Demographic and Regional Trends in Acute Pancreatits Related Mortality from 1999-2020

Hiba Sohail Akhtar^1*, Araish E Dil², Saad Umer Thanvi³, Sherdil Shahzad1¹, Izhan Alam¹, Ibrahim Mohammad Khwaja¹, Muhammad Sibtain Zulfiqar⁴, Aamna Kamdi¹, Mahnoor Khan⁴, Sidra Ebrahim², Faqeeha Arif², Mirha Mohsin³ and Jawad Ahmed^5
*Correspondence: Hiba Sohail Akhtar, Department of Medicine, Dow International Medical College, Dow University of Health Sciences, Karachi, Pakistan, Email:

Keywords

Acute pancreatitis • CDC WONDER • Mortality • AAMR • BISAP

Introduction

Acute pancreatitis has seen a considerably significant rise in past several decades with worldwide incidence ranging between 50 to 80 per 100000 populations with highest yields from United States and Finland [1-5].

Recent surveys done in US demonstrated around 275,000 hospital admissions with $30,000 per person healthcare costs, which is comparable to the significant upward trends found in European and other developed countries [6].

This increase in incidence is mainly attributed to lifestyle choices that include increased intake of fatty foods, alcohol consumption and cigarette smoking. Other factors like anti diabetic drugs, family history of pancreatitis also serve as risk factors for the disease [7-10]. Previous studies demonstrated alcoholic pancreatitis as most common etiology in United states [11-14].

The global burden of mortality for acute pancreatitis has been found to be 1% with hospital deaths accounting for the 30-40% of deaths [15]. In an observational study done by Ingraham et Al. using mortality data from 10 states of United states between 2008-2015 for acute pancreatitis found out the in-hospital mortality to be 2.5% in these patients [16]. When analyzed on the basis of severity of disease previously done studies have also shown that Acute pancreatitis presenting as moderate and severe variants make total of 20% of hospitalized patients among which 20-40% have mortality as an end outcome [17,18]. This rising trend in mortality is making acute pancreatitis one of the emerging gastrointestinal disorders in past few decades with high associated mortality rates.

Multiple studies conducted over the years have concluded that the prognosis of different etiologies of acute pancreatitis vary according to geographic and socioeconomic factors and thus it is important to realize the need for analyses that take these factors in account when discussing mortality in these patients [19].

Through this trend analyses we aim to establish the demographic and geographical incidence of acute pancreatitis and subsequently of deaths occurring for the year 1999-2020 due to acute pancreatitis with subgroup analyses comparing the trends to age, gender, race, place of death and role of urbanization.

We aim to provide data that can be useful in development of more personalized treatment algorithms which will eventually be helpful as a powerful tool in revolutionizing the treatment approaches to reduce the risk and rate at which acute pancreatitis progresses to severity.

Materials and Methods

Data source

The CDC WONDER (Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research) database was used to extract the datasets utilized in this descriptive study. Deaths occurring from 1999 to 2020 within the Unites States related to acute pancreatitis were obtained from the database. The multiple cause-of-death public use record death certificates were used to analyze deaths in which acute pancreatitis was mentioned as either contributing or underlying cause of death on nationwide death certificates. Death certificates from the multiple cause-of-death public use database were reviewed to detect acute pancreatitis, which were classified as those having acute pancreatitis listed anywhere on the death certification as either a contributing or underlying cause of death. In patients 15 years of age and older, acute pancreatitis was identified using ICD-10-CM (International Classification of Diseases, Tenth Revision, Clinical Modification) (ICD-10-CM) codes K85.0- K85.3 and K85.8-K85.9. K85.0, K85.1, K85.2, K85.3, K85.8, and K85.9. Because the CDC-WONDER database contains publicly available, anonymized data, the study was exempt from local institutional review board approval.

