Rheumatic heart disease (RHD) results in morbidity and mortality that is disproportionate among individuals in developing countries compared to those living in economically developed countries. The global burden of disease is uncertain because most previous studies to determine the prevalence of RHD in children relied on clinical screening criteria that lacked the sensitivity to detect most cases. The present study was performed to determine the prevalence of RHD in children and young adults in León, Nicaragua, an area previously thought to have a high prevalence of RHD. This was an observational study of 3,150 children aged 5 to 15 years and 489 adults aged 20 to 35 years randomly selected from urban and rural areas of León. Cardiopulmonary examinations and Doppler echocardiographic studies were performed on all subjects. Doppler echocardiographic diagnosis of RHD was based on predefined consensus criteria that were developed by a working group of the World Health Organization and the National Institutes of Health. The overall prevalence of RHD in children was 48 in 1,000 (95% confidence interval 35 in 1,000 to 60 in 1,000). The prevalence in urban children was 34 in 1,000, and in rural children it was 80 in 1,000. Using more stringent Doppler echocardiographic criteria designed to diagnose definite RHD in adults, the prevalence was 22 in 1,000 (95% confidence interval 8 in 1,000 to 37 in 1,000). In conclusion, the prevalence of RHD among children and adults in this economically disadvantaged population far exceeds previously predicted rates. The findings underscore the potential health and economic burden of acute rheumatic fever and RHD and support the need for more effective measures of prevention, which may include safe, effective, and affordable vaccines to prevent the streptococcal infections that trigger the disease.
Before the availability of Doppler echocardiographic technology, the diagnosis of rheumatic heart disease (RHD) was made on the basis of clinical history and physical findings. Two previous reports presented evidence that the clinical examination lacks sensitivity in detecting RHD in high-risk populations. Marijon et al found that echocardiography detected 10 times the number of cases of RHD compared to clinical examination alone in large studies of children in Cambodia and Mozambique. The present study was undertaken on the basis of extensive experience by one of us (J.A.P.) conducting a cardiology clinic in León, Nicaragua, over the past 24 years indicating that the prevalence of RHD was probably high and that the current approach of identifying and treating patients with known RHD only on the basis of clinical findings was inadequate to address the magnitude of the problem. Inasmuch as there are current efforts to produce an effective vaccine against group A streptococcus, which could potentially prevent acute rheumatic fever (ARF), we wished to establish the true prevalence of RHD in the population using physical examinations and Doppler echocardiographic criteria.
Methods
We performed an observational community-based study from 2006 to 2009 of 3,150 children living in the municipality of León. Dwellings were randomly selected from the population database of the demographic surveillance system of Centro de Investigación en Demografía y Salud of Universidad Nacional Autonoma de Nicaragua at Léon. This surveillance population corresponds to clusters selected with probability proportional to size from the entire population of León. After approval by the minister of health in Nicaragua and the ethics committees of Universidad Nacional Autonoma de Nicaragua and the University of Tennessee Health Science Center, all children in selected dwellings aged 5 to 15 years were invited to participate in the study. Consent was obtained from parents and from children aged ≥13 years. All children whose parents gave permission to Centro de Investigación en Demografía y Salud surveyors were transported to the pediatric cardiology clinic of Hospital Escuela Oscar Danilo Rosales Argüello. A clinical report form was completed by a study nurse after interviewing the parent and subject. Examination of the lungs and heart was performed by a cardiologist, and an opinion was rendered as to the presence or absence of clinical evidence of RHD. A Doppler echocardiographic study was performed on all subjects using a Vivid I digital machine (GE Healthcare, Milwaukee, Wisconsin). Studies were performed by a pediatric cardiologist (NMB) or by 1 of 4 qualified visiting echocardiographic technicians. Echocardiographic examinations included parasternal long- and short-axis and apical 3- and 4-chamber views. Normal subjects and those with evidence of congenital heart disease without RHD exited the study. Doppler echocardiographic studies with abnormal results consistent with RHD were stratified as indicating definite, probable, or possible RHD, as defined by an expert panel convened under the auspices of the World Health Organization and the National Institutes of Health in September 2005 ( Table 1 ).
