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| TEXT BOOK of MEDICINE |
Section XXIII Infectious Diseases
| 313 RHEUMATIC FEVER Alan L. Bisno • |
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Definition
Rheumatic fever is an inflammatory disease that occurs as a delayed, nonsuppurative sequela of upper respiratory tract infection with group A streptococci. Its clinical manifestations include polyarthritis, carditis, subcutaneous nodules, erythema marginatum, and chorea in varying combinations. In its classic form, the disorder is acute, febrile, and largely self-limited. However, damage to heart valves may be chronic and progressive and cause cardiac disability or death many years after the initial episode.
Etiology
The development of acute rheumatic fever requires antecedent infection with a specific organism—the group A streptococcus—at a specific body site—the upper respiratory tract. Cutaneous streptococcal infection, a precursor of poststreptococcal acute glomerulonephritis, has never been shown to cause rheumatic fever.
Individual strains of group A streptococci vary in their rheumatogenic potential. In discrete epidemics of acute rheumatic fever in the United States, a limited number of group A streptococcal serotypes tend to predominate (e.g., 3, 5, 18, 24), and the infecting organisms are often heavily encapsulated, as evidenced by their growth as mucoid colonies on blood agar plates.
Epidemiology
The epidemiology of acute rheumatic fever mirrors that of streptococcal pharyngitis. The peak age of incidence is 5 to 15 years, but both primary and recurrent cases occur in adults. Acute rheumatic fever is rare in children younger than 4 years, a fact that has led some observers to speculate that repetitive streptococcal infections are necessary to “prime” the host for the disease. No clear-cut gender predilection has been observed, although certain manifestations, such as Sydenham's chorea and mitral stenosis, are more likely to develop in female patients.
The frequency with which acute rheumatic fever develops after untreated group A streptococcal upper respiratory tract infection differs with the prevalence of highly rheumatogenic strains in the population and the epidemiologic circumstances. In the years after World War II, careful prospective studies were conducted among personnel in military camps suffering from outbreaks of streptococcal infection; acute rheumatic fever developed in approximately 3% of untreated patients. Among children with endemic exposure, attack rates are usually less than 1%. The magnitude of the antistreptolysin O titer increase, persistence of the infecting organism in the pharynx, and clinically severe exudative pharyngitis are associated with a higher risk of rheumatic fever; however, one third or more of cases occur after streptococcal infections that are mild or asymptomatic.
Patients with a history of acute rheumatic fever are susceptible to recurrent attacks after an immunologically significant streptococcal infection. In one long-term prospective study of subjects with a history of rheumatic fever, one of every five documented streptococcal infections gave rise to a recurrence of the disease. The risk of recurrence is greater in patients with preexisting rheumatic heart disease and in those experiencing symptomatic throat infections; the risk declines with advancing age and with increasing interval since the most recent rheumatic attack. Nevertheless, rheumatic patients remain at increased risk well into adult life.
Rheumatic fever occurs in all parts of the world, without any racial predisposition. In temperate climates, acute rheumatic fever peaks in the cooler months of the year, particularly in the winter and early spring. The major environmental factor favoring occurrence appears to be crowding, as in military barracks or similar closed institutions and large households. Crowding favors interpersonal spread of group A streptococci and perhaps enhances streptococcal virulence by frequent human passage.
Acute rheumatic fever is common in developing areas such as the Middle East, the Indian subcontinent, and many nations of Africa. Extremely high acute rheumatic fever attack rates occur among indigenous populations such as the Maori of New Zealand and the Australian aborigines. In striking contrast, the incidence of acute rheumatic fever and the prevalence of rheumatic heart disease have declined both in North America and in western Europe during the 20th century. Rates of fewer than 2 per 100,000 schoolchildren are typical, especially in affluent suburbs. The higher incidence rates reported for blacks than for whites appear to be due to socioeconomic rather than to genetic factors.
The mid-1980s, however, witnessed some startling developments in the epidemiology of acute rheumatic fever in the United States. Outbreaks of the disease were reported from many communities. The largest was in Salt Lake City, Utah, and environs, where more than 500 cases occurred between 1985 and 2001. Equally surprising was that in many of these outbreaks, the victims were predominantly white, middle-class children dwelling in the suburbs. At the same time, epidemics of acute rheumatic fever occurred in military training bases in Missouri and California. Group A streptococci recovered from patients with acute rheumatic fever, their families, and the community and from training camp surveys were generally highly mucoid and belonged to well-established rheumatogenic serotypes (e.g., serotypes 3 and 18). These outbreaks demonstrate that reemergence of rheumatic fever does occur and that appropriate treatment of underlying streptococcal pharyngitis is essential.