Data extraction

Data on population size, year, death location, demographics, urban-rural categorization, region, and states were collected. Demographic information included gender, age, and race/ethnicity. The places of death included medical facilities (outpatient, emergency department, inpatient, death on arrival, or status unknown), home, hospice, and nursing home/long-term care institution. Demographic traits based on race and ethnicity included non-Hispanic White, non-Hispanic Black or African American, Hispanic or Latino, non-Hispanic American Indian or Alaskan native, and non-Hispanic Asian or Pacific Islander individuals. The age groups included were categorized into 15 to 24, 25 to 39, 40 to 54, 55 to 69, 70 to 84, and >=85 years. According to the 2013 U.S. census classification, the population was evaluated by region using the National Center for Health Statistics Urban-Rural Classification Scheme, which classified counties as urban (large metropolitan area (population >=1 million), medium/small metropolitan area population 50,000-999,999), and rural (population<50,000) [20].

Statistical analysis

We estimated crude and Age Adjusted Mortality Rates (AAMRs) per 1,000,000 populations from 1999 to 2020 to assess national trends in acute pancreatitis-related death. To calculate Crude Mortality Rates (CMR), the number of acute pancreatitis-related deaths was divided by the comparable US population of that year. The AAMRs were obtained by standardizing acute pancreatitisrelated deaths to the U.S. population in 2000. The Join point regression program (Join point V 5.0., National Cancer Institute) was used to calculate the Annual Percent Change (APC) in AAMR with a 95%confidence interval. By fitting log-linear regression models where temporal variation occurs, this technique reveals significant fluctuations in AAMR over time. APCs were considered increasing or decreasing if the slope indicating the change in mortality was substantially different from 0 using 2-tailed t testing. The statistical significance level was chosen as p value P<0.05

Results

Overall

A total of 127,588 deaths resulted from acute pancreatitis between 1999 and 2020 among the ages of 15 up to 85 and above (Supplementary Table 1). In general, there has been a decrease in the Age-Adjusted Mortality Rate (AAMR) throughout the examined period from 1999 to 2020, displaying minor fluctuations. The AAMR has declined from 12.7 in 1999 to 11.3 in 2020. Initially, there was an increase in AAMR in 2000 (12.9) and a peak in 2001 (13.8), followed by a gradual decline in subsequent years (Supplementary Table 2 and Supplementary Figure 1).

Age

Elderly individuals aged 85 and above exhibited the highest mortality rates, with an Age-Adjusted Mortality Rate (AAMR) of 119.4 in 1999, decreasing to 54.8 in 2020. Patients in the 75 to 84 age group experienced an overall decline in AAMR from 53.3 in 1999 to 30.8 in 2020. The lowest AAMR was recorded among young adults aged 15 to 24, at 0.9 in 1999, further decreasing to 0.8 in 2019 and rose to 1.1 in 2020. The annual percentage changes were analyzed and illustrated (Supplementary Table 3 and Supplementary Figures 2, 3).

Gender

In males, the overall Age-Adjusted Mortality Rate (AAMR) was almost twice as that of in females during the study period (14 in males, 8.6 in females). Males exhibited a consistent decline with minor variations during the initial period of study. The AAMR decreased from 15.3 in 1999 to 12.1 in 2019, followed by a slight increase to 14.8 in 2020. Similarly, females demonstrated a parallel trend, experiencing an overall decrease in AAMR from 10.4 in 1999 to 6.7 in 2019, and a marginal rise to 7.3 in 2020, accompanied by slight fluctuations in the trend (Supplementary Table 2 and Supplementary Figure 1).

Urbanization

Concerning urbanization, the non-metropolitan areas experienced a greater overall Age-Adjusted Mortality Rate (AAMR) compared to metropolitan areas. There was an overall decrease in the AAMR in large central metropolitan areas, declining from 11.6 in 1999 to 9.1 in 2020. In medium metropolitan areas, the AAMR initially increased from 13.4 in 1999 to 15.3 in 2001, followed by a general downward trend in subsequent years, reaching 10.1 in 2019, and then rising to 13 in 2020 (Supplementary Table 4).

