Rising Mortality and Demographic Disparities in Infectious and Parasitic Diseases in the United States, 1999–2023: A Comprehensive CDC WONDER Analysis

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A comprehensive analysis of their mortality trends, particularly across demographic and geographic subgroups in the United States, is crucial for informing targeted public health interventions. Methods: This national population-based study utilized CDC WONDER mortality data from 1999 to 2023. Age-adjusted mortality rates (AAMRs) per 100,000 were calculated for deaths with an underlying cause of ICD-10 codes A00-B99. Trends were analyzed using Join point regression to compute annual percent change (APC) and average annual percent change (AAPC). Results: From 1999 to 2023, mortality from infectious and parasitic diseases in the United States exhibited a complex trend, characterized by an overall non-significant change (AAPC: 0.0282). This period masked a dramatic surge between 2018 and 2021, with a significant annual increase of 8.92%, followed by an equally sharp decline of 10.27% from 2021 to 2023. The analysis revealed profound disparities, with consistently higher mortality rates among males, significant increases among Non-Hispanic White individuals, and a critical divergence where rural areas experienced a marked rise in mortality compared to urban areas. Geographically, the South and Mid-Atlantic regions bore the highest burden, and the elderly population was disproportionately affected, with the vast majority of deaths occurring in inpatient medical facilities. Conclusion: Analysis of U.S. mortality data from CDC WONDER (1999–2023) reveals that infectious and parasitic disease mortality remained stable over two decades but was sharply interrupted by a significant peak around 2020–2021, largely attributable to the COVID-19 pandemic and health-system disruptions. Demographic and geographic disparities persisted, with higher mortality among males, older adults, and non-metropolitan populations. Racial trends showed long-term improvements among several non-White groups, though increases were observed among non-Hispanic White and rural populations, coinciding with the opioid and injection-drug use epidemic. Post-2021 declines followed vaccine rollout and health-service recovery, yet inequities remain. Urgent actions—including enhanced surveillance, harm reduction, and equitable healthcare strengthening—are needed to reduce future mortality. Bacteriology Parasitology Epidemiology Infectious diseases Parasitic diseases CDC WONDER Mortality trends United States Cross-sectional study Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Introduction Infectious diseases are a broad category of illnesses caused by pathogenic organisms, including bacteria, viruses, fungi and parasites(1)These diseases develop when pathogenic microorganisms enter the body, invade the host immune system, proliferate, and disrupt regular physiological response (2), so parasitic infections are a type of infectious disease specifically caused by parasites that live on or inside a host and take its nutrition from host (3). Infectious diseases are illnesses that can be transmitted from one person, animal or environment to another. Its transmission depends on either direct physical contact with the affected person, consumption of contaminated food or water, bites from insects or other vectors or from contaminated airborne particle’s inhalation (4). These infectious diseases are most common in tropical and subtropical regions because of poor sanitation, hygiene and access to clean water are limited in these areas which favors the quick transmission of infections (5). People living in tropical regions usually lack knowledge and comprehension of how to prevent infectious diseases. The main reason behind this is poor public awareness campaigns, limited access to medical resources and insufficient health education (6) The overall global occurrence of parasitic infections is approximated to affect around 3.5 billion people worldwide, with about 450 million among them shows symptoms (7). Around 129 million people in the U.S visit physician offices daily yearly, because of infectious and parasitic diseases (8). More than 300,000 people in the U.S. are infected with a parasite that causes chagas disease (9). Although many studies have examined prevalence of infectious and parasitic infections but effect of demographic variations among them is still underexplored, which is crucial to know the severity and cause of infection and help in timely care and also help in controlling infectious and parasitic diseases globally. This retrospective observational study has been reported in accordance with the STROCSS 2025 guidelines. Methods Study design and cohort Material and Methods This study employed the CDC WONDER Multiple Cause of Death database spanning the years 1999 to 2023, which comprises publicly accessible, de-identified mortality data from the United States, as derived from death certificates. This study examines infectious and parasitic diseases related to death among individuals from 1999-2023. Infectious diseases mortality was identified using ICD-10 codes A00-B99. Institutional review board approval was not required since the data was anonymous and publicly accessible. Mortality data were derived from death certificates compiled across all 50 states and the district of Columbia. The study design and reporting followed the STROBE guidelines for observational research. Data Extraction The data were stratified based on age, sex, race/ethnicity, states, U.S. census region and the 2013 National Center for Health Statistics Urban-Rural Classification Scheme. Metropolitan areas were Urban areas while non-metropolitan areas were defined as rural areas. Race factors were also considered including Hispanics or Latino, Africans, American-India, Asians and White. The records which were missing demographic or regional identifiers were excluded from subgroup analysis in order to preserve data accuracy. Statistical analysis Standardized to the U.S. population in 2000, age-adjusted mortality rates were computed per 100,000 population. We used Joinpoint regression analysis to assess trends in infectious and parasitic diseases mortality among individuals. 95% Cis and annual percent change (APC) were calculated, and permutation testing was used to determine statistical significance. In order to guarantee that the most recent mortality records were included, all analyses were completed in September 2025. Results Overall Trends A total of 5,740,282 deaths from infectious and parasitic diseases were recorded in the United States from 1999 to 2023. The overall AAMR fluctuated from 65.0 in 1999 to 67.0 in 2023. Joinpoint regression software identified three distinct segments. Between 1999 and 2018, there was a non-significant decrease in AAMR (APC: -0.172; 95% CI: -0.3703 to 0.0268; p = 0.085464). Subsequently, there was a significant increase from 2018 to 2021, as AAMRs increased from 65.0 to 85.1 (APC: 8.9189*; 95% CI: 3.6581 to 14.4467; p = 0.002021). Finally, from 2021 to 2023, there was a significant decrease, as AAMRs declined from 85.1 to 67.0 (APC: -10.2743*; 95% CI: -14.4955 to -5.8448; p = 0.000187). Overall, the AAPC demonstrated a non-significant change in mortality (AAPC: 0.0282; 95% CI: -0.6703 to 0.7316; p = 0.937112) Figure.1 (Supplementary Table Trends by Sex During the study period, a total of 2,954,657 male and 2,785,625 female deaths were attributed to infectious and parasitic diseases. Mortality in males decreased non-significantly from 78.2 (95% CI: 77.7–78.7) in 1999 to 78.6 (95% CI: 78.2–79.0) in 2023. Joinpoint analysis identified three distinct segments: from 1999 to 2018, there was a significant decline (APC: -0.3349*; 95% CI: -0.4259 to -0.0436; p = 0.019074); this was followed by a significant increase from 2018 to 2021 (APC: 9.6449*; 95% CI: -4.2278 to 15.3436; p = 0.001379); and finally, a significant decrease from 2021 to 2023 (APC: -11.1570*; 95% CI: -15.461 to -6.6339; p = 0.000104). The AAPC demonstrated a non-significant decline in male mortality (AAPC: -0.0211; 95% CI: -0.7352 to 0.6982; p = 0.954063). Similarly, in females, mortality also showed a non-significant change from 54.8 (95% CI: 