Trends in Deaths from Rheumatic Heart Disease in the Eastern Mediterranean Region: Burden and Challenges

Rheumatic heart disease (RHD) is a preventable disease that is prevalent in developing regions of the world. Its eradication from most of the developed world indicates that this disease can be controlled and eliminated. Aim: To conduct an in-depth analysis of the trends and challenges of controlling RHD in the Eastern Mediterranean region (EMR). Methodology: Global data from the World Health Organization (WHO) data banks were retrieved for total deaths and age standardized death rate per 100,000 (ASDR) by age group, sex, and year (from 2000 to 2015). The data was compared with the five other WHO regions of the world. We also performed in-depth analysis by socio-economic groups in relation to other attributes in the region related to population growth, illiteracy, and nutritional status. Indicators of service delivery were correlated with ASDR from RHD. Findings: Prevalence of RHD in 2015 in the EMR region was one-third of that of the total deaths reported in the Asian and West Pacific regions. The total deaths for the region peaked twice: in early adulthood and again later in old age, and was higher in females than in males. There was a rising trend in deaths from RHD from 2000 to 2015. The highest total deaths were reported from Egypt, Pakistan, Iran, Afghanistan, and Yemen, representing 80% of the total death rates for the region (35,248). The highest ASDR was Afghanistan (27.5), followed by Yemen (18.78) and Egypt (15.59). The ASDR for RHD was highest in low income countries. It correlated highly, in all income groups, with anemia during pregnancy. Conclusions: Trends and patterns of deaths from RHD in the EMR have shifted to a later age group and are linked with poverty related to inequalities in development and service delivery for certain age groups and gender.


Introduction
Rheumatic heart disease (RHD) is a preventable disease that is linked with poverty, and is prevalent in developing regions of the world. Its eradication from most developed countries indicates that this disease can be controlled and eliminated.
The World Health Organization [1] was the first to release guidelines for the prevention and control of streptococcal disease and Rheumatic fever (RF) that have since been updated and adapted by many countries and regions around the world [2,3]. In Egypt in the 1960s, the Abdin and Eissa working group [4,5] established a link between streptococcal disease and RHD, and attributed it to poor living

Methods
Global data from the World Health Organization (WHO) data banks were compiled and analyzed for deaths from RHD in the EMR by gender and other factors from 2000 to 2015.
Data for the individual countries were retrieved from the World Bank and WHO (http://www. worldlifeexpectancy.com). The site uses data from these primary sources: WHO, World Bank, UNESCO, CIA, and individual country databases for global health and causes of death.
Data for service delivery and demographic data were taken in 2017 from the WHO-EMR Framework of Health Information Systems and core indicators for monitoring health situations and health system performance. The data represented surveys from 2014 and 2015.
The data was compiled in Excel spreadsheets, and was statistically analyzed using standard methods.
The countries were categorized by income level into three groups: Inc; Chicago, IL, USA, running on IBM compatible computer with Microsoft Windows 7 Operating System. The Student t-test (for parametric data) and Mann-Whitney U test (for non-parametric data) were used for comparison of two distinct groups. Analysis of variance with a post hoc Bonferroni test (for parametric data) and Kruskal-Wallis test, followed by a Mann-Whitney U test (for non-parametric data), were used to compare groups. Categorical variables were compared using Chi square and Fisher exact tests. The Spearman rank correlation coefficient was used to measure the strength and direction of linear relationship between two variables. The level of significance cut off was set at p < 0.05.

