Global Trends and Regional Differences in the Burden of Infective Endocarditis, 1990–2021: An Analysis of the Global Burden of Disease Study 2021

Abstract

Background

The study aimed to offer detailed insights into the global, regional, and national burden of IE in 2021, while also examining the temporal trends of IE from 1990 to 2021.

Methods

Data on the absolute numbers and age-standardized rates (ASR) of incidence, deaths, and disability-adjusted life years (DALYs) related to IE were sourced from the Global Burden of Disease Study (GBD) 2021. The estimated annual percentage changes (EAPC) of ASR were calculated to quantify the temporal trends. Furthermore, joinpoint regression models were used to identify the temporal trends and the primary joinpoint year of ASR.

Results

Globally, the age-standardized incidence rate (ASIR) for IE increased with an EAPC of 1.00 (95%CI: 0.93–1.08) from 9.35 per 100 000 population in 1990 to 12.61 per 100 000 population in 2021. Despite a rise in the absolute number of death cases and DALYs related to IE, the age-standardized mortality rate (ASMR) has remained stable (EAPC 0.06, 95%CI: -0.10-0.22), and the age-standardized DALYs rate (ASDR) has exhibited a decline (EAPC − 0.34, 95%CI: -0.45–0.24) between 1990 and 2021. Males bore a higher burden of IE compared to females, with the peak burden gradually shifting towards older individuals. In 2021, the ASIR for IE exhibited an increase with the rise in socio-demographic index (SDI) quintiles, with the highest ASIR observed in the high SDI region (15.77 per 100 000 population). Moreover, the highest growth rates of ASIR, ASMR, and ASDR were also noted in the high SDI region. On the other hand, the ASMR (1.34 per 100 000 population) and ASDR (40.71 per 100 000 population) for IE were relatively high in the low SDI region. Joinpoint analysis demonstrated that the ASIR, ASMR, and ASDR did not experience any sudden surges either globally or across different SDI regions after 2007.

Conclusions

The burden of IE remained relatively high, characterized by a rising ASIR and a stable ASMR on a global scale. This burden was notably prominent among males, the elderly, and in the high and low SDI regions. Region-specific prevention and management strategies might be warranted to reduce the burden of IE.

Supplementary Information

The online version contains supplementary material available at 10.1007/s44197-025-00413-x.

Introduction

Infective endocarditis (IE) is a rare yet life-threatening disease that can be categorized into native valve endocarditis (NVE), prosthetic valve endocarditis (PVE), and intracardiac device-related IE (CDRIE) based on the site of infection. Over the past three decades, there has been a rising trend in the incidence for IE, with the age-standardized incidence rate (ASIR) for IE reported at 13.80 per 100 000 population globally in 2019 [1]. During this period, the epidemiological characteristics of IE patients have undergone significant changes. Patients diagnosed with IE have shown a shift towards advanced age and a higher burden of comorbidities [2, 3]. The proportion of NVE cases has decreased in various countries and regions, while the proportions of PVE and CDRIE have notably increased [2–4]. Healthcare-associated nosocomial IE cases have increase, possibly due in part to the growing exposure to invasive procedures [4, 5]. Additionally, staphylococcal and enterococcal endocarditis have become more prevalent [4, 6]. Despite advancements in the diagnosis and management of IE, the mortality rate remained relatively high. In-hospital mortality rates could reach up to 25%, with one-year mortality rates up to 35% [2, 4, 7–10].

The epidemiological characteristics and burden of IE vary considerably across different regions and populations. A recent epidemiological study revealed a noteworthy rise in the ASIR for IE between 1990 and 2019 in nineteen high-income countries [11]. Factors such as degenerative valvular disease, prosthetic heart valves, cardiac implantable electronic devices, and invasive procedures gradually emerged as prominent predisposing factors for IE in these countries [5, 12]. Moreover, the age-standardized mortality rate (ASMR) increased in most high-income countries, with exceptions in Finland and Austria, indicating a substantial burden on these populations [11]. In comparison to high and upper-middle-income countries, patients with IE in low-middle income nations tended to be younger, exhibited higher rates of intravenous drug use and HIV infection, and commonly presented with persistent fever and an increased likelihood of heart failure complications [13]. Rheumatic heart disease and congenital heart disease were the most frequent risk factors in these regions [6, 8]. The mortality rates for IE were higher in these economically disadvantaged countries, possibly due to delayed diagnoses and lower rates of surgical interventions [13]. A thorough comprehension of the burden of IE across diverse geographical regions and countries is of paramount importance, which serves as the cornerstone for the formulation of highly targeted and meticulously customized strategies for the prevention and treatment of this condition.

