eMedicine Specialties > Infectious Diseases > Cardiovascular and Intravascular Infections

Rheumatic Fever

Author: Mark Raymond Wallace, MD, Infectious Disease Fellowship Director, Orlando Regional Healthcare; Clinical Professor of Medicine, Florida State University
Coauthor(s): Larry I Lutwick, MD, Professor of Medicine, State University of New York, Downstate Medical School; Director, Infectious Diseases, Veterans Affairs New York Harbor Health Care System, Brooklyn Campus; Jayashree Ravishankar, MD, Fellow, Department of Medicine, Division of Infectious Diseases, State University of New York Health Science Center at Brooklyn
Contributor Information and Disclosures

Updated: Apr 13, 2009

Introduction

Background

Acute rheumatic fever (ARF) is an autoimmune inflammatory process that develops as a sequela of streptococcal infection. ARF has extremely variable manifestations and remains a clinical syndrome for which no specific diagnostic test exists. Persons who have experienced an episode of ARF are predisposed to recurrence following subsequent (rheumatogenic) group A streptococcal infections. The most significant complication of ARF is rheumatic heart disease, which usually occurs after repeated bouts of acute illness.

Pathophysiology

ARF is characterized by nonsuppurative inflammatory lesions of the joints, heart, subcutaneous tissue, and central nervous system. An extensive literature search has shown that, at least in developed countries, rheumatic fever follows pharyngeal infection with rheumatogenic group A streptococci.^1,2,3,4 The risk of developing rheumatic fever after an episode of streptococcal pharyngitis has been estimated at 0.3-3%.¹ More recent investigations of rheumatic fever occurring in the aboriginal populations of Australia suggest that streptococcal skin infections might also be associated with the development of rheumatic fever.^5,6 In Oceania and Hawaii, streptococcal strains that are not typically associated with rheumatic fever have been found to cause the disease.⁷

Molecular mimicry accounts for the tissue injury that occurs in rheumatic fever. Both the humoral and cellular host defenses of a genetically vulnerable host are involved. In this process, the patient's immune responses (both B- and T-cell mediated) are unable to distinguish between the invading microbe and certain host tissues.⁸ The resultant inflammation may persist well beyond the acute infection and produces the protean manifestations of rheumatic fever.

Frequency

United States

The incidence of ARF has declined markedly in the past 50 years in both the United States and Western Europe. Most Western physicians see only the late sequelae of rheumatic heart disease; the diagnosis of an acute case is usually reason enough for a ground rounds presentation. This remarkable decline of rheumatic fever likely reflects improved socioeconomic conditions, as well the decline in prevalence of the classically described rheumatogenic strains of group A streptococci.

Following two decades of almost total absence, a resurgence of ARF occurred in the 1980s among middle-class white children in Salt Lake City, Utah.⁹ Clusters were also reported in US Army and Navy training camps during the same period.¹⁰ These limited outbreaks were associated with mucoid rheumatogenic strains that were rarely seen in the preceding 20 years. Today, ARF remains a rarity in most of the United States, although Hawaii and American Samoa continue to see a significant number of cases, many of which are caused by streptococcal strains not usually associated with rheumatic fever in persons of Polynesian descent.^7,11

International

In developing countries, the magnitude of ARF is enormous. Recent estimates suggest that 15.6 million people worldwide have rheumatic heart disease and that 470,000 new cases of rheumatic fever (approximately 60% of whom will develop rheumatic heart disease) occur annually, with 230,000 deaths resulting from its complications. Almost all of this toll occurs in the developing world.^12,13 The incidence rate of rheumatic fever is as high as 50 cases per 100,000 children in many areas. Areas of hyperendemicity (eg, indigenous populations of Australia and New Zealand) see an incidence of 300-500 cases per 100,000 children, while the rates are approximately 50-fold lower in their nonindigenous compatriots.⁶ Rheumatic fever in the 21st century appears to be largely a disease of crowding and poverty.

Mortality/Morbidity

Cardiac involvement is the most serious complication of rheumatic fever and causes significant morbidity and mortality. As stated above, about 60% of the approximately 470,000 patients diagnosed with ARF annually eventually develop carditis, joining the approximately 15 million worldwide with rheumatic heart disease. Those with rheumatic heart disease are at a high risk for additional cardiac damage with subsequent bouts of ARF and require secondary prophylaxis. Morbidity due to congestive heart failure (CHF), strokes, and endocarditis is common among individuals with rheumatic heart disease, and about 1.5% of persons with rheumatic carditis die of the disease annually.^12,6

Race

ARF is predominantly a disease of developing countries and is concentrated in areas of deprivation and crowding. It is rampant in the Middle East, in sub-Saharan Africa, in the Indian subcontinent, in certain areas of South America, in Polynesia, and among the indigenous populations of Australia and New Zealand. Although a genetic predisposition to ARF clearly exists,¹ the disease does not seem to have a major racial predisposition, as it was once common in the United States and Europe and seems to decline in any locale where living conditions improve.