Results
The findings presented in the Figure 1 show that the pattern of RHD increased in early adulthood (30-49 years), and then peaked again in the elderly after 70 years of age in both males and females. The pattern of deaths demonstrated a double peak that was slightly higher in females than males, exhibiting a more prominent peak in late adolescence and early adulthood, probably reflecting the increased risk of death during pregnancy and labor.  Although data of total deaths may be misleading (as they depend on total population and population density), they nonetheless give some insight into the magnitude of the problem of RHD in the region.  Although data of total deaths may be misleading (as they depend on total population and population density), they nonetheless give some insight into the magnitude of the problem of RHD in the region. Figure 3 compares the total deaths from RHD in the EMR with the other regions. It shows that the total deaths from RHD in South East Asia region (SEAR) was 4.3 times higher for males and 4.7 times higher for females than that observed in the EMR. Also, total deaths in the West Pacific region (WPR) were two times higher among males, and four times higher among females, compared to EMR region rates. The African region had the same death toll as the EMR. This could be confounded by differences in under detection and under reporting in the EMR and African region, thereby underestimating the actual prevalence of the disease.  Figure 4 shows the total deaths from RHD at national levels. This data was obtained from another source (the World Bank and WHO, 2014). The total deaths for EMR from this source showed a higher burden of deaths (35,248) than the data of Global Burden of Disease Study (22,956), although they represented a one year difference (2014 and 2015 respectively). Total deaths by country was highest in Afghanistan (9168) and lowest in Qatar (8). Total deaths reported from Egypt, Pakistan, Iran, Afghanistan, and Yemen represented 80% of the total deaths for the region (35,248 Figure 3 compares the total deaths from RHD in the EMR with the other regions. It shows that the total deaths from RHD in South East Asia region (SEAR) was 4.3 times higher for males and 4.7 times higher for females than that observed in the EMR. Also, total deaths in the West Pacific region (WPR) were two times higher among males, and four times higher among females, compared to EMR region rates. The African region had the same death toll as the EMR. This could be confounded by differences in under detection and under reporting in the EMR and African region, thereby underestimating the actual prevalence of the disease. Figure 3 compares the total deaths from RHD in the EMR with the other regions. It shows that the total deaths from RHD in South East Asia region (SEAR) was 4.3 times higher for males and 4.7 times higher for females than that observed in the EMR. Also, total deaths in the West Pacific region (WPR) were two times higher among males, and four times higher among females, compared to EMR region rates. The African region had the same death toll as the EMR. This could be confounded by differences in under detection and under reporting in the EMR and African region, thereby underestimating the actual prevalence of the disease.  Figure 4 shows the total deaths from RHD at national levels. This data was obtained from another source (the World Bank and WHO, 2014). The total deaths for EMR from this source showed a higher burden of deaths (35,248) than the data of Global Burden of Disease Study (22,956), although they represented a one year difference (2014 and 2015 respectively). Total deaths by country was highest in Afghanistan (9168) and lowest in Qatar (8). Total deaths reported from Egypt, Pakistan, Iran, Afghanistan, and Yemen represented 80% of the total deaths for the region (35,248 Figure 4 shows the total deaths from RHD at national levels. This data was obtained from another source (the World Bank and WHO, 2014). The total deaths for EMR from this source showed a higher burden of deaths (35,248) than the data of Global Burden of Disease Study (22,956), although they represented a one year difference (2014 and 2015 respectively). Total deaths by country was highest in Afghanistan (9168) and lowest in Qatar (8). Total deaths reported from Egypt, Pakistan, Iran, Afghanistan, and Yemen represented 80% of the total deaths for the region (35,248).    Table 1 shows the mean ASDR for RHD per 100,000. By income group, ASDR for RHD was highest in the LIC (12.80 ± 8.58) compared to MIC (6.0 ± 4.54) and HIC (3.93 ± 5.29). Hence, ASDR increased with decreasing levels of income in the countries under study, reflecting the importance of improving social conditions for preventing the disease. Table 1 shows that correlation coefficients of ASDR from RHD with selected social indicators were significant for anemia during pregnancy (r0.74), mortality from exposure household and ambient air pollution (MAAP) (r0.6), literacy (r-0.58), and total fertility rates (TFR) (r0.57). It was also      Table 1 shows the mean ASDR for RHD per 100,000. By income group, ASDR for RHD was highest in the LIC (12.80 ± 8.58) compared to MIC (6.0 ± 4.54) and HIC (3.93 ± 5.29). Hence, ASDR increased with decreasing levels of income in the countries under study, reflecting the importance of improving social conditions for preventing the disease. Table 1 shows that correlation coefficients of ASDR from RHD with selected social indicators were significant for anemia during pregnancy (r0.74), mortality from exposure household and ambient air pollution (MAAP) (r0.6), literacy (r-0.58), and total fertility rates (TFR) (r0.57). It was also  Table 1 shows the mean ASDR for RHD per 100,000. By income group, ASDR for RHD was highest in the LIC (12.80 ± 8.58) compared to MIC (6.0 ± 4.54) and HIC (3.93 ± 5.29). Hence, ASDR increased with decreasing levels of income in the countries under study, reflecting the importance of improving social conditions for preventing the disease. Table 1 shows that correlation coefficients of ASDR from RHD with selected social indicators were significant for anemia during pregnancy (r0.74), mortality from exposure household and ambient air pollution (MAAP) (r0.6), literacy (r-0.58), and total fertility rates (TFR) (r0.57). It was also present, but not statistically significant, for maternal mortality ratio (MMR) (r0.49) and low birth weight (LBW) (r0.46).