Previous studies on the global burden of IE have primarily focused the trends before 2019. To the best of our knowledge, there has been no updated study reporting the incidence, mortality, and disability-adjusted life years (DALYs) burden of IE from 1990 to 2021 based on the most recent Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021. Therefore, the study was designed to provide comprehensive insights into the incidence, mortality, and disability-adjusted life years (DALYs) burden of IE. Additionally, it aimed to conduct a detailed analysis of the temporal trends of IE at the global, regional, and national levels over the period from 1990 to 2021, thereby offering a comprehensive understanding of the disease’s evolution and its impact across different geographical and demographic contexts.

Methods and Materials

Data Sources

The data utilized in this study were obtained from the GBD 2021 database. This database is accessible for retrieval and download via the official GBD website, which can be found at the following URL: https://www.healthdata.org/research-analysis/gbd. The GBD 2021 study comprehensively analyzed the burden linked to 288 causes of death, 371 diseases and injuries, and 88 risk factors across 204 countries and territories. Non-fatal estimates drew from a wide array of sources, including scientific literature, household surveys, epidemiological surveillance, disease registries, clinical informatics, and other resources [14]. For fatal estimates, data sources included vital registration, verbal autopsy, cancer registry, census, survey, police records, surveillance, and open-source databases [15]. In GBD 2021, a variety of modeling tools, including Disease Modelling Meta-Regression (DisMod-MR 2.1), spatiotemporal Gaussian process regression (ST-GPR), and the Cause of Death Ensemble model (CODEm), were employed to generate precise and reliable health estimates. DisMod-MR 2.1 is a Bayesian disease modeling meta-regression tool, which could produce internally consistent estimates of incidence, prevalence, remission, and mortality across sex, location, year, and age groups. ST-GPR disease models enable the analysis of heterogeneous and incomplete data that require statistical smoothing across time, age, and location [14]. CODEm tool evaluates the out-of-sample predictive validity of various statistical models and covariate permutations. Subsequently, it integrates the outcomes of these evaluations to generate cause-specific estimates of mortality burden. GBD 2021 was in accordance with the Guidelines for Accurate and Transparent Health Estimates Reporting (GATHER) statement [16].

Case Definition and Input Data

In GBD 2021, IE was defined as a bacterial or fungal infection that impacts the heart, with the infection typically situated in the heart valves or chordae. To ensure accurate diagnosis of IE, the widely recognized Duke Criteria were employed [17]. These criteria provide a standardized set of diagnostic guidelines that assist in differentiating IE from other cardiac and infectious conditions. For the identification of IE cases within the GBD 2021 framework, the International Classification of Diseases (ICD) codes were utilized as a key reference. Specifically, cases were identified using ICD-9 codes 421-421.9, and in the ICD-10 system, the relevant codes included I33-I33.9 and I38-I39.9.

From 1990 to 2021, data encompassing the absolute numbers and rates of incidence, mortality, and disability-adjusted life years (DALYs) associated with infective endocarditis (IE) were systematically collected at the global, regional, and national levels. To comprehensively explore the age-specific burden of IE, patients were categorized into 20 distinct age groups, each with an interval of 5 years. A total of 204 countries and territories were included in the study. These were subsequently grouped into 21 Global Burden of Disease (GBD) regions, such as Andean Latin America, Central Asia, High-income Asia Pacific, and Oceania. This regional classification enabled a more nuanced analysis of the IE burden across various geographical areas. Furthermore, the 204 countries and territories were divided into five socio-demographic index (SDI) regions, based on their SDI values. The high SDI region had an SDI range of 0.810296 < SDI < 1, the high-middle SDI region 0.711975 < SDI < 0.810296, the middle SDI region 0.618829 < SDI < 0.711975, the low-middle SDI region 0.465816 < SDI < 0.618829, and the low SDI region 0 < SDI < 0.465816. This categorization by SDI permitted a detailed assessment of how the burden of IE differed according to the level of socio-demographic development in each area.

Statistical Analysis

The absolute numbers and age-standardized rates (ASR) of incidence, deaths, and DALYs associated with IE were provided, along with their corresponding 95% uncertainty interval (UI). In the GBD 2021 dataset, all calculations were iterated 500 times to generate draw-level estimates. The 95% uncertainty interval (UI) was determined as the range between the 2.5th and 97.5th percentile values across these 500 draws. The estimated annual percentage change (EAPC) and its 95% confidence interval (CI) were calculated to illustrate the changing trends of ASIR, ASMR, and age-standardized DALYs rate (ASDR) for IE. A regression model was employed to characterize the natural logarithm of the ASR, expressed as In(ASR) = α + β*(calendar year) + ε. The EAPC was calculated as EAPC = 100*(e^β-1). To calculate the 95% CI for EAPC, we first obtained the estimate and its standard error from the ln(ASR) regression model based on the calendar year. Then, we used the critical value 1.96 to find the CI for the coefficient in the regression and substitute the lower and upper limits of that CI into the formula EAPC = 100*(e^coefficient-1). When the EAPC and the lower limit of its 95% CI were both positive, the ASR was regarded as displaying an increasing trend. Conversely, if both the EAPC estimate and the upper limit of its 95% CI were negative, the ASR was considered to indicate a decreasing trend. Pearson correlation analysis was applied to explore the associations between the EAPC of ASR with ASR and SDI. Furthermore, joinpoint regression models were used to identify the temporal trends and the primary joinpoint year of ASIR, ASDR, and ASMR. The annual percent change (APC) was computed to characterize the changing trend within each segment. The data analyses were performed using R software (Version 4.4.0) and the Joinpoint Regression Program (Version 5.2.0).

