Practice Essentials
Acute rheumatic fever (ARF) is a sequela of a previous group A streptococcal infection, usually of the upper respiratory tract and less frequently of soft tissues. Group A strep pharyngitis is most common in children 5-15 years old, but can occur in persons of any age. Children with confirmed group A strep pharyngitis should be treated with antibiotics to reduce risk of developing ARF. [1]
Major manifestations of ARF comprise the following (see Presentation):
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Carditis, clinical and/or subclinical (ie, detected by echocardiography)
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Arthritis
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Chorea
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Erythema marginatum
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Subcutaneous nodules
In the emergency department, treatment includes measures to relieve pain and inflammation, ameliorate heart failure, and control chorea (see Treatment and Medication).
Background
Rheumatic fever causes chronic progressive damage to the heart and its valves and is the most common cause of pediatric heart disease in the world. Until 1960, it was a leading cause of death in children and a common cause of structural heart disease. The disease has been known for many centuries. Baillou (1538-1616) first distinguished its acute arthritis from gout. Sydenham (1624-1668) described chorea but did not associate it with acute rheumatic fever (ARF). In 1812, Charles Wells associated rheumatism with carditis and provided the first description of the subcutaneous nodules. In 1836, Jean-Baptiste Bouillaud and, in 1889, Walter Cheadle published classic works on the subject.
The association between sore throat and rheumatic fever was not made until 1880. The connection with scarlet fever was made in the early 1900s. In 1944, the Jones criteria were formulated to assist disease identification. These criteria, with some modification, remain in use today.
The introduction of antibiotics in the late 1940s allowed for the development of treatment and preventive strategies. Dramatic declines in the incidence of rheumatic fever are thought to be largely due to antibiotic treatment of streptococcal infection; however, there are regions where the incidence is significant, especially in sub-Saharan Africa, the Middle East, Central and South Asia, the South Pacific, and in indigenous people of Australia and New Zealand. This is likely related to circulating subtypes of streptococci and genetic characteristics of the host populations. [2, 3, 4]
Pathophysiology
Acute rheumatic fever (ARF) is the sequela of a previous group A streptococcal infection, usually of the upper respiratory tract. The clinical entity appears to be a result of molecular mimicry by the bacteria, plus autoimmune and inflammatory responses and genetic predisposition in the host. This autoimmune response occurs around 1-5 weeks after the initial infection
During the initial infection, alpha-helical M proteins (M8 and M13) on the surface of the streptococcus bind type IV collagen in the host, and this interaction can trigger auto-antibody formation. Additionally, a streptococcal carbohydrate epitope, N-acetyl glucosamine (GlcNAc), mimics host proteins myosin, keratin, tropomyosin, vimentin and laminin. This mimicry triggers B- and T-cell immune responses directed against the heart, joints, central nervous system (CNS), skin, and subcutaneous tissues where those proteins are found. When ARF develops, exudative and proliferative inflammatory lesions can appear in connective tissues of the joints, blood vessels, and subcutaneous tissue, but they are especially detrimental in cardiac tissue, where structural changes can occur, resulting in rheumatic heart disease (RHD). [5, 6, 7, 8]
Pro-inflammatory cytokines and chemokines also appear to contribute to ARF and RHD. Elevated levels of interleukin-6 (IL-6), IL-8/CXCL8, and tumor necrosis factor alpha (TNFα) have been detected in these patients. Histologic studies of affected valve tissue implicates T-helper 1 (Th1) and Th17- associated pro-inflammatory cytokines, chemokine CXCL9, and transforming growth factor beta (TGF-β; the fibrosis-associated cytokine) in the damaging cycle of inflammation and fibrotic repair. Immune molecules appear to contribute to the acute inflammatory disease stage of ARF, as well as cardiac remodeling, stenosis, and ultimately valve dysfunction in RHD. [9, 10]
Individual genetics have been thought to play a part in susceptibility to disease progression from ARF to RHD since the 1980s and 1990s. Early research demonstrated that the human leukocyte antigen (HLA) locus on chromosome 6 is associated with susceptibility.
Additional candidate regions were implicated in the early 2000s, and current areas of genetic research include the use of genome-wide association studies (GWAS) to analyze associations among millions of variants across thousands of individuals with rheumatic fever. [11] This new approach has demonstrated involvement of the HLA-DQA1 to HLA-DQB1 region, as well as the locus that codes immunoglobulin heavy chain in chromosome 14, specifically the IGHV4-61 gene segment. [12] [10, 13] The RhEumatiC Heart diseAse Genetics (RECHARGE) study is currently underway in Rwanda, where approximately 1000 participants are undergoing next-generation genetic sequencing. It is expected to be completed in 2024. [14]
Etiology
Acute rheumatic fever (ARF) has been linked definitively with a preceding streptococcal infection, usually of the upper respiratory tract. The M protein in certain streptococcal subtypes is responsible for antigenicity, with additional antigenic effects of the carbohydrate epitope N-acetyl glucosamine (GlcNAc), and possibly bacterial DNA and other proteins. These can all trigger the autoimmune response in the host. [6]
Although streptococcal skin infections were not historically linked with ARF, there is increasing evidence that group A streptococcal skin infections, including impetigo, can trigger ARF. [15] Maori and Pacific Islanders demonstrate particular vulnerability to this progression. [16, 17]
See discussion under Pathophysiology for reference to genetic predisposition.
