Background
Using 2012 World Heart Federation criteria, standard portable echocardiography (STAND) reveals a high burden of rheumatic heart disease (RHD) in resource-poor settings, but widespread screening is limited by cost and physician availability. Handheld echocardiography (HAND) may decrease costs, but World Heart Federation criteria are complicated for rapid field screening, particularly for nonphysician screeners. The aim of this study was to determine the best simplified screening strategy for RHD detection using HAND.
Methods
In this prospective study, STAND (GE Vivid q or i or Philips CX-50) was performed in five schools in Gulu, Uganda; a random subset plus all children with detectable mitral regurgitation or aortic insufficiency also underwent HAND (GE Vscan). Borderline or definite RHD cases were defined by 2012 World Heart Federation criteria on STAND images, by two experienced readers. HAND studies were reviewed by cardiologists blinded to STAND results. Single and combined HAND parameters were evaluated to determine the simplified screening strategy that maximized sensitivity and specificity for case detection.
Results
In 1,439 children (mean age, 10.8 ± 2.6 years; 47% male) with HAND and STAND studies, morphologic criteria and the presence of any mitral regurgitation by HAND had poor specificity. The presence of aortic insufficiency was specific but not sensitive. Combined criteria of mitral regurgitation jet length ≥ 1.5 cm or any aortic insufficiency best balanced sensitivity (73.3%) and specificity (82.4%), with excellent sensitivity for definite RHD (97.9%). With a prevalence of 4% and subsequent STAND screening of positive HAND studies, this would reduce STAND studies by 80% from a STAND-based screening strategy.
Conclusions
In resource-limited settings, HAND with simplified criteria can detect RHD with good sensitivity and specificity and decrease the need for standard echocardiography. Further study is needed to validate screening by local practitioners and long-term outcomes.
Highlights
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Standard echocardiography-based screening for RHD may be cost prohibitive.
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Handheld echocardiography has good sensitivity and specificity for RHD.
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Optimal screening criteria are MR jet length ≥ 1.5 cm or any AI.
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Handheld echocardiography could greatly decrease the need for standard echocardiography-based screening
Rheumatic heart disease (RHD) is the most common cause of acquired heart disease in children worldwide, with the highest burden in developing countries. Outcomes in patients with symptomatic RHD are quite poor, although patients with disease detected at an earlier stage may have better outcomes with antibiotic prophylaxis and prevention of recurrence. Although RHD is caused by acute rheumatic fever, an autoimmune reaction that follows group A streptococcal infection, patients frequently do not recall histories of infection or symptoms of acute rheumatic fever, making targeted screening difficult. Echocardiography-based studies have demonstrated higher prevalence than for RHD detected by clinical evaluation.
The World Heart Federation (WHF) published evidence-based guidelines for echocardiographic diagnosis of RHD in endemic areas, and the World Health Organization supports screening in high-prevalence areas. Although standard portable echocardiography (STAND) is effective, widespread screening is often not feasible because of cost and physician availability. Handheld echocardiography (HAND), a promising alternative with lower cost machines with a simple interface, has been shown to be effective in the detection of RHD, both in a smaller cohort and in wide-scale screening using WHF criteria. However, because of limited functionality of HAND devices (such as a lack of spectral Doppler), some WHF criteria designed for STAND may be less useful with HAND, and some criteria may require different cutoff points. Furthermore, WHF criteria may be difficult to apply, particularly for screening by local practitioners or nonphysicians. Screening guidelines have not yet been validated specifically for HAND.
The aim of this study was to determine the best simplified screening criteria for RHD detection using HAND.
Methods
Study Population
This prospective study included five primary schools in Gulu, Uganda. All students 5 to 17 years of age were eligible for inclusion. Parents of minors provided written informed consent; adolescents >15 years of age provided informed consent, as is customary in Uganda. This study was approved by the institutional review boards at the University of Michigan, Children’s National Medical Center, and Makerere University.
