Abstract

Background

Enteric infections are among the most common infectious diseases. The aim of this article was to track the global trends in morbidity and mortality from enteric infections in 204 countries or territories from 1990 to 2019.

Methods

Data were obtained from the Global Burden of Disease 2019 study. Average annual percentage changes (AAPCs) in age-standardized incidence rate (ASIR) and age-standardized mortality rate (ASMR) were calculated to quantify trends in enteric infections. Age-period-cohort models were used to estimate the annual percentage changes from 0 to 4 to 80 − 84 years (local drifts), period and cohort effects between 1990 and 2019 in different socio-demographic index (SDI) regions.

Results

In 2019, there were 6.59Ìýbillion incident cases of enteric infections, and caused 1,748,251 deaths worldwide. From 1990 to 2019, the trend in the global ASIR of enteric infections was relatively stable, but that of ASMR declined (AAPC=-3.30, 95% confidence interval [CI]: -3.54 to -3.07), and global mortality decreased in all age groups. Meanwhile, decreasing trends in ASMR were observed in 173 countries/territories (P < 0.05), particularly in North Macedonia and Kazakhstan. The low and low-middle SDI areas showed decreasing trends in ASIR and ASMR for enteric infections. However, an increasing trend was observed in high SDI regions, especially among older people aged over 60 years.

Conclusions

The global incidence of enteric infections did not change significantly between 1990 and 2019, but the mortality showed a significantly downward trend. The global burden of enteric infections remains serious in children under 5 years and in low and low-middle SDI regions.

Introduction

Enteric infections are infectious diseases of the intestine caused by parasitic, bacterial, and viral pathogens that disrupt intestinal function and cause diarrhoea and dehydration, with serious consequences for intestinal absorption, nutrition, and child development, and for the global burden of disease [1,2,3]. Enteric infections and diarrhoeal diseases are estimated to be among the top 10 causes of death and disability-adjusted life years for all ages and the top five causes of death and disability-adjusted life years for children under five years of age [4]. Furthermore, enteric infections early in life can lead to systemic chronic inflammation and impaired cognitive development subsequently [5], which can have serious consequences in adolescence and adulthood [1].

In recent decades, the burden of enteric infections has varied spatially and temporally across countries and regions, particularly in low- and middle-income countries, due to the inequitable distribution of resources such as healthcare, safe drinking water, and sanitation [6, 7]. Therefore, it is highly essential to investigate the spatial and temporal variations in the burden of enteric infections over the past few decades in countries with different socio-economic levels. However, comparisons of regional and temporal trends in the burden of enteric infections have been limited. A growing number of studies have used the socio-demographic index (SDI) to estimate the burden of disease in countries or regions with different socio-economic levels, while those studies describing the time trend of the disease have focused only on changes in age-standardized morbidity and mortality over time, or have performed only a traditional descriptive analysis of age-specific morbidity or mortality at different times [8, 9], which may ignore the independent impact of age, period, and birth cohort effects on disease morbidity and mortality. The age-period-cohort (APC) model has improved the traditional method of describing and analyzing diseases by estimating the risk of disease incidence or mortality and its trends, subject to adjustment for age, period, and cohort [10, 11]. Therefore, this study aimed to analyze the spatial and temporal trends of enteric infection morbidity and mortality from 1990 to 2019 in 204 countries and regions using data from the Global Burden of Disease (GBD) 2019 study, and to assess the effects of age, period and birth cohort on enteric infection morbidity and mortality from 1990 to 2019 in different SDI countries using the APC models.

Methods

Study data

The GBD 2019 provides a systematic estimate of the impact of diseases, injuries, and risk factors on health for 204 countries and territories from 1990 to 2019 [12, 13]. This study used the online Global Health Data Exchange results tool (GHDx, ) to extract data on the burden of enteric infections including the number of cases and deaths, age-standardized incidence rates (ASIRs), and age-standardized mortality rates (ASMRs) with 95% uncertainty intervals (UIs) by gender, age and location from 1990 to 2019 [14]. Besides, we analyse the etiologies for the cause of deaths from enteric infections, the GBD 2019 study has identified 13 etiologies. The GBD study used the disease-model-Bayesian meta regression tool (named DisMod-MR 2.1) to estimate the burden of enteric infections. This tool integrates diverse disease parameters, epidemiological relationships, and geospatial data to generate robust estimates [13].

