Because of the lack of symptoms, signs, or laboratory diagnostic tests that are pathognomomc of acute rheumatic fever, the diagnosis of rheumatic fever is based on the fulfillment of certain clinical criteria. The Jones criteria have been an aid to clinicians for decades.1*2 The criteria include the major and minor manifestations of rheumatic fever as well as evidence of preceding upper respiratory tract infection with group A streptococci (Table 1). For a given patient, detection of two major criteria along with evidence of antecedent streptococcal infection is diagnostic of rheumatic fever. Alternatively, the presence of one major and two minor criteria together with evidence of an antecedent streptococcal infection is sufficient for the diagnosis.
In 1992, recommendations by the American Heart Association reaffirmed the usefulness of the Jones criteria.2 However, these criteria are only used for acute rheumatic fever. They are not intended to measure rheumatic activity, to establish the diagnosis of inactive or chronic rheumatic heart disease, or to predict the course or severity of the disease. These recommendations emphasized limitations, including circumstances in which rheumatic fever can be identified without strict adherence to the Jones criteria. For example, chorea, the last manifestation of acute rheumatic fever to appear after infection with group A streptococci, can occur when streptococcal antibody concentrations have returned to normal and other signs of rheumatic fever are not present. The foliowing description applies to the the major and minor manifestations of rheumatic fever.
MAJOR JONES CRITERIA
Cardiac involvement occurs in about 50% of patients with acute rheumatic fever. Pancardias, simultaneous involvement of endocardium, myocardium, and pericardium is almost always associated with clinically apparent murmur of valvulitis.3 Isolated myocarditis or pericarditis without clinical evidence of valvular involvement is unusual as a presentation of rheumatic carditis. Murmurs heard during the acute stage of the illness include an apical systolic murmur of mitral régurgitation, a basal diastolic murmur of aortic régurgitation or an apical diastolic murmur. In spite of the superiority of three dimensional echocardiography and doppler studies in evaluating heart anatomy and function, abnormal results without auscultatory findings can not be considered as the sole criterion for valvulitis, hence it cannot be relied on for diagnosis.2
Jones Criteria (Updated) for Guidance in the Diagnosis of Rheumatic Fever
Polyarthritis is the most common but the least specific major manifestation of rheumatic fever. It is seen in 60% to 70% of patients. Arthritis is almost always migratory involving mainly the large joints, particularly the knees, ankles, elbows and wrists. Isolated involvement of small peripheral joints is not seen in rheumatic fever. Although signs of intense inflammation, namely heat, redness and swelling are evident clinically, the arthritis of rheumatic fever does not result in children. Arthritis should be differentiated from arthralgia, a minor criterion, when objective signs of inflammation are absent. Salicyiates characteristically have a dramatic effect on arthritis of rheumatic fever. In fact, tack of improvement within 48 hours after administration of salicylates is a reason to review the diagnosis.
Sydenham chorea, a late feature of rheumatic fever, represents involvement of the basal ganglia and caudate nuclei. Chorea manifests clinically as purposeless, involuntary and rapid movements of the trunk and extremities associated with weakness. Emotional lability is present. Because of its late onset, other rheumatic manifestations may be absent. In addition, documentation of a preceding group A Streptococcal infection may not be possible because Streptococcal antibodies would have fallen to normal by the time of onset of chorea. Rheumatic chorea is present in 10% to 15% of patients. It is self limited, lasting 3 to 6 months. In rare cases, symptoms may persist for up to two years. Sydenham chorea should be differentiated from chorea seen in the course of Wilson disease and systemic lupus erythematosus and from the multiple tic syndrome (Tourrette syndrome).
This distinctive, nonpruritic, evanescent, pink rash is a rare manifestation of rheumatic fever, occurring in about 5% of patients. The erythematous areas have pale centers and rounded or serpiginous margins. Lesions vary greatly in size and occur mainly on the trunk and proximal extremities, never on the face. The rash is usually present early during the course of rheumatic fever. This rash is transient and migratory and may be induced by the application of heat. It is not pruritic or indurated and blanches on pressure.