For non-metropolitan areas, micropolitan regions experienced a consistent increase in AAMR, starting from 14 in 1999 and reaching the highest AAMR of 15.8 in 2008. The AAMR gradually declined to 12.1 in 2019 without significant fluctuations but rose to 13.9 in 2020. Similar patterns were observed in large fringe metropolitan, small metropolitan, and non-core areas (Supplementary Table 4 and Supplementary Figure 4).

Race

The highest Age Adjusted Mortality Rate (AAMR) over the study period was observed for non-Hispanic American Indians or Alaskan Natives (15) while the lowest overall AAMR was observed for non- Hispanic Asians or Pacific Islanders (5.4).

The AAMR for non-Hispanic white individuals experienced an initial increase from 12 in 1999 to 13.1 in 2001, followed by a gradual decline to 10 in 2019. However, slight fluctuations were observed, and the AAMR rose to 11.6 in 2020.

Non-Hispanic Asians or Pacific Islanders had an AAMR of 8.8 in 1999, which increased to 9.8 in 2000. Subsequently, there was a gradual decrease, reaching an AAMR of 3.5 in 2020.

American Indians or Alaskan natives had an AAMR of 19.3 in 1999, which decreased to 14.6 in 2019. However, the AAMR rose to 20.4 in 2020 without clear trends.

Non-Hispanic Black or African Americans exhibited an AAMR of 18.7 in 1999 and 13.2 in 2020, reflecting an overall decrease in AAMR over the years. However, the highest overall AAMR was also observed for this race.

For Hispanic/Latino individuals, the AAMR was 12.2 in 1999, decreased to 6.5 in 2019, and rose to 8.6 in 2020. The AAMR displayed an overall decreasing trend with slight variations. We have analyzed the AAMR for various races and calculates the anniual percent changes which are illustrated (Supplementary Table 5 and Supplementary Figure 5).

Place of death

About 118,845 deaths’ location was known, out of which 74.1% of the deaths occurred within medical facilities (inpatient, outpatient or ER and dead upon arrival), 11.6% deaths occurred at home, 5.8% deaths occurred in nursing homes/long-term care facilities, 2.8% occurred in hospice care, and other places included 2.2% of total deaths (Supplementary Table 6).

States and regions

Among states the highest AAMR for the given study period, was observed in Kentucky (17.2) whereas the lowest was observed in California. The overall AAMR for all the states is given in the Supplementary Table 7 and illustrated in Supplementary Figure 6.

Discussion

This study reveals a consistent increase in mortality rates with advancing age, particularly in the age groups of 75-84 and 85 above, both peaking in 2020. Conversely, the age group of 15-24 consistently maintains lower mortality rates, emphasizing a clear agerelated discrepancy. The observed difference in mortality between age groups suggests that mortality in acute pancreatitis varies with age. The elevated mortality rates among the elderly are linked to increased occurrences of deaths related to existing health conditions or prior surgical diseases, rather than being directly influenced by the presence of acute pancreatitis.

Given the aging population, there is a growing need to enhance care for older individuals facing surgical challenges, specifically related to acute pancreatitis. While conservative management suffices for most mild cases of acute pancreatitis, severe symptoms may necessitate higher levels of care and intervention. This is particularly relevant for elderly individuals who may have concurrent health conditions, such as underlying cardiovascular issues, contributing to increased incidents of morbidity and mortality in this demographic.

In one study, it was found that there is a feared increase in death in patients above 59 with this condition. Prognostic scoring systems that account for age in assessing severity and progression of acute pancreatitis include modern scales such as BISAP, Panc 3, HISAP, and JSS, as well as older measuring methods like Ranson, Glasgow, and APACHE II. The Bedside Index of Severity in Acute Pancreatitis (BISAP), for instance, evaluates the risk of inpatient mortality and takes into account the population aged >60, while Ranson's criteria assess the progression of severity in the population aged over 55.