| Definite RHD (either A or B) |
| A. Significant mitral stenosis, defined as echocardiographic evidence of mitral stenosis with a mean diastolic pressure gradient across the mitral valve >4 mm and clinical findings of mitral stenosis with or without other valvular lesions. Such abnormalities as dogleg deformity of the anterior mitral valve leaflet, fixed or restricted mitral leaflet abnormality, calcification, and commissural thickening were expected. |
| B. The presence of a heart murmur consistent with any combination of MR or aortic regurgitation and Doppler echocardiographic evidence of rheumatic valvular damage, defined as any of the following: |
| 1. Significant MR, with an MR jet ≥2 cm from the coaptation point of the valve leaflets, seen in 2 planes, of high velocity (mosaic pattern), holosystolic, plus thickened mitral valve leaflets and/or dogleg deformity of the anterior mitral leaflet. Additional changes might include multiple regurgitant jets, especially posterolaterally directed. |
| 2. Significant aortic regurgitation, defined as an aortic regurgitation jet ≥1 cm from the coaptation point of the valve leaflets, of high velocity, seen in 2 planes, plus thickened mitral leaflets and/or dogleg deformity, without another apparent cause for the aortic insufficiency, such as a bicuspid aortic valve or annuloaortic ectasia. Aortic stenosis might be associated, but aortic stenosis without associated rheumatic mitral valve disease was not accepted as evidence of rheumatic valvular disease. |
| Probable RHD |
| The presence of a heart murmur consistent with any combination of MR or aortic regurgitation, and the subject comes from a population with known or suspected high rates of ARF and/or RHD and no history of definite or probable ARF, and any of the following findings are present on echocardiography: |
| 1. Thickened mitral valve leaflets and/or dogleg deformity of the anterior mitral valve leaflet without significant mitral stenosis. |
| 2. Significant MR, as defined under definite RHD, without thickened mitral valve leaflets and/or dogleg deformity of the anterior mitral valve leaflet. |
| 3. Significant aortic regurgitation, as defined under definite RHD, without thickened mitral valve leaflets and/or dogleg deformity of the anterior mitral valve leaflet. |
| Possible RHD |
| The absence of a valvular heart murmur in a subject from a population with known or suspected high rates of ARF and/or RHD with any of the following Doppler echocardiographic changes: |
| 1. Thickened mitral valve leaflets and/or dogleg deformity of the anterior mitral valve leaflet. |
| 2. Significant MR, as defined under definite RHD. |
| 3. Significant aortic regurgitation, as defined under definite RHD. |
All subjects classified as having probable or possible RHD were scheduled for repeat clinical and echocardiographic evaluations within 4 to 12 months (target 6 months) after the initial encounter. All subjects meeting any of the diagnostic criteria for RHD were referred to the RHD clinic at Hospital Escuela Oscar Danilo Rosales Argüello to receive antibiotic prophylaxis and follow-up care, which was not part of the investigative protocol. Subjects were then reclassified on the basis of the results of the second examinations. The data were analyzed according to health center region, urban versus rural location, age, gender, and changes in diagnostic status with subsequent studies. All Doppler echocardiographic studies that showed abnormalities consistent with definite, probable, or possible RHD were read independently by 2 cardiologists, and any discrepancies in reading were resolved either by review of the study and agreement between the readers or by submission to a third cardiologist as a tiebreaker. All follow-up studies were read by 2 cardiologists, and in all cases the echocardiograms were recorded in crude Digital Imaging and Communications in Medicine format. Studies with abnormal results and follow-up studies were recorded in Moving Picture Experts Group format and retained for subsequent review.
