eMedicine Specialties > Pediatrics: General Medicine > Rheumatology

Rheumatic Fever

Author: Thomas K Chin, MD, Associate Professor of Pediatrics, Chief of Pediatric Cardiology and Medical Director of the Pediatric Heart Institute, University of Tennessee College of Medicine; Director of Cardiology and Endowed Chair for Excellence in Cardiology, St Jude Children's Research Center
Coauthor(s): Douglas Li, Wake Forest University Medical Center
Contributor Information and Disclosures

Updated: Feb 25, 2010

Introduction

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.

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.

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.

Clinical

History

Acute rheumatic fever (RF) is a systemic disease. Thus, patients may present with a large variety of symptoms and complaints.

• History of an antecedent sore throat 1-5 weeks prior to onset is present in 70% of older children and young adults. Only 20% of younger children can recall an antecedent sore throat.
• Other symptoms on presentation may include fever, rash, headache, weight loss, epistaxis, fatigue, malaise, diaphoresis, and pallor.
• Patients also may have chest pain with orthopnea or abdominal pain and vomiting.
• Finally, history may reveal symptoms more specific to rheumatic fever.
  • Migratory joint pain
  • Nodules under the skin
  • Increased irritability and shortened attention span with personality changes, such as pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS)
  • Motor dysfunction
  • History of previous rheumatic fever
• Patients with previous rheumatic fever are at a high risk of recurrence.
  • Highest risk of recurrence within 5 years of the initial episode
  • Greater risk of recurrence with younger age at the time of the initial episode
  • Generally, recurrent attacks similar to the initial attack (however, risk of carditis and severity of valve damage increase with each attack)

Physical

Revised in 1992, the modified Jones criteria provide guidelines for making the diagnosis of rheumatic fever.³ The Jones criteria require the presence of 2 major or 1 major and 2 minor criteria for the diagnosis of rheumatic fever. Having evidence of previous group A streptococci (GAS) pharyngitis is also necessary. These criteria are not absolute, and the diagnosis of rheumatic fever can be made in patients with only confirmed streptococcal pharyngitis and chorea.

• Major diagnostic criteria
  • Carditis
  • Polyarthritis
  • Chorea
  • Subcutaneous nodules
  • Erythema marginatum
• Minor diagnostic criteria
  • Fever
  • Arthralgia
  • Prolonged PR interval on electrocardiography
  • Elevated acute-phase reactants (APRs), which are erythrocyte sedimentation rate and C-reactive protein
• Three notable exceptions to strict adherence to the Jones criteria
  • Chorea: It may occur late and be the only manifestation of rheumatic fever.
  • Indolent carditis: Patients presenting late to medical attention months after the onset of rheumatic fever may have insufficient support to fulfill the criteria.
  • Newly ill patients with a history of rheumatic fever, especially rheumatic heart disease (RHD), who have supporting evidence of a recent GAS infection and who manifest either a single major or several minor criteria: Distinguishing recurrent carditis from preexisting significant RHD may be impossible.
• Evidence of previous GAS pharyngitis (One of the following must be present):
  • Positive throat culture or rapid streptococcal antigen test
  • Elevated or rising streptococcal antibody titer
• Major clinical manifestations
  • Arthritis
    • Polyarthritis is the most common symptom and is frequently the earliest manifestation of acute rheumatic fever (70-75%).
    • Characteristically, the arthritis begins in the large joints of the lower extremities (ie, knees, ankles) and migrates to other large joints in the lower or upper extremities (ie, elbows, wrists).
    • Affected joints are painful, swollen, warm, erythematous, and limited in their range of motion. The pain is out of proportion to clinical findings.
    • The arthritis reaches maximum severity in 12-24 hours and persists for 2-6 days (rarely more than 4 wk, but has been reported to persist 44 d) at each site and is migratory but not additive.
    • The arthritis responds rapidly to aspirin, which decreases symptoms in affected joints and prevents further migration of the arthritis.
    • Polyarthritis is more common and more severe in teenagers and young adults than in younger children.
    • Patients suffering multiple attacks may exhibit destructive arthritis (Jaccoud arthritis).
  • Carditis
    • Pancarditis is the most serious complication and the second most common complication of rheumatic fever (50%).
    • In advanced cases, patients may experience of dyspnea, mild-to-moderate chest discomfort, pleuritic chest pain, edema, cough, or orthopnea.
    • Upon physical examination, carditis is most commonly revealed by a new murmur and tachycardia that is out of proportion to the fever. New or changing murmurs traditionally have been considered necessary for a diagnosis of rheumatic valvulitis. The murmurs of acute rheumatic fever are from valve regurgitation, and the murmurs of chronic rheumatic fever are from valve stenosis.
    • Frequently examine patients in whom the diagnosis of acute rheumatic fever is made due to the progressive nature of the disease. Some cardiologists have proposed that evidence of new mitral regurgitation from Doppler echocardiography, even in the absence of accompanying auscultatory findings, may be sufficient for making the diagnosis of carditis, particularly if the echocardiography findings resolve along with other manifestations of rheumatic fever. This criterion for carditis is not uniformly accepted and remains specifically excluded in the 1992 revised Jones criteria because of insufficient data at the time of publication.
    • Congestive heart failure (CHF) may develop secondary to severe valve insufficiency or myocarditis. Physical findings associated with heart failure include tachypnea, orthopnea, jugular venous distention, rales, hepatomegaly, a gallop rhythm, and peripheral swelling and edema. A pericardial friction rub indicates that pericarditis is present. Increased cardiac dullness to percussion, muffled heart sounds, and a paradoxical pulse are consistent with pericardial effusion and impending pericardial tamponade. Confirm this clinical emergency with ECG, and evacuate the effusion by pericardiocentesis if it is producing hemodynamic compromise.
  • Chorea: In the absence of a family history of Huntington chorea or findings consistent with systemic lupus erythematosus, the diagnosis of acute rheumatic fever is almost certain. A long latency period exists between streptococcal pharyngitis (1-6 mo) and the onset of chorea, and a history of an antecedent sore throat frequently is not obtained. Patients with chorea often do not demonstrate other Jones criteria. Chorea is slightly more common in females than males. Chorea is also known as rheumatic chorea, Sydenham chorea, chorea minor, and St Vitus dance.
  • Poststreptococcal movement disorders
    • Described poststreptococcal movement disorders have included pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS) and Tourette syndrome.
    • Daily handwriting samples can be used as an indicator of progression or resolution of disease. Complete resolution of the symptoms typically occurs, with improvement in 1-2 weeks and full recovery in 2-3 months; however, incidents have been reported in which symptoms wax and wane for several years.
    • The PANDAS disorder appears to have a relapsing-remitting symptom complex characterized by obsessive-compulsive personality disorder. Patients with Sydenham chorea and obsessive-compulsive symptoms tend to show aggressive, contamination, and somatic obsessions and checking, cleaning, and repeating compulsions. Neurologic abnormalities include cognitive defects and motoric hyperactivity. The symptoms may also include emotional lability, separation anxiety, and oppositional behaviors, and they are prepubertal in onset.
    • Some have proposed that the streptococcal infection triggers the formation of antibodies that cross-react with the basal ganglia of genetically susceptible hosts in a manner similar to the proposed mechanism for Sydenham chorea and causes the symptom complex.
  • Erythema marginatum: This characteristic rash, also known as erythema annulare, occurs in 5-13% of patients with acute rheumatic fever. Erythema marginatum begins as 1-cm to 3-cm diameter, pink-to-red nonpruritic macules or papules located on the trunk and proximal limbs but never on the face. The lesions spread outward to form a serpiginous ring with erythematous raised margins and central clearing. The rash may fade and reappear within hours and is exacerbated by heat. Thus, if the lesions are not observed easily, they can be accentuated by the application of warm towels, a hot bath, or the use of tangential lighting. The rash occurs early in the course of the disease and remains long past the resolution of other symptoms. Erythema marginatum (shown in the image below) has also been reported in association with sepsis, drug reactions, and glomerulonephritis.
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    Erythema marginatum, the characteristic rash of acute rheumatic fever.