The SDI has been used to provide a comprehensive assessment of the level of social development for each country or region. It’s a composite index estimated by the level of per capita income, the total fertility rate of women under 25 years, and the level of education of people aged 15 years and over, ranging from 0 to 1. This analysis used the SDI for each country, which was classified into five SDI levels based on the SDI values: high (greater than 0.81), high-middle (0.70–0.81), middle (0.61–0.69), low-middle (0.46–0.60), and low (less than 0.46) [15].

Statistical analysis

Average annual percentage change

Considering that differences in age structure may lead to spatial heterogeneity for morbidity and mortality of enteric infections in different countries, we used the ASIR and ASMR to analyse the trend for enteric infections from 1990 to 2019. We calculated the average annual percentage changes (AAPCs) to evaluate the overall trend of ASIR and ASMR for enteric infections from 1990 to 2019, and the AAPC and its 95% confidence interval (CI) were estimated using the linear regression model and the methodological details were described in a previous study [9, 16]. The AAPCs were calculated using the Joinpoint Regression program (version 4.8.0.1; ), and P < 0.05 was considered significant.

Age-period-cohort model

This study used the APC model to explain the effects of age, period, and cohort on morbidity and mortality for enteric infections. The APC provides a parametric framework that complements standard nonparametric descriptive methods [10, 11]. In the APC model, the input data including incident (death) counts and population data for specific age groups over calendar time, and the age and period intervals must all be the same. Considering the relatively low number of morbidity and mortality in the over 85 age groups may affect the robustness of the APC model. In this study, 17 age groups (i.e., 0–4, 5–9, 10–14, …, 75–79, and 80–84 years) and six five-year-periods (i.e., 1990–1994, 1995–1999, …, 2010–2014, and 2015–2019) were divided, and the mid-year datasets for each five-year-periods (i.e., 1992, 1997, 2002, 2007, 2012, and 2017) were used as input data. The outputs of the APC model include fitted longitudinal age-specific incidence (mortality) rates in the reference cohort, adjusted for period deviations to represent age-related natural history (i.e., age effects), and period (cohort) rate ratios of morbidity and mortality for each period (cohort) to represent period (cohort) effects. The APC model also estimated the annual percentage change in the expected age-specific incidence (mortality) rates over time (i.e., the local drift, % per year). Generally, a drift of ± 1% per year or more is considered a substantial change in incidence (mortality) [17]. The APC model is implemented using a freely available web tool (), and the methodological details are described in previous literature [17]. In this analysis, the median age and period ranges were used as reference points for calculations. The chi-squared test was used to test whether the incidence (mortality) rates were significantly different, and P < 0.05 was considered significant.

Results

Trends in the incidence of enteric infections

The number of enteric infections worldwide in 2019 was 6.59Ìýbillion (95% UI: 6.06Ìýbillion to 7.15Ìýbillion), with an increase of 42.43% since 1990 (Fig.Ìý1A and Table S1). The global trend in ASIR was relatively stable during 1990 to 2019, and the AAPC was 0.02 (95% CI: -0.07 to 0.10). Compared with other regions, low SDI and high SDI regions had the highest and lowest ASIR, respectively, during 1990 to 2019 (Fig.Ìý1B). The decreasing trends in ASIR were observed in low and low-middle SDI areas, particularly in low-middle SDI areas (AAPC = -0.64, 95% CI: -0.71 to -0.56). In contrast, the high SDI areas showed increasing trends in ASIR, with an AAPC of 0.32 (95% CI: 0.28 to 0.35) (Fig.Ìý1B and Fig. S1). At the 21 regional levels, decreasing trends in AISR were observed in seven regions, particularly in Central Latin America (AAPC = -1.27, 95% CI: -1.31 to -1.24), followed by South Asia and Central Europe. Conversely, increasing trends were observed in 14 regions, and the most pronounced one occurred in North Africa and the Middle East (AAPC = 1.24, 95% CI: 1.20 to 1.28), followed by Andean Latin America and Central Sub-Saharan Africa (Fig. S1).

