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Acute rheumatic fever (ARF) is an abnormal immunologic response to group A Streptococcus (GAS) infections, most commonly tonsillopharyngitis. ARF affects multiple organ systems and may have cardiac, neurologic, musculoskeletal, or dermatological manifestations. While ARF most commonly occurs in children, it can affect people of any age. The recurrence rate of ARF is very high, particularly in patients with limited access to healthcare. Severe or recurrent bouts of ARF can result in significant morbidity and mortality and the development of rheumatic heart disease (RHD). The mainstay of ARF treatment includes GAS eradication therapy, management of symptoms, and secondary prophylaxis against recurrence. Prompt diagnosis and treatment of ARF are essential in preventing complications and consequences of the disease. This course explores the complexities surrounding ARF pathogenesis, presenting symptoms and signs, complications, evaluation, and short- and long-term management. This activity for healthcare professionals is designed to enhance the learner's competence in identifying the clinical features of ARF, performing the recommended evaluation, and implementing an appropriate interprofessional approach when managing this condition to optimize patient outcomes. Objectives: Identify the clinical features of acute rheumatic fever. Select recommended diagnostic studies to evaluate patients with suspected acute rheumatic fever. Implement the appropriate management approach for acute rheumatic fever. Apply interprofessional team strategies to improve care coordination and outcomes for patients with acute rheumatic fever. Access free multiple choice questions on this topic.

Acute rheumatic fever (ARF) is an immune-mediated nonsuppurative complication of group A streptococcal (GAS) pharyngitis.[1] Approximately 470,000 new cases of ARF occur annually, with a more significant disease burden in developing countries with higher rates of untreated or inadequately treated GAS infections.[2] Globally, over 275,000 deaths yearly are attributed to rheumatic heart disease (RHD).[3] The most significant contributors to the spread of GAS pharyngitis are household overcrowding, poor sanitation, and inadequate access to healthcare.[4] The pathophysiology of ARF is characterized by an aberrant immune response to GAS infection triggered by molecular mimicry between GAS antigens and self-antigens. This immune response typically manifests 2 to 4 weeks after the initial GAS infection and may lead to the development of carditis, valvulitis, Sydenham chorea, subcutaneous nodules, erythema marginatum, and polyarthritis that is usually migratory.[5] The severity and distribution of these manifestations vary significantly between individuals, making the diagnosis of ARF challenging. Early recognition of ARF using the modified Jones criteria is essential in treating acute infection and preventing complications. A major long-term consequence is RHD, which carries significant morbidity and mortality.

ARF is an inflammatory response to a preceding GAS pharyngeal infection. GAS infections can manifest as a broad range of clinical conditions, from superficial infections such as impetigo and pharyngitis to more invasive processes, including toxic shock syndrome and necrotizing fasciitis.[6] ARF is more strongly associated with GAS pharyngitis than skin infections.[7] However, some data suggest that skin infections, particularly impetigo, may play a role for high-risk populations such as the Indigenous people of Australia.[8] In most cases, appropriate antibiotic treatment of acute GAS infection prevents the development of ARF. However, individuals with GAS infection who cannot seek medical care or who have subclinical GAS infection and do not present to care are at risk for developing ARF. Environmental and socioeconomic factors, such as household overcrowding, also significantly contribute to the spread of GAS infections and the development of ARF.

Approximately 470,000 new cases of ARF and 233,000 attributable deaths to ARF or RHD are reported yearly.[9] Overall, the incidence and severity of ARF have declined since the 1900s, likely owing to industrialization, improved housing conditions, improvement in healthcare access, and the introduction of penicillin. Historically, an estimated 3% of patients with untreated acute GAS pharyngitis develop ARF.[10] High-risk patients with a history of ARF have an estimated 50% recurrence rate of ARF following untreated GAS pharyngitis.[11] Globally, the reported incidence of ARF is likely underestimated due to a lack of data, primarily from developing areas. While anyone can develop ARF, the disease is most commonly seen in children between 5 and 15 years old.[12] No gender predilection for ARF has been noted, but females are more likely to progress to RHD.[13] In the United States, hospitalizations secondary to ARF are more common in boys, with the highest rates occurring in 6- to 11-year-old boys of Asian and Pacific Islander descent.[14] The populations of developing countries and Indigenous people are disproportionately affected by ARF, likely due to many environmental and socioeconomic factors, including lack of access to treatment and increased GAS transmission due to overcrowding.[15] The yearly incidence of ARF in the United States is 10/100,000 compared to an annual incidence in India of 51/100,000. The Indigenous population in Australia has one of the highest reported incidence rates, ranging from 150 to 380 cases per 100,000 children aged 5 to 14 years.[16] The significant sequela of ARF is the development of RHD. Approximately 39 million people worldwide are estimated to be living with RHD.[17] Currently, no reports on the incidence of ARF in Africa are available, where almost 50% of all cases of RHD are believed to occur in children younger than 15.[18]

