The Jones criteria have been the gold standard for acute rheumatic fever (ARF) diagnosis since 1944. In response to data revealing that these criteria lacked sensitivity in regions in which rheumatic heart disease (RHD) is endemic, in 2015, the American Heart Association published revisions that included separate criteria for high-risk settings, defined as settings with an ARF incidence of >2 per 100 000 children per year.1,2 However, to date, no prospective studies have evaluated the performance of these modified Jones criteria. We aimed to determine the specificity of the revised criteria by assessing the risk of developing RHD in children who presented with symptoms suggestive of ARF but did not meet the criteria for definite ARF under the revised standards.
Methods
We conducted a prospective epidemiologic study of ARF in Uganda from 2017 to 2020 that used active ARF case-finding strategies to identify and refer children to ARF clinics that we established at the Lira and Mbarara Regional Hospitals.2,3 There, the 2015 Jones criteria (Table 1) were applied to categorize children as having definite ARF, possible ARF, RHD without ARF, or a known or unknown alternate diagnosis. Children with possible ARF or an alternate diagnosis were followed annually with a clinical evaluation and repeat echocardiography, and only those with at least 100 days of follow-up were included in the analysis to ensure the capture of only postacute disease data. The primary outcome measure was the false-negative rate of ARF diagnosis, defined as not being diagnosed with ARF on initial evaluation but later having evidence of RHD on echocardiography. Secondary outcome measures included rates of cardiac-related hospitalization and mortality. Descriptive statistics were used to quantify the demographic data and outcomes of interest. The study activities were approved by Makerere University and Children’s National Medical Center.
2015 Jones Criteria for the Diagnosis of ARF in Moderate-/High-Risk Populationsa
| Major Criteriab | Minor Criteria |
|---|---|
| Carditis (clinical or subclinicalc) | Prolonged PR interval on ECGd |
| Monoarthritis, polyarthritis, and/or polyarthralgia | Monoarthralgia |
| Chorea | Fever (≥38.0°C) |
| Erythema marginatum | Peak ESR ≥30mm or CRP ≥3.0mg/dL |
| Subcutaneous nodules |
| Major Criteriab | Minor Criteria |
|---|---|
| Carditis (clinical or subclinicalc) | Prolonged PR interval on ECGd |
| Monoarthritis, polyarthritis, and/or polyarthralgia | Monoarthralgia |
| Chorea | Fever (≥38.0°C) |
| Erythema marginatum | Peak ESR ≥30mm or CRP ≥3.0mg/dL |
| Subcutaneous nodules |
CRP, C-reactive protein; ECG, electrocardiogram; ESR, erythrocyte sedimentation rate.
Moderate-/High-risk is defined as ARF incidence >2 per 100 000 school-aged children or RHD prevalence of >1 per 1000 population year.
ARF is diagnosed when a patient has (1) evidence of a recent streptococcal infection and (2) either 2 major or 1 major and 2 minor criteria.
Seen on echocardiography without auscultatory findings.
Accounting for age variability and only if carditis is not counted as a major criterion.
Results
We evaluated 410 children for ARF in the parent study (Fig 1). Of these, 116 patients had either definite ARF or RHD without ARF and were excluded. Of the remaining 294 children with either possible ARF or an alternate diagnosis, 100 had <100 days of follow-up and were also excluded. This produced a study cohort of 194 children who were eligible for participation. In this group, 93 of 194 (48%) were female, 147 of 194 (75.8%) lived in the Lira District, and 47 of 194 (24.2%) lived in the Mbarara District. The median (interquartile range) age was 10.3 (6.5–12.6) years, and the follow-up period was 461 (167–820) days. Nearly all participants (186/194, 96%) had fever and joint pain at presentation. Only 8 of 194 (4%) patients had carditis, and 0 had chorea. Less than one-half of the patients had elevated streptococcal titers, indicating a recent infection, with 13 of 194 (17%) having elevated antistreptolysin O titer, 45 of 194 (23%) having elevated anti-DNase B titer, and 18 of 194 (9%) having an elevation of both. For our outcomes of interest, 3 of 194 (1.5%) participants had evidence of RHD on a follow-up echocardiogram, and in each case, there was only mild mitral valve regurgitation. Two of these children were initially diagnosed with possible ARF, and 1 had an unknown alternate diagnosis. There were no cardiac-related hospitalizations or deaths.
Strengthening the reporting of observational studies in epidemiology (STROBE) flowchart for participant eligibility and inclusion.
Strengthening the reporting of observational studies in epidemiology (STROBE) flowchart for participant eligibility and inclusion.
Discussion
Evidence of RHD was rare at follow-up among children who initially presented with concern for ARF but did not meet the criteria for diagnosis under the revised 2015 Jones criteria. In addition, when present, RHD was mild in degree. No cases of moderate or severe RHD or cardiac-related hospitalization or death were found in this group. These findings suggest that the revised Jones criteria, which included the addition of echocardiography to detect subclinical carditis, account for less severe joint manifestations, and reduce thresholds for fever and laboratory cutoffs, have maintained adequate specificity.1 Despite this, even the revised Jones criteria remain an imperfect clinical decision rule. Many high-risk settings still lack the laboratory and cardiac testing infrastructure to evaluate these criteria in community health settings in which the disease is most endemic and in which subspecialty care is most unavailable.4
In conclusion, a better diagnostic test for ARF remains an important global priority. Even so, given the extensive differential diagnosis for patients who present with symptoms such as fever and joint pain, clinicians, patients, and families can be reassured that if the revised Jones criteria are not met, the chances of missing ARF or later developing RHD are low.
Drs Beaton and Okello conceptualized and designed the study; Mr Pulle supervised data collection and conducted the initial analyses and drafted the initial manuscript; Ms Ndagire, Ms Nakitto, Ms Sarnacki, Ms Fall and Ms Rwebembera coordinated and supervised data collection and critically reviewed and revised the manuscript for important intellectual content; Drs de Loizaga, Wirth, Sable, Parks, and Carapetis critically reviewed and revised the manuscript; Ms Atala and Ms Oyella collected data, and critically reviewed and revised the manuscript; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
FUNDING: This study was supported by the American Heart Association Children’s Strategically Focused Research Network grant (17SFRN33670607, 17SFRN33630027), THRiVE-2, General Electric, and Cincinnati Children's Heart Institute Research Core. This research was funded in part by the Wellcome Trust [grant number 222098/Z/20/Z to TP]. For the purpose of open access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. The funders had no role in the design and conduct of the study.
CONFLICT OF INTEREST DISCLOSURES: The other authors have no conflicts of interest to disclose.
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