54.4–55.1) in 1999 to 57.7 (95% CI: 57.3–58.0) in 2023. The analysis revealed three segments: a non-significant change from 1999 to 2018 (APC: -0.0356; 95% CI: -0.1867 to 0.1157; p = 0.525884); a significant increase from 2018 to 2021 (APC: 7.8269*; 95% CI: 2.6369 to 13.7793; p = 0.004994); and a significant decrease from 2021 to 2023 (APC: -8.9047*; 95% CI: -13.1022 to -4.4846; p = 0.000666). The AAPC for females demonstrated a non-significant change (AAPC: 0.1367; 95% CI: -0.5511 to 0.8292; p = 0.697724). Overall, mortality was consistently higher in males than in females Figure.1 (Supplementary Table S1B). Trends by Race/Ethnicity Mortality trends differed among racial and ethnic groups. Non-Hispanic (NH) Black or African American individuals exhibited the highest mortality rates, followed by American Indian or Alaska Native and Hispanic or Latino populations, while NH Asian or Pacific Islander individuals had the lowest mortality rates. Among NH Whites, the age-adjusted mortality rate significantly increased from 55.3 (95% CI: 55.0–55.6) in 1999 to 64.8 (95% CI: 64.5–65.0) in 2023, indicating a significant overall increase (APC/AAPC = 0.8977*; 95% CI: 0.5198 to 1.2777; p < 0.001). NH Black and African Americans experienced a significant decrease from 141.0 (95% CI: 139.5–142.5) in 1999 to 99.3 (95% CI: 98.3–100.3) in 2023 (APC/AAPC = -1.5924*; 95% CI: -2.5563 to -0.6189; p = 0.001393). Hispanic and Latino population exhibited a significant decreasing trend, with AAMRs 72.7 (95% CI: 71.2–74.1) in 1999 and 60.2 (95% CI: 59.4–60.9) in 2023 (APC/AAPC = -0.9447*; 95% CI: -1.4764 to -0.4101; p = 0.000547). For NH Asian and Pacific Islander individuals, AAMR declined significantly from 51.3 (95% CI: 49.4–53.1) in 1999 to 42.6 (95% CI: 41.7–43.4) in 2023 (APC/AAPC = -0.7691*; 95% CI: -1.4202 to -0.1138; p = 0.02151). The trend for American Indian or Alaska Native individuals was non-significant, with AAMRs of 78.5 (95% CI: 73.2–83.7) in 1999 and 96.2 (95% CI: 92.4–100.1) in 2023 (APC/AAPC = 1.0026; 95% CI: -0.1701 to 2.189; p = 0.094083) Figure.2 (Supplementary Table S2A). Trends by States Across the United States, state-level AAMRs showed notable geographic differences. The greatest AAMRs were seen in the states of District of Columbia 134.7 (95% CI: 132.7–136.7), Louisiana 86.7 (95% CI: 86.1–87.3), and Mississippi 86.7 (95% CI: 86.0–87.4). Numerous other states such as Maryland 80.4 (95% CI: 79.9–80.9), West Virginia 80.2 (95% CI: 79.4–81.0), and South Carolina 80.8 (95% CI: 80.3–81.4) reported relatively elevated rates. In contrast, the lowest AAMRs were seen in the states of Minnesota 40.2 (95% CI: 39.8–40.5), Idaho 44.2 (95% CI: 43.5–44.9), and Wisconsin 44.2 (95% CI: 43.9–44.6). Mortality rates were generally elevated in the South and Mid-Atlantic regions, whereas northern and western regions like Minnesota, Idaho, and Hawaii saw reduced rates. This pattern highlights substantial geographic disparities in infectious and parasitic disease mortality throughout the United States Figure.3 (Supplementary Table S6). Trends by Census Regions Between 1999 and 2023, AAMR trends categorized by U.S. census regions demonstrated varied patterns. In the Northeast, the AAMR decreased from 71.2 (95% CI: 70.5–71.9) in 1999 to 62.5 (95% CI: 61.9–63.1) in 2023. Joinpoint analysis identified three segments: a significant decline from 1999 to 2018 (APC: -1.0471*; 95% CI: -1.2381 to -0.8559; p < 0.001), a non-significant increase from 2018 to 2021 (APC: 6.4461; 95% CI: -0.2015 to 13.5365; p = 0.056783), and a significant decrease from 2021 to 2023 (APC: -7.0586*; 95% CI: -12.7371 to -1.0106; p = 0.025427), resulting in an overall non-significant decline (AAPC: -0.6603; 95% CI: -1.5553 to 0.2428; p = 0.15136). The Midwest exhibited a different trend, increasing from 56.1 (95% CI: 55.5–56.7) in 1999 to 63.3 (95% CI: 62.8–63.8) in 2023. This included a significant increase from 1999 to 2018 (APC: 0.3252*; 95% CI: 0.1556 to 0.495; p = 0.000835), a significant increase from 2018 to 2021 (APC: 9.1488*; 95% CI: 3.6905 to 14.8944; p = 0.002208), and a significant decrease from 2021 to 2023 (APC: -9.9327*; 95% CI: -14.344 to -5.2942; p = 0.000395), resulting in an overall non-significant increase (AAPC: 0.4807; 95% CI: -0.2423 to 1.2089; p = 0.193118). In the South, mortality rates showed a non-significant change from 72.8 (95% CI: 72.2–73.3) in 1999 to 73.1 (95% CI: 72.6–73.5) in 2023, characterized by a non-significant change from 1999 to 2018 (APC: -0.1722; 95% CI: -0.4183 to 0.0745; p = 0.158969), a significant increase from 2018 to 2021 (APC: 9.2380*; 95% CI: 2.4224 to 16.5072; p = 0.010097), and a significant decrease from 2021 to 2023 (APC: -11.2995*; 95% CI: -16.7589 to -5.482; p = 0.000963), resulting in an overall non-significant change (AAPC: -0.0312; 95% CI: -0.9402 to 0.8862; p = 0.946674). In the West, the age-adjusted mortality rate increased from 55.2 (95% CI: 54.6–55.8) in 1999 to 63.6 (95% CI: 63.1–64.1) in 2023. This included a significant increase from 1999 to 2018 (APC: 0.4438*; 95% CI: 0.3091 to 0.5786; p < 0.001), a significant increase from 2018 to 2021 (APC: 7.2738*; 95% CI: 2.7833 to 11.9605; p = 0.002965), and a significant decrease from 2021 to 2023 (APC: -8.0847*; 95% CI: -11.6907 to -4.3313; p = 0.000356), resulting in an overall non-significant increase (AAPC: 0.5271; 95% CI: -0.0678 to 1.1255; p = 0.082584) Figure.4 (Supplementary Table S5A) Trends by Urbanization There were notable differences in mortality trends between metropolitan (urban) and non-metropolitan (rural) populations. AAMRs became substantially elevated in non-metropolitan regions compared to metropolitan areas over time. In 1999, rates were 66.7 (95% CI: 66.3–67.0) in metropolitan areas and 56.9 (95% CI: 56.3–57.6) in non-metropolitan areas, but by 2020 rates had increased to 73.0 (95% CI: 72.7–73.3) in metropolitan areas and 82.9 (95% CI: 82.2–83.7) in non-metropolitan areas. Metropolitan areas experienced a non-significant change in AAMR from 1999 to 2020 (APC/AAPC: -0.0028; 95% CI: -0.3746 to 0.3704; p = 0.987806). In contrast, non-metropolitan regions exhibited a significant increase from 56.9 (95% CI: 56.3–57.6) in 1999 to 82.9 (95% CI: 82.2–83.7) in 2020, with a significant overall increase (APC/AAPC: 1.4731*; 95% CI: 1.2382 to 1.7085; p < 0.001) Figure.5 (Supplementary Table S4A). Trends by Age Groups A distinct age-related gradient in mortality was revealed by age-specific analysis. The rates of mortality increased significantly with age, reaching their highest point among older adults aged 65-85+ years, followed by those aged 45-64 years; infants and young children aged 0-4 years had the lowest mortality rate. In 1999, AAMRs were 346.9 (95% CI: 344.9–348.9) for individuals aged 65-85+ years, 60.6 (95% CI: 60.0–61.2) for those aged 45-64 years and 9.2 (95% CI: 8.8–9.7) for infants and young children aged 0-4 years. By 2023, rates had changed to 371.7 in older adults, exhibiting a non-significant increase (APC/AAPC: 0.2666; 95% CI: -0.3974 to 0.9351; p = 0.432215); mortality rates for adults aged 45-64 years showed a non-significant change to 66.7 (APC/AAPC: 0.0824; 95% CI: -0.8073 to 0.9801; p = 0.856534). Among all age groups, the 5-24 year age group exhibited the most pronounced decrease, with a significant overall decrease in AAMR to 1.8 (APC/AAPC: -1.0786*; 95% CI: -1.8348 to -0.3167; p = 0.006604). The 25-44 years age group also showed a significant overall decline (APC/AAPC: -2.0817*; 95% CI: -3.3147 to -0.8329; p = 0.00114), while the 0-4 years age group showed a non-significant change (APC/AAPC: -0.0983; 95% CI: -1.0223 to 0.8343; p = 0.835662) Figure.6 (Supplementary Table S3A). Trends by Places of Death Analysis by place of death revealed the majority of the patients died in medical facilities. Inpatient settings constituted 75.20% of total mortalities, followed by deaths in nursing homes/long term care at 8.50% and at decedent’s home at 7.10%. Hospice facilities accounted for 3.80%, outpatients or emergency rooms for 3.30% and other or unknown sites for less than 4% collectively Figure.7 (Supplementary Table S7). Discussion This study explains national mortality patterns in the United-States for infectious and parasitic diseases from 1999–2023, retrieved from CDC Wonder. Our