Pathobiology
The mechanism by which group A streptococci elicit the connective tissue inflammatory response that constitutes acute rheumatic fever remains unknown. Various theories have been advanced, including toxic effects of streptococcal products such as streptolysins O and S, inflammation mediated by antigen-antibody complexes or streptococcal superantigens, and “autoimmune” phenomena induced by the similarity of certain streptococcal and human tissue antigens (molecular mimicry).
Most authorities currently favor the theory that the tissue damage in acute rheumatic fever is mediated by the host's own immunologic responses to the antecedent streptococcal infection. This theory is rendered more credible by the demonstration of numerous examples of antigenic similarity between somatic constituents of group A streptococci and human tissues, including heart, synovium, and neurons of the basal ganglia of the brain. Taken together, these immunologic cross-reactions could account for most of the manifestations of acute rheumatic fever.
Patients with acute rheumatic fever have, on average, higher titers of antibodies to streptococcal extracellular and somatic antigens than do patients with uncomplicated streptococcal infections. Data relating to cellular immunity are more limited. Patients with acute rheumatic fever exhibit an exaggerated cellular reactivity to streptococcal cell membrane antigens, as demonstrated by in vitro inhibition of migration of peripheral blood lymphocytes. During active rheumatic carditis, both the number of helper (CD4) lymphocytes and the ratio of CD4 to CD8 cells are increased in heart valves and peripheral blood.
Several observations suggest that development of rheumatic fever may be modulated, at least in part, by the specific genetic constitution of the host. These observations include the tendency of rheumatic fever to affect more than one member of a given family, the fact that acute rheumatic fever develops in only a small percentage of all individuals experiencing an immunologically significant streptococcal infection, the tendency of rheumatic individuals to experience recurrent attacks, and the propensity of rheumatic subjects to exhibit exaggerated immunologic responses to streptococcal antigens. To date, however, no consistent associations have been demonstrated between specific class I or class II human leukocyte antigens (HLAs) and susceptibility to acute rheumatic fever. A unique non-HLA alloantigen has been found to be strongly expressed on the B cells of virtually all patients with acute rheumatic fever but in less than 20% of controls.
Pathophysiology
Acute rheumatic fever is characterized by exudative and proliferative inflammatory lesions in connective tissue, especially connective tissue of the heart, joints, and subcutaneous tissue. The early lesions consist of edema of the ground substance, fragmentation of collagen fibers, cellular infiltration, and fibrinoid degeneration. In the heart, diffuse degeneration and even necrosis of muscle cells may be observed. At a slightly later stage, focal perivascular inflammatory lesions develop. These so-called Aschoff's nodules, considered virtually pathognomonic of rheumatic fever, consist of a central area of fibrinoid surrounded by lymphocytes, plasma cells, and large basophilic cells, some of them multinucleate. Many of these cells have elongated nuclei with a distinctive chromatin pattern, sometimes called caterpillar or owl-eye nuclei, depending on their orientation in microscopic cross section. Cells containing these nuclei are called Anichkov's myocytes, even though most authorities believe them to be of mesenchymal origin.
Cardiac findings may include pericarditis, myocarditis, and endocarditis. Foci of coronary arteritis may also be observed. A thickened and roughened area (MacCallum's patch) is frequently present in the left atrium above the posterior leaflet of the mitral valve. Valvar lesions appear early as small verrucae along the line of closure (Fig. 313-1). Later, as healing occurs, the valves may become thickened and deformed, the chordae shortened, and the commissures fused. These changes result in valvar stenosis or insufficiency. The mitral valve is involved most commonly, followed by the aortic, the tricuspid, and very rarely the pulmonic valves.
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| FIGURE 313-1 Multiple verrucous vegetations along the line of mitral valve closure in a fatal case of acute rheumatic fever. (From Virmani R, Farb A, Burke AP, Narula J: Pathology of acute rheumatic fever. In Narula J, Virmani R, Reddy KS, Tandon R [eds]: Rheumatic Fever. Washington, DC, American Registry of Pathology, 1999.) |
On pathologic examination, the arthritis of acute rheumatic fever is characterized by a fibrinous exudate and sterile effusion without erosion of the joint surfaces or pannus formation. The subcutaneous nodules have many histologic features in common with Aschoff's nodules and consist of central zones of fibrinoid necrosis surrounded by histiocytes, fibroblasts, occasional lymphocytes, and rare polymorphonuclear cells. Inflammation of the smaller arteries and arterioles may occur throughout the body. Despite pathologic evidence of diffuse vasculitis, aneurysms and thrombosis are not typical features of acute rheumatic fever.
