Infective Endocarditis in North Africa and the Middle East, 1990‒2019: Updates from the Global Burden of Disease Study 2019

Background: Infective endocarditis (IE), a severe and economically impactful condition, lacks substantial epidemiological data in the North Africa and Middle East (NAME) region. This study focused on analyzing the trends and burden of IE in NAME from 1990 to 2019, taking into account factors like age, gender, and socio-demographic index (SDI). Methods: The Global Burden of Disease data from 1990 to 2019 was retrieved from the Institute for Health Metrics and Evaluation (IHME) website. Results: Between 1990 and 2019, the age-standardized rates (ASR) for IE incidence increased by 59%, and prevalence and years lived with disability (YLDs) rose by 12% and 9%, respectively, while the ASRs for deaths, disability-adjusted life years (DALYs), and years of life lost (YLLs) saw reductions of 22%, 34%, and 34% in the NAME region. Death rates among children under five declined by 72%. Gender and the SDI did not significantly influence these changes. Saudi Arabia witnessed the most significant increase in ASR of IE incidence since 1990, while Turkey had the highest rates in 2019. The year 2019 also saw the highest death rate among those aged 70 and over, with over 91000 DALYs from IE. DALYs decreased by 71.5% for children under five from 1990 to 2019 but remained stable for individuals in their seventies. Jordan showed the most notable decrease in ASRs for deaths, DALYs, and YLLs among children under five. Conclusion: This study highlights the changing epidemiology of IE in the NAME region, recommending the establishment of multidisciplinary IE registries, antibiotic prophylaxis guidelines for healthcare-associated IE, and strategies to control antimicrobial resistance as key mitigation measures.


Introduction
][8][9][10][11][12][13] The North Africa and Middle East (NAME) region, with over 470 million people in 2021 and 21 countries with diverse and dynamic socio-demographic and progress levels, has a global significance out of proportion to its size, with the population doubling in 2019 compared to 1990. 14,15[18]

Overview of the Global Burden of Disease Study
The Global Burden of Disease (GBD) 2019 is an international collaborative study that estimates the burden of 369 diseases and injuries and 87 risk factors in 204 countries and territories since 1990.These countries and territories are grouped into 21 regions and seven super-regions.The methodology of the GBD 2019 study is reported elsewhere. 19The estimation process for infective IE is described in Supplementary file 1.

Data Resources
The Institute for Health Metrics and Evaluation (IHME) provided the 1990-2019 GBD data.The GBD online results tool and GBD compare tool allow interactive viewing of the data under the diagnosis code B.2.11 in the "Cause" section.The definition of endocarditis is established based on clinical criteria.[21][22]

Estimation of Non-fatal Health Outcome and Cause of Death Using Modeling Strategies for the Global Burden of Endocarditis
The IHME employed robust modeling strategies and statistical methods to estimate non-fatal health outcomes and causes of death in order to assess the global burden of endocarditis.The following summary is derived from the extensive methodology appendix in the original sources published in the Lancet journal. 19or estimation of non-fatal measures (incidence, prevalence, and years lived with disability [YLD]), the input data consisted of model inputs that encompassed a revised systematic review of the GBD 2015, hospital inpatient data, and claims data.The estimation of endocarditis for GBD 2019 was conducted using DisMod-MR 2.1.This method is extensively explained elsewhere. 23he combination of prevalence and incidence of causes and sequelae with levels of severity related to disability (by using disability weights) while correcting for comorbidity resulted in the YLD calculation.The evaluation of models conducted by IHME involved a comparison of the model's fit with both the available data and the outcomes obtained from previous estimation cycles.Figure S1 in Supplementary file 2 illustrates the flow chart pertaining to the estimation of non-fatal health outcomes.
The assessment of mortality related to endocarditis involved using vital registration data to create a model specific to this condition.After addressing issues related to data quality, the Global Burden of Disease study in 2019 employed various statistical techniques to determine the number of deaths associated with each distinct cause.This process was executed using the Cause of Death Ensemble model algorithm (CODEm). 24In order to prevent the occurrence of a situation where the cumulative number of deaths attributed to various causes surpasses the overall estimated number of deaths, a correction method known as CoDCorrect was employed. 25LL were calculated by multiplying the estimated number of deaths by the standard life expectancy at the age of death.Figure S2 displays the flow chart outlining the process for estimating endocarditis as a potential cause of death.Lastly, the index pages containing statistical, analytical, processing, and estimation code for GBD 2019 can be found in alternative sources. 26he Guidelines for Accurate and Transparent Health Estimates Reporting (GATHER) were followed. 27fghanistan, Algeria, Bahrain, Egypt, Iran (the Islamic Republic of), Iraq, Jordan, Kuwait, Lebanon, Libya, Morocco, Oman, Palestine, Qatar, Saudi Arabia, Sudan, the Syrian Arab Republic, Tunisia, Turkey, United Arab Emirates, and Yemen comprise NAME.The SDI summarizes "average income per person, educational attainment, and total fertility rate," with higher numbers indicating higher socio-economic development.NAME region countries were classified into high, high-middle, middle, low-middle, and low SDI.In accordance with AHA guideline updates, we divided the time period from 1990 to 2019 into three eras: the first (1990-1997), the second (1998-2007), and the third (2008-2019).