findings reveal an overall plateau in these mortality trends over the last two decades with rates remaining substantially high, punctuated by a sharp elevation beginning in the late 2010s, peaking around 2020–2021, and followed by a marked decline thereafter. This fluctuation interrupts an otherwise gradual long-term stabilization, suggesting the influence of episodic but powerful determinants such as emerging pathogens, health-system disruptions, and behavioral epidemics. The demographic profile reveals continued male dominance, steep age gradients, and increasing rural–urban and regional disparities, while racial and ethnic trends reflect both continued advances and emerging vulnerabilities. During the 1999–2023 period, CDC WONDER–based analysis indicates long-term stability in infectious and parasitic diseases associated with deaths punctuated by a clear peak in the late 2010s into 2021 followed by a subsequent decline. The timing and form of that peak are best explained by the direct and indirect effects of the COVID-19 pandemic along with contemporaneous deterioration of other infection drivers. Several excess-mortality analyses find that the pandemic resulted in a significant short-term increase in deaths both directly due to SARS-CoV-2 and indirectly due to health-system burden, delayed treatment and social disruption; they temporally coincide with the increase seen and with the fall that followed as vaccines, treatments and revived access alleviated COVID pressure 10 – 13 . Healthcare disruption during the pandemic years also overlapped with quantifiable decline in antimicrobial resistance monitoring and infection-prevention capability, which likely increased death due to bacterial and healthcare-associated infections over the same years 14 , 15 . Sex, race/ethnicity and place-based patterns are suggestive of layered, interacting mechanisms. The greater elevation among males in the late-decade period is consistent with higher documented COVID case-fatality in men and with elevated baseline prevalence of injection-related complications and other behavioral risks in men; sex-specific immune responses and exposure profiles are corroborated by meta-analytic data 16 , 17 . Racial trends show declining mortality rates among various non-White groups throughout the long sequence, but a net gain for non-Hispanic Whites. These findings coincide with two partially independent mechanisms. First, prolonged public-health improvements (wider HIV and hepatitis C diagnosis/treatment, selective community interventions) were responsible for stepwise declines in some groups over several years. Second, the late-decade increase among some White and non-metropolitan groups mirrors the demographic and geographic profile of the opioid epidemic and accompanying injection-related bacterial infections; multiple epidemiologic accounts attribute burgeoning injection drug use to rising endocarditis, severe skin/soft-tissue infection, and bloodstream infection in young and rural groups 18 – 21 . These concurrent trends account for why certain racial/ethnic groups saw net improvement as the overall series registers a pandemic-era peak. Geographic heterogeneity is also seen in terms of increased burdens in Southern and selected Mid-Atlantic states and increasing non-metropolitan mortality. These findings mirror social determinants (poverty, restricted access to specialists, and capacity for long-term care) and regional differences in the harms of substance use. Rural locales, with restrictive harm-reduction services and fewer treatment capacities, have been reported as especially exposed to injection-related infectious complications and pandemic shocks, as seen in rural elevations 19 , 22 – 24 . Gradients by age continue to be steep: the oldest maintained the greatest mortality and were hit hardest in pandemic waves from immunosenescence, multimorbidity, and clustered outbreaks in congregate care, while other younger age groups overall experienced declines across many causes in the long term but also saw temporary peaks that correspond to substance-use–related infections and secondary pandemic harms 16 , 25 . Collectively, our study and literature points to late-decade rise in infectious-disease mortality as a convergence of high COVID-19 death and excess death due to similar causes, pandemic-induced care disruption and infection-control failures that exacerbated antimicrobial drug resistance and healthcare-associated infections, and increasing injection-drug–associated bacterial disease in certain demographic and geographic niches. Post-2021 downturn is conceivably explained by increasing population immunity, vaccine/therapeutic coverage and partial recovery of health services, but lingering and unequal burdens persist—especially in rural settings, among some racial/ethnic populations and among individuals impacted by substance use—highlighting the importance of equitable surveillance, scaling-up harm reduction, antimicrobial stewardship and augmenting long-term care protections 10 – 15 , 18 – 24 . Immediate interventions are needed to improve mortality status associated with infectious diseases. Increasing viral and bacterial early-warning surveillance, harm-reduction and treatment capacity in rural and underserved communities, prioritizing antimicrobial stewardship, and augmenting infection-prevention capacity in long-term care and acute-care facilities could help in reducing overall mortality. Data-driven, equity-based policy responses will be needed to overcome geographic and demographic inequities and to enhance resilience for impending public-health shocks. These interventions should become a part of broader national strategies to reduce mortality burden associated with infectious and parasitic diseases. Study limitations This study is based on death-certificate coding in CDC WONDER; because attribution can be confounded by coding conventions and by pandemic-period shifts in recording practice regarding COVID and related conditions. Ecological design does not have direct co morbidity, socioeconomic status, local health-system capacity, or cause-specific clinical information (e.g., endocarditis vs. pneumonia vs. septicemia); temporal changes observed may partially represent surveillance or coding artifacts rather than genuine exposure or risk change, 10,14,18 .However, this descriptive approach has been utilized in previously published studies using CDC WONDER database and aligns with the established epidemiologic reporting practices, as the use of national data ensures robust generalizability. Conclusion Our CDC WONDER analysis study on mortality trends associated with infectious and parasitic diseases in the United States during 1999–2023 shows long-term stability in the trends with substantially high rates punctuated by an abrupt rise between 2018 and 2021, followed by a substantial drop. Mortality was consistently higher among males than females over the years, and the greatest burden was in the elderly ≥ 65 years of age. Non-Hispanic Black groups had the highest death rates, but with a downward trend over the long term, and non-Hispanic Whites had a steady upward trend. Consistently higher mortality rates were observed in the South, Mid-Atlantic, and areas of the Midwest. Non-metropolitan areas had much higher and increasing mortality than metropolitan counties. These trends highlight that deaths due to infectious and parasitic diseases continue to be clustered in socially and structurally disadvantaged groups. The pandemic-era peak further highlights the shortcomings in healthcare access, infection detection, and antimicrobial stewardship. Sustained substantial reduction in overall mortality would require strengthening prevention measures especially in rural and high-burden states, guaranteeing equalized healthcare access along racial and geographic lines and integrating harm-reduction and antimicrobial-resistance measures into national infectious disease control policy. 