Clinical Manifestations
Rheumatic fever may involve a number of different organ systems, most notably the heart, joints, skin, subcutaneous tissue, and central nervous system, and the clinical picture is variable (Table 313-1). Five clinical features of the disease are so characteristic that they are recognized as major manifestations according to the revised Jones criteria (see later) for the diagnosis of acute rheumatic fever: carditis, polyarthritis, chorea, subcutaneous nodules, and erythema marginatum. Other nonspecific findings, including arthralgia, fever, and certain laboratory findings, have been designated minor manifestations.
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The latent period between the antecedent streptococcal infection and the onset of symptoms of acute rheumatic fever averages 19 days and ranges between 1 and 5 weeks. When acute polyarthritis is the initial complaint, the onset is often abrupt and may be marked by high fever and toxicity. If isolated carditis is the initial manifestation, the onset may be insidious or even subclinical. Between these two extremes, diverse gradations exist in the initial features of acute rheumatic fever (see Table 313-1). In most attacks, fever and joint involvement are the earliest clinical manifestations, although they may occasionally be preceded by abdominal pain localized to the periumbilical or infraumbilical areas. At times, the location and severity of the pain as well as fleeting signs of peritoneal inflammation may lead to a misdiagnosis of acute appendicitis. Carditis, if it is to appear, usually does so within the initial 3 weeks of the illness. In contrast, chorea tends to occur later in the disease course, sometimes after all other manifestations have subsided. Chorea and polyarthritis rarely occur simultaneously. Epistaxis may be a feature of acute rheumatic fever occurring both at the onset and throughout the acute phase of the illness; it may be severe.
The incidence of major manifestations varies in reported series. Overall, however, arthritis occurs in approximately 75% of initial attacks of acute rheumatic fever, carditis in 40 to 50%, chorea in 15%, and subcutaneous nodules and erythema marginatum in less than 10%. The frequency of individual manifestations varies with age. Carditis is more frequent in the youngest age groups and is relatively uncommon in initial attacks occurring in adults. Chorea occurs primarily in persons between the age of 5 years and puberty. It is seen more frequently in female patients and virtually never occurs in adult men. Thus, the majority of acute rheumatic fever attacks occurring in adults are manifested primarily by arthritis.
Arthritis
Joint involvement ranges from arthralgia alone to acute, disabling arthritis characterized by swelling, warmth, erythema, severe limitation of motion, and exquisite tenderness to pressure. The larger joints of the extremities are usually involved, most frequently the knees and ankles but also the wrists and elbows. The hips and small joints of the hands and feet are affected occasionally. Involvement of shoulders and lumbosacral, cervical, sternoclavicular, and temporomandibular joints occurs in a relatively small percentage of cases. The synovial fluid contains thousands of white blood cells, with a marked preponderance of polymorphonuclear leukocytes; bacterial cultures are sterile. Characteristically, the articular involvement in acute rheumatic fever assumes a pattern of migratory polyarthritis. Migratory does not mean that inflammation in one joint disappears before the next is attacked. Rather, a number of joints are affected in succession, and the periods of involvement overlap. Inflammation in one joint may subside while another is becoming symptomatic, so the process seems to migrate from joint to joint. In untreated cases, as many as 16 joints may be affected, and arthritis develops in more than six joints in about half the patients. This classic migratory pattern is not invariable, however; in some cases, the pattern may be additive, persisting in several joints simultaneously. When effective anti-inflammatory therapy is administered early in the course of the disease, the involvement not infrequently remains monarticular or pauciarticular.
In most instances, inflammation in any one joint begins to subside spontaneously within a week, and the total duration of involvement is no more than 2 or 3 weeks. The entire bout of polyarthritis rarely lasts more than 4 weeks and resolves completely, with no residual joint damage. Some authors have described the rare occurrence of Jaccoud's arthritis, so-called chronic post–rheumatic fever arthropathy of the metacarpophalangeal joints, after repetitive bouts of rheumatic polyarthritis. This entity is not a true arthritis but a form of periarticular fibrosis; its relationship to rheumatic fever remains unresolved.