The pathophysiology of ARF is incompletely understood but thought to be multifactorial. Preceding GAS infection is necessary for the development of ARF. Additionally, host factors and repeated exposures to GAS contribute to the pathogenesis of ARF. Group A Streptococcus The emm genes of GAS encode for the M and M-like proteins. There are 5 chromosomal patterns of emm genes, labeled A to E. Evidence suggests that pharyngitis-inducing strains of GAS have the more “rheumatogenic” emm gene patterns A, B, and C.[19][20] A significant decrease in the circulation of rheumatogenic strains in low-risk areas like the United States has been demonstrated.[21] However, the complete role of bacterial strains and virulence factors in the pathogenesis of ARF is incompletely understood, and studies have shown that any strain of GAS can cause ARF.[7][22] Molecular Mimicry In molecular mimicry, antibodies formed against GAS antigens crossreact with self-antigens, leading to a dysregulated immune response. A variety of GAS antigens are implicated in molecular mimicry. The M protein moiety and N-acetyl-β-D-glucosamine (NABG) of GAS species exhibit structural similarity to myosin, leading to cardiac myositis and valvulitis.[23][24] Antibody-antigen complexes may also deposit in joints, leading to the characteristic migratory polyarthritis. Aschoff bodies are granulomatous formations found on the surface of cardiac valves in patients with RHD presumptively secondary to an interaction between T-cells and upregulated expression of vascular cell adhesion molecule-1 (VCAM-1).[25] In animal models, antibodies to NABG crossreact with mammalian lysoganglioside and reproduce chorea, indicating that molecular mimicry may play a role in the development of Sydenham chorea.[26] In humans, the basal ganglia are impacted in Sydenham Chorea; patients with ARF demonstrate putamen enlargement with magnetic resonance imaging.[27] Group A carbohydrates share epitopes with keratin, and cross-reactivity may lead to erythema marginatum.[28] Host Susceptibility

In animal models, antibodies to NABG crossreact with mammalian lysoganglioside and reproduce chorea, indicating that molecular mimicry may play a role in the development of Sydenham chorea.[26] In humans, the basal ganglia are impacted in Sydenham Chorea; patients with ARF demonstrate putamen enlargement with magnetic resonance imaging.[27] Group A carbohydrates share epitopes with keratin, and cross-reactivity may lead to erythema marginatum.[28] Host Susceptibility Host susceptibility to ARF is likely polygenic.[29] Monozygotic twin studies demonstrate a >40% concordance risk for ARF.[30] Human leukocyte antigen alleles and tumor necrosis factor polymorphisms play a role in genetic susceptibility to ARF.[31][32][33] A study conducted across 8 countries in Oceania has suggested an allele on the immunoglobulin heavy chain is associated with susceptibility to ARF.[34][32]

When antibodies against GAS surface antigen bind to the surface of heart valves, they upregulate vascular cell adhesion molecule 1 (VCAM1), which allows T cells to adhere to the endocardium and form granulomatous depositions characteristic of ARF, termed Aschoff bodies.[32] These Aschoff bodies contain areas of active inflammation with fibrinoid necrosis, lymphocytic infiltration, plasma cells, and enlarged macrophages with condensed nuclei termed Anitschkow cells. The chromatin within the nucleus of the Anitschkow cells may appear ribbon-like and resemble a caterpillar; therefore, these cells are also called caterpillar cells.[35] Over time, valvular fibrosis, histiocytosis, and neovascularization suggest developing chronic disease and RHD.[36] The classic histopathology of skin biopsies of erythema marginatum shows a polymorphous infiltrate of neutrophils and mononuclear cells in the papillary and upper half of the reticular dermis.[37] Biopsies of subcutaneous nodules demonstrate increased numbers of dilated blood vessels with peripherally thickened walls, fibrinoid necrosis, and fibrosis with attachment to tendons. Histologically, they resemble the lesions of rheumatoid arthritis with central fibrinoid necrosis, surrounded by histiocytes, perivascular lymphocytes, and neutrophils.[38]