Sex

Rheumatic fever does not have a clear-cut sexual predilection, although certain clinical manifestations, such as mitral stenosis and Sydenham chorea, are more common in females who have gone through puberty.

Age

ARF is most common among children aged 5-15 years. It is relatively rare in infants and uncommon in preschool-aged children. ARF occurs in young adults, but the incidence of first episodes of ARF falls steadily after adolescence and is rare after age 35 years.⁶ The lower rate of ARF in adults may represent a decreased risk of streptococcal pharyngitis in this cohort. Recurrent episodes, with their predisposition to cause or exacerbate valvular damage, occur until middle age.

Clinical

History

Rheumatic fever manifests as various signs and symptoms that may occur alone or in various combinations.

• Sore throat: Although estimates vary, only 35%-60% of patients with rheumatic fever recall having any upper respiratory symptoms in the preceding several weeks. Many symptomatic individuals do not seek medical attention, go undiagnosed, or do not take the prescribed antibiotic for acute rheumatic fever (ARF) prevention.^6,10
• Polyarthritis: Overall, arthritis occurs in approximately 75% of first attacks of ARF. The likelihood increases with the age of the patient, and arthritis is a major manifestation of ARF in 92% of adults.¹⁰
  • The arthritis of ARF is usually symmetrical and involves large joints, such as the knees, ankles, elbows, and wrists. Tenosynovitis is common in adults and may be severe enough to suggest a diagnosis of disseminated gonococcal disease.¹⁰
  • The evolution of arthritis in individual joints tends to overlap; therefore, multiple joints may be inflamed simultaneously, causing more of an additive than a migratory pattern.¹⁰
  • In most instances, the entire bout of polyarthritis subsides within 4 weeks without any permanent damage. If not, a different diagnosis should be entertained.
• Carditis: Of first attacks of ARF, carditis occurs in 30%-60% of cases. It is more common in younger children but does occur in adults.¹⁰
  • Severe inflammation can cause congestive heart failure (CHF).
  • Patients with carditis may present with shortness of breath, dyspnea upon exertion, cough, paroxysmal nocturnal dyspnea, chest pain, and/or orthopnea. Carditis may also be asymptomatic and may be diagnosed solely by auscultation or, perhaps, echocardiography (controversial; see Physical).⁶
• Sydenham chorea: This occurs in up to 25% of ARF cases in children but is very rare in adults. It is more common in girls. Sydenham chorea in ARF is likely due to molecular mimicry, with autoantibodies reacting with brain ganglioside.¹⁴
  • Sydenham chorea may occur with other symptoms or as an isolated finding. It typically presents 1-6 months after the precipitating streptococcal infection and usually has both neurologic and psychological features.¹⁴
  • In the isolated form, laboratory evidence of a preceding streptococcal infection may be lacking.
  • Like the polyarthritis, Sydenham chorea usually resolves without permanent damage but occasionally lasts 2-3 years and be a major problem for the patient and her family.⁶
• Erythema marginatum: In first attacks of ARF in children, erythema marginatum occurs in approximately 10%. Like chorea, it is very rare in adults.
  • Patients or parents may report a nonpruritic, painless, serpiginous, erythematous eruption on the trunk. It is usually noted only in fair–skinned patients.²
  • The lesions may persist intermittently for weeks to months.
• Subcutaneous nodules are rarely noticed by the patient (see Physical).
• Other symptoms may include fever, abdominal pain, arthralgia, malaise, and epistaxis.

