J Clin Epidemiol Vol.45, No. 8, pp. 871-875, 1992 Printedin Great Britain.All rightsreserved

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ACUTE RHEUMATIC FEVER AND THE EVOLUTION OF RHEUMATIC HEART DISEASE: A PROSPECTIVE 12 YEAR FOLLOW-UP REPORT HASAN A. MAJEED,‘* SUDHAIR BATNAGER,’ ABDUL MOHSEN YOUSOF,* FAISAL KHUFFASH’ and ABDUL RAZZAK YUXJF*~ Departments of ‘Pediatrics and *Medicine, Faculty of Medicine, University of Kuwait, 13110 Safat, Kuwait (Received in revised form 30 January 1992)

Abstract-Sixty four children who presented with the initial attack of acute rheumatic fever and maintained continuous regular secondary prophylaxis, were followed up prospectively for 12.3 years (an observation period of 775 patient-years). The prevalence rate of rheumatic heart disease in the 29 children who had carditis in the initial attack and in the 35 children who had no carditis initially was 49 vs O%, respectively. The overall prevalence rate of rheumatic heart disease was 20%. Mitral incompetence developed in 11 patients (17%), aortic incompetence in 2 (3%) and mitral stenosis in 2 (3%). None of the patients developed aortic stenosis. Two recurrences developed with a recurrence rate of 0.003 per patient per year. One patient needed cardiac surgery and there was no mortality. These data strongly suggest that continuous regular secondary prophylaxis can prevent or significantly reduce the development of mitral and aortic valve stenosis, the prevalence rate of rheumatic heart disease and mortality.

Acute rheumatic fever

Rheumatic heart disease

INTRODUCTION

Long-term studies on acute rheumatic fever (ARF) and the evolution of rheumatic heart disease (RHD), before the era of antibiotics, described an aggressive and progressive course of ARF, followed by a high prevalence rate of RHD, with a high mortality during the acute episode of ARF and the subsequent course of RHD [l]. In the era of antibiotics and in the combined U.K.-U.S. study, the prevalence rate of RHD in the 10 year follow-up report (group C of the study was excluded), was 29% with a mortality of 4% [2]. In 1972, Tompkins et al. [3] in a 9.3 year follow-up study, reported a preva*All correspondence should be addressed to: Dr H. A. Majeed,-Department of Pediatrics, Jordan University of Science and Technology, P.O. Box 3030, Irbid, Jordan. + Deceased. CE 45/S-E

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lence rate of RHD of 26% with no mortality; furthermore there was lack of development of mitral stenosis and aortic stenosis. Since then, no long-term (> 10 years) studies about ARF and the evolution of RHD, have been reported. In this communication we report our findings on 64 patients, followed-up prospectively for a mean period of 12.3 years. The country

Kuwait is a small Arab subtropical country located between latitudes 28” 45’, and 30” 05’, north of the Equator, and between 46” 30’, and 48” 30’, to the east of Greenwich [4]. The 1980 census showed a population of 1,355,877 of which 44.3% were under the age of 14 years. The climatic conditions show great extremes of temperature, little and variable rainfall, and a high percentage of sunshine [4]. Kuwait is in a

HASANA. MNEED et al.

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unique situation of a developing country which through the discovery of oil, has suddenly become rich. However, the various problems of the developing world, including ARF and RHD, are still with it. PATIENTS

AND METHODS

Patients

Of the original study group of 210 children with an initial attack of ARF [5], 126 children could be followed prospectively until June 1984 and were the subject of a previous report [6]. Of these 126 children, 110 children could be followed-up prospectively until June 1990. Of these, a group of 64 children maintained regular secondary prophylaxis and are the subject of this follow-up report. Diagnostic criteria