Fig. 1

Trends in incident cases (A), age-standardized incidence rates (B), number of deaths (C), and age-standardized mortality rates (D) for enteric infections globally and by socio-demographic index (SDI) area from 1990 to 2019

In 2019, the countries with the highest number of enteric infections were India (1.68Ìýbillion, 95% UI: 1.54Ìýbillion to 1.84Ìýbillion), China (7.18 × 10⁸, 95% UI: 6.48 × 10⁸ to 7.95 × 10⁸), and Pakistan (3.03 × 10⁸, 95% UI: 2.72 × 10⁸ to 3.37 × 10⁸) (Fig. S2). The ASIR of enteric infections in 2019 was heterogeneous across 204 countries/territories, ranging from 9,905.58/100,000 (95% UI: 8,742.86 to 11,293.394 per 100,000) in Japan to 184,304.72/100,000 (95% UI: 170,993.69 to 198,285.17 per 100,000) in Solomon Islands (Fig.Ìý2C). Trends in ASIR for enteric infectious exhibited variation across countries between 1990 and 2019 (Fig.Ìý2A and Fig.Ìý2C). A decreasing trends in ASIR for enteric infections were observed in 56 countries/territories ( P < 0.05), particularly in Guatemala and Mexico, where the AAPCs were − 2.14 (95% CI: -2.22 to -2.07) and − 1.93 (95% CI: -2.00 to -1.86), respectively. In contrast, increasing trends were observed in 139 countries/territories (P < 0.05), the largest being Turkey (AAPC = 1.61, 95% CI: 1.57 to 1.65), followed by Libya (AAPC = 1.59, 95% CI: 1.54 to 1.63) and Iran (AAPC = 1.59, 95% CI: 1.45 to 1.72) (Fig.Ìý2E and Table S3).

Fig. 2

Global age-standardized incidence and mortality rates (per 100,000) for enteric infections in 1990 (A and B) and 2019 (C and D) and the average annual percentage change (AAPC) in age-standardized incidence and mortality rates (E and F) rates for enteric infections from 1990 to 2019

Trends in death of enteric infections

The number of deaths from enteric infections was 1,748,251 (95% UI: 1,286,411 to 2,416,191) worldwide in 2019, with a decrease of 44.79% since 1990 (Fig.Ìý1C and Table S1). From 1990 to 2019, the global ASMR for enteric infections exhibited a declining trend, and the AAPC was − 3.30 (95% CI: -3.54 to -3.07). Compared with other regions, there showed the highest and the lowest ASMR in low SDI and high SDI regions from 1990 to 2019, respectively (Fig.Ìý1D). Decreasing trends in ASMR of enteric infections were observed in high-middle SDI (AAPC=-4.21, 95% CI: -4.31 to -4.11), middle SDI (AAPC=-4.28, 95% CI: -4.47 to -4.10), low-middle SDI (AAPC=-4.09, 95% CI: -4.46 to -3.73), and low SDI (AAPC=-3.16, 95% CI: -3.36, -2.96) areas. Whereas increasing trends in ASMR occurred in the high SDI areas, with the AAPC being 1.17 (95% CI: 0.88 to 1.46) (Fig.Ìý1D and Fig. S1). At the 21 regional levels, decreasing trends in ASMR were observed in 18 regions, particularly in East Asia (AAPC = -9.11, 95% CI: -9.52 to -8.70), followed by Central Asia (AAPC = -7.58, 95% CI: -7.80 to -7.36) and Tropical Latin America (AAPC = -6.87, 95% CI: -7.08 to -6.67). Conversely, increasing trends in ASMR were observed in 3 regions, and the most pronounced one occurred in High-income North America (AAPC = 7.21, 95% CI: 6.75 to 7.68), followed by Australasia (AAPC = 2.78, 95% CI: 2.4 to 3.16) and Western Europe (AAPC = 2.58, 95% CI:2.15 to 3.02) (Fig. S1).