10–15,18–24 .Overall, this study provides the latest up to date picture for U.S national mortality trends of infectious and parasitic diseases, highlighting persistent inequalities and post pandemic trajectory. References Waheed Y (2024) Clinical Aspects of Infectious Diseases. J Clin Med 13(16):4853 Ahmed F, Saadi A (2025) Types and Harms of Pathogenic Microorganisms: A Review. Int J Pathol Biomarkers 1(1):32–50 Wang Y Introduction to parasitic disease. InRadiology of parasitic diseases: a practical approach 2016 Nov 29 (pp. 3–3). Dordrecht: Springer Netherlands Busenberg S, Cooke K (2012) Vertically transmitted diseases: models and dynamics. 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Asghar","email":"data:image/png;base64,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","orcid":"https://orcid.org/0009-0004-0504-9142","institution":"Khyber Medical College","correspondingAuthor":true,"prefix":"","firstName":"Palwasha","middleName":"","lastName":"Asghar","suffix":""},{"id":631188900,"identity":"a5dd3443-4cbf-4b74-974b-23d90a8e255f","order_by":1,"name":"Hadi Ul Hassan","email":"","orcid":"","institution":"DeZhejiang University, School of Medicine, Hangzhou, China","correspondingAuthor":false,"prefix":"","firstName":"Hadi","middleName":"Ul","lastName":"Hassan","suffix":""},{"id":631188902,"identity":"5eb77071-ec3d-44ce-bcd0-3523d04f3766","order_by":2,"name":"Taha Bin Nayyar","email":"","orcid":"","institution":"DeZhejiang University, School of Medicine, Hangzhou, China","correspondingAuthor":false,"prefix":"","firstName":"Taha","middleName":"Bin","lastName":"Nayyar","suffix":""},{"id":631188920,"identity":"55735e69-fb46-4067-84ea-e37ebbd50abc","order_by":3,"name":"Savera Ejaz Ahmed","email":"","orcid":"","institution":"DepartShaheed Mohtarma Benazir Bhutto Medical College Liyari, Karachi, Pakistan","correspondingAuthor":false,"prefix":"","firstName":"Savera","middleName":"Ejaz","lastName":"Ahmed","suffix":""},{"id":631188921,"identity":"92755a65-2331-4ef1-9969-4ce9b53b1ae9","order_by":4,"name":"Alysha Khaliq","email":"","orcid":"","institution":"Rawalpindi Medical University, Tipu Rd, Chamanzar Colony, Rawalpindi","correspondingAuthor":false,"prefix":"","firstName":"Alysha","middleName":"","lastName":"Khaliq","suffix":""},{"id":631188923,"identity":"bca7cde5-dcb8-4008-82e6-aec714b17511","order_by":5,"name":"Fizzah Ikram Ul Haq","email":"","orcid":"","institution":"Allama Iqbal Medical College, Lahore, Pakistan","correspondingAuthor":false,"prefix":"","firstName":"Fizzah","middleName":"Ikram Ul","lastName":"Haq","suffix":""},{"id":631188940,"identity":"b6fdf6f0-7647-4c29-a1f8-777d730612ca","order_by":6,"name":"Abeer","email":"","orcid":"","institution":"DepaShaheed Mohtarma Benazir Bhutto Medical College Liyari, Karachi, Pakistan","correspondingAuthor":false,"prefix":"","firstName":"","middleName":"","lastName":"Abeer","suffix":""},{"id":631188941,"identity":"e4c338ae-31a6-42bf-acdf-2959f2e23b69","order_by":7,"name":"Muhammad Haris Khan","email":"","orcid":"","institution":"DepartmenSaidu Medical College, Swat, 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2023.\u003c/p\u003e","description":"","filename":"image1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-9555964/v1/229fccdb2c93c18e1c3ae6ac.jpeg"},{"id":108182592,"identity":"c0d93c31-3eb2-46e0-9fd0-a29e285e0368","added_by":"auto","created_at":"2026-04-30 08:59:26","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":287951,"visible":true,"origin":"","legend":"\u003cp\u003eRace-based Trends of Age-Adjusted Mortality Rates per 100,000 for infectious and parasitic diseases in the United States from 1999–2023\u003cstrong\u003e.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"image2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-9555964/v1/569f85b17402fd22c9cf7986.jpeg"},{"id":108090285,"identity":"4757bbd9-721a-44d2-aa63-6841cd406fd8","added_by":"auto","created_at":"2026-04-29 09:12:33","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":104616,"visible":true,"origin":"","legend":"\u003cp\u003eMap Chart of Age-Adjusted Mortality Rates per 100,000 for infectious and parasitic diseases in the United States from 1999–2020.\u003c/p\u003e","description":"","filename":"image3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-9555964/v1/f5bc0d24b1196499149f8d58.jpeg"},{"id":108090286,"identity":"c54715dd-34a5-499f-9f03-a71a6d75c67a","added_by":"auto","created_at":"2026-04-29 09:12:33","extension":"jpeg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":283226,"visible":true,"origin":"","legend":"\u003cp\u003eRegional Trends of Age-Adjusted Mortality Rates per 100,000 for infectious and parasitic diseases in the United States from 1999–2023.\u003c/p\u003e","description":"","filename":"image4.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-9555964/v1/1aa4bc851952f6c1c50249c3.jpeg"},{"id":108090287,"identity":"1bb0fafc-16fd-42e5-b0cd-413843213a6b","added_by":"auto","created_at":"2026-04-29 09:12:33","extension":"jpeg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":154287,"visible":true,"origin":"","legend":"\u003cp\u003eUrbanization based Trends of Age-Adjusted Mortality Rates per 100,000 for infectious and parasitic diseases in the United States from 1999–2020.\u003c/p\u003e","description":"","filename":"image5.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-9555964/v1/edab6dcfa19925f5383cd06c.jpeg"},{"id":108491025,"identity":"00de3357-ff32-4382-b568-3aa799b0a6db","added_by":"auto","created_at":"2026-05-05 09:51:19","extension":"jpeg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":286867,"visible":true,"origin":"","legend":"\u003cp\u003eAge-group based Trends of Age-Adjusted Mortality Rates per 100,000 for infectious and parasitic diseases in the United States from 1999–2023.\u003c/p\u003e","description":"","filename":"image6.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-9555964/v1/610ba261c4cc921291f8c426.jpeg"},{"id":108182439,"identity":"d1d3b180-0bbc-42d3-8de9-0b39362043a8","added_by":"auto","created_at":"2026-04-30 08:59:22","extension":"jpeg","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":107110,"visible":true,"origin":"","legend":"\u003cp\u003eMortality by place of death for infectious and parasitic diseases in the U.S from 1999-2023.\u003c/p\u003e","description":"","filename":"image7.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-9555964/v1/e57853647a03e9d386334c67.jpeg"},{"id":108090289,"identity":"3d5a443a-41e6-4931-8315-4a748483b75c","added_by":"auto","created_at":"2026-04-29 09:12:33","extension":"jpeg","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":690713,"visible":true,"origin":"","legend":"\u003cp\u003eCentral Illustration\u003c/p\u003e","description":"","filename":"image8.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-9555964/v1/1cbd3ed57cfd823a522e92c2.jpeg"},{"id":108494802,"identity":"1172a688-90c5-42c0-a95e-55f1cdf31721","added_by":"auto","created_at":"2026-05-05 10:07:26","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2333723,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9555964/v1/d8d57a95-cdd1-44b0-95a1-0f0ffe74a43b.pdf"},{"id":108090282,"identity":"57f955c3-462a-40f4-b7ff-cbbc91b6a281","added_by":"auto","created_at":"2026-04-29 09:12:33","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":69701,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary Tables\u003c/p\u003e","description":"","filename":"Supptable2.docx","url":"https://assets-eu.researchsquare.com/files/rs-9555964/v1/ec4f10b0805fadfdd345a376.docx"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eRising Mortality and Demographic Disparities in Infectious and Parasitic Diseases in the United States, 1999–2023: A Comprehensive CDC WONDER Analysis\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eInfectious diseases are a broad category of illnesses caused by pathogenic organisms, including bacteria, viruses, fungi and parasites(1)These diseases develop when pathogenic microorganisms enter the body, invade the host immune system, proliferate, and disrupt regular physiological response (2), so parasitic infections are a type of infectious disease specifically caused by parasites that live on or inside a host and take its nutrition from host (3). Infectious diseases are illnesses that can be transmitted from one person, animal or environment to another. Its transmission depends on either direct physical contact with the affected person, consumption of contaminated food or water, bites from insects or other vectors or from contaminated airborne particle\u0026rsquo;s inhalation (4).