Epidemiology
Frequency
United States
The prevalence of acute rheumatic fever (ARF) in the United States is a function of socioeconomic status, with higher frequency in elderly individuals, in areas of crowding, and in immigrant communities. The national annual incidence is based on estimates, since the disease is no longer reportable. The incidence is low in most parts of the country but varies by state.There is also a seasonal component, with higher prevalence in the colder months of the year, when school-aged children are more likely to transmit streptococcal pharyngitis. [1]
In a study published in 2006, Martin and Barbadora showed that the disease remained a problem in western Pennsylvania, with 121 new cases from 1994-2003. [18] Consistent with earlier reports, most patients were children and most had carditis. ARF is also more common in American Samoa and Hawaii. A 2011-2012 study in American Samoa demonstrated rates about 10 times higher than in the continental United States. Hawaii's higher rates were also associted with populations of American Samoans living on the islands. [19]
Overall the incidence of rheumatic fever in North America and Europe has declined significantly in the past 4-6 decades. [20]
International
ARF remains prevalent in sub-Saharan Africa, the Middle East, Central and South Asia, the South Pacific, and among populations of immigrants, older adults, and indigenous peoples in higher-income countries. [21] Worldwide, its sequela of rheumatic heart disease (RHD) is the most common acquired heart disease in people under age 25. [22] An estimated 40 million people suffer from RHD, with 300,000 deaths annually, although the numbers may be much higher due to under-reporting and missed diagnoses. [2] Since RHD occurs twice as commonly in women, there is also a significant association with maternal and infant morbidity and mortality related to RHD in pregnancy. [16, 23]
Since rheumatic fever is highly treatable, and the sequela of RHD is preventable, targeted public health measures should help ameliorate the burden of disease. In 2018 the World Health Assembly adopted a resolution calling upon the World Health Organization (WHO) to coordinate a global response against rheumatic fever and RHD. This involves standardizations of clinical guidelines for prevention and treatment, as well as long-term plans to help people already living with RHD. [22] The WHO Road Map for Access to Medicines, Vaccines, and Other Health Products 2019-2023 also devotes specific attention to the importance of a safe and available supply of benzathine penicillin for treatment of rheumatic fever. [24]
Demographics
No sex predilection for rheumatic fever exists, except that Sydenham chorea occurs more often in females than in males. [25] Progression to RHD occurs twice as frequently in women. [23]
Although individuals of any age group may be affected, most cases are reported in school-aged children from 5-15 years-old. Paulo et al report that ARF can be found in children younger than 5 years with no significant difference in the frequency and severity of clinical signs. [26] Yee lists rheumatic pericarditis and myocarditis as cardiac emergencies in the first year of life. [27]
Over the past two decades, new attention has been focused on the racial and ethnic disparities that result in a higher disease burden among indigenous peoples, especially in Australia and New Zealand. Whether those rates are related to genetic predisposition, socioeconomic factors, or a combination remains an area of active investigation. [2, 12, 28, 29]
Prognosis
Sequelae are limited to the heart and depend on the severity of the carditis during the acute attack. Infections that are not treated adequately are most likely to cause the major sequelae noted in the list of Jones criteria in Presentation/Physical Examination. Morbidity is related to the care that the patient receives. [1, 30]
The mortality rate has declined steadily over the last 3 decades. A partial explanation for the decrease in mortality rate may be the increase in antibiotic use. In developing nations and lower socioeconomic areas where rheumatic fever is more prevalent, acute rheumatic fever and its sequela are a major cause of death and disability in children and adolescents.
Most cases of uncomplicated acute rheumatic fever resolve with proper treatment within 3 months. [1]
Tables
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- Overview
- Presentation
- DDx
- Workup
- Treatment
- Medication
- Medication Summary
- Antimicrobials
- Penicillins, Natural
- Penicillins, Amino
- Antibiotics, Lincosamide
- Macrolides
- Cephalosporins, 1st Generation
- Glucocorticoids
- Anti-inflammatory agents
- Anticonvulsants, Other
- Diuretics
- Diuretics, Loop
- Diuretics, Potassium-Sparing
- Nitrates
- Nitrates, Angina
- Immunosuppressants
- Antipsychotics, 2nd Generation
- SV2A Ligands
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- References