Carditis
Rheumatic fever may involve the endocardium, myocardium, and pericardium (Table 313-2), and thus the disease is capable of inducing a true pancarditis. Carditis is the most important manifestation of acute rheumatic fever because it is the only one that can cause significant permanent organ damage or death. Although the clinical picture may at times be fulminant, it is more frequently mild or even asymptomatic and may escape notice in the absence of more obvious associated findings, such as arthritis and chorea. The diagnosis of carditis requires the presence of one of the following four manifestations: organic cardiac murmurs not previously present, cardiomegaly, pericarditis, or congestive heart failure. In practice, the characteristic murmurs of acute rheumatic fever are almost always present in cases of rheumatic carditis, unless the ability to hear them is obscured (e.g., loud pericardial friction rub, large pericardial effusion, low cardiac output, severe tachycardia). The diagnosis of carditis should be made with caution in the absence of one of the following three murmurs: apical systolic, apical mid-diastolic, and basal diastolic. Such murmurs, if they are destined to develop, do so usually within the first week and almost always within the first 3 weeks of illness. (An exception to this rule may occur in patients with “pure” chorea; see later.)
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Certain patients with acute rheumatic fever have echocardio-graphic evidence of valvar regurgitation in the absence of an audible murmur. Although valvar regurgitation can also be detected in normal individuals by two-dimensional echo-Doppler and color flow Doppler techniques, criteria for discriminating physiologic from pathologic regurgitation have been proposed by experienced investigators. At present, so-called echocarditis is not considered diagnostic of rheumatic carditis for the purpose of fulfilling the Jones criteria, and its prognostic significance remains uncertain. The issue, however, remains controversial.
A number of different rhythm disturbances may occur during the course of acute rheumatic fever. By far the most common is first-degree atrioventricular block. Second- and third-degree heart block, nodal rhythm, and premature contractions may also be observed; atrial fibrillation, on the other hand, is usually a feature of chronic rather than acute rheumatic involvement. Conduction disturbances do not in themselves indicate acute carditis, and their presence or absence is unrelated to the subsequent development of rheumatic heart disease.
Echocardiographic studies have demonstrated that in the absence of preexisting rheumatic valvar disease, patients with acute rheumatic fever and congestive heart failure have preserved left ventricular systolic function but mitral or aortic regurgitation or both. Thus, the etiology of heart failure appears to be valvar dilation and not myocarditis.
In cases of acute rheumatic fever with severe carditis, areas of patchy pneumonitis are sometimes seen. Many observers believe that these pulmonary infiltrates represent a specific rheumatic pneumonia. The case is difficult to prove, however, because of the confusion induced by such confounding clinical entities as pulmonary edema, pulmonary embolization, superimposed bacterial pneumonia, and acute respiratory distress syndrome in these severely ill and toxic patients.
Sydenham's Chorea (Chorea Minor, St. Vitus' Dance)
This neurologic syndrome occurs after a latent period that is variable but on average longer than that associated with the other manifestations of acute rheumatic fever. It frequently occurs in “pure” form, either unaccompanied by other major manifestations or, after a latent period of several months, when all other evidence of acute rheumatic activity has subsided. In some cases of pure chorea, echocardiographic evidence of subclinical valvar regurgitation may be present. Chorea is characterized by rapid, purposeless, involuntary movements, most noticeable in the extremities and face. The arms and legs flail about in erratic, jerky, uncoordinated movements that may sometimes be unilateral (hemichorea). Facial tics, grimaces, grins, and contortions are evident. The speech is usually slurred or jerky. The tongue, when protruded, retracts involuntarily, and asynchronous contractions of lingual muscles produce a “bag of worms” appearance. The involuntary motions disappear during sleep and may be partially suppressed by rest, sedation, or volition.
Patients with chorea display generalized muscle weakness and an inability to maintain a tetanic muscle contraction. Thus, when the patient is asked to squeeze the examiner's fingers, a squeezing and relaxing motion occurs that has been described as milkmaid's grip. The knee jerk may have a pendular quality. No cranial nerve or pyramidal involvement occurs, and sensory modalities are unaffected. The electroencephalogram may display abnormal slow wave activity.
Emotional lability is characteristic of Sydenham's chorea and may often precede other neurologic manifestations, with teachers and parents left puzzled over apparently inexplicable personality changes. Recent interest has focused on the possibility that in a certain subgroup of children, obsessive-compulsive disorder or tic disorders may be triggered by streptococcal infections. Studies of this putative but unproven association, known as post-streptococcal autoimmune neuropsychiatric disorders associated with streptococci (PANDAS), are continuing.