\u003c/p\u003e \u003cp\u003eThese infectious diseases are most common in tropical and subtropical regions because of poor sanitation, hygiene and access to clean water are limited in these areas which favors the quick transmission of infections (5). People living in tropical regions usually lack knowledge and comprehension of how to prevent infectious diseases. The main reason behind this is poor public awareness campaigns, limited access to medical resources and insufficient health education (6)\u003c/p\u003e \u003cp\u003eThe overall global occurrence of parasitic infections is approximated to affect around 3.5\u0026nbsp;billion people worldwide, with about 450\u0026nbsp;million among them shows symptoms (7). Around 129\u0026nbsp;million people in the U.S visit physician offices daily yearly, because of infectious and parasitic diseases (8). More than 300,000 people in the U.S. are infected with a parasite that causes chagas disease (9).\u003c/p\u003e \u003cp\u003eAlthough many studies have examined prevalence of infectious and parasitic infections but effect of demographic variations among them is still underexplored, which is crucial to know the severity and cause of infection and help in timely care and also help in controlling infectious and parasitic diseases globally. This retrospective observational study has been reported in accordance with the STROCSS 2025 guidelines.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eStudy design and cohort\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMaterial and Methods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study employed the CDC WONDER Multiple Cause of Death database spanning the years 1999 to 2023, which comprises publicly accessible, de-identified mortality data from the United States, as derived from death certificates. This study examines infectious and parasitic diseases related to death among individuals from 1999-2023. Infectious diseases mortality was identified using ICD-10 codes A00-B99. Institutional review board approval was not required since the data was anonymous and publicly accessible. Mortality data were derived from death certificates compiled across all 50 states and the district of Columbia. The study design and reporting followed the STROBE guidelines for observational research. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Extraction\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data were stratified based on age, sex, race/ethnicity, states, U.S. census region and the 2013 National Center for Health Statistics Urban-Rural Classification Scheme. Metropolitan areas were Urban areas while non-metropolitan areas were defined as rural areas. Race factors were also considered including Hispanics or Latino, Africans, American-India, Asians and White. The records which were missing demographic or regional identifiers were excluded from subgroup analysis in order to preserve data accuracy. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStandardized to the U.S. population in 2000, age-adjusted mortality rates were computed per 100,000 population. We used Joinpoint regression analysis to assess trends in infectious and parasitic diseases mortality among individuals. 95% Cis and annual percent change (APC) were calculated, and permutation testing was used to determine statistical significance. In order to guarantee that the most recent mortality records were included, all analyses were completed in September 2025.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eOverall Trends\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;A total of 5,740,282 deaths from infectious and parasitic diseases were recorded in the United States from 1999 to 2023. The overall AAMR fluctuated from 65.0 in 1999 to 67.0 in 2023. Joinpoint regression software identified three distinct segments. Between 1999 and 2018, there was a non-significant decrease in AAMR (APC: -0.172; 95% CI: -0.3703 to 0.0268; p = 0.085464). Subsequently, there was a significant increase from 2018 to 2021, as AAMRs increased from 65.0 to 85.1 (APC: 8.9189*; 95% CI: 3.6581 to 14.4467; p = 0.002021). Finally, from 2021 to 2023, there was a significant decrease, as AAMRs declined from 85.1 to 67.0 (APC: -10.2743*; 95% CI: -14.4955 to -5.8448; p = 0.000187). Overall, the AAPC demonstrated a non-significant change in mortality (AAPC: 0.0282; 95% CI: -0.6703 to 0.7316; p = 0.937112) Figure.1 (Supplementary Table\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrends by Sex\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;During the study period, a total of 2,954,657 male and 2,785,625 female deaths were attributed to infectious and parasitic diseases. Mortality in males decreased non-significantly from 78.2 (95% CI: 77.7\u0026ndash;78.7) in 1999 to 78.6 (95% CI: 78.2\u0026ndash;79.0) in 2023. Joinpoint analysis identified three distinct segments: from 1999 to 2018, there was a significant decline (APC: -0.3349*; 95% CI: -0.4259 to -0.0436; p = 0.019074); this was followed by a significant increase from 2018 to 2021 (APC: 9.6449*; 95% CI: -4.2278 to 15.3436; p = 0.001379); and finally, a significant decrease from 2021 to 2023 (APC: -11.1570*; 95% CI: -15.461 to -6.6339; p = 0.000104). The AAPC demonstrated a non-significant decline in male mortality (AAPC: -0.0211; 95% CI: -0.7352 to 0.6982; p = 0.954063). Similarly, in females, mortality also showed a non-significant change from 54.8 (95% CI: 54.4\u0026ndash;55.1) in 1999 to 57.7 (95% CI: 57.3\u0026ndash;58.0) in 2023. The analysis revealed three segments: a non-significant change from 1999 to 2018 (APC: -0.0356; 95% CI: -0.1867 to 0.1157; p = 0.525884); a significant increase from 2018 to 2021 (APC: 7.8269*; 95% CI: 2.6369 to 13.7793; p = 0.004994); and a significant decrease from 2021 to 2023 (APC: -8.9047*; 95% CI: -13.1022 to -4.4846; p = 0.000666). The AAPC for females demonstrated a non-significant change (AAPC: 0.1367; 95% CI: -0.5511 to 0.8292; p = 0.697724). Overall, mortality was consistently higher in males than in females Figure.1 (Supplementary Table S1B).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrends by Race/Ethnicity\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;Mortality trends differed among racial and ethnic groups. Non-Hispanic (NH) Black or African American individuals exhibited the highest mortality rates, followed by American Indian or Alaska Native and Hispanic or Latino populations, while NH Asian or Pacific Islander individuals had the lowest mortality rates. Among NH Whites, the age-adjusted mortality rate significantly increased from 55.3 (95% CI: 55.0\u0026ndash;55.6) in 1999 to 64.8 (95% CI: 64.5\u0026ndash;65.0) in 2023, indicating a significant overall increase (APC/AAPC = 0.8977*; 95% CI: 0.5198 to 1.2777; p \u0026lt; 0.001). NH Black and African Americans experienced a significant decrease from 141.0 (95% CI: 139.5\u0026ndash;142.5) in 1999 to 99.3 (95% CI: 98.3\u0026ndash;100.3) in 2023 (APC/AAPC = -1.5924*; 95% CI: -2.5563 to -0.6189; p = 0.001393). Hispanic and Latino population exhibited a significant decreasing trend, with AAMRs 72.7 (95% CI: 71.2\u0026ndash;74.1) in 1999 and 60.2 (95% CI: 59.4\u0026ndash;60.9) in 2023 (APC/AAPC = -0.9447*; 95% CI: -1.4764 to -0.4101; p = 0.000547). For NH Asian and Pacific Islander individuals, AAMR declined significantly from 51.3 (95% CI: 49.4\u0026ndash;53.1) in 1999 to 42.6 (95% CI: 41.7\u0026ndash;43.4) in 2023 (APC/AAPC = -0.7691*; 95% CI: -1.4202 to -0.1138; p = 0.02151). The trend for American Indian or Alaska Native individuals was non-significant, with AAMRs of 78.5 (95% CI: 73.2\u0026ndash;83.7) in 1999 and 96.2 (95% CI: 92.4\u0026ndash;100.1) in 2023 (APC/AAPC = 1.0026; 95% CI: -0.1701 to 2.189; p = 0.094083) Figure.2 (Supplementary Table S2A).