Rheumatic fever is a delayed, nonsuppurative sequel of upper respiratory infection with group A streptococci. The dis-ease is characterized by inflammatory lesions involving primari-ly the joints, heart, and subcutancous tissues; its pathogenesis remains obscure. The clinical manifestations include pol-yarthritis, carditis, subcutaneous nodules, erythema margina-turn. and chorea in varying combinations. In its classic form, the disorder is acute, febrile, and largely self-limited. Howev-er, damage to heart valves may be chronic and progressive, causing cardiac disability or death many years after the initial episode.

Etiology The development of acute rheumatic fever (ARF) requires antecedent infection with a specific organism, the group A Streptococcus, at a specific body site, the upper respiratory tococcal acute glomerulonephritis, has never been shown to cause rhcumatic fever.

Strains representing a number of the more than 80 M pro-tein scrotypes of group A streptococci are capable of causing ARF. There is a substantial body of evidence to indicate,however, that group A streptococci vary in their rhemnato-genic potential. Analysis of epidemics of ARF caused by a vari-ety of serotypes shows a striking absence of certain highly prevalent types and an overrepresentation of types 5 and 18 and a number of others. Reports from the preantibiotic era document epidemics of streptococcal tonsillitis, even among rheumatic subjects, in which ARF failed to appear. Prospec-tive studies in which postsreptococcal acute glomerulonephritis and ARF occur simultaneously in the same indigent population suggest that the streptococcal strains responsible for each se-quel are serotypically distict.

Streptococci epidemiologically associated with recent ARF outbreaks in the United States belong to the classic "rhcumato-genic" serotypes and often exhibit mucoid colonial morpholo-gy.

Pathogenrsis The mechanism by which group A strepto-cocci elicit the connective tissue inflammatory response that constitutes ARF remains unknown. Various theories have been advanced, including 1.toxic effects of streptococcal products, particularly streptolysins S and O, both of which are capable of initiating tissue injury; 2. inflammation mediated by anti-genantibody complexes, perhaps localized to sites of tissue in-jury; and 3."autoimmune" phenomena induced by the similar-ity of certain streptococcal and human tissue antigens.

Efforts to discriminate among these potential pathogenetic mechanisms have been hampered by the lack of an animal mod-el of rheumatic fever. Most authorities currently favor the the-ory that ARF is an "autoimmune" disorder, in which tissue damage is mediated by the host's own immunologic responses to the antecedent streptococcal infection. This theory is ren-dered more credible by the relatively long latent period between the onset of pharyngitis and ARF and by the demonstration of numerous examples of antigenic similarity between somatic constituents of the group A Streptococcus and human tissues. The most intensively studied of these antigenic cross-reactions is that between streptococci and human heart. Many patients with ARF (as well as patients with uncomplicated streptococ-cal infections) have in their sera antistreptococcal antibodies that cross-react with heart tissue in variety of test systems. Components of the streptococcal cell wall (including group A carbohydrate and M protein) and of the cell membrane contain epltopes that share antigenic determinants with certain con-stituents of the human heart.

Patients with ARF have, on the 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. ARF pa-tients exhibit an exaggerated cellular reactivity to streptococcal cell membrance antigens, as demonstrated inhibition in vitro of migration of peripheral blood lymphocytes.

Chronic remittent nodular lesions have been produced in dermal connective tissue following injection into experimental animals of a streptococcal mucopeptide-polysaccharide cell wall complex. Antibodies to the cytoplasm of neurons located in the caudate and subthalamic nuclei of the brain have been indenti-fled in sera of patients with Sydenham's chorea, and such an-tibodies cross-react with group A streptococcal membranes. Streptococcal extracellular products appear to be present in im-mune complexes circulating in the blood of ARF patients. Taken together, these and other reported immunologic cross-reactions and toxic phenomena could theoretically account for most of the manifestations of ARF. As yet, however, there is no direct evidence that any of them is of pathogenetic signifi-cance.

Several observations suggest that development of rheumatic fever may be modulated, at least in part, by the specific genetic constitiution of the host. These include 1.the tendency of rheumatic fever to affect more that one member of a given family 2.the fact that only a small percentage of all individuals experiencing an immunotogically significant strep-tococcal infection develop ARF; 3.the tendency of rheumatic individuals to experience recurrent attacks; 4.the propensity of rheumatic subjects to exhibit exaggerated immunologic re-sponses to streptococcal antigens; and 5.the fact that certain class II histocompatibility antigens are encountered significant-ly more frequently in ARF patients than in controls. Recently, a unique antigen has been found to be strongly expressed on the B cells of virtually all ARF patients but in fewer than 20 per cent of controls.

Epidemiology The epidemiology of ARF mirrors that of streptococcal pharyngitis. The peak age of incidence is 5 to 15 years, but both primary and recurrent cases occur in adults. ARF is rare in children less than 4 years of age, a fact that has led some observers to repetitive streptococcal infections are necessary to "prime'' the host for the disease. There is no clear-cut sex predilection, although females are more likely to develop certain manifestations such as Sydenhan' s chorea and mitral stenosis.