Subcutaneous Nodules
These nodules are firm, painless subcutaneous lesions that vary in size from a few millimeters to approximately 2 cm. The skin overlying them is freely movable and not inflamed. The lesions tend to occur in crops over bone surfaces or prominences and over tendons. Sites of predilection include the extensor surfaces of the elbows, knees, and wrists; the occiput; and the spinous processes of the thoracic and lumbar vertebrae (Fig. 313-2). Nodules are virtually never the sole major manifestation of acute rheumatic fever; they almost always appear in association with carditis, and the cardiac involvement in such cases tends to be clinically severe. Nodules ordinarily do not appear until at least 3 weeks after the onset of an attack and persist for several weeks. They may appear in repeated crops in patients with protracted carditis. Similar nodules may be seen in systemic lupus erythematosus and in rheumatoid arthritis. Subcutaneous nodules in the latter disease are larger and more persistent than those in rheumatic fever.
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| FIGURE 313-2 Subcutaneous nodules over spinous processes on the back of a patient with acute rheumatic carditis. (Courtesy of S. Levine, MD.) |
Erythema Marginatum
The rash begins as an erythematous macule or papule and then extends outward while the skin in the center returns to normal. Adjacent lesions coalesce and form circinate or serpiginous patterns. The lesions may be raised or flat, are neither pruritic nor indurated, and blanch on pressure. They vary greatly in size and appear mostly on the trunk and proximal parts of the extremities, with the face being spared. The lesions are evanescent, migrating from place to place, at times changing before the observer's eyes, and leaving no residual scarring. The erythema may be brought out by applying heat. Individual lesions may come and go in minutes to hours, but the process may go on intermittently for weeks to months uninfluenced by anti-inflammatory therapy. Its persistence is not necessarily an adverse prognostic sign. In most cases, erythema marginatum is accompanied by carditis; it also tends to be associated with subcutaneous nodules.
Diagnosis
No single laboratory test is diagnostic of acute rheumatic fever. Usually, leukocytosis with an increase in the proportion of polymorphonuclear leukocytes is observed. A mild to moderate normocytic, normochromic anemia is the rule. Evidence of acute inflammation is prominent, including elevated serum levels of C-reactive protein and elevation of the erythrocyte sedimentation rate. An exception is pure chorea, which may appear after indices of inflammation have returned to normal.
The urine may contain protein, white cells, and red cells. Biopsy studies have revealed a variety of renal abnormalities, but the classic proliferative glomerular abnormalities that characterize post-streptococcal acute glomerulonephritis occur rarely in acute rheumatic fever. Electrocardiographic and radiographic studies may reveal evidence of rhythm disturbances, pericarditis, or congestive heart failure. Two-dimensional echo-Doppler and color flow Doppler echocardiography may document valvar dysfunction and pericardial effusion.
The major laboratory contribution to the diagnosis of acute rheumatic fever is the documentation of recent group A streptococcal infection. Throat culture should always be performed but is positive in only a minority of cases. The low rate of culture positivity remains unexplained, although it may be due in part to the time lapse of several weeks between the onset of the pharyngeal infection and the throat culture. The serum titer of antistreptolysin O is elevated in 80% or more of patients with acute rheumatic fever. If two streptococcal antibody tests (e.g., antistreptolysin O and anti–DNase B) are performed, an elevated titer of at least one is found in 90% of patients with acute rheumatic fever. The definition of an elevated titer varies, depending on the test used, the patient's age, and the geographic locale. At times, serial sampling may detect an increasing titer of streptococcal antibodies in patients seen early in the course of a rheumatic attack.