Results

Global Trends in IE Incidence, Mortality, and DALYs

In 2021, there were 1.04 million (95%UI: 0.89–1.20) incident cases of IE worldwide, showing a 135% (95%UI: 113–158%) rise from 0.44 million (95%UI: 0.38–0.54) reported in 1990 (Table 1 and Table S1 in the Supplementary Appendix). The ASIR for IE also increased with an EAPC of 1.00 (95%CI: 0.93–1.08) from 9.35 (95%UI: 8.01–11.09) per 100 000 population in 1990 to 12.61 (95%UI: 10.84–14.55) per 100 000 population in 2021. The global death cases of IE reached 77.84 thousand (95%UI: 69.01–86.34) in 2021, marking a 111% (95%UI: 90–130%) increase from 36.89 thousand (95%UI: 31.65–40.52) in 1990. However, the overall ASMR remained stable with an EAPC of 0.06 (95%CI: -0.10-0.22) from 0.97 (95%UI: 0.84–1.05) per 100 000 population in 1990 to 0.96 (95%UI: 0.85–1.07) per 100 000 population in 2021. In addition, the total DALYs attributed to IE reached 2.08 million (95%UI: 1.83–2.31) in 2021, representing a 56% (95%UI: 38–81%) increase from 1.33 million (95%UI: 1.06–1.51) in 2021. However, the ASDR decreased with an EAPC of -0.34 (95%CI: -0.45–0.24) from 1990 to 2021.

Table 1.

Counts and age-standardized rates of incidence, mortality and dalys for IE in 2021, and the Temporal change of age-standardized rates from 1990 to 2021

