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Chapter 43 Rheumatic Fever

Manual of Rheumatology and Outpatient Orthopedic Disorders

Allan Gibofsky and John B. Zabriskie

Etiology and pathogenesis
Prevalence
Clinical presentation
Laboratory studies
The revised Jones criteria
Differential diagnosis
Treatment

Acute rheumatic fever (ARF) is the term used to describe a systemic rheumatic disease manifested clinically by a constellation of symptoms following pharyngeal streptococcal infection.

I. Etiology and pathogenesis. The disease occurs as a sequela of streptococcal pharyngitis, and the latent period from infection to onset of disease varies from 2 to 6 weeks or longer. ARF is almost exclusively associated with group A strains causing pharyngitis, and rarely if ever follows infections causing impetigo or kidney disease.

The available evidence suggests that the host's abnormal immune response, at both a cellular and humoral level, to streptococcal antigens cross-reactive with target mammalian antigens is responsible for the pathologic damage. These cross-reactive antigens include the hyaluronic capsule of the streptococcus and a number of streptococcal antigens, including M proteins , that share antigenic determinants with cardiac tropomyosin and myosin. Other antigenic determinants include renal, central nervous system, and skin antigens. A genetic basis for the disease has been suggested for more than 100 years , and family studies indicate that gene inheritance is either autosomal recessive or dominant with limited penetrance. Whether susceptibility to rheumatic fever is associated with certain major histocompatibility complex (MHC) alleles is controversial , although associations with HLA-DR4 and HLA-DR2 have been reported . Non-MHC markers have been described, and a monoclonal antibody called D8/17 identifies an antigen present on the B cells of 100% of rheumatic fever patients tested .

II. Prevalence. Both the prevalence and severity of rheumatic fever have declined dramatically during the last six decades in the United States and other developed countries ; however, a resurgence in new and recurrent cases deserves renewed attention. Changes in living conditions, nutrition, and virulence of the organism, in addition to antibiotic therapy of streptococcal pharyngitis, have all been suggested as reasons for the decreased incidence. The overall incidence of rheumatic fever in the United States is currently estimated to be less than 1 in 100,000 children of school age per year, but groups with poor standards of living have a much higher incidence. In some developing nations, the incidence of rheumatic fever remains high, 60 in 100,000 children (5 to 14 years old) per year or more. Rheumatic heart disease, a chronic sequela of rheumatic fever, is the most common cause of heart disease in persons under age 40 in these countries. Rheumatic fever thus represents a significant worldwide health problem.