Analysis by income groups showed that in high-income countries, there was significant correlation of ASDR per 100,000 from RHD by country with total literacy (r0.87), female literacy (r0.84), and the presence of anemia during pregnancy (r0.83), at p < 0.05. In middle income countries, there were significant correlations of ASDR per 100,000 from RHD by country with mortality from ambient air pollution (r0.81) and anemia during pregnancy (r0.74), at p < 0.05 and 0.001 respectively. In low-income countries, there was a moderate correlation of ASDR per 100,000 from RHD by country with anemia during pregnancy (r0.52), at p < 0.05 as shown in Table 1. Table 1 also demonstrates associations between health care management of services and ASDR per 100,000 from RHD, as follows. For all countries, ASDR per 100,000 correlated with nursing and midwifery per 1000 population (r-0.48), at p < 0.05, while correlating negatively with per capita total expenditure on health (r-0.49), at p < 0.05, and out-of-pocket expenditure as a percentage of total health expenditure (r0.53), at p < 0.05. The correlative studies by income group for the same indicators were as follows. In high-income countries, it correlated with physician and nursing per 1000 population (r-0.84 and r-0.76), at p < 0.05 and p < 0.05 respectively, and with primary health care facilities per 10,000 population (r0.78), at p < 0.05. Whereas in middle-income countries, Age Standardized Death rate per 100,000 from RHD correlated negatively with physician per 1000 population (r-0.61), at p < 0.05, and per capita total expenditure on health care (r-0.69), at p < 0.05. In low-income countries, Age Standardized Death rate per 100,000 from RHD correlated with physician per 1000 population (r-0.66), at p < 0.05.

Discussion
Our study shows that the total deaths from RHD are not declining possibly related to improved detection and reporting. The pattern of the burden of death from RHD in the EMR countries is moving to a higher age group compared to the patterns reported in the past century [4][5][6]. Late adolescence and early adulthood are mostly at risk of death from RHD, possibly due to the drop-out from health care, and gaps in adolescent health care services in these age groups, particularly in middle-and low-income countries. The higher burden in females reflects increased risk from pregnancy and childbirth.
The differences in the total deaths between regions probably reflect under detection and under reporting, rather than de facto lower prevalence in the EMR and Afro regions compared with the SEAR and WPR. Still, the burden was shown to be in the range of 3-5 times, which is a significant difference, and more in-depth analysis is needed.
Our findings run in parallel with those of the EMR team of Global Burden of Disease Study Group [7], who presented an elegant study of the overall burden of deaths from cardiovascular diseases (CVD) in the EMR, including deaths from RHD and disability related life years (DALYS) from this disease. They highlighted the decrease in prevalence of the disease from 1990 to 2015 by one third, but did not perform a micro-analysis of the period from 2000 and 2015. They emphasized that cardiovascular diseases, particularly ischemic heart disease, is the leading cause of mortality in the region [7]. We argue that although death from RHD represents a minor portion of overall death from CVD, the DALYs for RHD are particularly high because of the wider age range involved, starting from early childhood and extending throughout the remainder of life. The prolonged period of disability these individuals suffer as children and adults influences their quality of life by decreasing their opportunities, increasing their poverty, and decreasing their life expectancy [7].