The diagnoses of ARF, arthritis, arthralgia, and carditis in the initial attack were made according to the diagnostic criteria reported previously [5, 61. Carditis was classified as mild in the presence of significant murmur(s) only; it was considered severe if in addition, there was radiological evidence of cardiomegaly with or without clinical evidence of congestive heart failure (CHF), or pericarditis [6]. A diagnosis of pericarditis was based on the clinical detection of a pericardial rub. A recurrence was defined as reappearance of two or one major and two minor manifestations of ARF, plus bacteriological and/or immunological evidence of recent streptococcal infection, in patients whose illness had been inactive for at least 2 months after cessation of suppressive therapy [7]. A diagnosis of carditis during recurrence was made according to the following criteria, (singly or combined): (A) appearance of a new significant murmur(s); (B) clinical evidence of pericarditis; (C) radiological evidence of definite increase in cardiomegaly; and (D) clinical evidence of CHF [8,9]. Management

of the initial attack

All patients were admitted to hospital for at least 3 weeks. After throat cultures and blood samples were taken, an intramuscular injection of penicillin G benzathine was given. All patients with carditis were given prednisolone orally for 3 weeks. The dose was 60mg/day in the first week, 40 mg/day in the second week and 20mg/day in the third week. Aspirin (100 mg/kg/day) was introduced in the third

week and maintained for 3 months with gradual lowering of the dose. Patients who presented with CHF tended to rebound after stopping prednisolone; in these patients the management was eventually changed to a longer course of prednisolone (6 weeks with gradual lowering of the dose) and thereafter maintained on aspirin for 6 months. Patients with arthritis and no evidence of carditis were given aspirin (100 mg/kg/day) for 6-10 weeks. Patients with chorea were given diazepam orally in large doses (at least 15 mg/day) for 3-4 months. On discharge, children and their families were instructed to start continuous secondary prophylaxis with monthly intramuscular benzathine penicillin G. The dose was 1.2 million units for children aged 6 years or above, and 600,000 units for children younger than 6 years. Each patient was provided with a special printed card prophylaxis. Injections were given in the primary care centers where the nurse in charge would confirm the date and sign the card. The card was checked at each hospital visit and renewed yearly. Later the card was substituted by a “Rheumatic Fever Prophylaxis” booklet, and renewed every 5 years. Follow -up study

Patients were seen at least once every 6 months. At each visit a careful history was taken with special attention to recurrence of symptoms and compliance with prophylaxis. The patients were examined by the same group of physicians mainly for evidence of RHD. Doppler echocardiograms were obtained in 31 patients. Analysis of data

To assess the role and prognostic value of the presence and severity of carditis in the initial attack, the patients were divided into those who had no carditis, those with mild carditis, and those with severe carditis. The prevalence rate of RHD was expressed as the percentage of cases at the end of follow-up. The recurrence rate was expressed as the number of recurrences per patient per year followup. For statistical significance, the Fisher’s exact test was applied to test the difference between two proportions [lo]. RESULTS

Table 1 shows the presenting clinical features during the initial attack. Table 2 shows the basic data of the children.

Acute Rheumatic Fever and the Evolution of RHD Table 1. The clinical presentations during the initial attack Clinical presentation in the initial attack

No. of children

Polyarthritis* Carditis alone Chorea alone Chorea and carditis Arthritis and carditis Total

32 1 3 3 25 64

*Triad of polyarthritis, acute phase reactants.

fever and raised

Table 2. The basic data of the children Number Mean age (yr) at initial attack Mean age (yr) at end of study Sex (M/F) Mean follow-up (yr) No carditis in initial attack Carditis in initial attack

64 8.3 20.6 33/31 12.3 35 29

Table 3. Residual RHD at 6 and 12 year follow-up Carditis in initial attack Mild carditis Severe carditis Total carditis No carditis Total

6 year follow-up

12 year follow-up

n

RHD

n

RHD

22 9 31 35 66

7(32%) 6(67%) 13 (42%) 2(6%) 15(23%)

20 9 29 35 64

7 (35%) 6 (67%) 13 (49%) 0 (0%) 13 (20%)

The duration of follow-up ranged from 9 to 14.5 years with a mean of 12.3 years.