Differential Diagnosis
Although acute rheumatic fever is readily recognized in individuals with multiple major manifestations or in epidemic circumstances, the disease may be extraordinarily difficult to diagnose with confidence at other times because of the variability of its clinical features, the frequency with which only a single major manifestation is detected, and the fact that no definitive diagnostic laboratory test is available. Nevertheless, precise diagnosis is especially important in this disease because of the need to advise the patient about prolonged antimicrobial prophylaxis (see later). The diagnostic criteria of T. Duckett Jones, initially proposed in 1944 and subsequently modified by committees of the American Heart Association, attempt to minimize overdiagnosis and underdiagnosis (Table 313-3). The most recent (1992) revision specifies that the guidelines are designed to assist in the diagnosis of the initial attack of acute rheumatic fever, but they are also applicable to patients presenting with recurrent polyarthritis or chorea. Two major manifestations or one major and two minor manifestations indicate a high probability of acute rheumatic fever if supporting evidence of recent streptococcal infection is present. Although a positive throat culture or rapid antigen test for group A streptococci technically satisfies this requirement, streptococcal carriage rates as high as 15% may occur among school-aged children during the fall and winter. Elevated titers of antibodies to streptococcal extracellular products, although not diagnostic of acute rheumatic fever, do indicate a recent, immunologically significant streptococcal infection.
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The modified Jones criteria are only guidelines. They are most difficult to apply confidently when polyarthritis is the single major manifestation. Under such circumstances, the diagnosis of acute rheumatic fever should be made only after the exclusion of other causes of polyarthritis, such as rheumatoid arthritis, Still's disease, Lyme disease, viral arthritides (e.g., rubella, hepatitis B), the early prepurpuric phase of Henoch-Schönlein purpura, and septic arthritis including gonococcal arthritis. As experience grows, the echocardiographic demonstration of valvar insufficiency (by use of strict criteria to differentiate physiologic regurgitation) may help clarify the diagnosis in some cases. Echocardiography is of established value in the evaluation and management of acute and chronic rheumatic heart disease.
Some patients have been described as manifesting polyarthritis that is atypical in time of onset and duration, does not respond dramatically to salicylate therapy, and is unassociated with other clinical features of acute rheumatic fever. Such individuals have on occasion been categorized as having “post-streptococcal reactive arthritis.” The existence of this entity as a distinct syndrome, however, and its relationship to rheumatic fever remain uncertain. Pending further clarification, such individuals should be considered to have acute rheumatic fever if they fulfill the Jones criteria and alternative diagnoses have been excluded.
Serum sickness is frequently a serious consideration, particularly if the patient has received penicillin or other antibiotics for a preceding respiratory infection. Systemic lupus erythematosus, sickle cell hemoglobinopathies, and infective endocarditis may involve the joints and the heart. Other differential diagnostic considerations include congenital heart lesions, viral and idiopathic forms of myocarditis and pericarditis, and functional heart murmurs. Nonfamilial forms of chorea have been described in systemic lupus erythematosus, rarely in association with the use of birth control pills, and in patients with neoplasms involving the basal ganglia. The involuntary jerks of Gilles de la Tourette syndrome may be confused with chorea. It remains uncertain how often episodes of chorea occurring during pregnancy (chorea gravidarum) represent attacks of rheumatic fever. Other disorders that may at times be confused with acute rheumatic fever are gout, sarcoidosis, Hodgkin's disease, and acute leukemia.
In certain circumstances, acute rheumatic fever can be diagnosed even when the guidelines set forth in Table 313-3 have not been met, provided that alternative diagnoses are excluded. Because of the long latent period between the antecedent streptococcal infection and the appearance of the neurologic abnormalities in some patients with Sydenham's chorea, evidence of inflammation encompassed in the minor manifestations may no longer be present, and previously elevated antibody titers may have declined to normal. A similar situation occasionally occurs in patients with indolent carditis, who may not come to medical attention until a prolonged period after the onset of the disease.
Treatment
Antibiotics neither modify the course of a rheumatic attack nor influence the subsequent development of carditis. Nevertheless, it is conventional to give a course of antibiotics designed to eradicate any rheumatogenic group A streptococci remaining in the tonsils and pharynx to prevent spread of the organism to close contacts. The recommended regimens are those conventionally used for the treatment of acute streptococcal pharyngitis (Chapter 312). Benzathine penicillin G is preferred in non–penicillin-allergic patients. After completion of this therapy, continuous antistreptococcal prophylaxis should commence (see later discussion).