The diagnosis of ARF is clinically based on the revised Jones criteria and typically presents within 2 to 4 weeks after an untreated GAS infection, most commonly GAS pharyngitis. A history of recurrent skin infections consistent with GAS may also be a preceding illness in specific high-risk populations. As many as one-third of patients with ARF do not recall preceding pharyngitis.[39] The hallmarks of GAS pharyngitis include fever, throat pain, headaches, and chills. Additionally, abdominal pain, nausea, and vomiting may be present, particularly in young children. An antecedent illness with these signs and symptoms should alert clinicians to the possibility of GAS pharyngitis.[40] The clinical manifestations of ARF vary drastically; some infections may be subclinical, and a diagnosis of ARF is not made until a patient is diagnosed with cardiac disease. Most patients with ARF display constitutional symptoms, including fevers, chills, and fatigue. Musculoskeletal Manifestations Arthritis or arthralgias are usually the earliest manifestations of ARF, occurring in 60% to 80% of patients. Joint symptoms are typically migratory and characterized by erythematous, swollen, and extremely tender joints; the large joints, eg, the knee, ankle, or wrist are most commonly affected. Joint aspiration, if performed, would generally demonstrate inflammatory and sterile synovial fluid. Radiographs of affected joints are typically normal. Cardiac Manifestations Carditis is the most serious presentation of ARF. The most common physical examination findings of carditis are tachycardia or the presence of a new murmur. Carditis occurs in 50% to 80% of patients with ARF and usually presents as pancarditis within 2 to 3 weeks of GAS infection involving the pericardium, epicardium, myocardium, and endocardium.[41] Carditis may also present with valvulitis, often seen on left-sided high-pressure valves. The mitral valve is affected in 50% to 60% of cases of valvulitis; mitral regurgitation is usually the earliest manifestation.[42] The physical examination of patients with mitral regurgitation frequently reveals a holosystolic murmur loudest at the apex and radiating to the left axilla. Progressive valvular damage can lead to mitral stenosis.

Carditis is the most serious presentation of ARF. The most common physical examination findings of carditis are tachycardia or the presence of a new murmur. Carditis occurs in 50% to 80% of patients with ARF and usually presents as pancarditis within 2 to 3 weeks of GAS infection involving the pericardium, epicardium, myocardium, and endocardium.[41] Carditis may also present with valvulitis, often seen on left-sided high-pressure valves. The mitral valve is affected in 50% to 60% of cases of valvulitis; mitral regurgitation is usually the earliest manifestation.[42] The physical examination of patients with mitral regurgitation frequently reveals a holosystolic murmur loudest at the apex and radiating to the left axilla. Progressive valvular damage can lead to mitral stenosis. The aortic valve is affected in 20% of patients with valvulitis.[42] Early aortic valve damage leads to aortic regurgitation, marked by a diastolic murmur heard best at the base of the heart and increased by the patient sitting forward. Progressive damage leads to aortic stenosis. The tricuspid valve is only affected in 10% of cases of valvulitis and typically results in tricuspid regurgitation.[42] The transition from ARF to RHD occurs when valvular lesions evolve over 10 to 20 years or during multiple episodes of ARF. RHD is the most common cause of acquired valvular disease, affecting the mitral valve most frequently. Due to severe pancarditis or valvulopathy, cardiomyopathy and heart failure can occur, even during ARF. Dermatologic Manifestations Skin findings of ARF include subcutaneous nodules and erythema marginatum. Subcutaneous nodules occur in less than 10% of patients with ARF and are firm, painless lesions over joints, predominately on extensor surfaces. These nodules are typically associated with severe carditis. Erythema marginatum occurs in less than 6% of patients with ARF and generally is a pink or pale red annular, nonpruritic rash with raised edges and central clearing found on the trunk and limbs but not the face (see Image. Erythema Marginatum). Erythema marginatum is often described as serpiginous and fleeting, appearing on 1 body part, fading, and reappearing elsewhere. Erythema marginatum seems to be a more common manifestation in older children with ARF.[43] Neurologic Manifestations

