Rheumatic Heart Disease in Children: from Clinical Assessment to Therapeutical Management

European Review for Medical and Pharmacological Sciences 2006; 10: 107-110 Rheumatic heart disease in children: from clinical assessment to therapeutical management

G. DE ROSA, M. PARDEO, A. STABILE*, D. RIGANTE*

Section of Pediatric Cardiology, *Department of Pediatric Sciences, Catholic University “Sacro Cuore” – Rome (Italy)

Abstract. – Rheumatic heart disease is presence of valve disease or carditis can be still a relevant problem in children, adolescents easily recognized through echocardiographic and young adults. Molecular mimicry between examinations, but the combination of clinical streptococcal and human proteins has been proposed as the triggering factor leading to autoim- tools and echocardiography consents the munity and tissue damage in rheumatic heart most accurate assessment of heart involve- disease. Despite the widespread application of ment2. It is well known however that minimal Jones’ criteria, carditis is either underdiagnosed physiological mitral regurgitation can be or overdiagnosed. Endocarditis leading to mitral identified in normal people and might over- and/or aortic regurgitation influences morbidity diagnose the possibility of carditis. Only in and mortality of rheumatic heart disease, whilst myocarditis and pericarditis are less significant 30% patients serial electrocardiogram studies in determining adverse outcomes in the long- are helpful in the diagnosis of acute RF with term. Strategy available for disease control re- non-specific findings including prolonged PR mains mainly secondary prophylaxis with the interval, atrio-ventricular block, diffuse ST-T long-acting penicillin G-benzathine. changes with widening of the QRS-T angle and inversion of T waves. Carditis as an ini- Key Words: tial sign might be mild or even remain unrec- Rheumatic heart disease, Pediatrics. ognized.

Introduction Pathogenesis

Rheumatic heart disease is the only clinical Interactions involving streptococci and the manifestation of rheumatic fever (RF) which host play an essential pathogenetic role for results in residual or permanent damage oc- RF occurrence. Of the β-hemolytic strepto- curring in 14 to 99% patients: such a wide dif- cocci that can produce infection in humans, ference in prevalence is due to a twofold ex- only those belonging to group A can lead to planation: on one hand the difficult recogni- RF, almost exclusively after tonsillitis or tion of RF first episode, often associated with pharingitis3. One of the first mechanism pro- only mild manifestations, and on the other posed to explain injury in RF was a direct in- hand the recent availability of echocardio- vasion of the affected tissue by the Strepto- graphic investigations for RF diagnosis, coccus. Evidence of a latency period of about which can result extremely effective in recog- 3 weeks between the acute streptococcal in- nizing subclinical carditis too1. Initial fection and the clinical appearance of tissue episodes of acute RF are commonly encoun- injury suggests that tissue damage is mediat- tered in children aged 5-15 years and are ed by an immunological reaction with an au- rarely observed before the age of 5 years. toimmune component. Kaplan and his co- The more consistent clinical signs of workers have proposed the concept of “anti- rheumatic carditis include the presence of a genic mimicry”: antibodies produced by the pathologic murmur, particularly the one re- streptococcal infection against the bacterial ferred to aortic or mitral insufficiency. The antigens cross-react with the host tissues