In 2019, the countries with the biggest number of deaths from enteric infections were India (701,671, 95% UI: 419,720 to 1,121,819), Nigeria (220,246, 95% UI 167,786, to 280,015) and Pakistan (101,485, 95% UI: 101,485 to 141,829) (Fig. S3). The ASMR of enteric infections in 2019 was heterogeneous among 204 countries/territories, ranging from 0.11/100,000 (95% UI: 0.08 to 0.15 per 100,000) in Montenegro to 231.13/100,000 (95% UI: 132.87 to 356.73 per 100,000) in the Central African Republic (Fig.Ìý2D). Trends in ASMR for enteric infectious exhibited variation across countries between 1990 and 2019 (Fig.Ìý2B and Fig.Ìý2D). A decreasing trends of ASMR for enteric infections were observed in 173 countries/territories (P < 0.05), with the largest decrease in North Macedonia (AAPC = -10.59, 95% CI: -11.43 to -9.75), followed by Kazakhstan, Uzbekistan, Armenia, and China. In contrast, 26 countries/regions showed an increasing trend (P < 0.05), the largest being Sweden (AAPC = 8.01, 95% CI: 6.95 to 9.08), followed by Austria (AAPC = 7.92, 95% CI: 7.09 to 8.76), and Canada (AAPC = 7.66, 95% CI: 6.04 to 9.30) (Fig.Ìý2F and Table S3).

Time trends in incidence and mortality of enteric infections across different age groups

FigureÌý3 shows the annual percentage change in incidence and mortality of enteric infections for each age group from 1990 to 2019 (i.e., the local drift of incidence and mortality). Globally, the incidence of enteric infection showed increasing trends (i.e., local drift values greater than 0%) in the age groups over 70 years, while decreasing slightly in the age groups under 20 years (P < 0.001). For high SDI areas, the incidence of enteric infection showed increasing trends in the age groups over 10 years (P < 0.001). Whereas decreasing trends (i.e., local drift values less than 0%) occurred in the under 70 age groups in low-middle and low SDI areas. Although changes in the incidence of enteric infections were observed in different age groups, these changes did not substantially change (local drift values less than ± 1% per year) (Fig.Ìý3A). For the change in mortality of enteric infections across different age groups, decreasing trends were seen in global, high-middle, middle, low-middle and low SDI areas across all age groups among both males and females (P < 0.001). Whereas increasing trends occurred in high SDI areas in the over 35 age groups for both males and females (P < 0.001) (Fig.Ìý3B).

Fig. 3

The annual percentage change (i.e., local drift) in the incidence (A) and mortality (B) of enteric infections for each age group globally and across socio-demographic index (SDI) areas from 1990 to 2019

Age, period, and cohort effects on enteric infections incidence

FigureÌý4 shows the APC model-derived estimates of age-period-cohort effects on the incidence of enteric infections by SDI quintiles. Generally, similar patterns of age effects were found across different SDI quintiles, with a higher risk in children under five years old and in elderly people aged over 70 years. The risk of age effects was lowest in those aged 20 − 60 years (Fig.Ìý4A; Fig. S4A). Period effects showed a declining risk of enteric infections in global, high-middle, middle, low-middle, and low SDI areas from 1990 to 2012 and then gradually increased from 2012 to 2019. For high SDI areas, period effects of incidence displayed a growth trend from 2002 to 2019 (Fig.Ìý4B). The risk of cohort effects for enteric infections incidence increased among those born before 1940 and then slowly decreased among those born after 1940 globally. Similar trends were observed in high-middle SDI areas. High-SDI countries showed an increased risk of incidence in those born after the 1960s, whereas the risk declined in low-middle and low-SDI areas (Fig.Ìý4C).

Fig. 4

Age, period, and cohort effects on incidence from enteric infections globally and across socio-demographic index (SDI) areas

Age, period, and cohort effects on enteric infections mortality

FigureÌý5 presents the age-period-cohort effects on enteric infection mortality by SDI quintiles. Globally, age effects with a higher risk in children under five years old and in elderly people aged over 70 years, and the risk increases with age in people over 70 years old (Fig.Ìý5A; Fig. S4B). Similar patterns in age effects were found in high-middle, middle, low-middle, and low SDI areas (Fig.Ìý5A). Period effects showed a declining risk of enteric infections mortality in global, high-middle, middle, low-middle and low SDI areas from 1990 to 2019. For high SDI areas, period effects of mortality displayed a growth trend from 1990 to 2007 and then gradually decreased from 2007 to 2019 (Fig.Ìý5B). The risk of cohort effects for enteric infections mortality significantly decreased among those born before 1960 and then slowly decreased among those born after 1960 in global, high-middle, middle, low-middle and low SDI areas. In high SDI countries, there was a progressive improvement in mortality for those born after the 1910s and before the 1990s, while the risk declined after the 1990s (Fig.Ìý5C).