Skin findings of ARF include subcutaneous nodules and erythema marginatum. Subcutaneous nodules occur in less than 10% of patients with ARF and are firm, painless lesions over joints, predominately on extensor surfaces. These nodules are typically associated with severe carditis. Erythema marginatum occurs in less than 6% of patients with ARF and generally is a pink or pale red annular, nonpruritic rash with raised edges and central clearing found on the trunk and limbs but not the face (see Image. Erythema Marginatum). Erythema marginatum is often described as serpiginous and fleeting, appearing on 1 body part, fading, and reappearing elsewhere. Erythema marginatum seems to be a more common manifestation in older children with ARF.[43] Neurologic Manifestations Sydenham chorea (SC) is a neurologic manifestation of ARF that occurs in 10% to 30% of cases. SC is a late-stage neurological complication usually occurring 1 to 8 months after GAS infection. SC presents as involuntary, irregular “jerking” movements of the face, hands, or feet.[44] These choreiform movements are more extreme on one side of the body and do not occur during sleep. Behavioral symptoms, including agitation, anxiety, or inappropriate laughing or crying, can complicate SC.[45] Facial grimaces and tics are common and may be accompanied by emotional lability and characteristics of obsessive-compulsive disorder. Dysarthria and dysgraphia are also frequently noted.[46] A characteristic physical examination finding for SC is the “milkmaid's sign,” where a patient cannot maintain her grip when asked to squeeze the examiner’s fingers due to intermittent loss of muscle contraction, leading to a squeeze-and-release motion. Patients with SC often lack the traditional dermatologic and joint manifestations of ARF. Chorea typically resolves within 6 weeks to 6 months.

Revised Jones Criteria The diagnosis of ARF is mainly clinical and considered when a GAS infection is followed by the clinical manifestations outlined in the Revised Jones Criteria. In this classification scheme, low-risk populations have an ARF incidence of ≤2 per 100,000 school-aged children, and moderate- and high-risk populations have an ARF incidence of >2 per 100,000.[45] Initial diagnosis in any risk population requires the following (see Table 1. Revised Jones Criteria for Diagnosing Acute Rheumatic Fever): 2 major criteria, or 1 major and 2 minor criteria The diagnosis of a recurrent episode of ARF requires the following: 2 major criteria, or 1 major and 2 minor criteria, or 3 minor criteria A presumptive diagnosis of ARF may be made without using the Jones Criteria in patients presenting with Sydenham chorea or indolent carditis months after GAS infection. These cases require further evaluation with an echocardiogram. A possible case can be defined as patients who meet the criteria for an initial infection but lack evidence of preceding GAS infection. Patients with 1 major and 1 minor criteria with evidence of a preceding GAS infection are also labeled as possible cases of ARF.[47] Table Table 1. Revised Jones Criteria for Diagnosing Acute Rheumatic Fever. Detecting Group A Streptococcus The number of laboratory tests available to diagnose GAS infection has vastly increased. The available modalities used to diagnose GAS infection include: Throat culture Rapid antigen detection tests (RADT) Nucleic acid amplification tests Antistreptolysin O (ASO) or antideoxyribonuclease B (ADB) antibody titers Throat culture remains the gold standard, but its use is limited by its time to result. Point-of-care testing is frequently used in primary care settings. NAAT detect GAS and normally result in less than 1 hour. NAATs for GAS are highly sensitive and do not require backup culture testing when negative.[48][49] RADT identify the presence of the Lancefield group A carbohydrate, provide very rapid results, and are inexpensive. The sensitivity of RADT may be less than 90%; most experts recommend backup throat culture for negative RADT results due to the low sensitivity.[50] Neither the NAAT nor the RADT allows for detecting emm types or antimicrobial susceptibility if those are the goals of obtaining a test.