	Incidence			Deaths			DALYs
	2021 counts (95% UI)	2021 ASIR per 100 000 people (95% UI)	EAPC of ASIR 1990–2021 (95%CI)	2021 counts (95% UI)	2021 ASMR per 100 000 people (95% UI)	EAPC of ASMR 1990–2021 (95%CI)	2021 counts (95% UI)	2021 ASDR per 100 000 people (95% UI)	EAPC of ASDR 1990–2021 (95%CI)
Global	1,042,478 (893665, 1204150)	12.61 (10.84, 14.55)	1.00 (0.93, 1.08)	77,844 (69010, 86338)	0.96 (0.85, 1.07)	0.06 (-0.10, 0.22)	2,076,413 (1827084, 2308504)	25.56 (22.34, 28.37)	-0.34 (-0.45, -0.24)
Male	583,280 (502014, 670185)	14.85 (12.84–17.06)	1.31 (1.22, 1.41)	40,094 (35274, 45551)	1.10 (0.97, 1.24)	0.08 (-0.02, 0.19)	1,200,319 (1007093, 1393512)	30.57 (25.65, 35.35)	-0.25 (-0.33, -0.17)
Female	459,198 (392157, 535072)	10.58 (9.05–12.28)	0.65 (0.60, 0.70)	37,750 (31155, 43488)	0.83 (0.69, 0.96)	0.02 (-0.18, 0.23)	876,094 (705775, 1006976)	20.65 (16.38, 23.65)	-0.47 (-0.60, -0.34)
SDI region
High SDI	274,390 (236263, 318814)	15.77 (13.63, 18.08)	1.23 (1.10, 1.36)	31,485 (26952, 34018)	1.34 (1.18, 1.44)	0.80 (0.55, 1.05)	536,899 (489608, 567759)	28.62 (26.65, 29.98)	0.65 (0.46, 0.85)
High-middle SD	252,069 (212760, 292725)	14.70 (12.56, 17.04)	1.04 (1, 1.09)	12,498 (11240, 13379)	0.70 (0.63, 0.75)	0.43 (0.25, 0.61)	297,630 (279573, 319559)	18.28 (17.13, 19.83)	-0.41 (-0.54, -0.27)
Middle SDI	328,360 (277094, 382212)	12.81 (10.94, 14.87)	0.75 (0.73, 0.78)	13,865 (12122, 17626)	0.56 (0.49, 0.71)	-1.04 (-1.14, -0.95)	456,988 (405398, 570414)	17.93 (15.87, 22.40)	-1.29 (-1.38, -1.20)
Low-middle SDI	120,842 (103164, 143215)	7.29 (6.25, 8.50)	0.88 (0.86, 0.90)	12,138 (9926, 14664)	0.83 (0.68, 1.01)	-0.51 (-0.55, -0.47)	443,018 (360737, 525612)	26.00 (21.24, 30.94)	-0.68 (-0.73, -0.63)
Low SDI	65,871 (57092, 78625)	7.18 (6.34, 8.30)	0.26 (0.23, 0.29)	7782 (5220, 10127)	1.30 (0.89, 1.68)	-0.59 (-0.67, -0.50)	339,524 (220719, 443733)	40.71 (27.37, 52.99)	-0.68 (-0.75, -0.62)
GBD region
Andean Latin America	6579 (5603, 7730)	10.58 (9.04, 12.44)	0.98 (0.93, 1.02)	247 (197, 300)	0.40 (0.32, 0.49)	-0.91 (-1.10, -0.72)	9992 (7992, 12380)	15.55 (12.46, 19.21)	-1.05 (-1.25, -0.85)
Australasia	7843 (6590, 9115)	16.65 (14.20, 19.47)	1.40 (1.27, 1.53)	623 (536, 682)	1.09 (0.96, 1.18)	2.93 (2.47, 3.40)	11,315 (10254, 12180)	23.54 (21.72, 25.26)	2.52 (2.12, 2.92)
Caribbean	6770 (5880, 7766)	13.46 (11.74, 15.50)	0.77 (0.68, 0.86)	500 (413, 602)	0.98 (0.80, 1.18)	1.11 (0.97, 1.25)	19,027 (14888, 23518)	39.15 (30.22, 48.95)	1.13 (1.03, 1.24)
Central Asia	4718 (3889, 5709)	5.33 (4.43, 6.43)	0.60 (0.58, 0.63)	149 (130, 168)	0.18 (0.15, 0.20)	-0.60 (-0.79, -0.40)	6000 (5209, 6883)	6.39 (5.57, 7.29)	-1.26 (-1.53, -0.99)
Central Europe	21,861 (18282, 25734)	12.16 (10.26, 14.18)	1.46 (1.35, 1.57)	1274 (1163, 1389)	0.63 (0.58, 0.69)	1.91 (1.54, 2.28)	33,123 (30400, 36042)	19.28 (17.73, 20.93)	1.54 (1.21, 1.87)
Central Latin America	26,424 (22365, 31035)	10.50 (8.96, 12.30)	1.29 (1.14, 1.43)	1337 (1178, 1505)	0.54 (0.48, 0.61)	1.39 (0.82, 1.97)	46,053 (40241, 52614)	18.43 (16.06, 21.16)	0.95 (0.42, 1.48)
Central Sub-Saharan Africa	8342 (7198, 10066)	7.99 (7.08, 9.21)	0.44 (0.36, 0.51)	1018 (558, 1507)	1.68 (0.94, 2.54)	-0.24 (-0.30, -0.18)	41,708 (22801, 61469)	47.91 (26.50, 70.81)	-0.35 (-0.41, -0.29)
East Asia	276,168 (225844, 328814)	14.52 (12.19, 17.07)	0.57 (0.52, 0.62)	2813 (2368, 3539)	0.17 (0.14, 0.21)	-3.43 (-3.77, -3.08)	70,985 (59080, 92254)	4.59 (3.72, 6.22)	-5.01 (-5.44, -4.57)
Eastern Europe	42,342 (35726, 49590)	15.28 (13.05, 17.87)	2.37 (2.24, 2.51)	2564 (2381, 2740)	0.91 (0.85, 0.98)	3.66 (3.17, 4.14)	96,915 (89999, 103916)	38.55 (35.78, 41.49)	3.68 (3.14, 4.23)
Eastern Sub-Saharan Africa	26,305 (22530, 31919)	7.90 (6.94, 9.14)	0.07 (0.03, 0.11)	3049 (1987, 4273)	1.38 (0.88, 1.93)	-1.24 (-1.29, -1.18)	142,679 (93701, 199452)	45.05 (29.51, 62.88)	-1.26 (-1.32, -1.20)
High-income Asia Pacific	46,149 (39169, 54242)	12.82 (10.80, 14.99)	0.65 (0.47, 0.82)	5584 (4268, 6416)	0.85 (0.68, 0.97)	-0.48 (-1.06, 0.10)	73,250 (59719, 83213)	15.34 (13.37, 17.40)	-1.13 (-1.58, -0.68)
High-income North America	83,307 (71986, 96229)	15.54 (13.68, 17.82)	1.22 (1.04, 1.40)	10,589 (9281, 11349)	1.61 (1.44, 1.72)	-0.09 (-0.20, 0.01)	211,635 (195398, 223605)	38.51 (35.96, 40.51)	0.10 (0, 0.19)
North Africa and Middle East	47,329 (40042, 56557)	8.88 (7.59, 10.40)	0.87 (0.82, 0.92)	2589 (2131, 3420)	0.58 (0.48, 0.79)	-1.38 (-1.44, -1.33)	96,363 (77215, 121352)	17.82 (14.50, 22.67)	-1.89 (-1.92, -1.86)
Oceania	1095 (958, 1268)	11.95 (10.55, 13.41)	0.52 (0.49, 0.56)	195 (142, 271)	2.14 (1.57, 3.04)	0.66 (0.55, 0.76)	9093 (6504, 12390)	75.41 (54.52, 104.32)	0.91 (0.82, 1.01)
South Asia	89,376 (75121, 107802)	5.52 (4.62, 6.55)	1.12 (1.07, 1.17)	11,823 (9270, 14110)	0.82 (0.64, 0.97)	-0.42 (-0.50, -0.35)	401,832 (315555, 481638)	24.21 (18.91, 28.91)	-0.57 (-0.62, -0.52)
Southeast Asia	116,215 (100778, 133542)	17.68 (15.46, 20.34)	0.81 (0.74, 0.88)	7494 (5825, 10961)	1.24 (0.95, 1.82)	-0.81 (-0.87, -0.75)	254,839 (202734, 361941)	36.97 (29.31, 52.77)	-0.98 (-1.06, -0.90)
Southern Latin America	14,804 (13022, 16591)	18.36 (16.14, 20.59)	1.36 (1.21, 1.51)	1421 (1299, 1522)	1.61 (1.48, 1.73)	-0.18 (-0.40, 0.03)	31,625 (29434, 33645)	38.26 (35.73, 40.69)	-0.44 (-0.62, -0.26)
Southern Sub-Saharan Africa	5481 (4640, 6621)	7.70 (6.57, 9.07)	-0.35 (-0.42, -0.29)	633 (531, 812)	0.97 (0.80, 1.25)	-0.37 (-0.55, -0.19)	27,176 (23056, 34834)	35.81 (30.26, 45.86)	-0.52 (-0.74, -0.30)
Tropical Latin America	38,037 (31985, 44488)	15.36 (13, 17.84)	1.26 (1.12, 1.40)	2686 (2512, 2815)	1.07 (1.00, 1.12)	0.94 (0.60, 1.29)	84,372 (80580, 87806)	33.94 (32.38, 35.30)	0.26 (-0.06, 0.58)
Western Europe	134,147 (116364, 154181)	17.28 (14.98, 19.78)	1.56 (1.46, 1.66)	18,320 (15574, 19954)	1.62 (1.41, 1.75)	2.38 (2.03, 2.74)	275,987 (246485, 295826)	30.60 (28.18, 32.38)	2.09 (1.71, 2.47)
Western Sub-Saharan Africa	39,183 (34219, 45872)	8.60 (7.56, 9.87)	-0.68 (-0.73, -0.63)	2933 (1638, 4135)	1.23 (0.70, 1.72)	-1.49 (-1.63, -1.34)	132,443 (72027, 184106)	37.21 (20.96, 52.34)	-1.37 (-1.52, -1.22)

