Practice Essentials
Acute rheumatic fever (ARF) is a sequela of a previous group A streptococcal infection, usually of the upper respiratory tract. 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 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 pockets where the incidence is significant, especially in tropical areas.
Research into the subtypes of streptococci has made it clear that differences among those types are also responsible for both the decline in the overall incidence of ARF, as well as of isolated outbreaks.
The most recent advance is the recognition that there is genetic predisposition to development of acute rheumatic fever, though the exact reason is still a matter of research. [2, 3]
Pathophysiology
Acute rheumatic fever is a sequela of a previous group A streptococcal infection, usually of the upper respiratory tract. This is an autoimmune response secondary to molecular mimicry following group A streptococcal pharyngitis. One beta-streptococcal serotype (eg, M types 3, 5, 18, 19, 24) is linked directly to acute rheumatic fever. Non–group A streptococci have never been shown to cause this disease.
Good evidence suggests that there is genetic susceptibility to development of the disease. Several studies have shed light on genetic predisposition. [2, 3] Susceptibility studies have focused on human leukocyte antigens, B-cell alloantigens, and cytokine genes. Study results, however, often conflict. [2]
Some have questioned the possibility that viruses may also be implicated as a correlating cause; however, most studies have shown no correlation, with the single exception of Epstein-Barr virus. In that setting, one author found DNA positivity in acute cases but not in controls. [4]
The disease involves the heart, joints, central nervous system (CNS), skin, and subcutaneous tissues. It is characterized by an exudative and proliferative inflammatory lesion of the connective tissue, especially that of the heart, joints, blood vessels, and subcutaneous tissue.
Etiology
Acute rheumatic fever (ARF) has been linked definitively with a preceding streptococcal infection, usually of the upper respiratory tract. Evidence is very strong that the M protein in certain streptococci subtypes is responsible for antigenicity.
Although streptococcal skin infections also are extremely common, they have not been linked with ARF in the United States. Note the suggestion by McDonald et al that pyoderma may be the cause in Aboriginal populations of Australia. [5]
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 areas of crowding. The United States had experienced a resurgence of rheumatic fever in the last 2 decades, with many of the reported cases involving persons in upper socioeconomic groups. The reason for this disparity is unclear but may be caused by the emergence of more virulent strains of group A streptococci. The overall incidence has been declining in developed nations but is still rampant in less developed ones.
The incidence is low in most parts of the country but is variable. 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. [6] Consistent with earlier reports, most patients were children and most had carditis. Curiously, most studies report that rheumatic fever is very unusual if not rare in developed countries, but remains a major problem in developing nations. [7, 8]
ARF is common among American Samoans in Hawaii. [9]
Frequency of streptococcal infection, virulence of the bacterial strain, and M protein subtypes determine the incidence of rheumatic fever in the population.
As a sequela of beta-streptococcal exposure, ARF occurs during the school-aged years when streptococcal pharyngitis is most prevalent. Similarly, prevalence is higher in the colder months of the year when streptococcal pharyngitis is most likely to occur.
International
ARF is a major problem in the high-risk areas of the tropics, in countries with limited resources, and in communities with minority indigenous populations. Although older literature estimates that 25-40% of cases worldwide appear in those nations, a more recent paper suggests the figure may be closer to 95%. [10]
The burden of ARF remains high witha global estimate of 33.4 million people with rheumatic heart disease resulting in 10.5 million disability-adjusted life-years lost. [11]
In those less developed nations, post-ARF heart disease is the most commonly acquired heart disease in hospitalized children, adolescents, and young adults. [7] ARF is clearly still a major problem is less developed areas of the world. [12] In some areas, the incidence of this entity exceeds that of congenital heart disease. Some studies point out the association with heart failure and death in pregnant women. McDonald et al have suggested that in Aboriginal communities of central and northern Australia, group A streptococcal pyoderma is much more likely to cause acute rheumatic fever than is streptococcal pharyngitis. [5]
Wang et al reported on a possible ARF resurgence in Taiwan. [13] Authors in India and Turkey make a plea for more liberal application of the Jones criteria in order to avoid misdiagnosis. [14, 15, 16] Similarly, Steer et al found a significant pocket of cases on the island of Fiji when clinicians liberally applied diagnostic criteria and followed with echocardiography. [17] Meira et al report on the high incidence in Brazil. [18] Others have reminded the medical community that good reporting of prevalence in underdeveloped nations is lacking.
Parks et al suggest that ARF is underdiagnosed in primary care clinics in the United Kingdom. [19] Other authors continue to report the problem of ARF in underdeveloped countries and in the indigenous populations of developed countries. [12]
Pastore et al studied cases in Trieste, Italy and report that ARF still occurs in industrialized countries. [20]
Marijon et al believe that the World Health Organization echocardiographic criteria for making the diagnosis in subclinical cases are inadequate. The group advocates for criteria that include valves with morphological changes consistent with rheumatic disease but without pathological regurgitation. [21]
Race-, sex-, and age-related demographics
In the United States, the attack rate is more a function of crowding than race, though the socioeconomic realities of those crowded conditions is no doubt a factor.
No sex predilection exists, except that mitral valve prolapse and Sydenham chorea occur more often in females than in males.
Although individuals of any age group may be affected, most cases are reported in persons aged 5-15 years. Paulo et al report that acute rheumatic fever can be found in children younger than 5 years with no significant difference in the frequency and severity of clinical signs. [22] Yee lists rheumatic pericarditis and myocarditis as cardiac emergencies in the first year of life. [23]
Prognosis
Sequelae are limited to the heart and depend on the severity of the carditis during the acute attack. Morbidity from acute rheumatic fever (ARF) is directly proportional to the rate of streptococcal infections. 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 also is related to the care that the patient receives.
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, ARF is a major cause of death and disability in children and adolescents.
Cardiac involvement is the major cause of long-term morbidity. ARF causes inflammation of valvular endocardium. One or more valves (most commonly the mitral valve) may be permanently deformed. Those valves are then dysfunctional, which may lead to problems including left ventricular dilation and congestive heart failure, sometimes decades later. Vegetations may develop on damaged valves and become infected, leading to endocarditis. Myocarditis is present but is not the direct cause of heart failure.
Carapetis et al estimated that worldwide, approximately 60% of all patients with ARF will develop rheumatic heart disease. [24] Further, they estimate a world burden of 2.4 million children aged 5-14 years affected or a total population of 15-20 million living with rheumatic heart disease.
Patients with carditis as part of the initial episode are at greater risk of developing recurrences and of sustaining further cardiac injury. Those without carditis during the initial episode have a relatively low risk of developing carditis during recurrences, although scattered case reports of carditis occurring only during a recurrence exist.
Migratory polyarthritis occurs early in the disease course and is a common complaint for patients with rheumatic fever. Joint involvement ranges from arthralgia without objective findings to overt arthritis with warmth, swelling, redness, and exquisite tenderness. The larger joints such as the knees, ankles, elbows, and wrists are involved most frequently. An inverse relationship between severity of joint involvement and risk of carditis appears to exist.
In approximately 75% of cases, the acute attack lasts only 6 weeks. Ninety percent of cases resolve in 12 weeks or less. Fewer than 5% of patients have symptoms that persist for 6 months or more.
Literature began to appear in 1998 suggesting that acute rheumatic fever might be another disorder associated with PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections). Although two large cohort studies reported a higher odds ratio of developing obsessive-compulsive disorder, tics, and "mental disorders" following streptococcal pharyngitis or other respiratory tract infections, evidence of an immune basis is lacking. [25]