Corresponding Author: G. De Rosa, MD; e-mail: [email protected] 107 G. De Rosa, M. Pardeo, A. Stabile, D. Rigante leading to tissue injury4. The description of which the Aschoff nodules can be observed the immunologic cross-reactivity between the in the perivascular areas (Figure 1). Aschoff M protein and myocardial sarcolemma lends nodule consists of large vimentin-positive support to this concept. After the immune re- cells of mesenchymal origin with polymor- action there is a subsequent inflammatory phous nucleus and basophilic cytoplasm process involving myocardium and valvular standing around a fibrinoid centre, and can endocardium. With progression and persis- be considered the pathognomonic marker of tence of inflammation valve fibrosis and cal- rheumatic myocarditis. Laboratory markers cification might occur. It is extimated that on- of myocardial damage result normal in pa- ly 0.3% of individuals with an untreated tients with acute RF, while in patients with streptococcal pharyngitis will present an acute RF and congestive heart failure unre- episode of RF. Moreover RF incidence fol- sponding to medical therapies valve replace- lowing pharyngitis in patients who have had a ment might be life-saving: these observations previous episode of RF is approximately let us suggest that acute rheumatic myocar- 50%. This observation, together with clinical dial damage plays a less significant role in studies indicating a familiar clustering of the morbidity or mortality rates associated with disease, suggests that genetic factors might RF9,10. play a role in the susceptibility to RF. It has been reported the presence of specific B-cell Endocarditis alloantigen in the 99% of patients with RF Endocarditis is the most typical outline of and in only 14% of controls. Genetic suscep- rheumatic heart disease, characterized by tibility to RF is also supported by the associa- leaflet inflammation of mitral and/or aortic tion with HLA-DR2 and DR4 antigens5,6. valves; pulmonary and tricuspid valves are more rarely involved. Histologic findings in rheumatic endocarditis can be divided in stage I, with edema and cellular infiltration of Clinical Manifestations valvular tissue or chordae tendineae, and stage II, with persistent inflammation leading Myocarditis to fibrosis or calcification with eventual Diagnosis of rheumatic myocarditis can be valvular stenosis. Mitral insufficiency occurs sustained upon the basis of soft first sound, in 92 to 95% cases, of which about 20 to 25% third sound gallop (or protodiastolic gallop), have also aortic insufficiency; isolated aortic cardiomegaly, Carey-Coombs’ murmur or insufficiency occurs in about 5 to 8% pa- congestive heart failure. These clinical signs tients. The presence of mitral insufficiency is are non-specific because also due to hemody- characterized by a high-frequency apical namic overload on the left ventricle from holosystolic murmur with maximal intensity acute/subacute mitral and/or aortic regurgita- at the apex and radiation to the left axilla. tion. Echocardiographic evaluation provides When mitral insufficiency arises acutely it is information related to degree of myocardial possible to appreciate the Carey-Coombs contractility, ejection fraction, measurement of ventricular size and presence of valvular regurgitations7. Myocardial biopsies per- formed during acute RF have failed to im- prove clinical diagnosis of RF because histo- logical changes may be minimal in the early stages and are not necessarily correlated with severity of peculiar clinical pictures8. Histo- logic findings associated with rheumatic myocarditis can be divided in 2 stages: (1) stage I, in which exudative and proliferative reac- tions with CD4-lymphocyte infiltration and few granulocytes are predominant in the subendocardial, subepicardial and perivascular connective tissue, and (2) stage II, in Figure 1. Aschoff nodule in the myocardial tissue.

108 Rheumatic heart disease in children: from clinical assessment to therapeutical management murmur, a low-frequency diastolic flow mur- pirin is administered at the dosage of 80 to mur from relative stenosis. Aortic insufficien- 100 mg/kg/day for 4 to 8 weeks, controlling its cy is characterized by a diastolic murmur, serum level which must remain below 25 best heard over the left third intercostal mg/dl. Steroid therapy (with oral prednisone) space. Severe mitral or aortic regurgitation is administered at the dosage of 2 mg/kg/day may lead to left heart failure with soft first for 2-3 weeks, followed by gradual withdraw- sound, third sound gallop and cardiomegaly. al over the following 2-3 weeks. One week In the diagnostic approach of RF echocardio- prior to withdrawal, salicylates can be used in graphic evaluation is extremely sensitive in combination with steroids in order to avoid recognizing the severity of endocarditis, clinical rebound. In patients with severe specifically the degree of mitral and/or aortic carditis or heart failure the use of digoxin, di- regurgitation, in association with Jones’ crite- uretics and vasodilators is recommended12. ria (which are listed in Table I)11. It is possibile to diagnose with high proba- bility rheumatic fever when 2 major criteria or when 1 major criterium and 2 minor crite- Prophylaxis ria are fulfilled, after having demonstrated a previous infection by group A β-hemolytic Primary prophylaxis leads to the eradica- Streptococcus with culture of a throat swab. tion of streptococci from tonsillar or pharyn- geal sites: antibiotics with demonstrated effi- Pericarditis cacy against group A beta-hemolytic Strepto- Pericardium involvement is the less com- coccus include penicillin and congeners (e.g., mon clinical manifestation of rheumatic heart ampicillin, amoxicillin, semisynthetic peni- disease and is present in 15% patients. Peri- cillines), a number of cephalosporins, carditis is justified by visceral and parietal macrolides and clindamycin. Dosage and du- pericardium surface inflammation which can ration of therapy should be sufficient to erad- give rise to precordial pain or friction rub. icate streptococci from tonsils or pharynx. There is a tendency to RF recurrence in the absence of secondary prophylaxis, so that patients who have had asymptomatic carditis in Treatment a first episode could become symptomatic after the second or third episode. Secondary Treatment of acute RF remains controver- prophylaxis (defined in Table II) is aimed at sial: which patients can be treated with as- the prevention of RF recurrence in patients pirin and which patients require steroids or with a first episode of RF. Administration of other therapeutical tools to reduce cardiac monthly intramuscular injections of long-act- morbidity have not been definitely estab- ing penicillin G-benzathine is recommended lished. It is now recommended that salicy- by the American Heart Association, but pro- lates have to be used in patients with mild or phylaxis duration is still debated: this can be moderate carditis, whilst steroids have to be established upon the presence or absence of reserved for patients with severe carditis. As- cardiac involvement13. Actual management