ASDR, age-standardized disability-adjusted life year rate; ASIR, age-standardized incidence rate; ASMR, age-standardized mortality rate; CI, confidence interval; DALYs, disability-adjusted life years; EAPC, estimated annual percentage change; GBD, Global Burden of Disease; SDI, Socio-Demographic Index; UI, uncertainty interval

In 2021, the number of incident cases and the ASIR for IE were higher in males than in females. Moreover, during the period from 1990 to 2021, the ASIR for IE exhibited a more marked increase in males compared to females. (Table 1 and Figure S1 in the Supplementary Appendix). Furthermore, males persistently showed higher figures in terms of the number of death cases, the counts of DALYs, the ASMR, and the ASDR when contrasted with females. Nevertheless, the extent and the pace of the temporal variation in both the ASMR and the ASDR seemed to be comparable between the male and female populations.

Age-specific numbers and rates of incidence, deaths, and DALYs for IE at the global level in 1990 and 2021 were depicted in Fig. 1. In 1990, the incident cases of IE peaked in the < 5 years group, whereas the peak shifted to the 65–69 years group in 2021. The number of death cases peaked in the 75–79 years group in 1990, and the peak gradually shifted to the 85–89 years group. Moreover, the peak of DALY counts shifted from the < 5 years group to the 65 − 59 years group. In both 1990 and 2021, the age-specific incidence rates for IE declined before the 10–14 years group and rose with increasing age thereafter. Similarly, the age-specific death and DALYs rates for IE decreased before the 5–9 years age group and increased with age subsequently in both 1990 and 2021.

Fig. 1.