Throat culture remains the gold standard, but its use is limited by its time to result. Point-of-care testing is frequently used in primary care settings. NAAT detect GAS and normally result in less than 1 hour. NAATs for GAS are highly sensitive and do not require backup culture testing when negative.[48][49] RADT identify the presence of the Lancefield group A carbohydrate, provide very rapid results, and are inexpensive. The sensitivity of RADT may be less than 90%; most experts recommend backup throat culture for negative RADT results due to the low sensitivity.[50] Neither the NAAT nor the RADT allows for detecting emm types or antimicrobial susceptibility if those are the goals of obtaining a test. Given that ARF is an autoimmune disease that occurs weeks after an antecedent infection, detection of a recent past GAS infection with serology is more reliable. ASO or ADB antibody titers are most commonly utilized. These titers usually rise 2 to 3 weeks after a GAS infection. Ideally, titers are obtained as soon as possible and then in 2-4 weeks after the initial test. A rise in titer by 2-fold or more is considered positive. This approach may be impractical or difficult to access in certain clinical circumstances, so 1 serological test that is at the upper limit of normal is an acceptable alternative method to ascertain a diagnosis.[51] The interpretation of titer results is age-dependent (see Table 2. Age-Dependent Upper Normal Limits for Antistreptolysin O and Antideoxyribonuclease B Antibody Titers for Areas of Endemic Group A Streptococcus Disease).[52] Table Table 2. Age-Dependent Upper Normal Limits for Antistreptolysin O and Antideoxyribonuclease B Antibody Titers for Areas of Endemic Group A Streptococcus Disease. Cardiac Evaluation All patients with ARF should undergo cardiac evaluation with chest radiography, electrocardiography (ECG), and echocardiography. Chest imaging may reveal cardiomegaly and pulmonary edema. The most common ECG finding is a prolongation of the PR interval, which must be adjusted for age (see Table 3. Age-Adjusted PR Intervals). Table Table 3. Age-Adjusted PR Intervals.

All patients with ARF should undergo cardiac evaluation with chest radiography, electrocardiography (ECG), and echocardiography. Chest imaging may reveal cardiomegaly and pulmonary edema. The most common ECG finding is a prolongation of the PR interval, which must be adjusted for age (see Table 3. Age-Adjusted PR Intervals). Table Table 3. Age-Adjusted PR Intervals. An echocardiogram may reveal signs of valvulopathy or heart failure. One of the keys to the successful treatment of ARF is the ability to diagnose subclinical carditis, which relies on the accessibility of echocardiography. A recent study suggested that 10.8% of patients with ARF suffer from subclinical carditis diagnosed only by echocardiography.[8] The expansion of mobile echocardiography has resulted in a vast improvement in the diagnosis of carditis and should be sought even in resource-limited settings.

The treatment of ARF is multimodal and involves GAS eradication therapy, symptomatic treatment, and prophylaxis to prevent recurrence. Initial management should occur in an inpatient hospital setting. The trend of inflammatory markers helps monitor disease progression. The normalization of inflammatory markers after therapy is completed indicates disease resolution. Group A Streptococcus Eradication Therapy All patients diagnosed with GAS pharyngitis should receive antibiotics to treat and attempt to eradicate GAS. Similarly, all patients diagnosed with ARF should receive a course of antibiotics even if they have a negative throat culture.[53] The recommended antibiotic for GAS eradication therapy is penicillin; dosage is based on the patient's weight.[50] If the patient weighs less than 27 kg, penicillin V 250 mg 2 to 3 times daily for 10 days is preferred; if the patient weighs more than 27 kg, 500 mg 2 to 3 times daily for 10 days is recommended. A single intramuscular dose of penicillin G benzathine 600,000 units (if <27 kg) or 1.2 million units (if >27 kg) may also be used for GAS eradication therapy and may be preferable, as penicillin G benzathine is the recommended therapy for patients with ARF requiring secondary antibiotic prophylaxis. Amoxicillin has a slightly broader spectrum of antimicrobial activity, but some practitioners prefer it for its palatability. The amoxicillin dose is 50 mg/kg/d orally for 10 days, administered once or twice daily. Cephalosporins are recommended in cases of documented penicillin allergy with a history of anaphylaxis.[50] The most common cephalosporins administered are cephalexin, cefuroxime, cefpodoxime, or cefdinir. Macrolides are recommended when a history of anaphylaxis to penicillin is present. Common macrolides administered are azithromycin at 12 mg/kg/d for 5 days with a maximum dose of 500 mg/dose and clarithromycin at 7.5 mg/kg/dose, twice daily for 10 days with a maximum dose of 250 mg/dose. Evidence of increasing GAS resistance to macrolides has been noted.[54] Macrolide resistance is often regional and fluctuates depending on the clone of GAS circulating through a community. Clindamycin is another alternative; some have touted it as the best at eradicating the GAS carrier state. However, clindamycin has significantly more gastrointestinal adverse effects.[55] Symptomatic Therapy