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persisted in 7 (35%) children who had mild carditis and in 6 (67%) children who had severe carditis. Of the 35 patients with no carditis, two girls who presented initially with chorea developed one recurrence each. Evidence of mild carditis (the mitral incompetence murmur) was detected during the recurrence in both girls. When the significance of the murmur was eventually suspected, Doppler echocardiograms carried out on both girls showed normal mitral valves. Of the patients in whom Doppler echocardiograms were obtained one patient who was clinically diagnosed as mitral incompetence was found to have mitral and aortic incompetence by echocardiography. The prevalence rate of RHD was 20%. Mitral incompetence was the commonest lesion and detected in 11 patients (17%) aortic incompetence in 2 (3%) and mitral stenosis in 2 (3%); none developed aortic stenosis. One patient had mitral valve replacement. There was no mortality. Table 3 compares the results of the 6 year follow-up report and the present one. Table 4 shows the evolution of RHD in 3 long-term follow-up studies. Table 5 shows the evolution of RHD in patients who escaped carditis initially and maintained regular secondary prophylaxis in different studies.

DISCUSSION

Recurrences

Two recurrences occurred over a mean follow-up period of 12.3 years yielding a recurrence rate of 0.003 per patient per year. Residual RHD

Twenty nine children had carditis and 35 had no carditis in the initial attack (Table 3). RHD persisted in 13 (49%) children who had carditis initially vs 0% in those patients who had no carditis initially (p c 0.00001). Carditis was mild in 20 children and severe in 9; RHD

The major defects inherent in long-term studies of the outcome of ARF, as detailed by Feinstein et al. [12, 141, have been essentially eliminated in our present follow-up report. The patients were initially diagnosed and followedup by the same group of physicians in the same medical center. The diagnostic criteria were well-defined in the initial attack and in the follow-up studies [5,6,8]. Special emphasis was given to criteria for differentiating significant systolic murmurs from innocent murmurs of

Table 4. The evolution of RHD in patients on regular secondary prophylaxis in three long-term follow-up studies Study (year) (follow-up) U.K.-U.S. report 1965 (10yr) Tompkins et al. 1972 (9.3 yr) Present study (12.3 yr)

Patients Ref. [2] 131

*P/yr: patient/years. tRR: Recurrence rate per patient per year. $PR: prevalence rate. NA: not available.

n

P/yr*

266 2660 115 565 64 775

Recurrences

RHD

n

RRt

n

1 2

NA 0.001 0.003

71 30 13

PW

29% 26% 20%

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Table 5. Evolution of RHD in patients who escaped carditis in the initial attack and maintained regular secondary prophylaxis in different studies Follow-up Years

Study (year)

Ref.

n*

Thomas (1961) Feinstein et al. (1964) U.K.-US. study (1965) Tompkins et al. (1972) Sanyal et al. (1982) Present studv

[ll] [12]

22 180

!! [13]

:: 40 35

5 7.8 lo 9.3 5 12.3

Patient/yr

RHD n (%)

110 1404 800 326 200 430

0 (0) 0 (0) 5 (6) 0 (0) 3 (8) 0 (0)

*n: Number of patients.

childhood and also for differentiating a recurrence from a rebound or an intercurrent infection in a patient with established RHD [5,6,8]. Furthermore this study enjoyed the additional accuracy of Doppler echocardiography, carried out on almost half of the patients. Data from our first report showed that the clinical profile of ARF during the initial attack in the developing countries was similar to that of the developed countries [5]. The findings from our second report, showed that the presence and severity of carditis in the initial attack and the frequency of subsequent recurrences, played a major role in the subsequent evolution of RHD [6]. Comparison of the data from our second report [6] with those of similarly designed prospective studies [3, 12, 131 showed that the evolution of RHD, seemed to behave similarly in the different climate and countries, provided that continuous secondary prophylaxis was maintained after the initial attack. Data from this study show that the prevalence rate of RHD in those children who had carditis initially and in those who had no carditis in the initial attack was 49 vs O%, respectively (p < 0.0001). Furthermore the prevalence rate of RHD in children who had mild carditis initially and in those who had severe carditis in the initial attack was 35 vs 67%, respectively. These data show that the presence and severity of carditis during the initial attack play a major prognostic role in the subsequent evolution of RHD, and were already discussed in our previous report [6]. A surprising finding in this study was the disappearance of the mitral incompetence murmur in the two patients who presented initially with chorea and developed chorea and carditis during the recurrence, after a long period of 6 years. However, of the 55 patients who lost their mitral incompetence murmur and were followed-up by Tompkins er al., 6 patients (11%) lost their murmur after a period of 5-10 years [31.