III. Clinical presentation

1. Antecedent streptococcal pharyngitis most commonly occurs 2 to 3 weeks before the onset of the symptoms of rheumatic fever. It may be mild, however, and a history of fever and sore throat cannot be elicited in all patients.
2. Fever, which has no specific pattern, is almost always present at the onset of an acute attack and fades away in days to weeks without antiinflammatory treatment. Fever resolves promptly with salicylate therapy.
3. Arthritis with fever is the most common manifestation of ARF, occurring in 50% to 75% of cases. It usually involves the large peripheral joints, especially the knees and ankles, but any joint may be affected. The arthritis, which occurs within 5 weeks of the streptococcal infection, when anti-streptococcal antibody titers are usually high, subsides without treatment in a few weeks and very rarely causes joint deformity. Carditis occurs less frequently in cases with severe arthritis.
4. Arthralgia without objective evidence of joint inflammation may precede the development of synovitis. Severe arthralgia, especially if migratory, is an important diagnostic feature.
5. Carditis is the most important manifestation of ARF because it frequently leads to chronic valvular damage. In rare cases, it is a cause of death from cardiac failure or arrhythmias associated with myocarditis during an acute episode. Carditis occurs in 40% to 50% of attacks of ARF in some series, but this incidence seems to be decreasing .
   1. Chest pain or dyspnea may occur with ARF, but these complaints are often not specific to cardiac involvement.
   2. Major signs
      1. Significant new or changing murmurs, described below, are characteristic of acute valvulitis and differ from the murmurs of valvular stenosis or regurgitation that may be heard later. They often disappear with resolution of acute inflammation.
         1. Mitral valvulitis murmur is blowing, high-pitched, holosystolic, and apical and transmits to the axilla. It must be distinguished from the click/murmur of the mitral valve prolapse syndrome, which has a mid-systolic click and late systolic murmur.
         2. Carey Coombs murmur is mid-diastolic, low-pitched, and apical and often associated with the mitral valvulitis. It is best heard with the patient in the left lateral recumbent position and should be distinguished from the murmur of mitral stenosis.
         3. Aortic valvulitis murmur is a soft, high-pitched, decrescendo blow, heard immediately after the second heart sound along the left sternal border with the patient leaning forward. It must be distinguished from the murmur of a congenital bicuspid aortic valve.
      2. Cardiomegaly should be carefully monitored by physical examination and serial chest roentgenograms.
      3. Congestive heart failure occurs more commonly in children under 6 years of age and in patients without severe arthritis.
      4. Pericarditis, when present, usually occurs in association with other features of rheumatic carditis. Pericarditis may be manifested by chest pain, friction rub, effusions, and electrocardiographic changes. Large effusions are rare.
      5. Other cardiac findings may include tachycardia at rest (out of proportion to fever) and a soft, dull, variable first heart sound secondary to a prolonged PR interval. Atrioventricular block is commonly seen in cases of ARF without other evidence of carditis or subsequent rheumatic heart disease. It is thought to be a toxic manifestation of ARF and is not specifically indicative of carditis.
6. Erythema marginatum, a rare manifestation of ARF, is a nonpruritic rash that begins as a pink macule and spreads outward in a sharp ring with central clearing or as serpiginous coalescing lines. The rash is evanescent and rarely raised, blanches with pressure, is brought out by application of heat, and is distributed over the trunk and proximal extremities, never on the face, and rarely on the distal extremities. The rash may appear at any time in the course of ARF. Its appearance and resolution are unrelated to the course of other manifestations or to treatment. Rash secondary to drug reaction or systemic juvenile rheumatoid arthritis can usually be differentiated by the characteristics just mentioned and other associated clinical manifestations .
7. Subcutaneous nodules are firm, nontender, nonpruritic, freely movable swellings located in crops of variable numbers over bony prominences and tendons without overlying skin discoloration. They are smaller and less persistent than those of rheumatoid arthritis. Nodules are a late and infrequent manifestation associated with severe carditis.
8. Sydenham's chorea is a late manifestation of ARF and may follow other manifestations of ARF or may appear alone. It is characterized by involuntary, purposeless, abrupt, and nonrepetitive movements, muscular weakness, and emotional lability. The abnormal movements subside during sleep. When subtle, chorea is demonstrated when (a) squeezing the examiner 's hand reveals an erratic milkmaid's grip, (b) raising the hand straight ahead causes pronation of one or both arms, (c) extending the hands straight ahead causes spooning of the hand with wrist flexion and extension of fingers, and (d) protruding the tongue produces snakelike darting movements. Because the latent period from streptococcal infection to chorea is 1 to 6 months, anti-streptolysin O (ASO) titers and levels of acute-phase reactants may be normal. Investigation of other streptococcal antigens usually will reveal one or more with rising titers in all but those patients with isolated chorea. The duration of chorea ranges from 1 week to 1 year, with an average of 3 months. Some patients with Sydenham's chorea have an antibody that reacts with basal ganglia and cross-reacts with streptococcal cell membranes. Sydenham's chorea must be distinguished from other neurologic entities, including Huntington's chorea, central nervous system lupus, Wilson's disease, and toxic drug reactions (especially to the phenothiazines).

IV. Laboratory studies

1. Evidence of preceding streptococcal infection may be obtained by throat cultures (in about 25% of cases), and it is recommended that three successive cultures be taken before antibiotic treatment is begun. ASO antibodies are elevated in approximately 80% of cases, and serial serum samples should be drawn during the acute stage and 2 weeks later. Testing for anti-hyaluronidase, deoxyribonuclease B, and streptozyme titers increases the documentation of a preceding streptococcal infection to 97%.
2. Acute-phase reactants, such as C-reactive protein, and the erythrocyte sedimentation rate reflect ongoing inflammation and are useful in monitoring response to therapy.
3. Anti-heart antibodies that cross- react with streptococcal cell membranes are found in sera of ARF patients, but the test has not been standardized for routine use.
4. Serial chest roentgenograms are important to reveal cardiomegaly as a sign of carditis.
5. Serial electrocardiograms may reveal the nonspecific atrioventricular block discussed in section III.E.2.e or changes of myocarditis and pericarditis.
6. Echocardiography is useful in differentiating patients with bicuspid aortic valves or mitral prolapse syndrome from those with rheumatic heart disease. It may also be used to evaluate pericardial effusion and myocardial function.

V. The revised Jones criteria (Table 43-1) indicate a high probability of ARF when evidence of a preceding streptococcal infection is found simultaneously with the presence of two major criteria; a diagnosis of ARF based on the presence of one major criterion and two minor criteria is less definitive. The Jones criteria were developed to provide uniformity and to minimize the overdiagnosis of ARF.