Rheumatic fever

The incidence of acute rheumatic fever (ARF) has declined in most developed countries, and many physicians have little or no practical experience with the diagnosis and management of this condition. Occasional outbreaks in the United States make complacency a threat to public health.
Diagnosis rests on a combination of clinical manifestations that can develop in relation to group A streptococcal pharyngitis. These include chorea, carditis, subcutaneous nodules, erythema marginatum, and migratory polyarthritis. Because the inciting infection is completely treatable, attention has been refocused on prevention.

Pathophysiology

Although the inciting bacterial agent is well known, susceptibility factors remain unclear. The location of the streptococcal infection seems to play an important role. The clinical syndrome typically follows a streptococcal pharyngitis, but streptococcal cellulitis has never been implicated.
The earliest and most common feature is a painful migratory arthritis, which is present in approximately 80% of patients. Large joints such as knees, ankles, elbows, or shoulders are typically affected. Sydenham chorea was once a common late-onset clinical manifestation but is now rare. Carditis (with progressive congestive heart failure, a new murmur, or pericarditis) may be the presenting sign of unrecognized past episodes and is the most lethal manifestation.
Genetics may contribute, as evidenced by an increase in family incidence. No significant association with class-I human leukocyte antigens (HLAs) has been found, but an increase in class-II HLA antigens DR2 and DR4 has been found in black and white patients, respectively. Evidence suggests that elevated immune-complex levels in blood samples from patients with ARF are associated with HLA-B5.¹

Frequency

United States

The incidence of an acute rheumatic episode following streptococcal pharyngitis is 0.5-3%. The peak age is 6-20 years. Although the incidence of ARF has steadily declined, the mortality rate has declined even more steeply. Credit can be attributed to improved sanitation and antibiotic therapy. Several sporadic outbreaks in the United States could not be blamed directly on poor living conditions. New virulent strains are the best explanation.

International

Most major outbreaks occur under conditions of impoverished overcrowding where access to antibiotics is limited. Rheumatic heart disease accounts for 25-50% of all cardiac admissions internationally. Regions of major public health concern include the Middle East, the Indian subcontinent, and some areas of Africa and South America. As many as 20 million new cases occur each year. The introduction of antibiotics has been associated with a rapid worldwide decline in the incidence of ARF. Now, the incidence is 0.23-1.88 patients per 100,000 population. From 1862-1962, the incidence declined from 250 patients to 100 patients per 100,000 population, primarily in teenagers. Notably, natives of Polynesian ancestry in Hawaiian and Maori populations are an exception. The incidence continues to be 13.4 patients per 100,000 hospitalized children per year.²

Mortality/Morbidity

• Mortality rates are steadily improving because of better sanitation and health care.
• The current pattern of morbidity is difficult to measure because the first attack of rheumatic fever follows an unpredictable course. As many as 90% of episodes are clinically contained within 3 months.
• Carditis causes the most severe clinical manifestation because heart valves can be permanently damaged. The disorder also can involve the pericardium, myocardium, and the free borders of valve cusps. Death or total disability may occur years after the initial presentation of carditis.

Race

• An association between certain class-II HLA antigens (DR2 in blacks and DR4 in whites) and ARF has been reported.

Sex

• No general clear-cut sex predilection for the syndrome has been reported, but its manifestations seem to be sex variable. For example, certain clinical manifestations (ie, chorea and tight mitral stenosis) are predominant in women, while men are more likely to develop aortic stenosis.

Age

• The initial attack of ARF occurs most frequently in persons aged 6-20 years and rarely occurs in persons older than 30 years.
• The disease may cluster in families.
• In some countries, a shift into older groups may be a trend.

Clinical

History

• Diagnosis is challenging for several reasons, as follows:
  • Approximately 70% of older children and young adults recollect pharyngitis. However, only approximately 20% of young children recollect pharyngitis. Therefore, younger children who present with signs or symptoms consistent with acute rheumatic fever (ARF) merit a higher index of suspicion.
  • The rate of isolation of group A streptococci from the oropharynx is extremely low in all populations.
• Usually, a latent period of approximately 18 days occurs between the onset of streptococcal pharyngitis and ARF. This latent period is rarely shorter than 1 week or longer than 5 weeks.
  • Typically, the first manifestation is a very painful migratory polyarthritis. Often, associated fever and constitutional toxicity develop.
  • Acute attacks usually resolve within 12 weeks.
• Guidelines for diagnosis published more than 50 years ago by T. Duckett Jones³ have been slightly revised by the American Heart Association (AHA).⁴ Prior history of a preceding group A streptococcal infection is helpful but not required. In addition, 2 major manifestations or 1 major and 2 minor manifestations must be present.
  • Major manifestations include carditis, polyarthritis, chorea, erythema marginatum, and subcutaneous nodules.
  • Minor manifestations include arthralgias and fever. Laboratory findings include elevated levels of acute-phase reactants (erythrocyte sedimentation rate [ESR] and C-reactive protein) and a prolonged PR interval. A prolonged PR interval is not specific and has not been associated with later cardiac sequelae. The utility of echocardiography is also controversial.
• The Jones criteria⁴ should be viewed as a guide to determine who is at high risk but cannot be used to define diagnosis with absolute certainty.
  • An exception includes chorea, which can present as the sole manifestation of ARF, in spite of negative laboratory results.
  • Another possible exception is indolent carditis.
• A throat culture with results positive for Streptococcus is found in approximately 25% of patients at the time of presentation.

Physical

• Physical findings can be nonspecific and misleading; therefore, a high index of suspicion is required for diagnosis.
• Suspicious signs for carditis include new or changing valvular murmurs, cardiomegaly, congestive heart failure, and/or pericarditis.
• Nearly 60% of patients with carditis develop isolated mitral valve involvement, followed in prevalence by combined mitral and aortic valve involvement.
• When present, Sydenham chorea is seldom evident at the time of initial presentation.
• Erythema marginatum and subcutaneous nodules are rare (<10% of patients).
  
  

  

  Erythema marginatum, the characteristic rash of acute rheumatic fever.

  

  Erythema marginatum, the characteristic rash of acute rheumatic fever.

• Arthritis, which occurs in 80% of patients, usually involves multiple large joints, particularly the knees, ankles, elbows, and wrists.
  • Hips and smaller joints of hands and feet are less commonly involved.
  • Migratory polyarthritis is usually associated with a febrile illness. It involves a series of painful joints, followed by another series of painful joints.
  • This form of arthritis rarely causes permanent joint deformity.
• Unusual presentations, such as indolent carditis and isolated chorea, may also occur. Even rarer manifestations include epistaxis and abdominal pain due to serositis.

Causes

• Although the mechanism by which streptococcal organisms cause disease is not entirely clear, overwhelming epidemiologic evidence suggests that ARF is caused by streptococcal infection, and recurrences can be prevented with prophylaxis.
• Strains of group A streptococci that are heavily encapsulated and rich in M protein (signifying virulence in streptococcal strains) seem to be most likely to result in infection.
• Group A Streptococcus is thought to cause the myriad of clinical diseases in which the host's immunologic response to bacterial antigens cross-react with various target organs in the body, resulting in molecular mimicry. In fact, autoantibodies reactive against the heart have been found in patients with rheumatic carditis. The antibody can cross-react with brain and cardiac antigens, and immune complexes are present in the serum. The problem has been the uncertainty of whether these antibodies are the cause or result of myocardial tissue injury.