Gastrointestinal (GI), liver, and pancreatic diseases pose a substantial healthcare burden in the United States (US), accounting for more than 54 million annual ambulatory visits and about 3 million hospital admissions before the COVID-19 pandemic [1]. During the pandemic, healthcare systems have suffered from heavy burdens in response to the emerging crisis and maintaining routine care services, which might have substantial additional deaths [2, 3]. The estimated excess all-cause mortality during the pandemic was about three times higher than the reported COVID-19 deaths [4]. The measurement quantified the overall mortality burden directly caused by COVID-19 infections and that indirectly caused by the pandemic [5]. Previous evidence has indicated patients with digestive-related abnormalities were vulnerable to the pandemic, not only because of their higher mortality risk of COVID-19, but their unmet healthcare needs due to the overwhelmed healthcare services [6]. However, few studies have quantified the impact of the pandemic on individuals with digestive diseases. There is also limited research examining the excess deaths associated with digestive diseases during the pandemic.

With an in-depth understanding of SARS-CoV-2 and a significant improvement in the healthcare capacity, COVID-19 has become manageable. Although the World Health Organization (WHO) announced that COVID-19 no longer has constitutes a public health emergency of international concern (PHEIC) since May 2023, it remains an ongoing health issue that requires long-term management and preparedness [7]. However, the long-term impact of COVID-19 on patients with underlying medical conditions warrants more evaluation. As the SARS-CoV-2 will continuously circulate in the community and bring a persistent impact to the public, it is important to assess the mortality burden over a longer period to comprehend the healthcare needs among patients with the digestive-related illness.

In this study, we estimated the excess deaths associated with selected subtype digestive diseases across the multiple waves of the COVID-19 pandemic in the United States. We also compared the difference of excess deaths by age, sex, race/ethnicity and evaluated temporal patterns and regional differences.

During March 2020 and September 2022, the excess deaths of cause-specific digestive diseases have been persistently observed in the United States (Figure 1). The excess death counts were notable for GI hemorrhage (22,156, 95% CI, 21,478–22,504), ALD (17,531, 95% CI, 16,936–17,837), and fibrosis/cirrhosis (10,741, 95% CI, 9,930–11,157). Increased death risks for GI diseases were found largest for C. difficile colitis (ER 35.9%, 95% CI, 34.1%–37.8%), followed by GI hemorrhage (ER 24.8%, 95% CI, 24.0%–25.5%), ulcers (ER 15.1%, 95% CI, 13.6%–16.7%) and CRC (ER 3.4%, 95% CI, 2.9%–3.9%) (Table 1). For liver and pancreatic diseases, AP has the largest ER (20.6%, 95% CI, 18.9%–22.4%), followed by ALD (19.9%, 95% CI, 19.2%–20.6%), chronic hepatitis C (15.1%, 95% CI, 13.9%–16.3%), fibrosis/cirrhosis (8.5%, 95% CI, 7.9%–9.1%), and hepatic failure (7.1%, 95% CI, 6.4%–7.9%). The excess death estimates measured by the underlying causes of death were shown in Supplementary Table S5. The annual ERs for subtype diseases were shown in Supplementary Tables S6–S8.

The increased GI-disease related deaths were disproportionally distributed by age and race/ethnicity, but not by sex (Table 2 and Supplementary Tables S9–S11). Although the elderly population accounted for more excess death counts, younger population tended to have higher ERs of GI diseases, particularly for GI hemorrhage (38.7% in adults aged 20–64 years vs. 26.2% in adults aged 65–84 years), ulcers (23.4% vs. 9.8%), and C. difficile colitis (54.7% vs. 39.6%). Disproportional ERs were also observed in the stratification of race and ethnicity. Compared with non-Hispanic Whites, there was a 2.5 times higher ER of GI hemorrhage among Hispanics and a 1.7 times higher ER of ulcers among non-Hispanic Blacks. Also, the ER of C. difficile colitis was 49.2% (95% CI, 42.8%–55.7%) among the non-Hispanic Blacks, −0.2% (95% CI, −5.5%–5.4%) among the Hispanic inhabitants, and 37.2% (95% CI, 35.1%–39.4%) among the non-Hispanic Whites. A mild disparity was found between males and females for ERs of GI diseases.

