Acute rheumatic fever (ARF) is a delayed autoimmune response to a streptococcal A infection that results in a multisystem inflammatory disease.
Cardiac involvement in acute disease can lead to rheumatic heart disease (RC). Chronic heart valve damage can predispose to heart failure, arrhythmia, stroke, and premature death.1
In the last 50 years, the disease has almost disappeared from high-income countries; However, this devastating disease remains a leading cause of early morbidity and mortality in low- and middle-income countries, driven by socioeconomic factors, including household overcrowding.1,2
AKI and its long-term sequelae CR affect >40 million people worldwide and account for more than 300,000 deaths annually, although the true disease burden is likely underestimated due to missed diagnoses and underreporting.1,2 AKI affects most commonly to young people with the highest rates in children ages 5 to 14, and nearly 80% of new cases occur in people under 25 years of age.2
High rates of AKI and CR are reported in low- and middle-income countries and in high-risk populations, including First Nations Peoples in high-income countries such as Australia and New Zealand.2,3
Prevalence estimates are generally based on screening echocardiographic studies, but the incidence of CR is not well understood given variable approaches to reporting and surveillance, as well as low recognition of the diagnosis.
The high burden of previously undiagnosed CR identified at screening suggests that many cases of AKI are neither diagnosed nor treated.
In Australia, where AKI is notifiable, the incidence of AKI appears to be increasing, which could be due to improved case detection as well as changes in epidemiology.
The age-standardized incidence of AKI in First Nations people in Australia was recently estimated to be 71.9 per 100,000 per year, with marked geographic variation.3
This brief review summarizes the latest advances in the diagnosis, management and prevention of ARF, with reference to the need for additional research to address the barriers to the diagnosis and management of ARF and CR, highlighted by an illustrative case from Timor. -Leste.
| Diagnosis |
Echocardiographic screening demonstrates high rates of previously undiagnosed cases of CR, suggesting missed opportunities for diagnosis of AKI.3 Recognition of AKI provides an important opportunity for secondary prophylaxis to prevent progression of CR. Improved diagnostic tools are needed to accurately diagnose AKI.
Current approaches rely on the clinical diagnosis of AKI based on criteria first described by Jones in 1944. Clinical diagnosis lacks sensitivity and specificity, resulting in both underdiagnosis and overdiagnosis of AKI.
Recent modifications to the Jones criteria include echocardiographic diagnosis of carditis and different criteria based on the underlying risk of the population,4 but there have been no other recent substantial changes in the diagnostic approach.
Individualized national guidelines routinely include modified Jones criteria appropriate to local epidemiology and testing capacity, with 4 examples of regional guidelines from the Asia-Pacific region over the past 8 years (New Zealand 2014, Fiji 2015, Australia 2020 and Timor-Leste 2021).
| Biomarkers |
The poor sensitivity and specificity associated with the clinical diagnosis of AKI has prompted research into alternative diagnostic tools, including biomarkers. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are minor diagnostic criteria, but they lack specificity.
Current research focuses on comprehensive search strategies to identify new biomarker profiles associated with AKI.5
Non-targeted immune phenotyping, transcriptomic, proteomic and metabolomic profiling in patients with AKI is currently underway, using multiple control groups for comparison with the aim of identifying an AKI-specific diagnostic test that could predictably be translated into a test. point-of-care for use in high-load settings.5
Biomarker research may also identify opportunities for immunomodulatory therapies, targeting the inflammatory pathophysiology of ARF.
| Echocardiography |
Auscultation is less sensitive than echocardiography for the diagnosis of acute carditis or CR.6 Limited access to echocardiography in low-resource settings is a significant barrier that decreases the sensitivity of the diagnosis of AKI and CR.
Ongoing research aimed at reducing barriers to access focuses on the use of less expensive portable equipment; brief training for non-expert health professionals; and abbreviated echocardiographic protocols.
Research has predominantly been carried out in the context of screening studies, diagnosing latent CR in asymptomatic children. However, the echocardiographic findings of acute carditis are the same as those used to detect latent CR (mitral and/or aortic regurgitation).
In settings such as Timor-Leste where non-expert professionals have been trained and portable devices and remote support are available, echocardiographic confirmation of the presence of carditis has allowed diagnoses of AKI and CR even in extremely remote locations.6
| Timor-Leste case study |
A 10-year-old boy from a rural area in Timor-Leste presented with fever, polyarthralgia, and chest pain, with a recent history of pharyngitis that resolved without treatment. Ibuprofen was prescribed with rapid resolution of the arthralgia.
Examination revealed a holosystolic murmur in the mitral region and arthritis of the left knee. No ECG, ERS, or PCR was performed and streptococcal serology is not available.
Portable echocardiography can be performed in Timor-Leste with real-time image sharing and remote expert review, to support diagnosis and management decisions.
In this case, echocardiography confirmed moderate mitral regurgitation and ARF with carditis was diagnosed.
| Driving |
The management of AKI includes the eradication of streptococcus A and the initiation of secondary prophylaxis, symptomatic management of arthropathy, carditis and chorea, and family education.
New advances in the medical management of AKI are limited, with no convincing evidence of effective disease-modifying treatments.