These firm, painless nodules are present over the extensor surfaces of certain joints, particularly the elbows, knees, and wrists, in the occipital region, or over the spinous processes of the thoracic or lumbar vertebrae. The skin overlying them moves freely and is not inflamed. Nodules are rare nowadays; they are seen in less than 5% of patients. When present, the nodules are most often seen in patients with severe carditis.
Minor manifestations of the Jones Criteria
Arthroigia and fever are nonspecific clinical features occurring frequently in rheumatic fever. Because they often occur in numerous other diseases, their diagnostic value is limited. These minor manifestations are used to support the diagnosis of rheumatic fever when only a single major manifestation is present. Arthralgia must not be considered a minor criterion when arthritis is present. Fever, although also common in other illnesses, is generally present early in the course of untreated rheumatic fever.
Elevated acute phase reactants offer objective but nonspecific confirmation of the presence of an inflammatory process. The erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are commonly used. Unless corticosteroide or salicylates are given, the ESR and CRP are almost always elevated in patients with polyarthritis or acute carditis, whereas they are often normal in patients presenting with chorea alone. The ESR and CRP are useful for monitoring disease activity.
Prolonged P-R interval on the electrocardiogram is another nonspecific finding. It occurs frequently in rheumatic fever, but does not alone constitute an adequate criterion for carditis. P-R prolongation does not correlate with the ultimate development of chronic rheumatic heart disease.
SUPPORTING EVIDENCE OF ANTECEDENT STREPTOCOCCAL GROUP A INFECTION
Laboratory evidence of an antecedent group A streptococcal infection, in the form of elevated or rising streptococcal antibody titers or demonstration of group A streptococci in the throat is essential for the diagnosis of acute rheumatic fever. The lack of serologie response to streptococcal antigens when combined with the lack of microbiologie evidence for the presence of group A streptococci in the throat makes the diagnosis of acute rheumatic fever extremely unlikely. Physicians should be aware, however, that only about 25% of patients wich acute rheumatic fever have throat cultures positive for group A streptococci. Also, patients who present with Syndenham chorea often lack evidence for group A streptococcal infection. Therefore, the diagnosis of this manifestation is exempted from this requirement.
Clinical history of sore throat or scarlet fever unsubstantiated by laboratory data is not adequate evidence of a recent group A streptococcal infection, because only a minority of episodes of pharyngitis are caused by group A streptococci and because the accurate clinical diagnosis of scarlet fever is frequently difficult.
Rapid group A streptococcal antigen detection tests are generally very specific but may not be very sensitive.4 A negative test does not rule out the presence of group A streptococci in the throat and this should be confirmed by a conventional throat culture. Interpretation of a positive throat culture or rapid streptococcal antigen test is complicated by the possibility that these tests may reflect chronic colonization by group A streptococci and thus that the presence of these organisms is unrelated to the acute clinical illness suspected of being rheumatic fever. Therefore, elevated or rising antistreptococcal antibody titers provide more reliable evidence of a recent group A streptococcal infection than a positive throat culture or a rapid streptococcal antigen test.
The most commonly used tests that provide evidence for antecedent-group A streptococcal infection are for antibody anti-streptolysin O (ASO) and antí-DNase B. Because the onset of the clinical manifestations of acute rheumatic fever usually coincides with the peak of the streptococcal antibody response, a serum specimen obtained at that time usually shows an elevated streptococcal antibody titer. A significant antibody increase is usually defined as a rise in titer of two or more dilution increments between the acute and convalescent phase specimens, regardless of the actual height of the antibody titer.