Because RHD in some subjects may manifest as a progressive chronic disease of the cardiac valves, we subsequently performed an additional study to assess the prevalence of RHD in young adults aged 20 to 35 years. The selection of adult participants followed procedures similar to those used to select the pediatric participants. Because it was likely that cardiac pathology unrelated to RHD would be more prevalent in this age group, only 2 classifications of RHD were specified, with the intent of excluding nonrheumatic causes by requiring anatomic changes typical of RHD and not Doppler abnormalities alone ( Table 2 ). Cardiopulmonary examinations and Doppler echocardiographic studies were performed on all subjects as previously described. Doppler echocardiographic studies with abnormal results consistent with RHD were reviewed independently by 2 cardiologists, and the results were categorized into group 1 or group 2 as described ( Table 2 ).
| Definite RHD with physical findings |
| Structural abnormalities of the mitral valve compatible with RHD and the presence of a heart murmur thought to be of valvular origin. The criteria were otherwise the same as for the pediatric study (see Table 1 ). Aortic valve thickening with aortic regurgitation, in the absence of rheumatic changes of the mitral valve, was not considered diagnostic of RHD. |
| Definite RHD without physical findings |
| Doppler echocardiographic evidence of anatomic changes of the mitral valve compatible with RHD (see Table 1 ) in the absence of a murmur thought to be of valvular origin. Aortic valve thickening with aortic regurgitation was not an accepted diagnostic criterion in the absence of rheumatic changes of the mitral valve. |
The sample size for the study in children was calculated on the basis of an anticipated prevalence of RHD of 3 in 1,000 (World Health Organization Technical Reports Series 923) to estimate the prevalence of RHD within 0.2% points with a 95% confidence interval (CI). These calculations also assumed a 1.2 design effect due to clustering in the sampling design. Assuming a 10% nonresponse rate, we targeted a total of 3,600 children. Because the nonresponse rate plus migrations and missed appointments was approximately 20%, an additional random sample of 1,000 children was drawn to complement the initial sample. At the time the adult study was designed, we calculated a rate of RHD of 33 in 1,000 in children. We determined that a sample size of 500 would allow us to obtain an estimate for adults with a 95% CI of ±0.016 (16 in 1,000).
We estimated the prevalence per 1,000 subjects of the different RHD diagnosis categories and by gender and location (rural vs urban). We computed 95% CIs for prevalence estimates and tested the differences between some of these groups using design-adjusted chi-square tests. The Taylor series expansion method to estimate standard errors, as implemented by SAS version 9.2 (SAS Institute Inc., Cary, North Carolina), was used to account for clustering effects as appropriate for the sampling design.
Results
Among the 3,150 children who participated in the study, the mean age was 9.5 years, the median age was 10.7 years, 51% were male and 49% female, 70% were from urban neighborhoods, and 30% were classified as rural ( Table 3 ). Results of the initial examinations revealed an overall prevalence of RHD of 48 in 1,000 (95% CI 35 in 1,000 to 60 in 1,000), with most subjects meeting the criteria for possible RHD ( Table 4 ). Fifty-five percent of subjects with RHD were female. There was a significantly higher prevalence of RHD in subjects from rural compared to urban environments (77 in 1,000 vs 35 in 1,000, p <0.0001) ( Table 5 ). Of the 42 children with congenital heart disease (1.3% of the total), most had congenitally abnormal aortic valves.
| Variable | Pediatric Subjects | Adult Subjects |
|---|---|---|
| (n = 3,150) | (n = 489) | |
| Age (years) | ||
| Mean | 9.5 | 27.4 |
| Median | 10.7 | 26.8 |
| Range | 5–15 | 20–35.9 |
| Male | 1,619 (51%) | 184 (38%) |
| Female | 1,531 (49%) | 305 (62%) |
| Urban | 2,206 (70%) | 316 (65%) |
| Rural | 944 (30%) | 173 (35%) |
| RHD Diagnostic Category | Number | Male/Female | Prevalence |
|---|---|---|---|
| Normal | 2,959 | 1,522/1,437 | NA |
| Possible | 137 | 59/78 | 43/1,000 |
| Probable | 8 | 6/2 | 3/1,000 |
| Definite | 5 | 2/3 | 2/1,000 |
| Congenital heart disease ⁎ | 42 | 30/12 | 13/1,000 |
| Total | 150 | 67/83 | 48/1,000 |
⁎ One participant met the diagnostic criteria for congenital heart disease and definite RHD.
| RHD Diagnostic Category | Urban | Rural |
|---|---|---|
| Possible | 67 | 70 |
| Probable | 6 | 2 |
| Definite | 4 | 1 |
| Prevalence of RHD | 35/1,000 | 77/1,000 |
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