Cephalosporins are recommended in cases of documented penicillin allergy with a history of anaphylaxis.[50] The most common cephalosporins administered are cephalexin, cefuroxime, cefpodoxime, or cefdinir. Macrolides are recommended when a history of anaphylaxis to penicillin is present. Common macrolides administered are azithromycin at 12 mg/kg/d for 5 days with a maximum dose of 500 mg/dose and clarithromycin at 7.5 mg/kg/dose, twice daily for 10 days with a maximum dose of 250 mg/dose. Evidence of increasing GAS resistance to macrolides has been noted.[54] Macrolide resistance is often regional and fluctuates depending on the clone of GAS circulating through a community. Clindamycin is another alternative; some have touted it as the best at eradicating the GAS carrier state. However, clindamycin has significantly more gastrointestinal adverse effects.[55] Symptomatic Therapy Symptomatic therapy is geared toward managing the manifestations of ARF. Arthritis Arthritis is the earliest and most common manifestation of ARF and historically has been managed with aspirin 60 to 100 mg/kg/day in divided doses until symptom resolution. However, this dosing regimen required frequent measurement of serum salicylate levels and subsequent dose adjustments while increasing the risk of developing Reye syndrome. Newer data suggest that initially treating arthritis with nonsteroidal anti-inflammatory drugs (NSAIDs), typically naproxen 5 to 10 mg/kg every 12 hours with a maximum daily dose of 1000 mg until symptoms resolve, is equally effective.[56][57] A recent study suggests that ibuprofen may be equally effective.[58] The major adverse effect of NSAID therapy is gastrointestinal upset; patients are often prescribed a concurrent proton pump inhibitor. Glucocorticoids are recommended if the patient has an allergy to aspirin or NSAIDs. Cardiac symptoms

Arthritis is the earliest and most common manifestation of ARF and historically has been managed with aspirin 60 to 100 mg/kg/day in divided doses until symptom resolution. However, this dosing regimen required frequent measurement of serum salicylate levels and subsequent dose adjustments while increasing the risk of developing Reye syndrome. Newer data suggest that initially treating arthritis with nonsteroidal anti-inflammatory drugs (NSAIDs), typically naproxen 5 to 10 mg/kg every 12 hours with a maximum daily dose of 1000 mg until symptoms resolve, is equally effective.[56][57] A recent study suggests that ibuprofen may be equally effective.[58] The major adverse effect of NSAID therapy is gastrointestinal upset; patients are often prescribed a concurrent proton pump inhibitor. Glucocorticoids are recommended if the patient has an allergy to aspirin or NSAIDs. Cardiac symptoms Carditis is the most serious complication of ARF, and GAS eradication therapy removes the infection, inducing the autoimmune response against cardiac tissues. Decreasing systemic inflammation has been associated with reducing the risk of developing cardiac disease. A recent systematic review assessed various therapies for carditis and their ability to prevent further cardiac damage. In summary, neither corticosteroids nor intravenous immunoglobulin (IVIG) were determined superior to aspirin therapy for this purpose.[59] Corticosteroids may help manage patients with severe acute RHD, marked by significant mitral regurgitation or persistent atrioventricular block.[60] If a patient develops heart failure or RHD, treatment can be pharmacological or surgical, depending on the severity of the cardiac disease. Pharmacotherapy options recommended for managing heart failure include fluid and salt restriction, angiotensin-converting enzyme (ACE) inhibitors, and diuretics.[42] All patients with ARF should be evaluated and followed by a cardiologist, even if carditis is not initially present, and periodic evaluation should be performed to monitor for potential progression to RHD. Dermatologic symptoms Subcutaneous nodules and erythema marginatum associated with ARF are commonly self-limited. Sydenham chorea