An antibody response to streptolysin O occurs in 80% or more of patients with acute group A streptococcal pharyngitis.5 The range of normal values is variable and depends not only on the patient's age, but also on geographic location, epidemiologie factors, and the season of the year. In the absence of specific information regarding the appropriate range of such values in a given geographic area, a single ASO titer is generally considered to be modestly elevated if it is at least 240 Todd units in adults and 320 Todd units in children. ASO titers are highest in school-age children and young;adults; most infants and older adults have low antibody titers compared to those of school age children.2 About 20% of patients studied within the first 2 months of onset of acute rheumatic fever and those who present with Sydenham chorea alone have low or borderline ASO titers. Thus, a single low streptococcal antibody titer does not exclude acute rheumatic fever. In these circumstances, it is highly advisable to measure antibodies to other streptococcal antigens.
Using three different antibody tests, an elevated titer for at least one antibody can be demonstrated in about 95% of all patients with acute rheumatic fever.5 It is not practical, however, to obtain several different streptococcal antibody tests during a patient's initial evaluation. The ASO test may be obtained first, and if this is not elevated, then an ami DNase B is usually done. Anti-streptokinase or anti-hyaluridonase tests may be obtained, depending on local availability.
Practitioners should be aware of the reliability of the tests used by their laboratories. For instance, Streptozyme® test is a rapid slide agglutination test for the detection of antibodies to several streptococcal antigens. This test, however, is less standardized and less reproducible than the other antibody tests.2 It should not be used as a definitive test for evidence of antecedent group A streptococcal infection.
TREATMENT OF ACUTE RHEUMATIC FEVER
A course of appropriate antibiotic therapy should be given to all patients with acute rheumatic fever to eradicate group A streptococci from the upper respiratory tract, even if the throat culture result is negative. Although proper treatment of group A streptococcal infection may prevent an attack of acute thematic fever, it is not known if administration of antibiotics following the onset of acute rheumatic fever influences the course or outcome of the disease. The recommended treatment is a single dose of 1.2 million U of benzathine penicillin G given intramuscularly. An advantage of intramuscular benzathine penicillin is that the same dosage can be used for secondary prevention. An alternative is to administer 250 mg of penicillin V orally every 8 to 12 hours for 10 days.6 For patients allergic to penicillin, erythromycin 20 to 40 mg/kg/day (maximum dose, 1.0 g/day) taken in four divided doses daily for 10 days, is the appropriate therapy. Clinical trials have demonstrated that oral cephalosporins are effective clinically and bacteriologically in the treatment of streptococcal pharyngitis.7 Oral cephalosporins are a satisfactory alternative to penicillin, especially for penicillin allergic patients (excluding patients with anaphylactic reactions to penicillin). They are, however, expensive.8 The newer macrolides, such as clarythromycin and azithromycin, have sensitivity patterns to group A streptococci similar to erythromycin but are associated with substantially fewer gastrointestinal side effects.9
Symptomatic treatment of acute rheumatic fever depends on the clinical presentation and the organ system involved. Two anti-inflammatory agents are available for the symptomatic treatment of acute rheumatic fever salicylates (aspirin) and glucocorticoids (prednisone). Both agents offer symptomatic relief only and neither has been shown to alter the outcome of rheumatic heart disease. However, both aspirin and prednisone can alter the clinical picture. Therefore, these agents should not be administered before a firm diagnosis has been established. Treatment should be given for the natural duration of the disease, otherwise rebound will occur. Thus, when rheumatic fever presents as arthritis only, treatment is usually required for only 3 to 6 weeks. However, because carditis has a longer duration, the anti-inflammatory treatment should be longer - at least 12 weeks in mild carditis and 4 to 6 months in severe carditis.
Aspirin is given in a dose of 80 to 100 mg/kg/day in four divided doses, and a blood level of 20 to 30 mg/dL should be maintained. Corticosteroids are indicated in severe carditis, especially in heart failure, in which they may be life saving. Prednisone is given in a dose of 2 mg/kg/day in three to four divided doses for 2 weeks according to the severity of carditis. It is preferable to start a full dose of aspirin 1 week before stopping prednisone, because it helps to avoid rebound.
Patients with severe carditis should be confined to bed rest. Gradual resumption of activity may begin after the carditis is controlled. Patients should avoid rapid resumption of activity or prolonged unnecessary bed rest.