All enrolled children underwent STAND. A random subset of 10% of all subjects undergoing STAND were designated to undergo HAND. To evaluate the ability of HAND to differentiate pathologic from physiologic regurgitation, any child with visible mitral regurgitation (MR) or aortic insufficiency (AI) was also referred for HAND. The cohort of the present study includes all patients who underwent both STAND and HAND ( Figure 1 ).
STAND
STAND ( Figures 2–4 ) was performed by a team of experienced imagers (pediatric cardiologists, fellows, and sonographers) with Vivid q or i (GE Medical Systems, Milwaukee, WI) or CX-50 (Philips Medical Systems, Best, The Netherlands) machines. A 3.6-MHz transducer was used without harmonics, because harmonic imaging can increase apparent tissue thickness. Frame rates ranged from 50 to 80 Hz for two-dimensional imaging and from 17 to 30 Hz for color Doppler. Depth, gain, and compression were optimized by the imager. The imaging protocol consisted of 13 clips 2 sec in length: parasternal long-axis view through the mitral and aortic valves, color Doppler over the mitral valve, color Doppler over the aortic valve, apical four-chamber view, apical four-chamber view with color Doppler over the mitral valve, apical five-chamber or three-chamber view, color Doppler over the aortic valve, continuous-wave Doppler of any MR or AI, parasternal short-axis view at the levels of the mitral and aortic valves, and color Doppler across the mitral and aortic valves. All images were read by six experienced pediatric cardiologists using 2012 WHF criteria ( Table 1 ). Measurements of anterior mitral leaflet thickness were made to the nearest 10th of a millimeter; measurements of MR jet length were made to the nearest millimeter. Because STAND interpretation was used as the gold standard, studies read as depicting borderline or definite RHD were confirmed by a second reader, with disagreements adjudicated by a third reader blinded to results of both prior readers.
| Definite: A, B, C, or D | |
| A. Pathologic MR and at least two morphologic features of RHD of the mitral valve | |
| B. Mitral stenosis with mean gradient ≥ 4 mm Hg | |
| C. Pathologic AI and at least two morphologic features of RHD of the aortic valve | |
| D. Borderline disease of both the aortic and mitral valves | |
| Borderline: A, B, or C | |
| A. At least two morphologic features of RHD of the mitral valve | |
| B. Pathologic MR | |
| C. Pathologic AI | |
| Pathologic MR (all criteria must be met) | Pathologic AR (all criteria must be met) |
| Seen in two views | Seen in two views |
| Jet length ≥ 2 cm (in at least one view) | Jet length ≥ 1 cm (in at least one view) |
| Velocity ≥ 3 m/sec for one complete envelope | Velocity ≥ 3 m/sec for one complete envelope |
| Pansystolic jet in at least one envelope | Pandiastolic jet in at least one envelope |
| Morphologic features of the mitral valve | Morphologic features of the aortic valve |
| Anterior leaflet thickening ≥ 3 mm | Irregular or focal thickening |
| Chordal thickening | Coaptation defect |
| Restricted leaflet motion | Restricted leaflet motion |
| Excessive leaflet tip motion during systole | Prolapse |
All children with concern for borderline or definite RHD by STAND were referred for complete echocardiography and evaluation by a pediatric cardiologist based in Gulu. Children with confirmed definite RHD were started on penicillin prophylaxis; children with confirmed borderline RHD were enrolled in biannual follow-up.
HAND
HAND ( Figures 2–4 ) was performed by experienced imagers using Vscan (GE Medical Systems) at a station isolated from STAND stations. The imager using HAND was unaware of the reason for referral for HAND. Imaging was performed with the single, attached 1.7- to 3.4-MHz transducer, with frame rates ranging from 25 to 30 Hz for two-dimensional imaging and from 12 to 16 Hz for color Doppler. Depth and gain were optimized by the imager; other imaging settings are not adjustable. The location but not the size of the color box is adjustable. This device offers an image-based “auto-cycle” function for the automatic detection of a full heart cycle beginning with end-diastole. The same imaging protocol was used for HAND, with the exception of spectral Doppler, which is not available on the Vscan. Images were interpreted offline using Gateway software (GE Medical Systems). All measurements were made to the nearest millimeter, because the software cannot measure tenths of a millimeter. Because of the lack of spectral Doppler or data evaluating discrimination of physiologic and pathologic MR on HAND, pansystolic MR was defined as MR present in two consecutive frames to avoid measurement of closing volumes or physiologic regurgitation. Studies were read by the same six experienced readers, blinded to STAND results. A random subset of 10% was reevaluated for interobserver agreement.