Age-specific numbers and rates of incidence (A), deaths (B), and DALYs (C) for IE at the global level in 1990 and 2021. DALYs, disability-adjusted life years; UI, uncertainty interval

Regional Trends in IE Incidence, Mortality, and DALYs

In 2021, within the different SDI regions, the ASIR for IE tended to be higher as the SDI levels increased. The highest ASIR, at 15.77 per 100 000 population, was recorded in the high SDI region (Table 1; Fig. 2). Over the period from 1990 to 2021, the ASIR showed an upward trajectory across all five SDI regions, with the most substantial increase observed in the high SDI region (EAPC: 1.23, 95%CI: 1.10–1.36). In 2021, the highest ASMR for IE was documented in the high SDI region (1.34 per 100 000 population), followed by the low SDI region (1.30 per 100 000 population). The ASMR demonstrated an increase in the high and high-middle SDI regions, while displaying a decrease in the middle, low-middle, and low SDI regions. On the other hand, the highest ASDR for IE was observed in the low SDI region (40.71 per 100 000 population), followed by the high SDI region (28.62 per 100 000 population). Between 1990 and 2021, the ASDR decreased in all SDI regions, except for the high SDI region, where a slight increase was noted (EAPC: 0.65, 95% CI: 0.46–0.85).

Fig. 2.

Trends in age-standardized incidence (A), mortality (B), and DALYs (C) rates for IE globally and for 21 GBD regions, by socio-demographic index, 1990–2021. For each region, the points indicate estimates for every year from 1990 to 2021, displayed in a left-to-right sequence. DALYs, disability-adjusted life years; GBD, Global Burden of Disease

Among the 21 GBD regions, the ASIR for IE was highest in Southern Latin America (18.36 per 100 000 population) and lowest in Central Asia (5.33 per 100 000 population) in 2021 (Table 1; Fig. 3). In the same year, Oceania reported the highest ASMR and ASDR for IE (ASMR: 2.14 per 100 000 population, ASDR: 75.41 per 100 000 population), whereas East Asia recorded the lowest ASMR and ASDR (ASMR: 0.17 per 100 000 population, ASDR: 4.59 per 100 000 population). Between 1990 and 2021, all regions except Southern Sub-Saharan Africa and Western Sub-Saharan Africa experienced an increase in ASIR. In terms of ASMR, 48% of GBD regions witnessed a notable decrease during this period, with the most significant decline observed in East Asia (EAPC: -3.43, 95% CI: -3.77–3.08). Similarly, 57% of GBD regions saw a significant reduction in ASDR, with East Asia showing the most substantial drop (EAPC: -5.01, 95% CI: -5.44–4.57).

Fig. 3.

Age-standardized incidence (A), mortality (B), and DALYs (C) rates for IE in 204 countries and territories, for both sexes, 2021. ASDR, age-standardized disability-adjusted life year rate; ASIR, age-standardized incidence rate; ASMR, age-standardized mortality rate; DALYs, disability-adjusted life years

National Trends in IE Incidence, Mortality, and DALYs

In 2021, at the country level, the ASIR for IE was highest in Thailand (33.55 per 100 000 population), followed by Saint Lucia, Sri Lanka, and Monaco, while Tajikistan recorded the lowest ASIR (4.31 per 100 000 population) (Table S2 and Fig. 3). Switzerland reported the highest ASMR for IE at 3.68 per 100 000 population, followed by Netherlands and American Samoa, whereas Tajikistan had the lowest ASMR at 0.03 per 100 000 population. Additionally, Tokelau exhibited the highest ASDR at 99.95 per 100 000 population, followed by Madagascar and Marshall Islands, with Azerbaijan reporting the lowest ASDR at 1.09 per 100 000 population. From 1990 to 2021, the most substantial increase in ASIR, ASMR, and ASDR for IE were observed in Singapore (137.58%), Taiwan (Province of China, 416.66%), and Russian Federation (357.01%), respectively. Conversely, the most significant decrease in ASIR, ASMR, and ASDR for IE were seen in Nigeria (-20.94%), China (-72.78%), and China (-78.41%), respectively.

Potential Influencing Factors of EAPC

Correlation analyses were conducted between the EAPC of ASR with SDI and ASR in 2021 (Figure S2). A positive correlation was found between the EAPC of ASIR and ASIR in 2021 (r = 0.55, p = 0.01). However, there was no significant correlation between the EAPC of ASIR and SDI (r = 0.43, p = 0.07). No significant associations were observed between the EAPC of ASMR with ASMR and SDI. Similarly, no significant associations were detected between the EAPC of ASDR with ASDR and SDI.

Joinpoint Regression Analysis of IE Incidence, Mortality, and DALYs during 1990–2021

Figure 4 illustrated the joinpoint regression models of IE incidence, mortality, and DALYs across SDI regions from 1990 to 2021. From 1990 to 2021, the global average annual percentage change (AAPC) for ASIR, ASMR, and ASDR was 0.99%, 0.15%, and − 0.26%, respectively. Significantly, the main joinpoint for the global ASIR was in 2007. After that, there was a notable slowdown in the ASIR growth rate. In different SDI regions, the joinpoints for ASIR ranged from 2003 to 2011. This led to a deceleration in the ASIR increase rate afterward, except in the low SDI region. The global joinpoint for ASMR was identified in 2002. Before 2002, there was an increasing trend, and after that, a decreasing trend was observed. The joinpoints for ASMR in various SDI regions were between 1995 and 2008. For the global ASDR, the joinpoint was in 2001. It showed an increasing trend before 2001 and a decreasing trend thereafter. In different SDI regions, the joinpoints for ASDR occurred between 1995 and 2002.