A recent study [8] estimated that there were 319,400 deaths in 2015. They reported that global age-standardized mortality from RHD decreased from 9.2 deaths per 100,000 population in 1990 to 4.8 deaths per 100,000 population in 2015, showing a decrease of 47.8%. They reported that the largest number of deaths occurred in East and South Asia, which is in agreement with the findings in this study. However our study does not show the decrease in death from RHD from 2000 to 2015 that was described in their study. This decrease may have been true for other regions of the world and for the HIC in EMR, but not for the LIC and MIC, as shown by the differences of ASDR by income group in this study.
The Watkins team estimated that the global prevalence of RHD was 33.4 million cases worldwide, which is really only the tip of the iceberg, as expressed by Marijon [10], and is more than twice that calculated by a systematic evaluation of the literature [15]. The estimate was based on modeling due to a lack of data; for instance, 15 out of 53 countries in Africa lack primary sources of data on deaths from RHD [16].
In this analysis, EMR reported deaths from RHD totaled 22,980. The latter is probably an underestimation, since, in the Watkins study, the estimate of deaths in Pakistan alone was 18,900. Also our data estimate the number of deaths from SEAR to be 126,907, while the Watkins study group [16] estimated that the numbers of deaths due to RHD in India and China alone (119,100 and 72,600 deaths respectively) were much higher than those reported by the WHO for the region. Other contributors [9] to the journal in which the study of the Watkins team was published argue that the calculations may be an underestimate. They argue that by limiting heart failure as the main underlying cause of death, their estimates may have suppressed other causes of death as causes or contributing factors to RHD [17], such as atrial fibrillation, endocarditis, severe pulmonary venous hypertension, stroke, failure of anticoagulation therapy, and decompensation associated with pregnancy [18].
The Watkins study reported that a high ASDR, more than 10 deaths per 100,000 population from RHD, was identified in Pakistan in the EMR, Central African Republic and Lesotho in Africa, India, from Asia, and Solomon Islands, Papua New Guinea, Kiribati, Vanuatu, Fiji, Federated States of Micronesia, and the Marshall Islands from West Pacific regions [9]. Other authors pursue the argument that the global community cannot be complacent on the issue of RHD control, as RHD still prevails in pockets of low socioeconomic activity, and among immigrants even in developed countries [19][20][21].
In this study, we found high correlations of ASDR from RHD with social indicators such as literacy and TFR. RHD is a disease of poverty, and primordial prevention plays a significant role in its prevention. The disease has been eradicated in regions by simply improving living conditions, personal hygiene, and access to clean water, as well as increasing awareness and education [8]. The crowding index, which is closely linked to TFR, has been closely linked with higher prevalence of streptococcal disease [4][5][6]. This might explain the high correlation with the limited social indicators reported in our study, but nonetheless warrants further investigation [16].
Furthermore we found some moderate correlations with MMR and LBW which again reflect the higher prevalence and higher burden among females. This is in agreement with the findings of other workers [15], who reported that the disease is more prevalent among females. Possible causes include late detection, exposure to social discrimination, stigma from the disease interfering with prospects of marriage (especially in females living in socially deprived areas), illiteracy, and disempowerment [15,16].
In this study we showed correlations of ASDR from RHD and service management issues. The Australian "continuous quality approach" [22] for modeling service delivery in high-risk communities has shown itself to be effective [23]. It emphasizes the need for improving communication in the delivery of services [24]. However it is important to emphasize that improving service delivery alone cannot prevent the disease; it is more important to improve the living conditions for patients. This requires in-depth needs assessments, involving multifaceted interventions and mapping of resources and stakeholders, in order to identify the best approaches to deliver community-based services which are tailored to the needs of sustained development [25,26].