Higher ERs of liver disease were more likely occurred in young adults, including ALD (23.0% in adults aged 20–64 years vs. 15.9% in adults aged 65–84 years), fibrosis/cirrhosis (16.0% vs. 6.8%), and hepatic failure (13.0% vs. 4.6%), but not for AP (19.7% vs. 44.4%) (Table 3 and Supplementary Tables S9–S11). There were higher excess death counts of liver diseases among the non-Hispanic Whites, while higher ERs were observed among the non-Hispanic Blacks or Hispanics. The ERs of ALD in non-Hispanic Blacks, Hispanics, and non-Hispanic Whites were 27.4%, 23.6%, and 16.8%, respectively. The ERs in Hispanics and non-Hispanic Whites were 27.1% vs. 14.0% for chronic hepatitis C, 23.6% vs. 7.2% for fibrosis/cirrhosis, and 13.4% vs. 6.7% for hepatic failure, respectively. The excess estimates for AP were more pronounced in non-Hispanic Whites and non-Hispanic Blacks than that in Hispanics. The sex disparity was observed for chronic hepatitis C (ER 23.6% in females vs. 12.4% in males).

The temporal patterns of excess digestive-related death risks were different by subtype disease. For most selected GI, liver and pancreatic diseases, the ERs were more pronounced since Wave II and highest in Wave IV (Tables 2, 3). For GI hemorrhage and fibrosis/cirrhosis, we observed fluctuating temporal trends with three clear peaks in Wave III, Wave IV, and Wave V (Figure 1 and Supplementary Figures S1, S2). For C. difficile colitis, there showed a persistently increasing trend during the pandemic. Although for ulcers, ALD, CRC, chronic hepatitis C, AP, etc., there were less varied temporal trends, excess deaths of these subtype diseases were consistently observed across different waves, even in the mild Omicron BA.2 wave (Wave VI).

The temporal variations of excess digestive-related death risks were different across regions. For GI hemorrhage, the substantial ER increase was firstly observed in the Northeast and Midwest in Wave I, then, expanded to all five regions (Figure 2). Higher ER waves were observed in the West in Wave III and Southwest in Wave II to V. During the pandemic, Missouri, Oklahoma, Texas, and Arizona were affected most for GI hemorrhage (ER range: 40.4%–49.3%) (Supplementary Tables S12–S16). For ALD, temporal fluctuations were variated across regions (Figure 3). Temporal and spatial excess risks associated with colorectal cancer, hepatic fibrosis/cirrhosis, and hepatic failure were shown in Supplementary Figures S3–S5. The major proportion of ALD excess risks occurred in Wave II to IV. Louisiana, North Carolina, Arizona, and New Mexico showed the highest increases in ERs of ALD. The stratification estimates by digestive system diseases, digestive organ malignancies, and gastrointestinal hemorrhage were shown in Supplementary Tables S17–S19. Results from sensitivity analyses showed the robustness of the estimates (Supplementary Tables S20–S25).

In this study, we provided updated evidence on excess mortality associated with GI, liver, and pancreatic diseases in the US during the nearly 3-year pandemic. We found prominent increased death risks among persons with GI hemorrhage, C. difficile colitis, ulcer, ALD, AP, chronic hepatitis C, and fibrosis/cirrhosis. Those excess deaths showed age and racial/ethnic disparities. Higher ERs were generally shown among non-Hispanic Blacks and Hispanics. We observed varied temporal patterns of excess deaths for different causes of death. The trends for GI hemorrhage and fibrosis/cirrhosis fluctuated across multiple pandemic waves, the trends for ulcers, ALD, chronic hepatitis C, AP, etc., have been persistently observed throughout the pandemic, whereas that for C. difficile colitis has continuously increased.

The increased deaths in our results included those with co-occurrence of SARS-CoV-2 infection and digestive diseases, those with impairment of digestive systems induced by SARS-CoV-2 infection, and those with underlying digestive conditions indirectly affected by the pandemic. Our study identified deaths according to the contributing causes of death listed on the death certificate (could contain a maximum of 20 causes). Since many digestive diseases are more likely to be considered as contributing factors than the underlying factors of death, our primary estimations based on the contributing causes of death could avoid underestimation and reflect the overall mortality burden among individuals with GI, liver, and pancreatic abnormalities during the COVID-19 pandemic.

Patients with underlying GI conditions are vulnerable to adverse COVID-19 outcomes [12, 13]. GI involvement has been reported among patients with COVID-19 infections with an incidence ranging from 11% to 39% [14–17]. The common GI manifestation included anorexia, nausea, vomiting, dysgeusia, and diarrhea, which could be explained by the high expression of angiotensin-converting enzyme 2 (ACE2) receptors in the gut [18]. In addition, critically ill patients with COVID-19 were more likely to develop GI complications and were associated with adverse outcomes [19, 20]. Our results showed higher ERs in GI hemorrhage and ulcer-related mortality during the pandemic. Although GI bleeding was uncommon among patients with COVID-19 [21, 22], it was one of the most prevalent GI diagnoses for emergency department visits or hospitalization before the pandemic, requiring timely endoscopic evaluation and treatments [10]. However, GI endoscopy is an aerosol-generating procedure which may facilitate virus transmission. In the early pandemic, more than 60% of endoscopy centers in the US reported an over 60% decrease in volume [23]. Such delay could lead to difficulty in localizing GI hemorrhage, which was further associated with prolonged hospitalization, increased deaths, or re-admission owing to rebleeding in patients even without SARS-CoV-2 infection [24]. In addition, GI mucosal damage, including acute musical injury and ischemic colitis, was found in COVID patients, which may aggravate ulcers and hemorrhage [25]. Also, anticoagulant use during COVID treatments may pose additional risks of GI bleeding for some patients [26].

