Outcomes of possible and probable rheumatic fever: a cohort study using northern Australian register data, 2013-2019

Background Outcomes after acute rheumatic fever (ARF) diagnosis are variable, ranging from recovery to development of severe rheumatic heart disease (RHD). There is no diagnostic test. Evaluation using the Australian clinical diagnostic criteria can result in a diagnosis of ‘definite’, ‘probable’ or ‘possible’ ARF. The ‘possible’ category was introduced in 2013 in Australia’s Northern Territory (NT). Our aim was to compare longitudinal outcomes after a diagnosis of definite, probable or possible ARF. Methods We extracted data from the NT RHD register for Indigenous Australians with an initial diagnosis of ARF during the 5.5-year study period (01/01/2013 – 30/06/2019). Descriptive statistics were used to describe the demographic and clinical characteristics at initial ARF diagnosis. Kaplan-Meier curves were used to assess the probability of survival free of disease progression and the cumulative incidence risk at each year since initial diagnosis was calculated. Cox proportional hazards regression was used to determine whether time to disease progression differed according to ARF diagnosis and whether progression was associated with specific predictors at diagnosis. A multinomial logistic regression model was performed to assess whether ARF diagnosis was associated with RHD outcome and to assess associations between ARF diagnosis and clinical manifestations. A generalised linear mixed model (GLMM) was developed to assess any differences in the long-term antibiotic adherence between ARF diagnosis categories and to examine longitudinal trends in adherence. Results There were 913 initial ARF cases, 732 with normal baseline echocardiography. Of these, 92 (13%) experienced disease progression: definite ARF 61/348 (18%); probable ARF 20/181 (11%); possible ARF 11/203 (5%). The proportion of ARF diagnoses that were uncertain (i.e. possible or probable) increased over time, from 22/78 (28%) in 2013 to 98/193 (51%) in 2018. Cumulative incidence risk of any disease progression at 5.5 years was 33.6 (23.6–46.2) for definite ARF, 13.5 (8.8–20.6) for probable and 11.4% (95% CI 6.0–21.3) for possible ARF. The probability of disease-free survival was lowest for definite ARF and highest for possible ARF (p=0.004). Cox proportional hazards regression indicated that disease progression was 2.19 times more likely in those with definite ARF than those with possible ARF (p=0.026). Progression to RHD was reported in 37/348 (11%) definite ARF, 10/181 (6%) probable ARF, and 5/203 (2%) possible ARF. The multinomial logistic regression model demonstrated a significantly higher risk of progression from no RHD to RHD if the initial diagnosis was definite compared to possible ARF (p<0.001 for both mild and moderate-severe RHD outcomes). The GLMM estimated that patients with definite ARF had a significantly higher adherence to antibiotic prophylaxis compared with probable ARF (p=0.024). Conclusion These data indicate that the ARF diagnostic categories are being applied appropriately, are capturing more uncertain cases over time, provide a useful way to stratify risk and guide prognosis, and can help inform practice. Possible ARF is not entirely benign; some cases progress to RHD. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The author(s) received no specific funding for this work. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Study approval was granted by the Human Research Ethics Committee of the Northern Territory Department of Health and Menzies School of Health Research (2019-3482). This approval was registered with the University of Melbourne’s Medicine and Dentistry Human Ethics Sub-Committee (1955194). Access to register data was approved by the data custodian, Top End Health Service, NT Department of Health. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The raw data underlying the results presented in the study are available from the Northern Territory Rheumatic Heart Disease Register, contactable through the NT Centre for Disease Control: .