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrends by States\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;Across the United States, state-level AAMRs showed notable geographic differences. The greatest AAMRs were seen in the states of District of Columbia 134.7 (95% CI: 132.7\u0026ndash;136.7), Louisiana 86.7 (95% CI: 86.1\u0026ndash;87.3), and Mississippi 86.7 (95% CI: 86.0\u0026ndash;87.4). Numerous other states such as Maryland 80.4 (95% CI: 79.9\u0026ndash;80.9), West Virginia 80.2 (95% CI: 79.4\u0026ndash;81.0), and South Carolina 80.8 (95% CI: 80.3\u0026ndash;81.4) reported relatively elevated rates. In contrast, the lowest AAMRs were seen in the states of Minnesota 40.2 (95% CI: 39.8\u0026ndash;40.5), Idaho 44.2 (95% CI: 43.5\u0026ndash;44.9), and Wisconsin 44.2 (95% CI: 43.9\u0026ndash;44.6). Mortality rates were generally elevated in the South and Mid-Atlantic regions, whereas northern and western regions like Minnesota, Idaho, and Hawaii saw reduced rates. This pattern highlights substantial geographic disparities in infectious and parasitic disease mortality throughout the United States Figure.3 (Supplementary Table S6).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrends by Census Regions\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;Between 1999 and 2023, AAMR trends categorized by U.S. census regions demonstrated varied patterns. In the Northeast, the AAMR decreased from 71.2 (95% CI: 70.5\u0026ndash;71.9) in 1999 to 62.5 (95% CI: 61.9\u0026ndash;63.1) in 2023. Joinpoint analysis identified three segments: a significant decline from 1999 to 2018 (APC: -1.0471*; 95% CI: -1.2381 to -0.8559; p \u0026lt; 0.001), a non-significant increase from 2018 to 2021 (APC: 6.4461; 95% CI: -0.2015 to 13.5365; p = 0.056783), and a significant decrease from 2021 to 2023 (APC: -7.0586*; 95% CI: -12.7371 to -1.0106; p = 0.025427), resulting in an overall non-significant decline (AAPC: -0.6603; 95% CI: -1.5553 to 0.2428; p = 0.15136). The Midwest exhibited a different trend, increasing from 56.1 (95% CI: 55.5\u0026ndash;56.7) in 1999 to 63.3 (95% CI: 62.8\u0026ndash;63.8) in 2023. This included a significant increase from 1999 to 2018 (APC: 0.3252*; 95% CI: 0.1556 to 0.495; p = 0.000835), a significant increase from 2018 to 2021 (APC: 9.1488*; 95% CI: 3.6905 to 14.8944; p = 0.002208), and a significant decrease from 2021 to 2023 (APC: -9.9327*; 95% CI: -14.344 to -5.2942; p = 0.000395), resulting in an overall non-significant increase (AAPC: 0.4807; 95% CI: -0.2423 to 1.2089; p = 0.193118). In the South, mortality rates showed a non-significant change from 72.8 (95% CI: 72.2\u0026ndash;73.3) in 1999 to 73.1 (95% CI: 72.6\u0026ndash;73.5) in 2023, characterized by a non-significant change from 1999 to 2018 (APC: -0.1722; 95% CI: -0.4183 to 0.0745; p = 0.158969), a significant increase from 2018 to 2021 (APC: 9.2380*; 95% CI: 2.4224 to 16.5072; p = 0.010097), and a significant decrease from 2021 to 2023 (APC: -11.2995*; 95% CI: -16.7589 to -5.482; p = 0.000963), resulting in an overall non-significant change (AAPC: -0.0312; 95% CI: -0.9402 to 0.8862; p = 0.946674). In the West, the age-adjusted mortality rate increased from 55.2 (95% CI: 54.6\u0026ndash;55.8) in 1999 to 63.6 (95% CI: 63.1\u0026ndash;64.1) in 2023. This included a significant increase from 1999 to 2018 (APC: 0.4438*; 95% CI: 0.3091 to 0.5786; p \u0026lt; 0.001), a significant increase from 2018 to 2021 (APC: 7.2738*; 95% CI: 2.7833 to 11.9605; p = 0.002965), and a significant decrease from 2021 to 2023 (APC: -8.0847*; 95% CI: -11.6907 to -4.3313; p = 0.000356), resulting in an overall non-significant increase (AAPC: 0.5271; 95% CI: -0.0678 to 1.1255; p = 0.082584) Figure.4 (Supplementary Table S5A)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrends by Urbanization\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;There were notable differences in mortality trends between metropolitan (urban) and non-metropolitan (rural) populations. AAMRs became substantially elevated in non-metropolitan regions compared to metropolitan areas over time. In 1999, rates were 66.7 (95% CI: 66.3\u0026ndash;67.0) in metropolitan areas and 56.9 (95% CI: 56.3\u0026ndash;57.6) in non-metropolitan areas, but by 2020 rates had increased to 73.0 (95% CI: 72.7\u0026ndash;73.3) in metropolitan areas and 82.9 (95% CI: 82.2\u0026ndash;83.7) in non-metropolitan areas. Metropolitan areas experienced a non-significant change in AAMR from 1999 to 2020 (APC/AAPC: -0.0028; 95% CI: -0.3746 to 0.3704; p = 0.987806). In contrast, non-metropolitan regions exhibited a significant increase from 56.9 (95% CI: 56.3\u0026ndash;57.6) in 1999 to 82.9 (95% CI: 82.2\u0026ndash;83.7) in 2020, with a significant overall increase (APC/AAPC: 1.4731*; 95% CI: 1.2382 to 1.7085; p \u0026lt; 0.001) Figure.5 (Supplementary Table S4A).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrends by Age Groups\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;A distinct age-related gradient in mortality was revealed by age-specific analysis. The rates of mortality increased significantly with age, reaching their highest point among older adults aged 65-85+ years, followed by those aged 45-64 years; infants and young children aged 0-4 years had the lowest mortality rate. In 1999, AAMRs were 346.9 (95% CI: 344.9\u0026ndash;348.9) for individuals aged 65-85+ years, 60.6 (95% CI: 60.0\u0026ndash;61.2) for those aged 45-64 years and 9.2 (95% CI: 8.8\u0026ndash;9.7) for infants and young children aged 0-4 years. By 2023, rates had changed to 371.7 in older adults, exhibiting a non-significant increase (APC/AAPC: 0.2666; 95% CI: -0.3974 to 0.9351; p = 0.432215); mortality rates for adults aged 45-64 years showed a non-significant change to 66.7 (APC/AAPC: 0.0824; 95% CI: -0.8073 to 0.9801; p = 0.856534). Among all age groups, the 5-24 year age group exhibited the most pronounced decrease, with a significant overall decrease in AAMR to 1.8 (APC/AAPC: -1.0786*; 95% CI: -1.8348 to -0.3167; p = 0.006604). The 25-44 years age group also showed a significant overall decline (APC/AAPC: -2.0817*; 95% CI: -3.3147 to -0.8329; p = 0.00114), while the 0-4 years age group showed a non-significant change (APC/AAPC: -0.0983; 95% CI: -1.0223 to 0.8343; p = 0.835662) Figure.6 (Supplementary Table S3A).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrends by Places of Death\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;Analysis by place of death revealed the majority of the patients died in medical facilities. Inpatient settings constituted 75.20% of total mortalities, followed by deaths in nursing homes/long term care at 8.50% and at decedent\u0026rsquo;s home at 7.10%. Hospice facilities accounted for 3.80%, outpatients or emergency rooms for 3.30% and other or unknown sites for less than 4% collectively Figure.7 (Supplementary Table S7).\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study explains national mortality patterns in the United-States for infectious and parasitic diseases from 1999\u0026ndash;2023, retrieved from CDC Wonder. Our findings reveal an overall plateau in these mortality trends over the last two decades with rates remaining substantially high, punctuated by a sharp elevation beginning in the late 2010s, peaking around 2020\u0026ndash;2021, and followed by a marked decline thereafter. This fluctuation interrupts an otherwise gradual long-term stabilization, suggesting the influence of episodic but powerful determinants such as emerging pathogens, health-system disruptions, and behavioral epidemics. The demographic profile reveals continued male dominance, steep age gradients, and increasing rural\u0026ndash;urban and regional disparities, while racial and ethnic trends reflect both continued advances and emerging vulnerabilities.