The frequency with which ARF develops following un-treated group A streptococcal upper respiratory infection differs with the epidemiologic circumstances. In the years following World War II, careful prospective studies were conducted a-mong personnel in military recruit camps suffering from exuda-rive tonsillitis or pharyngitis caused by M-typable group A streptococci. Under such circumstances, in which cases of streptococcal pharyngitis tend to be clinically severe and to ap-pear in cpidemics, approximately 3 per cent of untreated pa-tients developed ARF. Studies of endenically occurring strep-tococcal infection among open populations of children are com-plicated by the difficulties of differentiating cases of streptococ-cal pharyngitis from viral pharyngitis occurring in streptococcal carriers; nevertheless, the ARF attack rate in such circum-stances is clearly lower than in the military experience, with an overall attack rate of less than 1 per cent.

Certain features of the antecedent streptococcal infection are associated with an increased risk of ARF. Among these are the mangnitude of the antistreptolysin O (ASO) titer rise and the persistence of the infecting organism in the pharynx. Prospective civilian studies indicate that ARF is more likely to occur following clinically severe exudative pharyngitis than fol-lowing mild, nonexudative illness. On the other hand, one third or more of cases of ARF occur after streptococcal infec-tions that are asymptomatic or so mild as to have been forgot-ten by the patient.

Patients with a history of ARF are at greatly increased fish of recurrent disease following an immunologically signifi-cant streptococcal infection. In long-term prospective studies of rheumatic subjects carried out at Irvington House, a rheumatic fever sanitarium outside New York City, one of every five doc-umented streptococcal infections gave rise to a recurrence of ARF. The rish of recurrence is greater in patients with pre-ex-isting rheumatic heart disease and in those experiencing symp-tomatic throat infections; the rish 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, perhaps indefinitely.

Rheumatic fever occurs in all parts of the world; there is no known racial predisposition. In temperate climates, ARF peaks in the cooler months of the year, in the winter and early spring or shortly after schools open in the fall. The major envi-ronmental factor favoring occurrence appears to the crowding, as in military barracks or similar closed institutions and in large households. Crowding favors interpersonal spread of group A streptococci and perhaps enhances streptococcal virulence by frequent human passage.

ARF' remains rempant in developing areas such as the Middle East, the Indian subcontinent, and many nations of Africa and South America. It has been estimated that rheumatic heart disease causes 25 to 40 per cent of all cardio-vascular disease in the Third World. In striking contrast, the incidence of ARF and the prevalence of rheumatic heart disease have declined dramatically both in North America and in West-ern Europe over the past four to five decades. During this time, the disease has become extremely uncommon in the af-fluent suburbs of many United States cities, while persisting a-mong lower socioeconomic groups, particularly those massed in the densely populated core areas of major urban centers.

The mid-1980' s, however, witnessed some starling de-velopments in the epidemiology of ARF in the United States. Outbreaks of the disease were reported in Salt Lake City, U-tah ; Columbus and Akron, Ohio;Pittsburgh, Pennsylvaning ; Nashville and Memphis, Tennessee; and a number of other communities. Equally surprising was the fact that, in many of these outbreaks, the victims were predominantly white, mid-die-class children dwelling in the suburbs. Moreover. ARF epidemics occurred in military training bases in Missouri and California, a phenomenon that had not been observed for two decades. There is as yet no evidence that these events presage a maior national resurgence of ARF.

Pathology ARF is characterized by exudative and prolif-erative of inflammatory lesions in the connective tissues, espe-cially those heart, joints, and subcutaneous tissues. The early lesions consist of edema of the ground substance, fragmenta-tion of collagen fibers, cellular infiltration, and fibrinoid de-generation. In the heart, diffuse degeneration and even necro-sis of muscle ceils may be observed. At a sligthly later stage, focal perivascular inflammatory lesions develop. These so-called Aschoff nodules, considered virtually pathognomonic of rheumatic fever, consist of a central area of fibrinoid surround-ed by lymphocytes, plasma cells, and large basophilic cells, some of them multinucleate. Many of these cells have elongat-ed 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 "Anitschkow myocytes", despite the fact that most authorities believe them to be mesenchymal origin.

Cardiac findings may include pericarditis, myocarditis, and endocarditis. Foci of coronary arteritis may also be ob-served. A thickened and roughened area (" MacCallum' s patch") is frequently present in the left atrium above the pos-terior leaflet of the mitral value. Vavular lesions appear early as small verrucae along the line of closure. Later, as healing occurs, the valves may become thickened and deformed, the chordae shortened, and the commissures fused. These changes result in valvular stenosis or insufficiency. The mitral valve is most commonly involved, followed by the aortic, the tricus-pid, and, rarely, the pulmonic.

Pathologically, the arthritis of ARF is characterized by a fibrinous exudate and sterile effusion without erosion of the joint surfaces or pannus formation. Subcutaneous nodules have many histologic features in common with the Aschoff nodules. These consist of central zones of fibrinoid necrosis surrounded by histiocytes, fibroblasts, occasional lymphocytes, and race polymorphonuclear cells, Inflammation of the smaller arteries and arterioles may occur throughout the body. Despite patho-logic evidence of diffuse vasculitis, aneurysms and thrombosis are not typical features of ARF.