The primary health care approach is ideal for the prevention and control of RHD, as it represents the front line for detection and adequate treatment of sore throats for primary prevention [27], ensuring compliance for secondary prevention and referral for efficient management of cases at tertiary levels [28]. To do so, it requires intensive training and capacity building of primary health care and managerial staff, in order to manage efficient registries and referral systems [29]. With problems of understaffing, rapid turnover, and over-burdened, poorly paid, and inadequate monitoring and evaluation, many cases can be missed or can drop out of the system, increasing the burden of disability, which was estimated to be 1430 DALYS in 2010 [30], the equivalent of one quarter of the Global DALYS of cancer cases, leading to high expenditure with poor survival rates in complicated cases [14].
Mortality rates have been underestimated for decades. In the global systemic review of 2005, the burden of RHD estimates comprised 15.6 million cases, 282,000 incident cases, and 233,000 deaths annually [15,31]. A more recent analysis calculated a much higher figure of 314,000. The actual burden may still be higher, and methods to improve such estimates have been considered by other workers [32]. Our findings of differential data between WHO global data banks, other data banks, and national reporting, indicate that the burden of the disease may continue to represent a challenge [30].
RHD is a marginalized, neglected, poorly capitalized and poorly-addressed disease that continues to face barriers related to inequality and poor accessibility and dismantlement of health services [33]. The challenges related to controlling RHD are related to under detection, under reporting, poor compliance, poor access to care, poor prognosis, poor postoperative care, poor registration systems, and lack of equitable access to gold standard screening methods, lack of culturally sensitive adolescent health services and inadequate school (and university) health care systems [34,35]. In developing countries, where referral systems and continuity of care is lacking, the problem of RHD prevention and control will prevail, unless reforms based on models that ensure continuity of care and equity are enacted by governments [36].
From a developmental perspective, RHD is a disease of poverty, inequitable distribution of resources, and social inequality [37,38]. For instance, females in this study had a higher prevalence of death from RHD than males in all regions. This can be explained by social factors, as discussed earlier, but also by poor access to health care for early detection, lack of resources, and lack of awareness and education about the necessity of access to contraception. Increased mortality really begins at puberty and menstruation. It is at this time that females shift toward immune TH2 pathways making them more vulnerable to the immunological changes accompanying the development and progression of RHD [5]. The exacerbation of the underlying immune mediated responses to RHD is likely to explain why women have more complications than men at this age.
The REMEDY group [39] reported that females were more affected. This was a prospective registry study that enrolled 3343 patients with RHD from 25 hospitals in 12 African countries, and also included countries from the Asia as India. Among the 1825 women of childbearing age (12-51 years), only 3.6% (n = 65) were on contraception. One third of the cases indicated to receive anticoagulants were not receiving them, and only one third of the cases which were on anticoagulants had a therapeutic international normalized ratio. The utilization of valvuloplasty and valve surgery was higher in upper-middle-income, compared with lower-income, countries [28]. Such findings can explain the higher prevalence of deaths among females, particularly those living in poverty. The authors concluded that female patients are the most vulnerable population, due to suboptimal utilization of secondary antibiotic prophylaxis, oral anti-coagulation, and poor access to contraception and timely surgical interventions [39].
Several investigators [16] have discussed the fact that the many challenges to the prevention and control of RF/RHD can be helped by estimating the true global burden of the disease. They emphasize that although registries with good quality of data are important, this has been limited to countries such as Australia, New Zealand, Pacific Islands, South Africa, and Tunisia, and is lacking in many other countries inflicted with this disease. Screening methods are archaic and need to be updated [6,40]. There is a need for capacity building of physicians and primary health care providers to notify, correctly report positive diagnoses and manage RF/RHD prevention and control programs by developing short and long term courses, qualifications and degree programs to be adopted by universities in developed and developing countries [36].