Treatment with anti-inflammatory agents is effective in suppressing many of the signs and symptoms of acute rheumatic fever. These agents do not “cure” the disease, nor do they prevent the subsequent evolution of rheumatic heart disease. They should be avoided in mild or equivocal cases because by suppressing the clinical manifestations, they may obscure the diagnosis. The two drugs most widely used are aspirin and corticosteroids. Aspirin is used in patients with acute polyarthritis, as long as carditis is either absent or mild and no evidence of congestive heart failure is found. Aspirin is effective in decreasing fever, toxicity, and joint inflammation. It should be given in a dosage of 90 to 100 mg/kg/day in children and 6 to 8 g/day in adults administered in equally divided doses every 4 hours for the initial 24 to 36 hours; thereafter, it may be given in four doses during waking hours. Maintenance of a salicylate level of 25 mg/dL is usually satisfactory. The incidence of nausea and vomiting may be minimized by starting somewhat below the optimal dosage level and gradually increasing during a few days. The patient should be observed for evidence of significant gastrointestinal bleeding and for signs and symptoms of salicylism (e.g., hyperpnea, tinnitus). After 1 to 2 weeks, the dosage is reduced to 60 to 70 mg/kg/day for an additional 6 weeks. These dosage schedules represent general guidelines only. The precise aspirin dose must be determined by the patient's clinical response, blood salicylate levels, and tolerance of the drug.
Corticosteroids are generally reserved for patients who have severe carditis manifested by congestive heart failure, who are unable to tolerate large doses of salicylates, or whose signs and symptoms are inadequately suppressed by aspirin. As with aspirin, the dosage must be individualized. Prednisone, 40 to 60 mg/day in divided doses, may be used initially. After 2 to 3 weeks, it should be withdrawn slowly during an additional 3-week period. In cases of fulminating carditis with profound heart failure, intravenous corticosteroids may be used, and emergent valve replacement may at times be life-saving. As for other patients receiving corticosteroids, the physician should be alert to problems such as gastrointestinal bleeding, sodium and water retention, and impaired glucose tolerance. Suppression of the pituitary-adrenal axis or the host immune system is a potential problem but not ordinarily a major one during this relatively short course of treatment. Although nonsteroidal anti-inflammatory drugs would appear a reasonable alternative for patients who do not tolerate salicylates but do not require corticosteroids, there is a paucity of data on the use of these agents in acute rheumatic fever. Two small studies, one using naproxen and one tolmetin, reported nonsteroidal anti-inflammatory drugs equivalent to aspirin in efficacy with fewer side effects. Further experience with these agents is required before specific recommendations can be made.
After cessation of anti-inflammatory therapy, clinical or laboratory evidence of acute rheumatic fever may reappear. Such therapeutic “rebounds” occur more frequently after corticosteroid therapy than after treatment with aspirin. They may be minimized by prolonging salicylate therapy for 9 to 12 weeks and, when corticosteroids have been required, by continuing aspirin for a month after corticosteroid use has been discontinued. Congestive heart failure is managed by conventional measures but with the recognition that in patients without preexisting rheumatic heart disease, myocardial function is usually well preserved (see earlier discussion). If digitalis is used, the potential risk of drug-induced arrhythmias in patients with active myocarditis must be kept in mind. Patients with Sydenham's chorea require a quiet environment. Corticosteroids and sedatives such as phenobarbital or diazepam may be helpful. Trials of plasmapheresis and intravenous immune globulin in the management of severe and intractable chorea are currently in progress.
Prevention
Primary prevention of acute rheumatic fever consists of accurate diagnosis and appropriate treatment of streptococcal sore throat (Chapter 312). Although straightforward in theory, primary prevention is often frustratingly difficult to achieve. In many of the densely populated indigent communities in which the risk of acute rheumatic fever is greatest, children with self-limited illnesses such as sore throats may never come to medical attention, and throat culture services are usually unavailable to aid in diagnosis. Moreover, in one third or more of cases, acute rheumatic fever may arise after a clinically unapparent streptococcal infection.
Perhaps the most effective strategy for avoiding the mortality and chronic cardiac disability associated with acute rheumatic fever is that of secondary prevention. This strategy focuses on the group of persons who have already suffered a rheumatic attack and who experience a high rate of recurrence after an immunologically significant streptococcal upper respiratory tract infection. Recurrent attacks tend to be mimetic in nature, so patients who have suffered carditis with their previous attack are likely to have repetitive cardiac involvement and progressive cardiac damage. However, carditis with recurrent attacks of acute rheumatic fever may develop even in patients who experienced only arthritis or chorea in their initial attack; thus, all patients who have experienced a documented attack of acute rheumatic fever should receive continuous antimicrobial prophylaxis to prevent either symptomatic or asymptomatic streptococcal infections. The specific regimens to be used are indicated in Table 313-4. The most effective of these regimens is intramuscular benzathine penicillin G. Rheumatic recurrences are unusual in compliant patients receiving an injection every 4 weeks. In areas of the world where the incidence of acute rheumatic fever and the risk of recurrence are high, however, injections every 3 weeks provide more complete protection.