Decomposition Analysis
We conducted decomposition analysis on the 1990-2019 incidence rate of IE to identify the factors that influenced it, following the approach used in previous GBD studies. 28actors such as population growth, aging, and age-specific IE incidence rates drive the trend.The study estimated age-specific IE incidence rate changes while controlling for population size and age structure.The expected IE incidence in 2019 was calculated in two phases: accounting for population growth by applying 1990 age-specific IE incidence rates to 2019 population size, and accounting for both population growth and age structure change by applying 1990 age structure and age-specific IE incidence rates to the 2019 population size and age structure.

Statistical Analysis
We used the R statistical package version 4.0.4 to analyze data, ensuring that all values were within a 95% uncertainty interval (UI) calculated from the 25th and 975th ordered values between 1000 draws in each computational step.No overlap between UIs or opposing signs indicated statistical significance.
Supplementary files 2 and 3 contain supplementary figures and tables.

Incidence
In 2019, there were 81.5 thousand (67-98) new cases of IE in NAME, which showed a 144% rise compared with 1990.Decomposition analysis revealed that 58.8% of this increase was due to the rise in incidence rate rather than population growth or aging (Tables 1-4).Agestandardized rate (ASR) increased by 34% (31 to 37%) in 2019, reaching 15.4 per 100 000 (95% UI: 12.9-18.2).Age-standardized and all-age incidence rates of IE were not significantly influenced by gender (Figures S3-S5).Furthermore, the number of new IE cases was unrelated to the SDI type.
There was no consistent link between the SDI category of a country and the ASDR.

Disability-Adjusted Life Years
In 2019, there was a total number of 91.3 thousand disability-adjusted life-years and ASR of 17.6 per 100 000 (12.9-21.4)due to IE in the NAME region, which showed a 34% decrease (19-46%) compared to 1990.There was no gender difference between ASRs of DALYs in 2019.Acinetobacter baumannii was responsible for the highest portion of DALYs with an ASR of 3.91 (2.65-5.72)per 100 000 (Tables S6 and S7).
Tunisia experienced the lowest significant decrease in YLL, with a 29 percent reduction (3-50%) in ASIR to achieve a YLL ASR of 12.3 per 100 000 (95% UI: 8.7-17) in 2019.In the Syrian Arab Republic, the United Arab Emirates, Iraq, Oman, Yemen, Saudi Arabia, Afghanistan, Morocco, and Kuwait, the observed percent change, as a decrease or increase, was not statistically significant (Table S8).
There was no consistent relationship between the ASR of YLL and the SDI of countries.
With the exception of Turkey, Jordan, Bahrain, and Qatar, YLD ASR increased significantly across the board in the region in 2019, with percentage increases ranging from 7% (1-15%) in the United Arab Emirates to 42% (31-55%) in Oman.Only in Turkey did the ASR of YLD experience a small decline (6%, -25% to 20%) (Table S9 and S10; Figure S10 -Figure S12).
The ASR of YLD and the SDI of nations did not correlate with one another (Figure S13).