Clinical Manifestations Rheumatic fever may involve a number of different organ systems, most notably the heart, joints, skin, and central nervous system. The clinical picture of the disease may thus be quite variable (Table 7), depending upon which systems are attacked, whether they are involved singly or in combination, the order in which they are affected, and the severity of the involvement. Five clinical features of the disease are so characteristic that they are recognized as

"maior manifestations" according to the revised Jones criteria for diagnosis of ARF: carditis, polyarthritis, chorea, subcuta-neous nodules, and erythema marginatum. Certain other find-ings, frequently present but nonspecific, have been designated "minor manifestations". These include arthralgia, fever, his-tory of previous rheumatic fever or evidence of preexisting rheumatic heart disease, and certain laboratory findings.

In cases in which it can be determined, the latent period between the antecedent streptococcal infection and the onset of symptoms of ARF: carditis, polyarthritis, chorea, subcuta-neous nodules, and erythema marginatum. Certain other find-ingsl frequently present but nonspecifie, have been designated "minor manifestations". These include arthralgia, fever, his-tory of previous rheumatic fever or evidence of prexisting rheumatic heart disease, and certain labortory findings.

In cases in which it can be determined, the latent period between the antecedent streptococcal infection and the onset of symptoms of ARF ranges between 1 and 5 weeks. The average latent period is 19 days for both primary and recurrent attacks. When acute polyarthritis is the presenting complaint, the onset is often rather abrupt and may be marked by high fever and toxicity. If isolated carditis is the initial manifestation, the on-set may be insidious or even subclinical. Between these two ex-tremes, a wide variety of gradations exist in the initial presen-tation of ARF (Table 7). In most attacks, fever and joint in-volvement are the earliest clinical manifestations, although they may occasionally be preceded by abdominal pain localized to the periumbilical of infraumbilical areas. At times the loca-tion and severity of the pain, as well as fleeting signs of peri-toneal inflammation, may lead to misdiagnosis of acute appen-dicitis Carditis, if it is to appear, usually does so within the first 3 weeks of the illness. In contrast, chorea tends to occur later in the course of the disease, sometimes after all other manifestations have subsided. Fortunately, chorea and pol-yarthritis almost never occur simultaneously. Epistaxis may be a feature of ARF, occuring both at the onset and throughout the acute phase of the illness; it may be quite severe.

TABLE 7 THE MANY FACES OF ACUTE RHEUMATIC

FEVER : POSSIBLE PRESENTATIONS

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 shoul-ders and lumbosacral, cervical, sternoclavicular, and temporo-mandibular joints occurs in a relatively small percentage of cas-es. The synovial fluid contains thousands of white blood cells,with a marked preponderance of polymorphonuclear leuko-cytes; bacterial cultures are sterile.

Characteristically, the articular involvement in ARF as-sumes a pattern of migratory polyarthritis. This does not mean that inflammation in one joint disappears before the next is at-tacked. 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 that the process seems to migrate from joint to joint. In un-treated cases, as many as 16 joints may be affected, and about half the patients develop arthritis in more than six joints. When effective antiinflammatory therapy is administered early in the course of the disease, the involvement not infrequently remains monoarticular 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 ofpolyarthritis rarely lasts more than 4 weeks and resolves corn-pletely, leaving no residual joint damage. Some authors have described the rare occurrence of Jaccoud's arthritis, so-called chronic post-rheumatic fever arthropathy of the metacarpopha-langeal joints, following repetitive bouts of rheumatic pol-yarthritis. This entity is not a true arthritis but a form of peri-articular fibrosis;its relationship to rheumatic fever remains unresolved.

Carditis Rheumatic fever may involve the endocardium, myocardium, and pericardium (Table 8), and thus the disease is capable of inducing a true pancarditis. Carditis is the most

TABLE 8 CLINICAL MANIFESTATIONS OF CARDITIS

IN ACUTE RHEUMATIC FEVER

Other prominent auscultatory findings in patients with ac-tive rheumatic carditis include tachycardia, which persists dur-ing sleep; protodiastolic, presystolic, or summation gallops; an indistinct or "mushy" quality to the first heart sound (re-sulting in some cases from first-degree heart block) ; pericardial friction rub; or muffling of heart tones caused by pericardial effusion. In the early stages of congestive heart failure, rapid distention of the hepatic capsule may lead to right upper quad-rant aching and tenderness over the liver. All the usual clinical findings of pericarditis or congestive failure may be observed.

A number of different rhythm disturbances may occur during the course of ARF. By far the most common is first-de-gree 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 sub-sequent development of rheumatic heart disease.

In cases of ARF with severe carditis, areas of patchy pneumonitis are sometimes seen. Many observers feel that these pulmonary infiltrates represent a specific rheumatic pneu-monia. The case is difficult to prove, however, because of the confusion induced by such confounding clinical entities as pul-monary edema, pulmonary embolization, superimposed bacte-rial pneumonia, and the acute respiratory distress syndrome in these severely ill and toxic patients.

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