Over the years, there has been a noticeable increase in the diagnosis and incidence of acute pancreatitis. According to the figures in SupplementaryTable 3, the overall mortality rates per 100,000 have decreased between 1999 and 2020. This unexpected decline seems to be attributed to advancements in the medical field, including improvements in ensuring timely and effective medical interventions. The ability to detect and address milder cases earlier in their course has also played a crucial role. One study found that of these mild cases, 10 to 20 percent can progress to a severe course and raise mortality.

Moreover, the quality of healthcare in both supportive and intensive care units has significantly improved, providing a more robust foundation for patient recovery. However, despite a decrease in mortality compared to initially recorded rates, disparities are present in admissions and mortality in acute pancreatitis patients. Hence, further research and investigations are required to understand these differences.

Non-Hispanic Black/African American population reported the greatest number of cases and the mortality trends were the highest among these individuals in comparison with other races. Non- Hispanic African Americans were found to be more susceptible due to genetic parameters and also higher levels of alcohol consumption was observed in African American and also Hispanics. Furthermore, American Indians/Alaskan Natives were found to have the second highest mortality trends in the United States. Asians/Pacific Islanders reported the lowest number of deaths with Acute Pancreatitis. The death rate in whites with Acute Pancreatitis was comparatively steady in our 20-year data analysis, although there was an increase in deaths from 2001-2004. This could be due to availability of better healthcare which helps in conscientious identification of the disease severity and abidance and further advances in use of medical tools like Bedside Index of Severity in Acute Pancreatitis (BISAP), Acute Physiology and Chronic Health Evaluation II (APACHE-II), CT severity index etcetera have added to the decrease in mortality rates among all individuals in the Hispanic population, acute pancreatitisrelated mortality trends have declined in the 20-year data analysis.

The comparison between the races indicated that the death trends in non-Hispanic Blacks when compared with whites or Hispanics was higher. The differences among the races could be a representation of implied bias and health care inequity towards specific races. A prior study suggested an increased death rate among the white with acute pancreatitis which makes the clinical significance of the data unclear. However, with further advancements in the field of medicines and amelioration of the health care discrepancies, decline in mortality trends can be expected among all the races.

In our nationwide study, males had a higher rate of mortality with acute pancreatitis than females. Although with risk factors (obesity, cholelithiasis, systemic lupus erythematosus, Inflammatory bowel disease) being more prevalent in females, it would have been expected for females to have a higher mortality rate. However, in a previous study, hospitalization ratio for acute pancreatitis included higher male population than female. We believe this difference accentuate the complex nature and multiple factors in development of acute pancreatitis. Smoking and alcohol consumption contributes as known risk factors for acute pancreatitis. In the US currently, 24.1% males and 15.4% females smoke as reported in a study. Males are more likely to develop alcohol-related AP, whereas females are more likely to develop cholelithiasis/gall stones-related AP as reported in a prior study. Idiopathic mortality trends were found to be similar in both the genders.

We need to consider several limitations to this kind of study. The data was collected via CDC WONDERS database which provides us data based on the information collected from death certificates which classify causes of death according to ICD-10. This can lead to misclassification of cause of death due to acute pancreatitis and its complications. Hence discrepancies can arise in actual number and the number shown in CDC WONDERS database. Secondly the database does not provide adequate knowledge about the criteria (clinical signs and symptoms, amylase/lipase levels, CT SCAN) that were used to diagnose the patients of acute pancreatitis. Third we cannot distinguish the death rate from first attack of pancreatitis from the death rate of people with recurrent attacks. It limits the accuracy with which we assign the cause of death directly affecting our results. As a consequence, disparities in AAMR over variety of demographic features and the implications of recurrent attacks cannot be highlighted. Fourth the said database lacks the knowledge of multiple comorbidities like alcoholism, triglyceride levels etc. These comorbidities are usually present and play a significant role in determining the outcome and treatment plan of acute pancreatitis. Finally, the database fails to give an insight on how the various management strategies were adopted in different cases. It hinders our ability to look into the more overall beneficial treatment options. Therefore, we cannot determine the significance of adequate treatment and prevention of the disease and its impact on the prognosis.