Statistical Analysis
Data are presented as mean ± SD or as median (interquartile range) as appropriate. Sensitivity and specificity of individual HAND parameters were calculated for any RHD (borderline or definite), as well as sensitivity for definite RHD, as defined by the gold standard of STAND using the 2012 WHF criteria. Receiver operating characteristic curve analysis was performed to determine the optimal cutoff for MR jet length for differentiation of patients with borderline or definite RHD from normal patients. MR jet lengths by STAND and HAND were compared by Wilcoxon matched-pairs signed rank tests. Interobserver agreement for individual HAND parameters was assessed with κ coefficients, with 95% confidence intervals (CIs). P values <.05 were considered to indicate statistical significance.
HAND parameters were combined into potential screening strategies, to optimize sensitivity for RHD, while maintaining specificity ≥80%. The percentage of patients still requiring STAND in a HAND-based screening strategy, assuming confirmation of positive HAND results with STAND, was calculated using the prevalence of the entire cohort screened with STAND. The true-positive fraction was calculated as (sensitivity in the HAND cohort) × (prevalence of borderline or definite RHD in the entire screened cohort). The false-positive fraction was calculated as (1 − specificity) × (1 − prevalence). The percentage requiring STAND was then calculated as (true-positive fraction) + (false-positive fraction). For confirmation of these estimates, sensitivity and specificity were also calculated only in the cohort of patients randomly assigned to HAND. The percentage of patients requiring STAND was calculated as the number of true positives and false positives divided by the number of this cohort.
Results
Of 4,773 subjects screened with STAND, 140 (2.9%) had borderline RHD by 2012 WHF criteria, and 52 (1.1%) had definite RHD, for a total prevalence of 4.0%. HAND was performed in 1,439 children (mean age, 10.8 ± 2.6 years; 47% male). Within this cohort, 133 (9.2%) had borderline RHD, 47 (3.3%) had definite RHD, and six (0.4%) had other diagnoses. The subset of children randomly assigned to HAND had a similar prevalence of disease to the overall cohort, with borderline RHD in 11 of 447 (2.5%) and definite RHD in seven of 447 (1.6%), with a total prevalence of 4.0%.
Mitral Valve Criteria
With the exception of anterior mitral leaflet thickening, mitral valve morphologic criteria had poor sensitivity but good specificity for RHD ( Table 2 ). Sensitivity for definite RHD was particularly poor for morphologic criteria. Thickened anterior mitral leaflet (≥3 mm) and thickened mitral valve chordae were common findings using HAND in this cohort. The presence of any one positive morphologic criterion had sensitivity of 71.7% and specificity of 63.1% for RHD. Requiring two positive morphologic criteria, similar to WHF criteria, improved specificity to 88.3% but decreased sensitivity to 46.4%.
| Criterion | Prevalence (%) | Sensitivity for any disease (%) | Specificity for any disease (%) | Sensitivity for definite RHD (%) |
|---|---|---|---|---|
| Morphologic | ||||
| Thickened chordae | 19.6 | 42.8 | 83.7 | 53.2 |
| Restrictive motion | 4.9 | 16.7 | 96.8 | 36.2 |
| Thickened anterior leaflet | 31.7 | 62.2 | 72.7 | 78.7 |
| Excessive motion | 6.3 | 11.7 | 94.4 | 17.0 |
| MR | ||||
| Any regurgitation | 55.5 | 87.8 | 49.2 | 91.5 |
| Seen in 2 views | 37.3 | 76.0 | 68.3 | 85.1 |
| Pansystolic | 22.8 | 67.2 | 83.6 | 85.1 |
| Mitral stenosis | 1.1 | 5.6 | 99.6 | 19.1 |
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