Impact of Three Iterations of AHA Guidelines in 1990, 1997, and 2007 on the Burden of IE in the NAME Region
From 1990 to 2019, there was a steady upward trend in incidence, prevalence, and YLDs and a downward trend in ASRs of deaths, DALYs, and YLLs.However, there was no temporal correlation between these trends and the dates that the AHA released new guidelines in 1990, 1997, and 2007 (Tables S10 and S11, Figure S14 and Figure S15).
Table S12 shows NAME countries with the highest and lowest IE epidemiologic measures and burden in 2019.
Figures S16-S19 illustrate the trend according to SDI and age groups.

Discussion
This study showed that, at the regional level, between 1990 and 2019, ASRs of incidence, prevalence, and YLDs increased by 59%,12%, and 9%, respectively, whereas ASRs of deaths, DALYs, and YLLs declined by 22%, 34%, and 34%, respectively (Figure S20).Furthermore, incidence rates of IE increased by 56% (46-64) in the 70 + -yearold population in the NAME region.Less than 5-yearold children witnessed a conspicuous drop in rates of deaths, YLLs, and DALYs in respective order of 72% (-19 to -85%), 72% (-19 to -85%), and 71% (-19 to -85%).At the country level, in 2019, Turkey experienced the highest ASR of IE incidence, prevalence, death, and YLD, whereas Saudi Arabia showed the highest percentage increase in ASIR of IE during these three decades.However, the percent change for ASR of prevalence and YLD was at the lowest level for this country.In 2019, Afghanistan had the lowest ASR of incidence, prevalence, DALYs, and YLDs.Palestine had the lowest ASRs of death, DALY, and YLL.Oman experienced the highest percent change in ASPR, and Egypt witnessed the highest ASR of DALY and YLL (Table S10).
A study on the epidemiology and the burden of IE in the countries of NAME spanning the three decades of 1990 to 2019 has been conducted only in Iran. 30Ajam et al conducted a comprehensive investigation on the epidemiology and impact of IE in Iran, spanning the period from 1990 to 2019.Their findings revealed a notable rise in the ASIR and ASPR of IE, while the age-standardized mortality rate (ASMR) and age-standardized DALYs rate exhibited a decline over the course of three decades in Iran.The majority of provinces exhibited a consistent trend, wherein North Khorasan displayed the highest rates of ASIR, ASPR, ASMR, and DALYs in both years.
In a study involving 132 cases of definite IE conducted in Egypt, El-Kholy et al discovered that 69.7% of patients exhibited blood culture-negative IE (BCNIE).Upon implementing serology and polymerase chain reaction (PCR) on both blood and valvular tissue, this percentage decreased to 49.2%. 31Considering that cases are enrolled based on clinical diagnosis, it can be inferred that the reported incidence by IHME might underestimate the actual frequency of IE (Supplementary file 1).To prevent the potential underdiagnosis of IE and to ensure effective treatment, the development and implementation of a consistent, stepwise guideline for approaching BCNIE is of utmost importance.
Similarly, Zaqout et al studied 57 patients with IE between 2015 and 207 in Qatar, 17 of whom had prosthetic cardiac valves or implantable cardiac devices.Staphylococci were the most common etiologic agent. 324][35] Emerging risk factors, changing demographics of the at-risk population to an elderly population with coexisting comorbidities or healthcare-associated infections, and evolving causative microorganisms and their invasiveness and resistance can result in further increase IE incidence and prevalence.
The significant increase in ASRs of DM and CKD calls for immediate action by health policymakers to implement strategies for reducing the modifiable risk factors of DM and CKD.A study by Li-Jin et al identifies hypertension as the top risk factor for IE mortality from 1990 to 2030. 36he ASIR of IE in Saudi Arabia increased from 10.8 per 100 000 in 1990 to 17.7 per 100 000 in 2019, but this increase is not solely due to the SDI level, as Jordan experienced the smallest increase between 1990 and 2019.It seems that advancements in invasive medical procedures, particularly transcatheter cardiovascular interventions, play a greater role. 37he epidemiologic transition of IE involves a shift towards older, complex, and comorbid populations, which are more likely to acquire invasive microorganisms due to their higher risk of healthcare-associated infections.The age range shift is partly a reflection of the global improvement in life expectancy and the aging of the world population. 38E in the elderly and in patients with healthcareassociated IE is often caused by more virulent microorganisms with higher rates of antibacterial tolerance, persistence, and resistance.[39][40][41] Consequently, these factors can result in lower rates of cure, as well as increased rates of prevalence and YLDs of IE.
The significant decrease in under-5 mortality may indicate success in achieving Sustainable Development Goal 3.2.1,approved by the United Nations in 2015. 42o prevent a rise in the number of new cases and stop the increasing prevalence of IE, it is necessary to implement primary, secondary, and tertiary prevention measures at both the national and regional levels.
Primary prevention interventions may include public education regarding lifestyle optimization to prevent obesity and hypertension (as modifiable risk factors for DM and chronic kidney disease) and to adhere to doctors' prescriptions for IE antibiotic prophylaxis.Physicians must be informed about evolving IE risk factors, emerging microorganisms, at-risk populations, and AP guidelines, with specific guidelines aimed at preventing healthcareassociated infective endocarditis.(HAIE).
][45] Moreover, policies should be implemented to prevent and control antimicrobial resistance. 46ertain infrastructure initiatives, such as the establishment of healthcare-related IE registries and the Artificial Intelligence-Enhanced Electronic IE Registry Network (AIERN) of the NAME region, can be crucial for registering IE-related strategic health data. 47,48