Fig. 5

Age, period, and cohort effects on mortality from enteric infections globally and across socio-demographic index (SDI) areas

The etiologies for the cause of enteric infections deaths

FigureÌý6 shows the etiologies for the cause of deaths of enteric infections in 2019 by SDI quintiles. Generally, the etiologies for the cause of death from enteric infections were different between SDI regions. Globally, Rotavirus (accounting for 19.46%) was the most important etiology for the cause of enteric infections deaths, followed by Shigella (12.19%) and campylobacter (11.7%). In high SDI areas, Clostridium difficile (64.29%) and Norovirus (15.79%) were the two most important pathogens causing deaths due to enteric infections. The high-middle SDI areas were Rotavirus (25.33%) and Clostridium difficile (17.21%). Middle SDI areas were Rotavirus (29.46%) and Norovirus (15.12%). Low-middle SDI areas were Campylobacter (17.01%) and Rotavirus (14.85%). Low SDI areas were Rotavirus (14.98%) and Cholera (14.72%).

Fig. 6

The etiologies for the cause of death from enteric infections globally and across socio-demographic index (SDI) areas in 2019. A, Age-standardized mortality rates; B, Proportion of age-standardized mortality rates

Discussion

In this study, we assessed the AAPCs in the ASIR and ASMR of enteric infections in 204 countries and territories from 1990 to 2019 and analysed the age-period-cohort effects of enteric infection incidence and mortality globally and in different SDI regions. In particular, we estimated temporal trends in morbidity and mortality for each age group using the APC models. We found that the global incidence of enteric infections has not changed significantly over the past 30 years, but mortality has improved significantly. The burden of enteric infections remains severe in low SDI and low-middle SDI regions. This study provides a more refined understanding of temporal trends in enteric infections and provides additional insights into relevant public health strategies.

In recent decades, the global mortality of enteric infections has improved significantly as a result of effective interventions such as improved water, sanitation, and hygiene (WASH), particularly the increased use of oral rehydration solution and vaccination, but the changes in morbidity of enteric infections have been insignificant [6, 18,19,20]. According to estimates, 2Ìýbillion people still lacked safely managed drinking water, 670Ìýmillion people with no handwashing facilities at all, and 494Ìýmillion people practiced open defecation in 2020 [21]. These vulnerable populations living in high-risk environments for enteric infections may be the drivers of insignificant changes in the incidence of enteric infections. In addition, the insignificant change in incidence may also be related to the increasing use of the main therapeutic drugs (proton pump inhibitors, PPIs) for treating gastroesophageal diseases around the world. For example, omeprazole is available over the counter without a prescription in many countries, and severe hypochlorhydria caused by PPIs can lead to bacterial colonization and increase the susceptibility to enteric bacterial infections [22].

Notably, we found a decreasing trend in the ASIR of enteric infections in low and low-middle SDI regions, suggesting that health investments in low- and middle-income countries may yield greater health benefits [13]. However, we found an increasing trend in ASIR of enteric infections in high-SDI regions. This may be related to increased life expectancy and population ageing in high SDI countries. We found a significantly higher incidence of enteric infections in older people over 70 years than in other age groups. The Scallan et al. study also showed that older people were more likely to suffer from certain enteric infections (including foodborne infections) and to have a more severe course of disease [23]. Nevertheless, as this study did not include data from the age group of 85 years and above in the APC model, the resulting estimates may not fully capture the increased burden of enteric infections in people aged 85 and above. In addition, drinking water supplies in small rural areas, and remote or other marginalized communities in high-income countries also face severe challenges [24]. Over the past decade, drinking water-related outbreaks have affected hundreds to thousands of people in high-income countries such as Canada, the United States and the United Kingdom [25]. In short, the rising trend in the incidence of enteric infections remains a continuous concern for high-income countries.