Physical

• Polyarthritis
  • Joint involvement in ARF may range from arthralgia to frank polyarthritis characterized by swelling, redness, warmth, and joint tenderness.
  • The joints frequently involved include the knees, ankles, elbows, and wrists. The small joints of the hands and the spine are rarely involved. Hand involvement tends to occur in poststreptococcal arthritis, a related syndrome without a risk of carditis.⁶
  • Inflammation begins to subside within a few days to a week and disappears within 2-4 weeks.
  • The arthritis is classically described as migratory, but, in many cases, new joints are affected before the previously involved joints improve, leaving the appearance of an additive arthritis.¹⁰
  • In most cases, the process does not leave any residual damage. On very rare occasions, periarticular fibrosis occurs after rheumatic arthritis, the so-called Jaccoud joint.
• Carditis
  • Carditis is the only manifestation of ARF with significant potential to cause long-term disability and/or death. It is usually a pancarditis involving the pericardium, myocardium, and endocardium.
  • The signs of carditis include the development of new murmurs, cardiac enlargement, CHF, pericardial friction rub, and/or pericardial effusion.
  • Characteristic murmurs of acute carditis include the high-pitched, blowing, holosystolic, apical murmur of mitral regurgitation; the low-pitched, apical, mid-diastolic, flow murmur (Carey-Coombs murmur); and a high-pitched, decrescendo, diastolic murmur of aortic regurgitation heard at the aortic area. Murmurs of mitral and aortic stenosis are observed in chronic valvular heart disease. Isolated aortic disease is distinctly unusual.
  • The features of CHF include tachycardia, a third heart sound, rales, and edema.
  • Pericarditis presents as a pericardial rub or effusion.
  • The use of echocardiography to detect subclinical carditis reveals subclinical rheumatic cardiac disease (both acute and chronic) not appreciated by the standard examination.^15,16,17 Whether these subclinical carditis findings carry the same clinical importance as those detected by standard auscultation is unclear; echocardiography findings alone do not currently count toward fulfillment of the Jones criteria, and it is unclear whether they necessitate secondary antibiotic prophylaxis (see Diagnosis). This issue is the most contentious in the rheumatic fever literature^18,19 and has major implications for diagnosis and screening. For now, clinicians must rely on their best judgment when evaluating possible carditis detected only with echocardiography.
• Subcutaneous nodules
  • Subcutaneous nodules are uncommon and are usually associated with severe carditis. They tend to occur several weeks after illness onset, are usually painless, and usually go unnoticed by the patient.
  • They are found primarily over the bony surfaces or prominences and in tendon sheaths. The common sites include the elbows, knees, wrists, ankles, over the Achilles tendon, the back of the scalp, and spinous process of the vertebrae.²
  • They usually persist for 1-2 weeks. The main differential diagnosis includes primarily the nodules of rheumatoid arthritis.¹⁰
• Erythema marginatum
  • The individual lesions of erythema marginatum are evanescent, moving over the skin in serpiginous patterns. Likened to smoke rings, they have a tendency to advance at the margins while clearing in the center.
  • The lesions may be macular and can develop and disappear in minutes, appearing to change shape while being examined.
  • They are found on the trunk and proximal aspects of the extremities and often go unnoticed by patients and parents, as they are usually covered by clothing.²
• Sydenham chorea
  • This is a neurological disorder characterized by emotional lability, personality change, muscular weakness, and uncoordinated, involuntary, purposeless movements.
  • The classic weakness is characterized by the inability to sustain a tetanic contraction. Patients are unable to maintain a clenched fist when attempting to grip the examiner's hand. Other findings include dysarthric speech, gait problems, and poor fine-motor skills.¹⁴
  • The motor symptoms usually disappear during sleep and may be partially suppressed by sedation.
  • They can involve the face, hands, and feet.
• The average duration of an untreated ARF attack is 3 months. Chronic rheumatic fever, generally defined as disease persisting for longer than 6 months, occurs in less than 5% of cases.

Causes

• Group A beta-hemolytic streptococcal infection may lead to rheumatic fever. The overall attack rate after streptococcal pharyngitis 0.3-3%, but certain genetically predisposed individuals, comprising perhaps 3%-6% of the population, account for those who develop rheumatic fever.⁶
• Studies in developed countries have established that rheumatic fever followed only pharyngeal infections and that not all serotypes of group A streptococci cause rheumatic fever. For example, some strains (eg, M types 4, 2, 12) in a population susceptible to rheumatic disease do not result in recurrences of rheumatic fever. The classic rheumatogenic serotypes are thought to include 3, 5, 6, 14, 18, 19, and 24.² More recent data, largely from studies of the indigenous peoples of Australia, suggest that skin infections (pyoderma) can predispose to ARF and that various other serotypes may be involved.^6,5
• Two basic theories have been postulated to explain the development of ARF and its sequelae following group A streptococcal infection: (1) a toxic effect produced by an extracellular toxin of group A streptococci on target organs such as the myocardium, valves, synovium, and brain and (2) an abnormal immune response to streptococcal components. Increasing and compelling evidence now strongly favors the autoimmune explanation. It seems clear that an exaggerated immune response in a susceptible individual leads to rheumatic fever. This probably occurs through molecular mimicry, in which the immune response fails to differentiate between epitopes of the streptococcal pathogen and certain host tissues.^6,8

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