> Non-steroidal anti-inflammatory drugs
High-dose aspirin has been widely used to treat arthritis in AKI; however, the potential for toxicity in children has caused concern and recent guidelines have recommended other nonsteroidal anti-inflammatory agents.
Naproxen and ibuprofen have been compared with aspirin in retrospective studies, demonstrating a similar time to resolution of symptoms and normalization of inflammatory markers, but with fewer adverse effects compared to aspirin.7
> Corticosteroids and intravenous immunoglobulin
Corticosteroids are often used for the treatment of severe carditis or chorea, but with limited evidence.
A meta-analysis including 8 randomized controlled trials found no evidence of benefit from steroid administration; However, there was significant heterogeneity between studies and results were predominantly based on auscultation findings.8
Until new scientific evidence is available, expert consensus supports the use of corticosteroids for acute or life-threatening carditis, particularly where surgical intervention is not indicated or available.
Intravenous immunoglobulin has been evaluated for the treatment of carditis, but does not demonstrate benefit in improving heart disease after 1 year of treatment8 and is not recommended.
> Sydenham Korea
Syndenham’s chorea has a broad clinical phenotype ranging from subtle symptoms to paralytic chorea. Pharmacotherapy is indicated for children with functional impairment, although evidence to guide this is limited, with no placebo-controlled trials.
Valproic acid and carbamazepine have similar efficacy without significant side effects. Successful use of levetiracetam, olanzapine, and risperidone was documented in case reports; however, they require further investigation.9
Corticosteroids have also been used in the treatment of severe Sydenham’s chorea. Multiple studies demonstrated a reduction in remission time; however, all are limited by small sample sizes and inconsistent reporting mechanisms. More research is required to determine the benefit of steroids in this population.
> Hydroxychloroquine
A small case series including 10 cases of AKI showed that streptococcal A infection activates persistent interleukin-1β and granulocyte-macrophage colony-stimulating factor (GM-CSF) production in peripheral mononuclear cells; an effect that can be suppressed by hydroxychloroquine.10
In 2020, a case series describes the use of hydroxychloroquine in 2 cases of AKI with severe carditis who were treated with corticosteroids and hydroxychloroquine, with effective suppression of inflammatory markers and clinical stabilization, although the specific effect of hydroxychloroquine is unknown.10 More research is underway.
> Penicillin
Secondary prophylaxis using regular penicillin is essential for the prevention of streptococcal A infections and the recurrence of associated AKI and progression of CR. Recent evidence has demonstrated the effectiveness of secondary prophylaxis for latent CR detected by screening (borderline cases and definite mild cases) in addition to its proven role in people who have had AKI.11
However, intermittent benzathine penicillin (PB) injections are painful and poor adherence to treatment puts the patient at risk for further strep A infections and recurrent AKI.2 There is growing recognition of the need for meaningful engagement with patients , families and communities to improve adherence, but the implementation of strategies is complex and challenging.12
Occasionally, recurrences may occur despite adherence to 4-week prophylaxis,2 most likely due to exposure to streptococcus A that occurs when serum penicillin levels are below 0.02 mg/L.
Recent studies have shown that the median duration of adequate penicillin concentration after PB administration is <14 days, with lower levels observed in obese patients.13
Pharmacokinetic studies have observed a longer half-life of PB if administered subcutaneously rather than intramuscularly.14 While safety and tolerability data are currently limited, the potential of subcutaneous administration of penicillin will be further explored. slow release.
| Prevention |
Current strategies for AKI prevention focus on primary prevention, with immediate antibiotic treatment of strep A pharyngitis and impetigo; and ongoing efforts to effectuate primary prevention by addressing the underlying social determinants of health, including poverty and overcrowding.2
> Vaccine development
Studies seeking a vaccine against strep A began in the 1920s; However, the first vaccines were highly reactogenic and did not prevent the disease.
In the 1960s, newer vaccines were tested; However, safety concerns related to higher rates of AKI in those vaccinated led to a nearly 30-year pause in vaccine development.1
Since 2006, vaccine candidates have included multivalent M protein-based vaccines, M protein vaccines containing C-repeat epitopes, cell wall carbohydrate vaccines, and multicomponent vaccines without M protein.1
In 2018, the World Health Organization published a Group A Strep Vaccine Research and Development Roadmap, and in 2019, a Strep A Vaccine Consortium was formed.
There are currently a small number of vaccine candidates under development; However, only one has reached phase II.1 testing.
The recent establishment of a challenge model of human strep A pharyngitis infection aims to contribute to vaccine development by aiding the understanding of strep A pathogenesis and providing a platform for vaccine efficacy studies.15
| Conclusion |
Eliminating ARF as a public health problem is achievable, but requires community leadership and multi-sector collaboration in health, research, government, and non-governmental organizations.2
Improved recognition and diagnosis can facilitate access to treatment and secondary prevention. Diagnostic accuracy has been improved by the inclusion of echocardiography for the diagnosis of carditis, and global use of this is increasing.
Improved penicillin delivery strategies may be on the horizon. Prevention is better than cure, and while an effective vaccine would have a great impact, it is essential to address the underlying socioeconomic risk factors in partnership with affected communities.
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