We found a 44.79% reduction in global deaths from enteric infections in 2019 compared to 1990. Even in India, which had the highest number of deaths from enteric infections, there was a 42.18% reduction in deaths compared to 1990. This is consistent with other studies, which may be due to the water, sanitation, and hygiene (WASH) intervention, improved healthcare, and the use of oral rehydration solutions [7, 26]. For example, Bangladesh has implemented large-scale safe water supply projects and open defecation reduction projects, in which open defecation was reduced from 34% in 1990 to only 1% of the country’s population in 2015 [27]. We observed a 64% reduction in deaths from enteric infections in Bangladesh from 1990. The Swachh Bharat Mission project conducted in India aims to achieve an open defecation free India, with over 100Ìýmillion toilets built by 2019, benefiting 500Ìýmillion people. And the policy has been adopted by countries like Nigeria, Indonesia and Ethiopia [28]. We have observed significant reductions in mortality rates from enteric infections in these countries. Similarly, the Sustainable Water and Sanitation Services Programme in Brazil has had a positive impact on enteric diseases [29], and we have observed an 82% reduction in deaths in Brazil since 1990. Oral rehydration solutions have been shown to have clear benefits in preventing severe dehydration and death. Since the 1970s, oral rehydration solutions have been recommended to prevent and treat dehydration from diarrhoea, and it is estimated that oral rehydration solutions can prevent 93% of diarrhoea-related deaths [26]. In addition, we found that among the 13 pathogens identified, rotavirus was the most prominent cause of death from enteric infections worldwide, accounting for 19.46%. The declining burden of death from enteric infections may be related to the increased vaccination coverage for rotavirus, poliovirus, Salmonella typhi, etc [20]. In particular, rotavirus vaccine coverage has been widespread, with the rotavirus vaccine reported to be widely available in 91 countries by 2017 [20]. Studies have shown that rotavirus vaccines are effective in reducing the burden of disease, with a 74% reduction in specific mortality [30]. In India, the rotavirus vaccine was introduced into the universal immunisation programme in 2016 and has significantly reduced the mortality rate of severe diarrhoea cases among Indian children [31]. Pakistan has also made significant progress with rotavirus vaccines, reportedly exceeding 80% coverage and significantly reducing infant diarrhoea cases and deaths [32].

Although we found a decreasing trend in ASMR for enteric infections globally, there is an increasing trend in ASMR for enteric infections in high SDI regions. For example, the ASMR for enteric infections was increasing exponentially in countries such as Austria, Canada, Sweden, and the United States. This may be driven by an ageing population, with older people often suffering from underlying conditions that increase their susceptibility to enteric infections, such as hyperglycemia which can lead to intestinal barrier dysfunction, and disruption of intestinal barrier integrity which increases the risk of systemic infections [33]. This study also found that the mortality rate from enteric infections in the elderly over 60 years of age in high SDI countries is increasing at a rate of about 4% per year. On the other hand, the well-established health systems and healthcare services in these high SDI countries may have increased the antibiotic resistance of intestinal bacteria and the probability of hospital-acquired enteric infections [34, 35]. We found that Clostridium difficile was the most dominant cause of death from enteric infections in high SDI countries, accounting for 64.29% of the 13 pathogens identified. While Clostridium difficile is a major cause of hospital-acquired enteric infections [36]. Clostridium difficile has been reported to cause nearly 250,000 infections and over 12,000 deaths per year in the United States [37].

This study has several limitations. Firstly, the main limitation of GBD is the availability of original data [13], especially in some low- and middle-income countries where the lack of reliable epidemiological data and the underreporting of enteric infections may lead to an underestimation of the true burden. Which may affect our estimates of age-period-cohort trends in enteric infections. Secondly, This study employed the AAPC to analyse long-term trends in overall change, without accounting for the potential impact of seasonal trends in enteric infections. To address this limitation, future studies might consider utilising quarterly data. Thirdly, this study only analysed 13 pathogens, which may ignore some epidemiological information. Finally, this study analysed the morbidity and mortality at the national level but did not analyse differences at the sub-national level. This may affect the interpretation of the results at the sub-national level.

Conclusions

This study showed that the global incidence of enteric infections did not change significantly from 1990 to 2019, but the mortality showed a decreasing trend and decreased in all age groups. However, the ASIR and ASMR of enteric infections in high SDI areas showed an increasing trend, particularly in older people aged over 60 years. The global burden of enteric infections remains higher in children under 5 years and in low and low-middle SDI areas compared with other age groups and areas. Therefore, reducing spatial disparities in the burden of enteric infections requires sustained public health interventions.