Conclusion

In conclusion, this study reveals an overall decline in acute pancreatitis-related mortality rates from 1999 to 2020. However, agerelated, racial, and gender-associated variations in mortalities persist. The study highlighted individuals aged >75 for being at the highest risk, with non-Hispanic Black/African Americans having the largest number of reported cases and greatest mortality rates, and an overall higher mortality rate in males. Considering the limitations in data collection, it is imperative to stress the need for comprehensive research to develop targeted interventions and improve outcomes in acute pancreatitis.

Ethical Approval

Ethical approval was not required as this study uses publicly available data.

Human Ethics

No ethics were bullied in preparation of this manuscript.

Consent for Publication

all authors read and approved final manuscript.

Availability of Supporting Data

Data included in our results is publicly available by logging into CDC Wonder Database.

Competing Interests

None.

Funding

No funding was received to assist with preparation of this manuscript.

Authors Contributions

All authors have contributed to the preparation of this manuscript. Data collection and analysis was done by Sherdil Shahzad, Izhan Alam, Ibrahim Khwaja, and Sibtain Zulfiqar. Information presented in this manuscript was written by Hiba Sohail, Saad Thanvi, Aamna Kamdi, Mahnoor Khan, Sidra Ebrahim, Araish E Dil, Faqeeha Arif, Mirha Mohsin, Jawad Ahmed, and all authors read and approved previous versions of the manuscript. Final draft was compiled by Hiba Sohail, Araish E Dil and Aamna Kamdi.

Conflict Of Interest

None of the authors have any conflicts of interest to declare.

Financial or Non-Financial Interests

None of the authors have affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials presented in this manuscript.

Acknowledgements

None.

References

1. Iannuzzi, Jordan P, James A. King, Jessica Hope Leong, and Joshua Quan, et al. "Global incidence of acute pancreatitis is increasing over time: a systematic review and meta-analysis." Gastroenterology 162 (2022): 122-134.

   [Crossref] [Google Scholar] [PubMed]

2. Xiao, Amy Y, Marianne LY Tan, Landy M. Wu, and Varsha M. Asrani, et al. "Global incidence and mortality of pancreatic diseases: A systematic review, meta-analysis, and meta-regression of population-based cohort studies." Lancet Gastroenterol Hepatol 1 (2016): 45-55.

   [Crossref] [Google Scholar] [PubMed]

3. Petrov, Maxim S, and Dhiraj Yadav. "Global epidemiology and holistic prevention of pancreatitis." Nat Rev Gastroenterol Hepatol 16 (2019): 175-184.

   [Crossref] [Google Scholar] [PubMed]

4. Gapp, Jonathan, Alexander G Hall, Ryan W Walters, and Darius Jahann, et al. "Trends and outcomes of hospitalizations related to acute pancreatitis: epidemiology from 2001 to 2014 in the United States." Pancreas 48 (2019): 548-554.

   [Crossref] [Google Scholar] [PubMed]

5. Wadhwa, Vaibhav, Soumil Patwardhan, Sushil K. Garg, and Yash Jobanputra, et al. "Health care utilization and costs associated with acute pancreatitis." Pancreas 46 (2017): 410-415.

   [Crossref] [Google Scholar] [PubMed]

6. Petrov, Maxim S, Satyanarayan Shanbhag, Mandira Chakraborty, and Anthony RJ Phillips, et al. "Organ failure and infection of pancreatic necrosis as determinants of mortality in patients with acute pancreatitis." Gastroenterology 139 (2010): 813-820.