\u003c/p\u003e \u003cp\u003eDuring the 1999\u0026ndash;2023 period, CDC WONDER\u0026ndash;based analysis indicates long-term stability in infectious and parasitic diseases associated with deaths punctuated by a clear peak in the late 2010s into 2021 followed by a subsequent decline. The timing and form of that peak are best explained by the direct and indirect effects of the COVID-19 pandemic along with contemporaneous deterioration of other infection drivers. Several excess-mortality analyses find that the pandemic resulted in a significant short-term increase in deaths both directly due to SARS-CoV-2 and indirectly due to health-system burden, delayed treatment and social disruption; they temporally coincide with the increase seen and with the fall that followed as vaccines, treatments and revived access alleviated COVID pressure \u003csup\u003e\u003cspan additionalcitationids=\"CR11 CR12\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. Healthcare disruption during the pandemic years also overlapped with quantifiable decline in antimicrobial resistance monitoring and infection-prevention capability, which likely increased death due to bacterial and healthcare-associated infections over the same years \u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e,\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eSex, race/ethnicity and place-based patterns are suggestive of layered, interacting mechanisms. The greater elevation among males in the late-decade period is consistent with higher documented COVID case-fatality in men and with elevated baseline prevalence of injection-related complications and other behavioral risks in men; sex-specific immune responses and exposure profiles are corroborated by meta-analytic data \u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. Racial trends show declining mortality rates among various non-White groups throughout the long sequence, but a net gain for non-Hispanic Whites. These findings coincide with two partially independent mechanisms. First, prolonged public-health improvements (wider HIV and hepatitis C diagnosis/treatment, selective community interventions) were responsible for stepwise declines in some groups over several years. Second, the late-decade increase among some White and non-metropolitan groups mirrors the demographic and geographic profile of the opioid epidemic and accompanying injection-related bacterial infections; multiple epidemiologic accounts attribute burgeoning injection drug use to rising endocarditis, severe skin/soft-tissue infection, and bloodstream infection in young and rural groups \u003csup\u003e\u003cspan additionalcitationids=\"CR19 CR20\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. These concurrent trends account for why certain racial/ethnic groups saw net improvement as the overall series registers a pandemic-era peak.\u003c/p\u003e \u003cp\u003eGeographic heterogeneity is also seen in terms of increased burdens in Southern and selected Mid-Atlantic states and increasing non-metropolitan mortality. These findings mirror social determinants (poverty, restricted access to specialists, and capacity for long-term care) and regional differences in the harms of substance use. Rural locales, with restrictive harm-reduction services and fewer treatment capacities, have been reported as especially exposed to injection-related infectious complications and pandemic shocks, as seen in rural elevations \u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e,\u003cspan additionalcitationids=\"CR23\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e. Gradients by age continue to be steep: the oldest maintained the greatest mortality and were hit hardest in pandemic waves from immunosenescence, multimorbidity, and clustered outbreaks in congregate care, while other younger age groups overall experienced declines across many causes in the long term but also saw temporary peaks that correspond to substance-use\u0026ndash;related infections and secondary pandemic harms \u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eCollectively, our study and literature points to late-decade rise in infectious-disease mortality as a convergence of high COVID-19 death and excess death due to similar causes, pandemic-induced care disruption and infection-control failures that exacerbated antimicrobial drug resistance and healthcare-associated infections, and increasing injection-drug\u0026ndash;associated bacterial disease in certain demographic and geographic niches. Post-2021 downturn is conceivably explained by increasing population immunity, vaccine/therapeutic coverage and partial recovery of health services, but lingering and unequal burdens persist\u0026mdash;especially in rural settings, among some racial/ethnic populations and among individuals impacted by substance use\u0026mdash;highlighting the importance of equitable surveillance, scaling-up harm reduction, antimicrobial stewardship and augmenting long-term care protections \u003csup\u003e\u003cspan additionalcitationids=\"CR11 CR12 CR13 CR14\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e,\u003cspan additionalcitationids=\"CR19 CR20 CR21 CR22 CR23\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eImmediate interventions are needed to improve mortality status associated with infectious diseases. Increasing viral and bacterial early-warning surveillance, harm-reduction and treatment capacity in rural and underserved communities, prioritizing antimicrobial stewardship, and augmenting infection-prevention capacity in long-term care and acute-care facilities could help in reducing overall mortality. Data-driven, equity-based policy responses will be needed to overcome geographic and demographic inequities and to enhance resilience for impending public-health shocks. These interventions should become a part of broader national strategies to reduce mortality burden associated with infectious and parasitic diseases.\u003c/p\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eStudy limitations\u003c/h2\u003e \u003cp\u003eThis study is based on death-certificate coding in CDC WONDER; because attribution can be confounded by coding conventions and by pandemic-period shifts in recording practice regarding COVID and related conditions. Ecological design does not have direct co morbidity, socioeconomic status, local health-system capacity, or cause-specific clinical information (e.g., endocarditis vs. pneumonia vs. septicemia); temporal changes observed may partially represent surveillance or coding artifacts rather than genuine exposure or risk change,\u003csup\u003e10,14,18\u003c/sup\u003e .However, this descriptive approach has been utilized in previously published studies using CDC WONDER database and aligns with the established epidemiologic reporting practices, as the use of national data ensures robust generalizability.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eOur CDC WONDER analysis study on mortality trends associated with infectious and parasitic diseases in the United States during 1999\u0026ndash;2023 shows long-term stability in the trends with substantially high rates punctuated by an abrupt rise between 2018 and 2021, followed by a substantial drop. Mortality was consistently higher among males than females over the years, and the greatest burden was in the elderly\u0026thinsp;\u0026ge;\u0026thinsp;65 years of age. Non-Hispanic Black groups had the highest death rates, but with a downward trend over the long term, and non-Hispanic Whites had a steady upward trend. Consistently higher mortality rates were observed in the South, Mid-Atlantic, and areas of the Midwest. Non-metropolitan areas had much higher and increasing mortality than metropolitan counties. These trends highlight that deaths due to infectious and parasitic diseases continue to be clustered in socially and structurally disadvantaged groups. The pandemic-era peak further highlights the shortcomings in healthcare access, infection detection, and antimicrobial stewardship. Sustained substantial reduction in overall mortality would require strengthening prevention measures especially in rural and high-burden states, guaranteeing equalized healthcare access along racial and geographic lines and integrating harm-reduction and antimicrobial-resistance measures into national infectious disease control policy. \u003csup\u003e10\u0026ndash;15,18\u0026ndash;24\u003c/sup\u003e .Overall, this study provides the latest up to date picture for U.S national mortality trends of infectious and parasitic diseases, highlighting persistent inequalities and post pandemic trajectory.