A notable finding from the present report is the lack of development of aortic stenosis (0%) and the rarity of mitral stenosis (3%) amongst this group of children who maintained regular secondary prophylaxis. This confirms the longterm Irvington House Study; of 397 patients followed-up for a mean period of 8.3 years by Feinstein et al. none developed pure aortic stenosis [ 151and is also similar to the retrospective study of Tompkins et al. who found no evidence of aortic stenosis and mitral stenosis in 115 patients over a follow-up period of 9.3 years [3]. Of our original study group of 210 children [5], 46 children on no or irregular prophylaxis were followed-up until June 1990, with a mean follow-up period of 12.1 years, of these, 2 children (7%) developed aortic stenosis and 10 (38%) developed mitral stenosis; the mean age of these children at the end of follow-up was 19.4 years (unpublished data). In a well studied group of 30 patients presenting with aortic and mitral stenosis early in life, 27 had recurrences

P61. The possibility that in patients who escape carditis initially, a clinically silent carditis may possibly cause insidious scarring of the valves and development of RHD many years later still worries the pediatricians and physicians. This possibility is based mainly on the report of Bland and Jones in 1951 [l] who reported that of the 347 patients described initially as free of RHD, clinical evidence of RHD developed in 24% of the patients 10 years later and in 48% of patients 20 years later. In explaining the disparity between the “no carditis-no RHD” thesis and the Bland-Jones report of “insidious” RHD, Feinstein et al. have repeatedly referred to the possibility of auscultatory errors (“missed diastolic murmurs”, over interpretation of physiologic murmurs) in the Bland-Jones data [14, 15, 17-191. The auscultatory errors, corrected by Doppler echocardiography in this report, and the experience with the recent outbreaks of ARF in the U.S.A., where

Acute Rheumatic Fever and the Evolution of RHD

of 67 patients with carditis described in one report, 14 had their conditions detected by Doppler echocardiography [20], strongly support the pioneering observations of Feinstein er al. [14, 15, 17-191; they also show the precise diagnostic help that Doppler echocardiography can offer to clinicians, cardiologists and students of ARF. Data from this study, privileged by the additional accuracy of Doppler echocardiography, show that of the 35 children who initially escaped carditis, none developed evidence of RHD 12 years later. Furthermore Table 5 shows that almost all the long-term studies of the outcome of ARF have shown that the patients who escaped carditis initially, did not develop evidence of RHD over variable periods of follow-up. The question of whether the severity and clinical course of ARF has changed, remains to be answered. Comparison of data from our study carried out in the late 70s thoughout the 80s with those of the combined U.K.-U.S. study carried out in the late 50s and early 60s [2] and those of Tompkins et al. study carried out in the 60s [3], point out that this is not the case. The prevalence rate of RHD in our present report was 20 vs 29% and 26% in the U.K.-U.S. and Tompkins et al. reports, respectively [2,3]. Furthermore, the prevalence rate of RHD in those patients who initially had carditis was 49% in our study vs 51% in the U.K.-US. study and the prevalence rate of RHD in those patients who had severe or mild carditis initially in our study was 67 and 35% respectively, vs 68 and 34% in the U.K.-U.S. study, respectively [2]. However, the recent outbreaks of ARF in the U.S. were surprisingly characterized by a high incidence of carditis (91% in one outbreak) and CHF [20]. The important role of secondary prophylaxis, is obvious when mortality in the old studies is compared to our and other recent studies. The mortality rate in the Tompkins et al. study [3] and the present report was 0 vs 4% in the U.K.-U.S. report [2] and 30% in Bland and Jones’s report [l]. Availability of antibiotics of the treatment of infective endocarditis, operative surgery and modern management of heart failure are contributory factors.

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Acute rheumatic fever and the evolution of rheumatic heart disease: a prospective 12 year follow-up report.

Sixty four children who presented with the initial attack of acute rheumatic fever and maintained continuous regular secondary prophylaxis, were follo...
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