Treatment of choreiform movements
Sydenham chorea is self limited in the majority of patients. In mild cases treatment may not be necessary. In more severe cases, bed rest in quiet surroundings and avoidance of stress are helpful. In patients with severe choreiform activity, restriction to a padded bed is necessary to avoid injury. Sodium valproate in a dose of 15mg/kg/day, given in two divided doses and built up over a week, has been found to be effective. An alternative therapeutic agent is haloperidole. The latter, unfortunately, has a narrow therapeutic index and a high incidence of associated extrapyramidal side effects. Glucocorticoids and antiinflammatory agents have no role in the treatment of isolated Sydenham chorea.
A patient with an episode of rheumatic fever is at higher risk of recurrent attacks than the general population. In a recent 1 2-year follow-up study, the recurrence rate in children with rheumatic fever who maintained regular secondary prophylaxis, was 0.003/patient/year, compared with 0.2/patient/year in patients who did not receive secondary prophylaxis.10 A recurrent attack of rheumatic fever tends to produce involvement of the same organ as the initial episode. Thus, patients presenting with rheumatic carditis are likely to have recurrence of carditis in subsequent attacks, with additional tissue damage super imposed on that left by the previous episode. The risk of a recurrence is inversely related to the attack-free interval from the previous episode. In addition, the risk is greater in those patients with multiple previous attacks. Therefore, once the diagnosis of acute rheumatic fever is established, secondary prophylaxis should be initiated to prevent streptococcal pharyngitis and recurrence of rheumatic fever.
Secondary Prevention of Rheumatic Fever
Secondary prophylaxis in rheumatic fever relies on two main components. The first is antibiotic prophylaxis and the second is patient education. The patient should know about the cause of rheumatic fever, te, streptococcal upper respiratory infection, and the seriousness of rheumatic heart disease. More importantly, the patient should be aware of the increased risk of recurrence of rheumatic fever. A well-educated patient is more likely to seek medical treatment for acute pharyngitis and is more likely to comply with prophylactic antibiotics.
Because rheumatic fever can follow an asymptomatic group A streptococcal upper respiratory infection, prevention of recurrences based on treatment of symptomatic pharyngitis leaves many patients at risk. Continuous antibiotic prophylaxis is more reliable in preventing rheumatic fever than screening and streptococcal pharyngitis treatment.
Antibiotic prophylaxis should start as soon as possible after the patient is appropriately treated for streptococcal pharyngitis in the acute stage (Table 2). The antibiotic of choice is penicillin. Long-acting benzathine penicillin G (LA bicillin) given intramuscularly is the drug of choice in patients with rheumatic heart disease and patients at risk for poor compliance due to socioeconomic factors. The dosage is 1.2 million U given every 4 weeks for patients weighing more than 27 kg and 600,000 U for smaller children. In endemic areas, LA benzathine penicillin G may be given as frequently as every 3 weeks to avoid any risk of acquiring rheumatic fever.11 In contrast to its ineffectiveness in preventing primary attacks of rheumatic fever, oral sulfadiazine is second to LA bicillin in efficacy for preventing rheumatic fever recurrences. Oral penicillin V is less effective than intramuscular penicillin or oral sulfadiazine, even in compliant patients.12 It is usually prescribed for patients without rheumatic carditis who are expected to be compliant. Because the risk of rheumatic fever recurrence is highest during the 5 years following the initial acute rheumatic episode, particularly in patients with carditis, we recommend that all patients with carditis receive intramuscular prophylaxis for at least that period of time. One may switch from intramuscular to oral prophylaxis if the patient remains free of attacks for 5 years.
An important issue related to compliance with penicillin prophylaxis is the risk of allergic reactions, particularly anaphylactic ones. It should be emphasized that serious or fatal allergic reactions to long acting penicillin are extremely rare in adults and have not been shown to occur in children.13 Skin testing of patients with aqueous penicillin G will detect about 90% of patients at risk for an allergic reaction.14 Patients allergic to penicillin are placed on sulfadiazine prophylaxis. Erythromycin prophylaxis is recommended for patients with known allergy to both penicillins and sulfa compounds.