If a patient develops heart failure or RHD, treatment can be pharmacological or surgical, depending on the severity of the cardiac disease. Pharmacotherapy options recommended for managing heart failure include fluid and salt restriction, angiotensin-converting enzyme (ACE) inhibitors, and diuretics.[42] All patients with ARF should be evaluated and followed by a cardiologist, even if carditis is not initially present, and periodic evaluation should be performed to monitor for potential progression to RHD. Dermatologic symptoms Subcutaneous nodules and erythema marginatum associated with ARF are commonly self-limited. Sydenham chorea Sydenham chorea is a late-stage finding and is generally self-limited. Sydenham chorea is treated with rest and avoidance of overstimulation. Immunomodulating agents have been studied as a treatment for Sydenham chorea and appear to have a positive impact. Studies suggest that corticosteroids will improve symptoms in patients suffering from Sydenham chorea. The most common treatment regimen is intravenous methylprednisolone, followed by oral prednisone.[61][62][63] Some practitioners advocate for treatment with prednisone alone.[64][65][66][67] Others have observed that patients demonstrate clinical improvement after receiving IVIG or plasmapheresis therapy.[68][69][70][61]][71] Pharmacotherapy is recommended for Sydenham chorea, which is negatively impacting activities of daily living. Options include carbamazepine, pimozide, haloperidol, and valproic acid for refractory cases. Haloperidol has shown efficacy, but its significant adverse effects limit its use in children.[72][73] Carbamazepine and valproic acid are effective against the symptoms of Sydenham chorea and have been used in children with neurologic diseases for many years.[74][75] One case report suggests that pimozide may be effective with minimal adverse effects.[76] Secondary Antibiotic Prophylaxis Patients with a history of ARF are at increased risk for disease recurrence and worsening RHD and should receive secondary antibiotic prophylaxis against GAS infections. Patients with Sydenham chorea as the only presenting symptom of ARF should also initiate secondary antibiotic prophylaxis.

Secondary Antibiotic Prophylaxis Patients with a history of ARF are at increased risk for disease recurrence and worsening RHD and should receive secondary antibiotic prophylaxis against GAS infections. Patients with Sydenham chorea as the only presenting symptom of ARF should also initiate secondary antibiotic prophylaxis. Antibiotic prophylaxis typically involves the administration of intramuscular penicillin G benzathine every 28 days. In populations with a higher incidence of ARF, injections should be administered every 21 days. Oral penicillin V twice daily may be used prophylactically but is associated with decreased adherence and increased recurrence.[77] However, penicillin V is the recommended prophylactic therapy in patients with severe, symptomatic valvular disease with evidence of significant heart failure, as vasovagal episodes associated with intramuscular injections have been associated with an increased risk of sudden death. In patients with penicillin allergies, macrolides and sulfadiazines can be used. All patients with a history of penicillin allergy should undergo evaluation by an allergist to determine if they can be cleared for penicillin therapy. In cases of breakthrough GAS pharyngitis, clindamycin can be used for the acute episode before restarting penicillin prophylaxis. The duration of secondary prophylactic therapy may vary based on evidence of carditis. Patients with echocardiographic evidence of carditis without residual valvulopathy should continue prophylactic therapy for 10 years or until age 21. Patients with evidence of residual valvulopathy should continue prophylactic therapy for 10 years or until age 40. If no echocardiographic evidence of carditis is demonstrated, prophylaxis should continue for 5 years or until the patient reaches age 21. In all cases, prophylactic therapy should be continued until the latest age criteria are met (see Table 4. Secondary Antibiotic Prophylaxis of Acute Rheumatic Fever).[53] Table Table 4. Secondary Antibiotic Prophylaxis of Acute Rheumatic Fever.

Patients with ARF may present with ≥1 clinical symptoms. The presentation of ARF varies widely. The differential diagnosis of ARF is broad and primarily dictated by the presenting symptomatology, including: Polyarthritis Lyme disease Poststreptococcal reactive arthritis Septic arthritis Drug reactions and serum sickness Postinfectious reactive arthritis Carditis Endocarditis Viral myocarditis Sydenham chorea Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) Tardive dyskinesia Tourette syndrome Dermatologic manifestations Urticaria Scarlet fever Kawasaki disease Erythema multiforme Erythema migrans (Lyme disease) Viral exanthem Systemic illnesses Juvenile idiopathic arthritis Kawasaki disease Systemic lupus erythematosus