Fig. 4.

Joinpoint regression analysis of age-standardized incidence (A), mortality (B), and DALYs (C) rates for IE by SDI regions during 1990–2021. APC, annual percentage change; DALYs, disability-adjusted life years; SDI, Socio-Demographic Index

Discussion

To the best of our knowledge, the study is the first epidemiological research endeavor to delineate the global, regional, and national burden of IE in 2021 and to examine the temporal trends of IE from 1990 to 2021. Over the past three decades, both absolute number of incident cases and ASIR for IE have displayed an upward trajectory. This observed trend could be attributed, at least partially, to factors such as population growth, aging populations, increased utilization of invasive procedures, and advancements in diagnostic techniques [1, 5, 18]. Despite witnessing an increase in the absolute number of death cases and DALYs associated with IE between 1990 and 2021, the ASMR has remained relatively stable, while the ASDR has shown a decline over the same period. These trends may be linked to advancements in the management of IE, including the introduction of new-generation antibiotics, a higher rate of surgical interventions for patients with clear indications, and the establishment of specialized “Endocarditis Teams“ [5, 9, 18–20].

Consistent with GBD 2019 analysis of IE [1], the ASIR, ASMR, and ASDR demonstrated significantly higher values in males compared to females in 2021. Furthermore, the increase in ASIR was noted to be more rapid in males than in females, indicating a heavier burden of IE among males. In 2021, there were two peaks in the number of incident and death cases of IE across different age groups, with one peak observed among the age group under 5 years and the other among older individuals. The absolute number of incident and death cases decreased in the under 5 age group but increased among older individuals from 1990 to 2021. Remarkably, the primary peak of incident and death cases gradually shifted towards older individuals over time. These findings align with several epidemiological studies conducted in various countries and regions [2, 3, 9], providing further support for the observed trends in the burden of IE across different demographic groups.

Unlike the findings from the GBD 2019 analysis of IE [1], the ASIR exhibited an increase with the escalation of SDI quintiles in 2021, with the highest ASIR observed in the high SDI region. Similarly, the highest ASMR was also recorded in the high SDI region in 2021. Moreover, the high SDI region exhibited the most significant increase in all of ASIR, ASMR, and ASDR among the five SDI regions from 1990 to 2021, indicating a substantial burden of IE in this specific region. The SDI is a composite indicator that encompasses years of education for individuals aged 15 years and older, lag-distributed income per capita, and the total fertility rate among women under 25 years old [14]. The high SDI region exhibits the high levels of education and income alongside a reduced fertility rate. This composite index provides a comprehensive view of the social and economic development status of a particular region, helping to elucidate the relationship between socioeconomic factors and the burden of IE. In the high SDI region, the aging population has emerged as a significant concern, with degenerative valve diseases, prosthetic valves, and intracardiac devices being highlighted as the most common underlying cardiac conditions [2, 6, 12]. The increasing utilization of invasive interventions has also played a role in contributing to a growing burden of healthcare-associated Infective Endocarditis (IE) in this region [21]. Staphylococcus aureus has been identified as the leading causative microorganism in this particular high SDI region [5, 22]. Conversely, in the low SDI region, although there has been a slight declining trend in the ASMR and ASDR, these rates remained relatively high in 2021. Factors such as delayed diagnosis, low rates of positive blood cultures, and limited access to surgery could be contributing to the substantial burden of IE in the low SDI region [6, 13]. Rheumatic heart disease was identified as the major underlying cardiac condition associated with IE in this region [8]. These contrasting trends in IE burden between high and low SDI regions underscored the importance of considering both socioeconomic factors and healthcare infrastructure in understanding and addressing the complexities of IE on a global scale.

In the current study, the correlation analysis revealed a positive association between the EAPC of the ASIR and the ASIR itself. This finding indicated that regions with higher levels of ASIR also exhibited a more rapid growth rate of ASIR over time. Consequently, these regions necessitate heightened attention and targeted interventions.

Antibiotic prophylaxis in individuals at risk has been a topic of significant interest and contention over the past two decades. In 2007, the American Heart Association guidelines for the prevention of IE recommended antibiotic prophylaxis solely for patients with underlying cardiac conditions linked to the highest risk of adverse outcome from IE [23]. Antibiotic prophylaxis was not recommended for moderate and low risk individuals undergoing invasive dental procedures [23]. Moreover, the European Society of Cardiology proposed similar recommendations in 2009 [24], while the National Institute for Health and Care Excellence guidelines suggested complete cessation of antibiotic prophylaxis in the United Kingdom in 2008 [25]. Since then, several studies have examined the impact of restricting antibiotic prophylaxis on the incidence and outcomes of IE, yielding conflicting results [26–28]. In the current study, the joinpoint analysis indicated that there was no abrupt increase in the ASIR, ASMR, and ASDR subsequent to the implementation of updated guidelines for antibiotic prophylaxis on a global scale and across different SDI regions. The findings were consistent with a nationwide epidemiological study in England, which similarly showed no discernible change in the trends of IE incidence since 2008 [28].

