Section 5 -

Rheumatic Fever and Rheumatic Heart Disease Vera Demarchi Aiello Laboratory of Pathology, Heart Institute (InCor) São Paulo University School of Medicine São Paulo, Brazil

Rheumatic fever is a systemic inflammatory disease that results from an inadequate immunological response of some genetically susceptible individuals to a Group A Streptoccocus infection. The heart, joints, central nervous system and skin may be affected, but the heart lesions are the ones that may be life threatening or limit health capacity in children and young adults. The inflammatory reaction is self-limited and leaves no sequel in the various organs, except the heart, where the valves and the myocardium end up with permanent lesions after several episodes of recurrence of the acute rheumatic carditis, thus characterizing the chronic rheumatic heart disease. In spite of the decrease in the incidence of rheumatic heart disease in industrialized countries, the disease still remains a public health problem in developing countries in the beginning of the present century. Epidemiology Acute rheumatic fever affects children and adolescents from 5 to 18 years of age, coinciding with the age distribution of the highest prevalence of streptococcal infections. The incidence of streptococcal pharyngitis can vary between countries and according to season, age group, socioeconomic and environmental conditions. Data published by the WHO in 1994 estimated that worldwide 12 million individuals suffered from rheumatic fever and rheumatic heart disease. At least one quarter of them had congestive heart failure that required hospitalization and a large proportion needed cardiac valve surgery (valvuloplasty or valve replacement) [1]. In Brazil , data from the official Unified Health System (SUS- Sistema Único de Saúde) showed that in the last 10 years the number of hospital admissions of patients aged from 10 to 29 years with rheumatic fever or chronic rheumatic heart disease doubled those corresponding to patients with congenital heart defects. Etiopathogenesis Rheumatic fever is the consequence of a delayed autoimmune reaction against Group A -haemolytic streptococcal pharingytis. The proposed triggering factor is antigenic molecular mimicry between streptococcal M-protein epitopes and human tissues such as heart valves, synovial tissue, cartilage and some tissue proteins: myosin, tropomyosin and brain proteins. The severity and clinical manifestation of the disease in an individual is determined by host genetic susceptibility and virulence of the microorganism. [2] Although streptococci from other serogroups (B, C, G and F) can also cause pharingytis and trigger a host immune response, there is no evidence linking non-group A types with the pathogenesis of rheumatic fever. Group A streptococci contain surface proteins (M, T, R) that are involved in the adherence of the bacteria to throat epithelial cells. The M protein is particularly important as a virulence factor, since it provides the bacterium with an adherence advantage. Moreover, it is the most important antigenic structure of the bacteria and shares structural homologies with some alpha-helical human proteins, which forms the basis for the immune-mediated post-streptococcal sequelae of rheumatic fever and rheumatic heart disease. [2] Since only 0.3-3% of the individuals with acute streptococcal pharingytis develop rheumatic fever, genetic determinants of host susceptibility have been extensively studied. Recent data revealed that the level of response to the streptococcal antigen is closely linked to the type of major histocompatibility complex, the Class II human leukocyte antigen, HLA. In Brazilian, Turkish and Egyptian rheumatic patients, the HLA allele DR7 is the most frequent, while the HLA-DR4 was found in American Caucasians, Saudi-Arabian and Indian patients [2]. One explanation for the association of some Class II HLA alleles and auto-immune diseases is that such molecules might cause inappropriate T-cell activation. Specifically, Th1-type cytokines are the mediators of rheumatic disease heart lesions. Main Clinical Features Clinical manifestations of the disease usually appear after a latency period of 3 weeks following the streptococcal infection, beginning with non-specific symptoms such as fever and malaise. Painful, migratory arthritis involving major peripheral joints is present in 60-80% of the patients with the acute attack of rheumatic fever. It resolves spontaneously after 2 or 3 weeks. [3] Carditis is the single most important risk factor in rheumatic fever. In a large series from Sao Paulo, Brazil , it was present in 50% of the patients [4]. It is, characteristically, a pancarditis, presenting clinically as high pulse rate, congestive heart failure, arrhythmias and pericardial friction rubs. Valvular involvement may be suspected in the presence of a new cardiac murmur consequent to mitral or aortic regurgitation. It is contentious if myocardial dysfunction in acute rheumatic fever is valvular or myocardial in origin. [3] In fact, in a subset of patients, the initial presentation may be quite severe, with overt heart failure, fever and toxaemia, making the differential diagnosis with infective endocarditis very difficult, particularly in patients with recurrent rheumatic heart disease. Sydenham's chorea is usually a delayed manifestation of rheumatic fever and is characterized by involuntary movements and muscle weakness, sometimes accompanied with disturbances of speech and psychological problems such as hyperactivity, irritability and obsessive-compulsive behavior. Usually this symptomatology disappears after a few months. There is no specific clinical or laboratory test for rheumatic fever, and the diagnosis is based on the revised Jones Criteria, that lists major and minor manifestations, including evidences of recent streptococcal infection such as elevated acute phase reactants and elevated antistreptolysin-O. [5] Pathological Aspects Acute Rheumatic fever As an autoimmune disease, it induces exudative and proliferative inflammatory reactions in the connective tissue of the affected organs. Acute pancarditis is characterized by the presence of fibrinous pericarditis, myocarditis and valvulitis. The frequency of involvement is greater for the mitral and aortic valves (which have the higher closing pressures), the right ones being only rarely affected. Grossly, one can find small vegetations (1 to 2mm in