Background
Rheumatic fever (RF) is a systemic illness that may occur following group A beta hemolytic streptococcal (GABHS) pharyngitis in children. Rheumatic fever and its most serious complication, rheumatic heart disease (RHD), are believed to result from an autoimmune response; however, the exact pathogenesis remains unclear. Studies in the 1950s during an epidemic on a military base demonstrated 3% incidence of rheumatic fever in adults with streptococcal pharyngitis not treated with antibiotics.[1] Studies in children during the same period demonstrated an incidence of only 0.3%. The current incidence of rheumatic fever after GABHS infection is now thought to have decreased to less than 1%. Cardiac involvement is reported to occur in 30-70% of patients with their first attack of rheumatic fever and in 73-90% of patients when all attacks are counted.
Clinical manifestations and time course of acute rheumatic fever are shown in the image below.
Clinical manifestations and time course of acute rheumatic fever. Pathophysiology
Rheumatic fever develops in children and adolescents following pharyngitis with GABHS (ie, Streptococcus pyogenes). The organisms attach to the epithelial cells of the upper respiratory tract and produce a battery of enzymes, which allows them to damage and invade human tissues. After an incubation period of 2-4 days, the invading organisms elicit an acute inflammatory response, with 3-5 days of sore throat, fever, malaise, headache, and elevated leukocyte count. In a small percent of patients, infection leads to rheumatic fever several weeks after the sore throat has resolved. Only infections of the pharynx initiate or reactivate rheumatic fever.
Direct contact with oral (PO) or respiratory secretions transmits the organism, and crowding enhances transmission. Patients remain infected for weeks after symptomatic resolution of pharyngitis and may serve as a reservoir for infecting others. Penicillin treatment shortens the clinical course of streptococcal pharyngitis and more importantly prevents the major sequelae.
GABHS organisms are gram-positive cocci, which frequently colonize the skin and oropharynx. These organisms may cause suppurative diseases (eg, pharyngitis, impetigo, cellulitis, myositis, pneumonia, puerperal sepsis). GABHS organisms also may be associated with nonsuppurative diseases (eg, rheumatic fever, acute poststreptococcal glomerulonephritis). Group A streptococci (GAS) elaborate the cytolytic toxins, streptolysins S and O. Of these 2 toxins, streptolysin O induces persistently high antibody titers that provide a useful marker of GAS infection and its nonsuppurative complications.
GAS, as identified using the Lancefield classification, has a group A carbohydrate antigen in the cell wall that is composed of a branched polymer of L-rhamnose and N-acetyl-D-glucosamine in a 2:1 ratio. Surface proteins on the cell wall of the organism may subserotype GAS. The presence of the M protein is the most important virulence factor for GAS infection in humans. More than 120 M protein serotypes or M protein genotypes have been identified,[20] some of which have a long terminal antigenic domain (ie, epitopes) similar to antigens in various components of the human heart.
Rheumatogenic strains are often encapsulated mucoid strains, rich in M proteins, and resistant to phagocytosis. These strains are strongly immunogenic, and anti-M antibodies against the streptococcal infection may cross-react with components of heart tissue (ie, sarcolemmal membranes, valve glycoproteins). Currently, emm typing is felt to be more discriminating than M typing.[20]
Acute RHD often produces a pancarditis, characterized by endocarditis, myocarditis, and pericarditis. Endocarditis is manifested as mitral and aortic valve insufficiency. Severe scarring of the valves develops during a period of months to years after an episode of acute rheumatic fever, and recurrent episodes may cause progressive damage to the valves. The mitral valve is affected most commonly and severely (65-70% of patients); the aortic valve is affected second most commonly (25%).
The tricuspid valve is deformed in only 10% of patients, almost always in association with mitral and aortic lesions, and the pulmonary valve is rarely affected. Severe valve insufficiency during the acute phase may result in congestive heart failure (CHF) and even death (1% of patients). Whether myocardial dysfunction during acute rheumatic fever is primarily related to myocarditis or is secondary to CHF from severe valve insufficiency is not known. When pericarditis is present, it rarely affects cardiac function or results in constrictive pericarditis.
Chronic manifestations occur in adults with previous RHD from residual and progressive valve deformity. RHD is responsible for 99% of mitral valve stenosis in adults, and it may be associated with atrial fibrillation from chronic mitral valve disease and atrial enlargement.
Epidemiology
Frequency
United States
Rheumatic fever is now uncommon among children in the United States. Incidence of rheumatic fever and RHD has decreased in the United States and other industrialized countries during the past 80 years. Prevalence of RHD in the United States is now less than 0.05 per 1000 population, with rare regional outbreaks reported in Tennessee in the 1960s and in Utah, Ohio, and Pennsylvania in the 1980s. In the early 1900s, incidence was reportedly 5-10 cases per 1000 population. Decreased incidence of rheumatic fever has been attributed to the introduction of penicillin or a change in the virulence of the streptococci.
International
In contrast to trends in the United States, rheumatic fever and RHD have not decreased in developing countries. Retrospective studies in developing countries demonstrate the highest figures for cardiac involvement and the highest recurrence rates of rheumatic fever. Worldwide, an estimated 5-30 million children and young adults have chronic RHD, and 90,000 patients die from this disease each year.
A study using echocardiographic screening in schoolchildren in Cambodia and Mozambique suggests that RHD prevalence may be as much as 10 times that detected using clinical examination with echocardiographic verification.[2]
Mortality/Morbidity
RHD is the major cause of morbidity from rheumatic fever and is the major cause of mitral insufficiency and stenosis in the United States and the world. Variables that correlate with severity of valve disease include the number of previous attacks of rheumatic fever, the length of time between the onset of disease and start of therapy, and sex (the prognosis for females is worse than for males). Insufficiency from acute rheumatic valve disease resolves in 70-80% of patients if they adhere to antibiotic prophylaxis.
Race
Native Hawaiians and Maori (both of Polynesian descent) have a higher incidence of rheumatic fever. Incidence of rheumatic fever in these patients is 13.4 per 100,000 hospitalized children per year, even with antibiotic prophylaxis of streptococcal pharyngitis. Otherwise, race (when controlled for socioeconomic variables) has not been documented to influence the disease incidence.
Sex
Rheumatic fever occurs in equal numbers in males and females. Females with rheumatic fever fare worse than males and have a slightly higher incidence of chorea.
Age
Rheumatic fever is principally a disease of childhood, with a median age of 10 years; However, GABHS pharyngitis is uncommon in children younger than 3 years, and acute rheumatic fever is extremely rare in these younger children in industrialized countries. Although less commonly seen in adults compared with children, rheumatic fever in adults accounts for 20% of cases.
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