Table I. Jones’ criteria (1944) for the diagnosis of rheumatic fever. Table II. Secondary prophylaxis for rheumatic fever. Major criteria Minor criteria Drug Dosage Migrating polyarthritis Fever Carditis Arthralgias Penicillin G-benzathine 1.200.000 Units every 21 Chorea minor (Sydenham’s Positive acute phase with intra-muscular days (600.000 children chorea or St. Vitus’ dance) reactants injection aged less than 6 years) Erythema marginatum Prolonged PR interval Erythromycin per os 250 mg for 2 Subcutaneous nodules Previous rheumatic (in case of allergy to administrations in a day fever penicillines)

109 G. De Rosa, M. Pardeo, A. Stabile, D. Rigante

Table III. Duration of secondary prophylaxis for 2) FOLGER GM Jr, HAJAR R, ROBIDA A, HAJAR HA. Oc- rheumatic fever. currence of valvular heart disease in acute rheumatic fever without evident carditis: colour- Category of Duration of flow Doppler identification. Br Heart J 1992; 67: patients secondary prophylaxis 434-438. 3) WILSON MJ, NEUTZE JM. Echocardiography diagno- Rheumatic fever For a minimum period of sis of subclinical carditis in acute rheumatic fever. without carditis 5 years or until 21 years Int J Cardiol 1995; 50: 1-6.

Rheumatic fever with For a minimum period of 4) KAPLAN MH, MEYESERIAN M. An immunological cross mild carditis, but 10 years (or until reaction between group A streptococcal cells and without valvolar damage advanced adulthood) human heart tissue. Lancet 1962; 1: 706-710. Rheumatic fever with For a minimum period of carditis and valvolar 10 years or until 40 5) KHANNA AK, BUSKIRK DR, WILLIAMS RC Jr, GIBOFSKY A, damage years or lifelong CROW MK, MENON A, FOTINO M, REID HM, POON- KING T, R UBINSTEIN P. Presence of a non-HLA B cell antigen in rheumatic fever patients and their fami- lies as defined by a monoclonal antibody. J Clin Invest 1989; 83: 1710-1716. strategies which are currently used in the def- 6) AYOUB EM, BARRETT DJ, MACLAREN NK, KRISCHER JP. Association of class II human histocompatibility inition of secondary prophylaxis duration are leukocyte antigens with rheumatic fever. J Clin In- listed in Table III. vest 1986; 77: 2019-2025. In conclusion, patients with acquired 7) BRAND A, DOLLBERG S, KEREN A. The prevalence of valvular dysfunction as a consequence of RF valvular regurgitation in children with structurally are considered moderate-risk category sub- normal heart: a color Doppler echocardiographic jects for whom bacterial endocarditis prophy- study. Am Heart J 1992; 123: 177-180. laxis is recommended. Therefore, dental pro- 8) NARULA J, CHOPRA P, T ALWAR KK, REDDY KS, VASAN RS, cedures (extractions, periodontal scaling and TANDON R, BATHIA ML, SOUTHERN JF. Does endomy- root planing, endodontic surgery beyond the ocardial biopsy aid in the diagnosis of active apex, prophylactic cleaning of implants with rheumatic carditis? Circulation 1993; 88: 2198- 2205. possibility of bleeding), surgical operations involving tonsils or adenoids, bronchoscopy, 9) GUPTA M, LENT RW, KAPLAN EL, ZABRISKIE JB. Serum cardiac troponine I in acute rheumatic fever. Am J biliary tract surgery, cystoscopy, etc. require Cardiol 2002; 89: 779-782. constantly a prophylactic regimen with amox- 10) ESSOP MR, WISENBAUGH T, S ARELI P. Evidence icillin (50 mg/kg per os 60 minutes before the against a myocardial factor as the cause of left specific procedure in children or 2 grams per ventricular failure in active rheumatic carditis. J os 60 minutes before procedure in adults). Am Coll Cardiol 1993; 22: 826-829.

(Special Statement by the Committee on 11) VASAN RS, SHRIVASTAVA S, VIJAYAKUMAR M, NARANG R, Treatment of Acute Streptococcal Pharyngi- LISTER BC, NARULA J. Echocardiographic evaluation tis and Prevention of Rheumatic Fever, of patients with acute rheumatic fever and American Heart Association, 1995). rheumatic carditis. Circulation 1996; 94: 73-82. 12) NARULA J, CHANDRASEKHAR Y, R AHIMTOOLA S. Diagno- sis of active rheumatic carditis. The echoes of References change. Circulation 1999; 100: 1576-1581. 13) EDWARDS BS, EDWARDS JE. Congestive heart failure 1) JUNEJA R, TANDON R. Rheumatic carditis: a reap- in rheumatic carditis: valvular or myocardial ori- praisal. Indian Heart J 2004; 56: 252-255. gin. J Am Coll Cardiol 1993; 22: 830-831.

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