Public Health Implications

The study on the burden of IE had significant public health implications. Given the global increase in the ASIR and varying burdens across regions and demographics, healthcare resources must be reallocated. High-ASIR regions, especially those with high SDI, require more advanced diagnostic and treatment facilities, as well as more specialized cardiac care units. The involvement of a multidisciplinary Endocarditis Team is essential for the accurate diagnosis and comprehensive management of IE [18, 29]. While for the low SDI region, resources should be focused on improving basic healthcare infrastructure and access to treatment. Since males experienced a higher burden of IE compared to females, and the peak burden was shifting towards older individuals, resources should be targeted towards these demographics. In particular, screening programs for high-risk groups, such as elderly men with pre-existing heart conditions, should be enhanced. Additionally, the formulation of preventive measures is imperative. Launching public health initiatives to educate the population about the risk factors of IE, such as inadequate oral hygiene, intravenous drug usage, and underlying heart conditions, is crucial [30]. Moreover, the administration of antibiotic prophylaxis before invasive dental procedures is recommended as a preventive measure against IE in individuals at high risk [31, 32]. Future research should focus on clarifying risk factors across diverse regions and evaluating the efficacy of interventions to enhance the management and prevention of IE.

Limitations

Although this study has provided a comprehensive examination of the global, regional, and national burden of IE, along with an analysis of its temporal trends, several limitations do exist and require further exploration and clarification. First, a primary limitation of this study lies in the potential variability in data quality and quantity across different regions and countries. Despite employing mathematical extrapolation and statistical methods to mitigate bias, these disparities could introduce estimation errors. Diverse data collection procedures, resource availability, and reporting standards among regions might lead to inconsistent data, which in turn affected the accuracy of our burden estimations for IE. Second, despite improved diagnostic tools for IE, a large number of cases remained undiagnosed, leading to an underestimation of the incidence of IE. Furthermore, the GBD database did not provide information on the burden of specific classifications of IE, such as NVE, PVE, and CDRIE. This absence restricted our ability to comprehensively analyze the burden associated with different types of IE. Finally, the GBD 2021 dataset lacked data on the risk factors related to IE. Without this information, our analysis of the disease burden was incomplete, as we could not fully explore the causal pathways underlying the occurrence and spread of IE.

Conclusion

The study has elucidated the disparities in the burden of IE in 2021 and the temporal trends from 1990 to 2021, across various aspects such as gender, age groups, SDI regions, geographic regions, and countries. In general, males endured a heavier burden of IE than females. Additionally, over time, the age group bearing the peak burden of IE gradually transitioned towards older individuals. In 2021, the ASIR for IE exhibited an increase with the rise in SDI quintiles, indicating a substantial burden of IE in the high SDI region. Yet, it is noteworthy that the ASMR and ASDR for IE were relatively high in the low SDI region. It is imperative for policymakers to recognize the diverse burden rates across regions and countries, investigate epidemiological characteristics and potential influencing factors in different settings, and tailor region-specific prevention and management strategies accordingly.

Electronic Supplementary Material

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Abbreviations

APC

Annual percent change

AAPC

Average annual percentage change

ASDR

Age-standardized disability-adjusted life years rate

ASIR

Age-standardized incidence rate

ASMR

Age-standardized mortality rate

ASR

Age-standardized rates

CDRIE

Intracardiac device-related infective endocarditis

CI

Confidence interval

CODEm

Cause of Death Ensemble model

DALYs

Disability-adjusted life years

DisMod-MR

Disease Modelling Meta-Regression

EAPC

Estimated annual percentage change

GATHER

Guidelines for Accurate and Transparent Health Estimates Reporting

GBD

Global Burden of Diseases, Injuries, and Risk Factors Study

ICD

International Classification of Disease

IE

Infective endocarditis

NVE

Native valve endocarditis

PVE

Prosthetic valve endocarditis

SDI

Socio-demographic index

ST-GPR

Spatiotemporal Gaussian process regression

UI

Uncertainty interval

Author Contributions

Huanhuan Miao: Conceptualization, formal analysis and writing original draft; Zhanyang Zhou and Zheng Yin: Investigation and methodology; Xue Li: data curation and software; Yuhui Zhang: Methodology and review & editing; Yuqing Zhang and Jian Zhang: Conceptualization and review & editing.

Funding

This work was supported by Beijing Natural Science Foundation (grant number 7222143), Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (2023-I2M-C&T-B-068), and People’s Republic of China and National High Level Hospital Clinical Research Funding (grant number 2022-GSP-GG-9).

Data Availability

Data from the Global Health Data Exchange are publicly available online (https://www.healthdata.org/).

Declarations

Competing Interests

The authors declare no competing interests.