We found the temporal fluctuation of excess deaths of GI hemorrhage. It might reflect the magnitude of overburdened healthcare services for GI patients across multiple pandemic waves. In contrast, there was a persistently increasing trend for excess deaths related to C. difficile colitis. During the SARS-CoV-2 infection, part of patients may experience changed gut microbiota composition. Frequent prescription of antibiotics to treat or prevent infections complicated with COVID also allowed opportunistic pathogens colonization, which could result in antibiotic-associated diarrhea, pseudomembranous colitis, and even systemic infections, and may further increase the risk of death [27, 28]. The findings suggest the management of GI bleeding and gut microbiota needs to adapt to the COVID-19 era.

Pre-existing chronic liver disease is more likely to experience poor outcomes of COVID due to immune dysregulation and coagulopathy. SARS-CoV-2 can provoke liver injury through systemic inflammation reaction, cytokine signaling, hypoxia ischemia-reperfusion, drug toxicity, and direct infection of hepatocytes [29], which might contribute to an increased death risk among patients with the chronic liver disease [30, 31]. The excess mortality estimates during the pandemic could be an integrated impact of changes in virus virulence, treatment modality, healthcare capacity, vaccination, infection control strategies, chronic disease management, and personal factors (such as hesitation in seeking medication, changed physical activity behavior, dietary intake, and income, etc.). We found the ER of liver-related diseases was predominant in young adults, which were 1.4 times, 2.4 times and 2.8 times higher for ALD, fibrosis/cirrhosis and hepatic failure in young adults than those in older adults, respectively. The reason could be that the pandemic disproportionately affected the lives of individuals. The higher ER of ALD was associated with increased alcohol overconsumption, which was more likely to occur in young adults [32]. Social isolation and difficulty in accessing regular medical care resources might bring additional challenges to patients with chronic liver diseases accessing affordable healthy food since they were advised to keep low-salt diets or other special dietary modifications [33]. Loss of jobs or insurance among those patients could also disrupt their routine costly medications. Those factors may lead to worsening malnutrition, frailty, and other poor outcomes. Substantial stress from social and economic uncertainty can also lead to psychological decompensation and 10%–19% increased drinking compared with the pre-pandemic period [34].

Limited studies reported the difference in GI, liver, and pancreatic cancer-related mortality before and during the pandemic, although there was an evident interruption in cancer management. A global study reported an overall 44.9% decline in the volume of CRC screening [35]. About 10% of patients reported their postponed curative surgery due to a COVID-related reason [36]. Moreover, GI cancer patients after operation might be at a high risk of death if infected with SARS-CoV-2 [37]. Therefore, it is crucial to comprehensively evaluate both risks and benefits of postponing or canceling elective surgery during the pandemic. Although there could be a growing mortality risk among patients with undetected cancer or postponed surgery, we did not observe such excess deaths for GI, liver, or pancreatic cancer so far. Nevertheless, continually monitoring the mortality is important for healthcare authorities to make a timely intervention in response to changing situations.

With substantial population recovering from COVID-19, the long-term impact of COVID-19 is raising the concern. Although fatal sequelae of the GI system were not reported in COVID-19 survivors, there were increased risks of GI disorders, dysphagia and abdominal pain with hazard ratios varied from 2.8 to 6.9 [38]. In addition, malnutrition remained at 54% and 32% among patients with distinct GI manifestations at 3- and 6-month of follow-up, respectively [39]. The readmission rate of AP after 1 year of recovery from COVID-19 was about 14%, most of whom were due to alcohol-related or gallstone pancreatitis [40]. Our study observed persistent excess deaths related to the GI system and an increasing trend for C. difficile colitis during the pandemic. The trends are likely to remain even after WHO announced the end of PHEIC. However, our results cannot distinguish the cause of death from the acute or post-acute stage. Further studies are warranted to understand the long-term impact of COVID-19 on the digestive system. As we will live with SARS-CoV-2, sustainable healthcare policy and resources are needed to meet the “new normal.”