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The total duration of intramuscular or oral rheumatic fever prophylaxis remains unresolved. The risk of rheumatic recurrence is known to diminish with increasing age and increasing interval since the most recent rheumatic attack. Patients who escape carditis during their initial attack are less likely to experience rheumatic recurrences and are less susceptible to the development of carditis if a recurrence does ensue. These facts suggest that prophylaxis need not be perpetual for all rheumatic subjects. Recommendations of the American Heart Association for the duration of secondary prophylaxis are listed in Table 313-5. The decision to remove a rheumatic subject from continuous prophylaxis should be an individualized one based on the physician's assessment of the risk and probable consequences of recurrence and taken with the patient's informed consent. Particular care should be taken with those at high risk of streptococcal acquisition (e.g., parents of schoolchildren, schoolteachers, military recruits, nurses, pediatricians, and residents of areas with a high incidence of acute rheumatic fever). Patients taken off prophylaxis must be instructed to return immediately for medical follow-up whenever symptoms of pharyngitis occur.
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Patients with rheumatic valvar heart disease must receive prophylaxis designed to avoid bacterial endocarditis whenever they undergo dental or surgical procedures likely to evoke bacteremia. Such prophylaxis is not necessary in a rheumatic subject who is free of residual heart disease. Regimens to prevent endocarditis (Chapter 76) are different from those prescribed for preventing acute rheumatic fever, and the fact that a patient is receiving rheumatic fever prophylaxis does not exempt that patient from endocarditis prophylaxis. This concept is a frequent point of confusion not only among patients but among physicians and dentists as well.
Prognosis
The average duration of an untreated attack of acute rheumatic fever is approximately 3 months. The duration tends to be longer, up to 6 months, in patients with severe carditis. Less than 5% of patients have continuing rheumatic activity for longer than 6 months. In a few of these patients, the disease is limited to chorea and is otherwise benign. Other patients exhibit evidence of persistent inflammatory activity, including arthritis, carditis, and subcutaneous nodules. “Chronic rheumatic fever” occurs more frequently in patients who have had one or more previous attacks; cardiac involvement in chronic rheumatic fever tends to be frequent and severe.
Congestive heart failure occurring in patients without preexisting rheumatic heart disease is not due to myocarditis per se but rather to inflammatory valvulitis and annular dilation, accompanied in more severe cases by chordal elongation and mitral valve leaflet prolapse. Death from intractable congestive failure during the acute phase of acute rheumatic fever is rare. Once the acute attack has subsided, the only long-term sequela is that of rheumatic heart disease, manifested primarily by scarring or calcification of the mitral and aortic valves (Chapter 75) and leading to insufficiency or stenosis. The prognosis from a cardiac standpoint is related to the clinical findings when the patient is initially seen. In one large study, for example, 347 patients were examined during an acute rheumatic attack and again 10 years later. Among patients who had been free of carditis during their acute attack, only 6% had residual heart disease on follow-up. Patients with mild carditis during their acute attack (i.e., apical systolic murmur without pericarditis or heart failure) had a relatively good prognosis in that only approximately 30% had heart murmurs 10 years later. About 40% of subjects with apical or basal diastolic murmurs and 70% of subjects with heart failure or pericarditis during their acute attacks had residual rheumatic heart disease. The prognosis was worse in patients with preexisting rheumatic heart disease and in those who had experienced recurrent attacks of acute rheumatic fever in the 10-year interval.
These data indicate that patients in whom carditis does not develop during an acute attack and who are protected from recurrences of acute rheumatic fever are unlikely to suffer from rheumatic heart disease. Patients with pure chorea represent an exception to this rule. Some patients who have no evidence of carditis when they are initially examined may have rheumatic valvar disease on prolonged follow-up. Although the explanation for this phenomenon is unknown, it is conceivable that in view of the long latent period associated with chorea, signs of carditis might have been present earlier but subsided by the time that the neurologic abnormality became evident. Moreover, echocardiographic studies have detected subclinical valvulitis in some of these patients.
Once the acute attack has subsided completely, the patient's subsequent level of physical activity depends on cardiac status. Patients without residual heart disease may resume full and unrestricted activity. It is important that patients not be subjected to unwarranted invalidism because of either their own inaccurate perceptions of the nature of the rheumatic process or those of parents, teachers, or employers.
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