Conclusion
The study revealed a significant shift in IE epidemiology in the NAME region, notably an increase in elderly cases.From 1990 to 2019, there was a rise in IE incidence, prevalence, and YLDs.In 2019, IE rates increased significantly in septuagenarians, while deaths and DALYs remained stable.Turkey experienced the highest ASR of incidence, prevalence, and deaths.No correlation was found between IE rates and gender, SDI, or the AHA guideline updates.ASR for deaths, DALYs, and YLLs decreased, especially in children under five in Jordan.To mitigate IE, comprehensive prevention, a regional registry, a multidisciplinary team approach, antimicrobial resistance protocols, and public education on lifestyle factors are crucial.Additionally, integrating AP for IE into the core curricula of medical and dental education and continuing professional development are highly recommended.

Table 1 .
All-Ages Number, All-Ages Rate, and Age-Standardized Rate of Incidence, Prevalence, Deaths, DALYs, YLLs, and of Infective Endocarditis in 1990 and 2019 in NAME with 95% Uncertainty Intervals AA, all-ages; ASR, age-standardized rate; DALYs, disability-adjusted life years; YLLs, years of life lost; YLDs, years lived with disability; NAME, North Africa and the Middle East 95% UI:16.1-22.2) in 2019 (Tables

Table 2 .
Percent Changes (%) of Different Metrics of Epidemiologic Measures of Infective Endocarditis in North Africa and the Middle East between 1990 and 2019

Interpretation Differences in Direction of Percent Changes Across All-Age Numbers, Percentages, Rates, and Age-Standardized Rates and Percentages Point Estimate Lower Bound Upper Bound
AAN, All ages number; AAP, All ages percent; AAR, All ages rate; ASP, Age-standardized percent; ASR, Age-standardized rate.

Table 3 .
Decomposition Analysis of Incidence Rate Change of Infective Endocarditis between 1990 and 2019 in North Africa and the Middle East and the 21 Countries of This Region

Table 4 .
All-Ages Number, All-Ages Rate, and Age-Standardized Rate of Incidence, Prevalence, Deaths, DALYs, YLLs, and YLDs of Infec-tive Endocarditis in North Africa and the Middle East in 1997 and 2007 ASR: age-standardized rate; DALYs, disability-adjusted life years; YLLs, years of life lost; YLDs, years lived with disability; NAME, North Africa and the Middle East Infective endocarditis in North Africa and the Middle East