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eWaheed Y (2024) Clinical Aspects of Infectious Diseases. J Clin Med 13(16):4853\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAhmed F, Saadi A (2025) Types and Harms of Pathogenic Microorganisms: A Review. Int J Pathol Biomarkers 1(1):32\u0026ndash;50\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang Y Introduction to parasitic disease. InRadiology of parasitic diseases: a practical approach 2016 Nov 29 (pp. 3\u0026ndash;3). Dordrecht: Springer Netherlands\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBusenberg S, Cooke K (2012) Vertically transmitted diseases: models and dynamics. Springer Science \u0026amp; Business Media. Dec 6\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eArmstrong GL, Pinner RW (1999) Outpatient visits for infectious diseases in the United States, 1980 through 1996. Arch Intern Med 159(21):2531\u0026ndash;2536\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRaharyani D (2025) The Role of Health Education in Improving Clean and Healthy Living Behavior (PHBS) in Rural Communities. AMK: Abdi Masyarakat UIKA 4(2):127\u0026ndash;132\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJayalakshmi S, Dharanidevi S (2016) The prevalence of intestinal parasitic infections in a tertiary care hospital in southern India-a retrospective study. Int J Curr Microbiol App Sci 5(10):718\u0026ndash;723\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDos Santos AL (2023) Tropical infectious diseases of global significance: Insights and perspectives. Trop Med Infect Disease 8(10):462\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMontgomery SP, Parise ME, Dotson EM, Bialek SR (2016) What do we know about Chagas disease in the United States? Am J Trop Med Hyg 95(6):1225\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCenters for Disease Control and Prevention (2025) Excess deaths associated with COVID-19. National Center for Health Statistics (NCHS)\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWoolf SH, Chapman DA, Sabo RT, Zimmerman EB (2021) Excess Deaths From COVID-19 and Other Causes in the US, March 1, 2020, to January 2, 2021. JAMA 325(17):1786\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRuhm CJ (2022) Excess deaths in the United States during the first year of COVID-19. Prev Med (Baltim) 162:107174\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCDC (2022) COVID-19: U.S.Impact on Antimicrobial Resistance, Special Report 2022. U.S. Department of Health and Human Services, CDC, Atlanta, GA\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCenters for Disease Control and Prevention (2022) Antimicrobial resistance threats in the United States \u0026mdash; update 2022. CDC, Atlanta (GA)\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchranz A, Barocas JA (2020) Infective Endocarditis in Persons Who Use Drugs. Infect Dis Clin North Am 34(3):479\u0026ndash;493\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGalbadage T, Peterson BM, Awada J, Buck AS, Ramirez DA, Wilson J et al (2020) Systematic Review and Meta-Analysis of Sex-Specific COVID-19 Clinical Outcomes. Front Med (Lausanne). ;7\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSex (2021) differences in COVID-19 fatality rate and risk of death: An analysis in 73 countries, 2020\u0026ndash;2021. Infezioni in Medicina. ;29(3):402\u0026ndash;7\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCenters for Disease Control and Prevention (2024) Vulnerable areas for persons who inject drugs \u0026mdash; data summary. CDC, Atlanta (GA)\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKolak MA, Chen YT, Joyce S, Ellis K, Defever K, McLuckie C et al (2020) Rural risk environments, opioid-related overdose, and infectious diseases: A multidimensional, spatial perspective. Int J Drug Policy [Internet] 85:102727\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAbdul Jabbar A, Bin, Khan DA, Li-Jedras M, Kabach A, Aboeata A (2025) Trends of infective endocarditis mortality in the young adult population of the US: A concerning rise and its association with substance abuse. Int J Cardiol Cardiovasc Risk Prev [Internet] 25:200404\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eArmstrong GL (1999) Trends in Infectious Disease Mortality in the United States During the 20th Century. JAMA 281(1):61\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSpencer MR, Garnett MF, Mini\u0026ntilde;o AM (2022) Urban\u0026ndash;rural differences in drug overdose death rates, 2020. National Center for Health Statistics, Hyattsville, MD, NCHS Data Brief, no 440\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBagchi S, Mak J, Li Q et al (2021) Rates of COVID-19 Among Residents and Staff Members in Nursing Homes \u0026mdash; United States, May 25\u0026ndash;November 22, 2020. MMWR Morb Mortal Wkly Rep 70:52\u0026ndash;55\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCenter for Infectious Disease Research and Policy (CIDRAP) (2024) COVID-19 drops to 10th leading cause of death in the United States. CIDRAP, Minneapolis (MN)\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePrince MA, Tan MC, Tan MX, George H, Prince EO, Nicholas RM et al (2024) Exploring the impact of therapeutic advances in HIV-related mortality in the United States. IJID Reg 11:100347\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Infectious diseases, Parasitic diseases, CDC WONDER, Mortality trends, United States, Cross-sectional study","lastPublishedDoi":"10.21203/rs.3.rs-9555964/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9555964/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eInfectious and parasitic diseases remain a significant public health burden. A comprehensive analysis of their mortality trends, particularly across demographic and geographic subgroups in the United States, is crucial for informing targeted public health interventions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis national population-based study utilized CDC WONDER mortality data from 1999 to 2023. Age-adjusted mortality rates (AAMRs) per 100,000 were calculated for deaths with an underlying cause of ICD-10 codes A00-B99. Trends were analyzed using Join point regression to compute annual percent change (APC) and average annual percent change (AAPC).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFrom 1999 to 2023, mortality from infectious and parasitic diseases in the United States exhibited a complex trend, characterized by an overall non-significant change (AAPC: 0.0282). This period masked a dramatic surge between 2018 and 2021, with a significant annual increase of 8.92%, followed by an equally sharp decline of 10.27% from 2021 to 2023. The analysis revealed profound disparities, with consistently higher mortality rates among males, significant increases among Non-Hispanic White individuals, and a critical divergence where rural areas experienced a marked rise in mortality compared to urban areas. Geographically, the South and Mid-Atlantic regions bore the highest burden, and the elderly population was disproportionately affected, with the vast majority of deaths occurring in inpatient medical facilities.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAnalysis of U.S. mortality data from CDC WONDER (1999–2023) reveals that infectious and parasitic disease mortality remained stable over two decades but was sharply interrupted by a significant peak around 2020–2021, largely attributable to the COVID-19 pandemic and health-system disruptions. Demographic and geographic disparities persisted, with higher mortality among males, older adults, and non-metropolitan populations. Racial trends showed long-term improvements among several non-White groups, though increases were observed among non-Hispanic White and rural populations, coinciding with the opioid and injection-drug use epidemic. Post-2021 declines followed vaccine rollout and health-service recovery, yet inequities remain. Urgent actions—including enhanced surveillance, harm reduction, and equitable healthcare strengthening—are needed to reduce future mortality.\u003c/p\u003e","manuscriptTitle":"Rising Mortality and Demographic Disparities in Infectious and Parasitic Diseases in the United States, 1999–2023: A Comprehensive CDC WONDER Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-29 09:12:22","doi":"10.21203/rs.3.rs-9555964/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"33eb3c0d-ac46-472a-bb8f-4c0acb1a9963","owner":[],"postedDate":"April 29th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":67228797,"name":"Bacteriology"},{"id":67228798,"name":"Parasitology"},{"id":67228799,"name":"Epidemiology"}],"tags":[],"updatedAt":"2026-04-29T09:12:23+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-29 09:12:22","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9555964","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9555964","identity":"rs-9555964","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}