Pediatric Rheumatic Fever

  • Author: Thomas K Chin, MD; Chief Editor: Lawrence K Jung, MD  more...
 
Updated: Jun 28, 2016
 

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 incidence of rheumatic fever after GABHS infection is thought to be 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 r Clinical manifestations and time course of acute rheumatic fever.
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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 have been shown to initiate or reactivate rheumatic fever. However, epidemiological associations in certain populations have led to speculation that group A Streptococcus impetigo could predispose to or cause rheumatic fever as well.[1]

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. Recent studies using enzyme-linked immunosorbent assays showed a correlation between  anti-streptolysin O and anti-human cardiac myosin antibodies.[2]

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,[3] 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.[3]

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

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Epidemiology

Frequency

United States

Rheumatic fever is now uncommon among children in the United States. The incidence of rheumatic fever and RHD was thought to be decreased in the United States and other industrialized countries during the past 80 years. The prevalence of RHD in the United States was less than 0.05 per 1000 population, with only rare regional outbreaks reported in Tennessee in the 1960s and in Utah[4] , Ohio, and Pennsylvania in the 1980's. While In the early 1900s, incidence was reportedly 5-10 cases per 1000 population. Decreased incidence of rheumatic fever was attributed to the introduction of penicillin or a change in the virulence of the streptococci, while the incidence in other developed countries, such as Italy, was comparable.[5]  However a recent assessment of temporal trends of patients diagnosed with acute rheumatic fever in the United States from 2001-2011 showed that since 2001, national acute rheumatic fever admissions has steadily increased, with a peak in 2005, and decreased thereafter.[6]

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.[7] Worldwide, there are over 15 million cases of RHD, with 282,000 new cases and 33,000 deaths from this disease each year.[8]

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.[8]

The prevalence is greatest in the South (34.32%) compared to the Northeast (25.05%), Midwest (22.95%), and West (17.69%). Blacks have the highest mortality rate (5.00%) compared to whites (3.01%), Hispanics (1.66%) and Asians (0.89%). As median income decreases, the frequency increases, with patients earning less than $25,000 per year making up 23.74% of admissions.[6]

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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Contributor Information and Disclosures
Author

Thomas K Chin, MD Professor of Pediatrics, Chief of Pediatric Cardiology, Pennsylvania State University College of Medicine

Thomas K Chin, MD is a member of the following medical societies: American Academy of Pediatrics, American Heart Association, American College of Cardiology

Disclosure: Nothing to disclose.

Coauthor(s)

Douglas Li, MD Assistant Clinical Professor, Division of Pediatric Pulmonology, Department of Pediatrics, University of California, Los Angeles, David Geffen School of Medicine, Mattel Children's Hospital UCLA

Douglas Li, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Chest Physicians, American Thoracic Society

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Thomas JA Lehman, MD FAAP, FACR, Clinical Professor of Pediatrics, Department of Pediatrics, Division of Pediatric Rheumatology, Weill Cornell Medical College; Chief, Hospital for Special Surgery

Thomas JA Lehman, MD is a member of the following medical societies: PM American Allergy Society

Disclosure: Nothing to disclose.

Chief Editor

Lawrence K Jung, MD Chief, Division of Pediatric Rheumatology, Children's National Medical Center

Lawrence K Jung, MD is a member of the following medical societies: American Association for the Advancement of Science, American Association of Immunologists, American College of Rheumatology, Clinical Immunology Society, New York Academy of Sciences

Disclosure: Nothing to disclose.

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Clinical manifestations and time course of acute rheumatic fever.
Chest radiograph showing cardiomegaly due to carditis of acute rheumatic fever.
Erythema marginatum, the characteristic rash of acute rheumatic fever.
 
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