diameter) on the lines of valvar closure, which can occasionally extend to the tendinous chords. At microscopy, they consist of fibrin and platelets overlying a lesion of the connective tissue characterized by fibrinoid necrosis and mononuclear inflammatory infiltrates. These lesions may be considered as a type of nonbacterial thrombotic endocarditis. Giant cells may be found scarcely, but Aschoff bodies, the histological fingerprint of rheumatic fever, are rarely observed in the valvar tissue. It is not the rule for the myocardium, where Aschoff bodies (or nodules) are frequent. They are usually located in the connective tissue around vessels and are granuloma-like, showing fibrinoid necrosis surrounded by lymphocytes (mainly CD4+ T phenotype) [2], some plasma cells and plump macrophages with abundant cytoplasm and a clear nucleus where a central ribbon of condensed chromatin is observed. These are called as "Anitschikow cells" or "caterpillar cells" when cut longitudinally. Multinucleated macrophages may also be present, and receive the name of "Aschoff giant cells". These pathognomonic nodules often appear four weeks after the beginning of the acute onset and may persist for months in the myocardium. The earliest lesions show prominent fibrinoid necrosis, while the old ones are proliferative. Although the diagnosis is made on clinical grounds, it was demonstrated that endomyocardial biopsies may show Aschoff bodies in a percentage of 30-40% of patients with acute rheumatic fever [6]. The low sensitivity indicates that endomyocardial biopsy is not likely to provide important diagnostic information. Chronic Rheumatic Heart Disease Recurrent attacks of acute rheumatic fever lead to sequelae in the valves and myocardium. The organization of the vegetations from the acute phase results in cusp thickening, fusion of commissures and shortening of the chords. Subsequent damage occurs due to haemodynamic disturbances and/or thrombus deposition. In the chronic phase, the valves are deformed and fibrotic. Calcium deposits may be extensive. Involvement of the mitral valve alone reaches 60-70% of the patients with chronic rheumatic heart disease, while mitral and aortic lesions coexist in about 25% of the individuals. Surgically excised valves with chronic rheumatic involvement show dense fibrosis, variable inflammatory infiltrates composed by lymphocytes and histiocytes, vessels with thick walls and occasionally deposits of calcium. Aschoff bodies are usually absent, unless the patient has suffered an acute attack in the last few weeks. In severe mitral stenosis, the valvar orifice appears slit-like (termed "fish-mouth") and the sub-valvar apparatus is also stenotic due to the extensive fusion of the chords. Apparently, repeated acute attacks correlates with early valve dysfunction and evolution to heart failure. This happens more frequently in patients from the developing world. Myocardial scars result from the organization of the nodules of the acute phase, and are peri-vascular in location. Additional damage is due to altered haemodynamics, and comprises variable degrees of myocardial hypertrophy and chamber dilation. Particularly in mitral stenosis, the left atrium may become enlarged and be the site of thrombosis, a possible source of systemic embolism. Chronic pulmonary congestion may be so severe as to result in pulmonary hypertension with thickening of veins and arteries. It is also worthy to note that chronic rheumatic valvar disease is a major risk factor for infectious endocarditis. Invasive Treatment of the Chronic Valvar Lesions The available alternatives for the treatment of the chronic lesions of rheumatic heart disease are valvuloplasty -surgical or percutaneous (balloon)- and valvar replacement. Percutaneous mitral valvulotomy is usually indicated when surgery carries a high-risk or in young patients that have very favorable anatomy (minimal cusp and chordal thickening, among others). The results in this latter group are comparable to the surgical procedure, and at least postpone the definitive surgery, without complications such as adhesive pericarditis or chest wall scarring [7]. Surgical valvuloplasty, on the other hand, has the advantage of allowing an individual approach to a particular morphological abnormality and also is the procedure of choice for valvar insufficiency. [8] When valve replacement is performed in children, besides the inherent risk of the post-operative period, the late complications related to the prosthesis must be considered. In Brazil , the use of biological valve prostheses is widespread because of the low cost and the easier management regarding coagulation control. However, in children these prostheses undergo massive calcification within few months or years after the implantation and the need for more than one valvar replacement before the adult age is not uncommon. [9] References WHO technical report series. Rheumatic fever and rheumatic heart disease. Report of a WHO expert consultation. Geneva , 2001. Guilherme L, Fae K, Oshiro SE, Kalil J. Molecular pathogenesis of rheumatic fever and rheumatic heart disease. Expert Rev Mol Med. 2005;7(28):1-15. Binotto MA, Guilherme L, Tanaka AC. Rheumatic Fever. Images Paediatr Cardiol 2002;11:12-25. Published on line at: http://www.health.gov.mt/impaedcard/issue/issue11/pdf/1231.pdf da Silva CH. Rheumatic fever: a multicenter study in the state of Sao Paulo . Pediatric Committee-- Sao Paulo Pediatric Rheumatology Society. Rev Hosp Clin Fac Med Sao Paulo 1999; 54:85-90 Guidelines for the diagnosis of rheumatic fever. Jones Criteria, 1992 update. Special Writing Group of the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on Cardiovascular Disease in the Young of the American Heart Association. JAMA 1992; 268:2069-2073 Narula J, Chopra P, Talwar KK, Reddy KS, Vasan RS, Tandon R, Bhatia ML, Southern JF . Does endomyocardial biopsy aid in the diagnosis of active rheumatic carditis? Circulation. 1993; 88:2198-205. Vahanian A, Palacios IF. Percutaneous Approaches to Valvular Disease. Circulation 2004; 109:1572-79. Pomerantzeff PM, Brandao CM, Faber CM, Grinberg M, Cardoso LF, Tarasoutchi F et al. Mitral valve repair in rheumatic patients. Heart Surg Forum 2000; 3:273-276 de Godoy MF, Branco JN, Soares HC, Leao LE, Carvalho AC, Gimenes AC, Ribeiro EE, Succi JE, Andrade JC, Albertini MV, et al. [Long-term results of valve replacement in children] Arq Bras Cardiol. 1981; 37(4):325-9.