] [2] [3] [4] .

The mechanisms behind these outcomes are still being investigated, but it has been hypothesized that the binding of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus to angiotension-converting enzyme 2 (ACE2) in the pancreas can lead to pancreatic injury 5 Furthermore, there is evidence that individuals with concurrent pancreatitis and COVID-19 are at elevated risk of poor outcomes. Only two small studies from Europe have compared outcomes between COVID-19 patients with and without acute pancreatitis at the time of infection 6, 7 . While both studies found that COVID-19 patients with acute pancreatitis were at higher risk of hospitalization and mortality, the analyses were rather limited due to the small sample sizes (N=300-400).

As previous studies have only investigated outcomes among individuals with pancreatitis and COVID-19 at the same time, it is currently unknown whether an existing history of pancreatitis prior to SARS-CoV-2 infection is also associated with COVID-19 severity. Thus, we performed the first study examining the relationship between pre-existing pancreatitis and COVID-19 outcomes in a large and racially/ethnically diverse retrospective cohort of COVID-19 patients from Kaiser Permanente Southern California (KPSC).

All COVID-19 patients from KPSC who received a positive SARS-CoV-2 polymerase chain reaction (PCR) laboratory test or COVID-19 diagnosis code from March 1, 2020 to February 28, 2021 were included in the study. Pancreatitis history was ascertained using ICD-9/10 codes for pancreatitis at any time prior to the COVID-19 diagnosis. Severe outcomes J o u r n a l P r e -p r o o f included COVID-related hospitalization, intensive respiratory support (IRS), and intensive care unit admission within 30 days, and mortality within 60 days.

We used logistic and Cox regression to assess the associations between pancreatitis and COVID-19 outcomes. For each outcome, we ran models for pancreatitis history (any vs. none), pancreatitis type (single episode acute, recurrent acute, chronic vs. none), and timing since last acute pancreatitis episode (>5 years, ≤5 years vs. none). For pancreatitis history, we performed subgroup analyses to assess effect modification by age group, gender, race/ethnicity, obesity, smoking, and alcohol use. Rates of all outcomes were 2-3 times higher for those with pre-existing pancreatitis compared to those without pancreatitis (Table S1 ).

Compared to those without pancreatitis, individuals with pancreatitis had an increased risk of hospitalization (OR 1.23, 95% CI 1.12-1.35) and mortality (HR 1.16, 95% CI 1.02-1.32) ( Figure 1 ). The risk of hospitalization increased with the progression of pancreatitis (OR 1.16 for single episode acute, 1.28 for recurrent acute, and 1.50 for chronic, ptrend<0.0001). For patients with acute pancreatitis, only those who had an episode within 5 years had elevated risks of hospitalization (OR 1.27, 95% CI 1.10-1.46) and mortality (HR 1.25, 95% CI 1.03-1.52). There were no associations for IRS and ICU, except for a borderline significant 50% increased risk of ICU admission (OR 1.50, 95% CI 1.00-2.27) for chronic pancreatitis (Figure 1 ).

Furthermore, we observed stronger associations between pancreatitis history and hospitalization for those aged 35-64 (OR 1.39, 95% CI 1.21-1.59) than those aged ≥65 (OR 1.10, 95% CI 0.97-1.25, pinteraction<0.01). The associations for hospitalization were also more pronounced for non-obese (OR 1.36, 95% CI 1.20-1.55) compared with obese patients (OR 1.09, 95% CI 0.95-1.25, pinteraction<0.0001). Moreover, the association between pancreatitis and mortality was significant among non-obese patients (HR 1.24, 95% CI 1.06-1.45), but not for obese patients (HR 1.00, 95% CI 0.80-1.24, pinteraction<0.01). We did not observe significant effect modification across any of the other subgroups ( Figure S1 ).

In this study of nearly 327,000 COVID-19 patients, we observed that pre-existing pancreatitis was associated with an increased risk of COVID-19-related hospitalization and mortality. Notably, the risk of hospitalization exhibited a dose-effect corresponding with more advanced forms of pancreatitis, while the positive associations for hospitalization and mortality were higher for those with acute pancreatitis episodes within the past 5 years. Taken together, these results suggest that individuals with more sustained or recent injuries to the pancreas could be at greater risk of developing severe COVID-19.

The poorer outcomes among COVID-19 patients with pancreatitis history could possibly be related to a pre-existing aggravated inflammatory condition. Past studies have shown that pancreatic acinar cells release several cytokines during acute pancreatitis, including tumor necrosis factor alpha (TNF-α), IL-6 and IL-10, while T-cells and macrophages are heavily involved in the inflammatory processes of chronic pancreatitis 8 . There is also evidence that patterns of cytokine elevations are similar during severe acute pancreatitis and severe COVID-19 disease 9 . As TNF-α, IL-6, IL-10 are involved in the cytokine storm induced by SARS-CoV-2 J o u r n a l P r e -p r o o f virus 10 , the prior activation of immune cells in the pancreatic microenvironment could perhaps increase the risk of a more severe inflammatory response during COVID-19 illness.

The key strengths of this study are the large, racially/ethnic heterogeneous cohort of COVID-19 patients and the comprehensive data from the electronic medical record. This provided us with sufficient power to evaluate pancreatitis type and timing while adjusting for several important confounders. However, we did not have information on pancreatitis etiology, nor did we have lab data on pancreatic enzymes to evaluate the severity of pancreatitis. As our cohort only included patients up to February 2021, we also could not examine the impact of COVID-19 vaccines on the association between pancreatitis and severe COVID-19.

In this first study investigating pre-existing pancreatitis and COVID-19 severity, our findings suggest that individuals with prior inflammatory insults to the pancreas could be at greater risk of hospitalization and mortality. Given the inflammation-related similarities between pancreatitis and COVID-19, future studies should evaluate the serum levels of inflammatory markers between COVID-19 patients with and without pre-existing pancreatitis to further elucidate this relationship. 

Footnote: All models are adjusted for age group, gender, race/ethnicity, income, college education, Medicaid insurance status, body mass index (BMI) category, diabetes, smoking, alcohol use, Charlson comorbidity score, and month of COVID-19 infection. Measure of association is odds ratio (OR) for hospitalization, IRS and ICU, and hazard ratio (HR) for mortality.

Supplemental Death 5006 (1.6%) 249 (5.3%) 5255 (1.6%) All patient characteristics and outcome event rates were significantly different across individuals with and without a prior history of pancreatitis (p<0.0001). 1 Any prior history of acute or chronic pancreatitis prior to COVID-19 diagnosis identified using ICD-9/10 codes (acute: 577.0, K85x; chronic: 577.1, K86.0, K86.1) 2 Within 30 days for hospitalization, IRS, and ICU; within 60 days for death. 3 Need for invasive mechanical ventilation, noninvasive ventilation, high-flow mask, or high-flow nasal cannula. 

3%) Smoking status, N (%) Current 16483 (5.1%) 269 (5.7%) 16752 (5.1%) Former

This study was supported by the National Cancer Institute (T32CA229110 and K99CA256525 to B. Z. Huang) and the National Institute of Environmental Health Sciences (3R01ES029963-01 to A. H. Xiang and Z. Chen) at the National Institutes of Health, and the Keck School of Medicine Department of Preventive Medicine COVID-19 Pandemic Research Center (CPRC) at USC.