The usual course of ARF is about 3 months, and recurrence rates approximate 65%.[78] Recurrence increases the risk of progression to RHD and heart failure. Risk factors contributing to recurrence include poor adherence to prophylaxis, shorter intervals between episodes of ARF, younger age, and the presence of carditis.[79] Cardiac involvement is the most critical prognosticating factor in ARF. Patients with carditis are at the highest risk for developing RHD, the most common cause of morbidity and mortality in patients with ARF. The long-term prognosis of ARF has significantly improved over the last century in developed areas, with enhanced therapy for GAS eradication, long-term secondary prophylaxis, and improved living conditions. Despite this, patients in resource-poor areas commonly present with late-stage RHD. Valve replacement or valvuloplasty is indicated in cases of severe rheumatic valvular disease. A study conducted on Australian patients with cardiac disease during their ARF episode showed that 50% of patients with severe RHD underwent valvular surgery within 2 years and experienced a 10% mortality rate. Among patients with minimal carditis, 64% had mild cardiac disease even after 10 years of developing ARF. Of these patients, 11.4% progressed to clinically severe RHD, and half needed surgery.[80] A systematic review recently summarized the outcomes of mitral valvuloplasty versus mitral valve replacement. Patients who underwent valve repair were noted to have lower short- and long-term mortality but often required additional procedures. Surgical repair is preferred for older patients, but concomitant aortic valve disease favors mitral valve replacement.[81] Sydenham chorea typically will resolve in about 12 to 15 weeks. Persistent Sydenham chorea does occur, but the mechanism is unclear. Some experts suspect damage to the basal ganglia accounts for this phenomenon.[82] Additionally, psychiatric symptoms may be more prevalent in patients who have suffered from Sydenham chorea.[83]

The most common complicating sequela of ARF is RHD, which occurs 10 to 20 years after the original illness and is due to valvular damage by severe or recurrent bouts of ARF. RHD is the most common cause of acquired valvular pathology worldwide. RHD can lead to heart failure, pulmonary hypertension, dysrhythmias, embolic strokes, and sudden cardiac death.[84] Another complication of ARF is Jaccuod arthropathy, a chronic, benign arthropathy that may result in joint deformities due to repeated bouts of arthritis caused by ARF.[85] The arthritic changes of Jaccoud arthropathy appear similar to the joint deformities seen with rheumatoid arthritis and include thumb subluxation, ulnar deviation, hallux valgus, and swan neck and boutonniere deformities of the fingers. However, unlike in rheumatoid arthritis, patients with Jaccoud arthropathy do not have bony erosions, and the deformations can be manipulated into a normal anatomic position. Sydenham chorea may rarely lead to persistent symptoms and has been related to increased psychiatric symptoms in some patients.

Care for patients with ARF should be carried out in consultation with an infectious disease specialist and a cardiologist. As part of the diagnostic criteria, it will be necessary to obtain echocardiography to look for evidence of carditis. If patients develop carditis with severe valvulopathy with signs of heart failure, a cardiothoracic surgeon should be consulted to consider valvuloplasty. In patients with Sydenham chorea, consultation with a neurologist may be necessary. In patients with persistent arthralgias and arthritis, consultation with a rheumatologist may help design a long-term management plan.

ARF and the subsequent development of RHD are significant causes of morbidity and mortality, especially in developing countries. Deterrence involves strategies to avoid GAS pharyngitis, early detection and treatment of GAS pharyngitis, and prophylaxis against recurrent ARF. Patient education is one of the cornerstones of successful lifelong management of ARF. Patients should be informed about the consequences of their diagnosis of ARF and the importance of adherence to prophylactic antibiotic therapy. Caregivers should also be educated about the signs of GAS pharyngitis and early manifestations of ARF. Household and school-aged contacts are the most likely sources of GAS exposure in people with a history of ARF.

Effective management of ARF requires a coordinated, interprofessional team approach to optimize patient-centered care, safety, and outcomes. Primary care, urgent, and emergency care clinicians are often the first to evaluate patients with ARF, making early recognition of symptoms crucial. Prompt initiation of pharmacotherapy, including penicillin G for secondary prophylaxis and early cardiac assessment, is essential in reducing complications. If carditis or RHD is detected, cardiologists and cardiothoracic surgeons should lead the management of heart failure and valvular disease. Infectious disease specialists play a key role in guiding initial antibiotic treatment and long-term prophylaxis to prevent recurrence. Nurses and pharmacists contribute significantly to patient education, ensuring adherence to antibiotic therapy and reinforcing the importance of continuous prophylaxis. Strong interprofessional communication and care coordination are essential for seamless transitions between acute management and long-term follow-up, minimizing recurrence and disease progression. By working collaboratively, healthcare professionals enhance team performance, reduce morbidity, and improve patient outcomes, ultimately preventing complications associated with ARF and RHD.