Although primordial prevention, followed by improving service delivery, is the primary control strategy for the control of RHD, poverty and inequity impede program inputs. For instance, countries with poor economies in many settings in EMR and African countries lack the consistent supply of quality-assured benzathine benzylpenicillin for primary prevention and secondary prophylaxis [41]. This is even happening in some pockets in developed countries [42]. Manufacturers in such countries fail to supply these drugs because of the price inflations that impede their manufacturing and supply at low cost for the poor. Governments need to network with international manufacturers to upgrade these medicines and make them available through subsidization for the poor and needy populations affected by the disease [37,43,44].
Another major barrier is that governments are overwhelmed with other priorities, and do not see RHD as a priority, as it predominantly affects poor and marginalized communities. Hence, the lack of advocacy and persistent marginalization of RHD control programs by governments, coupled by poor funding and budget allocation of resources for the program, make the health system unable to implement efficient services for early detection, referral, follow-up, and provision of essential care, particularly in low-income settings [37,38].
Advocacy can be strengthened by finding synergy between RHD, and established high-priority targets in global health could help RHD gain a stronger foothold. For example, the sustainable development agenda and the recent global focus on NCD prevention have both provided a new platform for RHD advocacy [45][46][47]. Moreover, in June 2017, the Executive Board of the WHO recommended a resolution (expected to be adopted at the 71st World Health Assembly (WHA) in 2018) on "rheumatic fever and RHD" [45].
Because RHD is a disease of poverty, its persistence in poor countries handicaps and aggravates the economic situation in these countries. RHD starts in early childhood, and thereby increases the DALYs which adversely influence the economy [37]. Globally, RHD is the fifth leading cause of cardiovascular-related mortality, and the sixth leading cause of cardiovascular-related disability. The combination of years of life lost (premature deaths) and years lived with disability, expressed as DALYs, is 10.5 million/year for RHD [44,47].
The Addis Ababa communiqué, as follows, has since been endorsed by heads of state of the African Union and EMR countries: (1) create prospective disease registers at sentinel sites in affected countries to measure disease burden and track progress towards a reduction of mortality by 25% by the year 2025, (2) ensure an adequate supply of high-quality benzathine penicillin for the primary and secondary prevention of ARF/RHD, (3) improve access to reproductive health services for women with RHD and other non-communicable diseases (NCD), (4) decentralize technical expertise and technology for diagnosing and managing ARF and RHD (including ultrasound of the heart), (5) establish national and regional centers of excellence for essential cardiac surgery for the treatment of affected patients and training of cardiovascular practitioners of the future, (6) initiate national multi-sectorial RHD programs within the NCD control programs of affected countries, and (7) foster international partnerships with multinational organizations' for resource mobilization, monitoring and evaluation of the program to end RHD in Africa [48]. Plans are underway to implement a roadmap to end ARF and RHD in Africa in our lifetime, and change trends and outcomes of the disease in our region and around the world [43,44,49,50].

Conclusions
We emphasize the important role of social determinants and the importance for primordial preventive strategies as key to the eradication of RHD. This should include improving education opportunities, especially for females, and access to birth control services, improving living conditions and intensifying awareness campaigns by using the underutilized social media eHealth platforms of networking and health promotion. Primary health care in the region should aim at reforming delivery of its services, particularly for adolescents, thereby reducing inequity, exclusion, and social disparities in health, so as to achieve universal coverage. The health services should be organized around people's needs and expectations, and this requires service delivery reforms. RHD should become a priority for governments, and an index for human development. This requires a collaborative model of policy dialogue, increased stakeholder participation, and pressure from international agencies. Finally, the challenge to eradicate RHD in the EMR remains with low-and middle-income countries in the region, i.e., 70% of the countries in the region, and over 90% of its total population. These communities suffer from chronic emergencies and political instability [20], which increase the burden of poverty and rates of integration in primary health care provisions, and thereby continue to make RHD a potential risk for increased disability and poor development. The World Health Assembly resolution for RF and RHD on its 71st meeting is expected to bring hope for renewed efforts to control and eliminate Rheumatic fever and Rheumatic heart disease globally [44].