   [Crossref] [Google Scholar] [PubMed]

7. Roberts SE, A Akbari, K Thorne, and M Atkinson, et al. "The incidence of acute pancreatitis: Impact of social deprivation, alcohol consumption, seasonal and demographic factors." Aliment Pharmacol Ther 38 (2013): 539-548.

   [Crossref] [Google Scholar] [PubMed]

8. Fan, Junjie, Ling Ding, Yingying Lu, and Junyuan Zheng, et al. "Epidemiology and etiology of acute pancreatitis in urban and suburban areas in Shanghai: A retrospective study." Gastroenterol Res Pract 2018 (2018): 1420590.

   [Crossref] [Google Scholar] [PubMed]

9. Wang, Guo-Jun, Chun-Fang Gao, Dong Wei, and Cun Wang, et al. "Acute pancreatitis: Etiology and common pathogenesis." World J Gastroenterol 15 (2009): 1427.

   [Crossref] [Google Scholar] [PubMed]

10. Sakorafas, George H, and Adelais G Tsiotou. "Etiology and pathogenesis of acute pancreatitis: current concepts." J Clin Gastroenterol 30 (2000): 343-356.

    [Crossref] [Google Scholar] [PubMed]

11. Spencer, Merianne Rose, Sally C. Curtin, and Matthew F. Garnett. "Alcohol-induced death rates in the United States, 2019–2020." NCHS Data Brief 2022 (2022): 1-8.

    [Crossref] [Google Scholar] [PubMed]

12. Li, Chang-li, Meng Jiang, Chun-qiu Pan, and Jian Li, et al. "The global, regional, and national burden of acute pancreatitis in 204 countries and territories, 1990–2019." BMC Gastroenterology 21 (2021): 1-12.

    [Crossref] [Google Scholar] [PubMed]

13. Ingraham, Nicholas E, Samantha King, Jennifer Proper, and Lianne Siegel, et al. "Morbidity and mortality trends of pancreatitis: an observational study." Surg Infect (Larchmt) 22 (2021): 1021-1030.

    [Crossref] [Google Scholar] [PubMed]

14. Schepers, Nicolien J, Olaf J Bakker, Marc G. Besselink, and Usama Ahmed Ali, et al. "Impact of characteristics of organ failure and infected necrosis on mortality in necrotising pancreatitis." Gut 68 (2019): 1044-1051.

    [Crossref] [Google Scholar] [PubMed]

15. van Santvoort, Hjalmar C, Olaf J Bakker, and Thomas L Bollen, et al. "A conservative and minimally invasive approach to necrotizing pancreatitis improves outcome." Gastroenterology 141 (2011): 1254-1263.

    [Crossref] [Google Scholar] [PubMed]

16. Ellis MP, JJ French, and RM Charnley. "Acute pancreatitis and the influence of socioeconomic deprivation." J Br Surg 96 (2009): 74-80.

    [Crossref] [Google Scholar] [PubMed]

17. Hagjer, Sumitra, and Nitesh Kumar. "Evaluation of the BISAP scoring system in prognostication of acute pancreatitis–A prospective observational study." Int J Surg 54 (2018): 76-81.

    [Crossref] [Google Scholar] [PubMed]

18. Fan ST, TK Choi, CS Lai, and J Wong. "Influence of age on the mortality from acute pancreatitis." J Br Surg 75 (1988): 463-466.

    [Crossref] [Google Scholar] [PubMed]

19. Bath, Michael F, Robin Som, Daniel Curley, and Rajab Kerwat. "Acute pancreatitis in the older patient: Is a new risk score required?" J Intensive Care Soc 22 (2021): 187-191.

    [Crossref] [Google Scholar] [PubMed]

20. Losurdo, Giuseppe, Andrea Iannone, Mariabeatrice Principi, and Michele Barone, et al. "Acute pancreatitis in elderly patients: A retrospective evaluation at hospital admission." Eur J Intern Med 30 (2016): 88-93.

    [Crossref] [Google Scholar] [PubMed]