The duration of prophylaxis should be individualized, relying mainly on the estimated risk of recurrence of rheumatic fever. The physician should take into account the number of previous attacks, the length of time since the last attack, and the risk of acquiring streptococcal group A pharyngitis. In addition to children, teachers, health workers, military recruits, and those living in crowded situations are at high risk of acquiring streptococcal pharyngitis. Patients with a history of rheumatic carditis have a high risk of recurrence and require a lifelong prophylaxis, even if they had valvotomy. On the other hand, discontinuation of prophylaxis can be attempted in patients without rheumatic carditis when they reach their early 20s and if 5 years have elapsed since the last attack.
The responsibility of the physician does not stop with the management of the acute episode. Continued follow-up in the clinic is helpful to ensure patient compliance with antibiotic prophylaxis. Clinic visits should be scheduled more frequently (biweekly to monthly) after the acute episode. If the patient is judged to be compliant and is well, visits may be scheduled less frequently.
Patients with residual rheumatic heart disease are a special group. In addition to the management of heart disease and antibiotic prophylaxis of rheumatic fever, the patients require continuous education about oral hygiene, with emphasis on prophylaxis for subacute bacterial endocarditis.
1. Jones TD. Diagnosis of rheumatic fever JAMA 1944:126:481-484.
2. Dajani AS, Ayoub E. Bierman FZ. et al. Guidelines for [he diagnosis of rheumatic fever: Jones Criteria, update 1993. Circulation 1993;87:302-307.
3. Centers for Disease Control: Acute riieumatic fever- Utah. MMWR. 1987:37:108.
4. Strategy for controlling riieumalic fever/eheumalic heart disease, ivirh emphasis on primary prevention: mémorandum from a joinc WHO/ISFC meeting. Bull World Health Organ (Switzerland). 1995;73;583-587.
5. Ayoub EM, Wannamaker LW. Evaluation of the srreptococcal deoxyribonuclease B and diphosphopytidine nucleotidase antibody tests in acute rheumatic fever and acute glomerulonephrit is. Pediatrics. 1962;29:527.
6. Gerber MA, Spadaccini LJ, Wright LL, et al. Twice-daily penicillin in the tieatmem of streptococcai pharyngitis. Am J Dis Chad. 1935;139:1145-1148.
7. Pichichero ME. Cephalosporines are superior to penicillin for the treatment of tonsillopharyngnis: is the difference worth it? Pfdiarr In/eel Dii J. 1993:12:268274.
8. Shulman ST. Evaluation erf penicillin, cephalosporins and macrolides for thetapy of streptococcal pharyngitis. Pediatrics. 1996;97;955-959.
9. Neu HC. Clinical microbiology of aziehromycin. Am Jq Med. 1991;91(suppl 3A): 12S-18S.
10. Majeed HA, BatnagerS, Yousof AM, et al. Acute rheumatic fever and the evolution of rheumatic heart disease: a 12 year follow-up study. J CIm Epidemici. 1992:45:871-875.
11. Currie BJ. Are the currently recommended doses of benzalhine penicillin G adequate (or secondary prophylaxis of rheumatic fever. Pediatrics. 1996;97:989-991 .
12. Dajani A, TaufaertK, Pemeri R et al. Treatment ?? acute screprococcal pharyngitis and prevention of rheumatic fever: statement for health professionals. Peiuairics. 1995:96:758-764.
13. International rheumatic fever study group. Allergic reactions to long term benzathin penicillin prophylaxis for rheumatic fever. Lancer. 1991 i337:1308-13 10.
14. Markowic M, Lue HC. Allergic reactions in rheumatic fever patients on longterm bemathin penicillin G: The role of Skin testing for allergy. Pediatrics. 1996;97;981-983.
Jones Criteria (Updated) for Guidance in the Diagnosis of Rheumatic Fever
Secondary Prevention of Rheumatic Fever