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    Erythema marginatum, the characteristic rash of acute rheumatic fever.

  • Subcutaneous nodules: Subcutaneous nodules are now an infrequent manifestation of rheumatic fever. The frequency has declined during the past several years to 0-8% of patients with rheumatic fever. When present, the nodules appear over the extensor surfaces of the elbows, knees, ankles, knuckles, scalp, and spinous processes of the lumbar and thoracic vertebrae (attached to the tendon sheath). The nodules are firm, nontender, and free from attachments to the overlying skin, and they range from a few millimeters to 1-2 cm. The nodules number from 1 to dozens, with a mean of 3-4. Histologically, the nodules contain areas resembling the Aschoff bodies observed in the heart. Subcutaneous nodules generally occur several weeks into the disease and resolve within a month. They are strongly associated with severe rheumatic carditis, and in the absence of carditis, question the diagnosis of subcutaneous nodules.
• Other clinical manifestations
  • Abdominal pain: Abdominal pain usually occurs at the onset of acute rheumatic fever, resembles other conditions with acute microvascular mesenteric inflammation, and may mimic acute appendicitis.
  • Arthralgias: Patients may report arthralgias upon presentation. In the history, determining if the patient has taken aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) is important because these may suppress the full manifestations of the disease. Arthralgia cannot be considered a minor manifestation if arthritis is present.
  • Epistaxis: Epistaxis may be associated with severe protracted rheumatic carditis.
  • Fever: Fevers greater than 39°C with no characteristic pattern are present initially in almost every patient with acute rheumatic fever. The fever may be low grade (38-38.5°C) in children with mild carditis or absent in patients with pure chorea. The fever decreases without antipyretic therapy in approximately 1 week, but low-grade fevers persist for 2-3 weeks.
  • Rheumatic pneumonia: Patients present with the same signs as an infectious pneumonia. Differentiate rheumatic pneumonia from respiratory distress related to CHF.

Causes

Rheumatic fever is believed to result from an autoimmune response; however, the exact pathogenesis remains unclear.

• Rheumatic fever only develops in children and adolescents following group A beta hemolytic streptococcal (GABHS) pharyngitis, and only infections of the pharynx initiate or reactivate rheumatic fever.
• At least some rheumatogenic strains of GAS have antigenic domains similar to antigens in components of the human heart, and some authors have proposed that anti-M antibodies against the streptococci may cross-react with heart tissue, causing the pancarditis that is observed in rheumatic fever. So-called molecular mimicry between streptococcal and human proteins is felt to involve both the B and T cells of peripheral blood, with infiltration of the heart by T cells. Some believe that an increased production of inflammatory cytokines is the final mechanism of the autoimmune reaction that causes damage to cardiac tissue in RHD. An insufficiency of interleukin-4 (IL-4)–producing cells in the valve tissue may also contribute to the valve lesions.
• Streptococcal antigens, which are structurally similar to those in the heart, include hyaluronate in the bacterial capsule, cell wall polysaccharides (similar to glycoproteins in heart valves), and membrane antigens that share epitopes with the sarcolemma and smooth muscle.

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