Prospective comparison of clinical andechocardiographic diagnosis of rheumatic carditis:long term follow up of patients with subclinicaldisease

F E Figueroa, M Soledad Fernández, P Valdés, C Wilson, F Lanas, F Carrión, X Berríos,F Valdés

AbstractObjective—To determine the frequency of occurrence and long term evolution of subclinicalcarditis in patients with acute rheumatic fever.Design—Valvar incompetence was detected by clinical examination and Doppler echocardio-graphic imaging during the acute and quiescent phases of rheumatic fever. Patients were followedprospectively and submitted to repeat examinations at one and five years after the acute attack.Persistence of acute mitral and aortic lesions detected solely by echocardiography (subclinicaldisease) was compared with that of disease detected by clinical examination as well (thereby ful-filling the latest 1992 Jones criteria for rheumatic carditis).Setting—Three general hospitals with a university aYliation in Chile.Patients—35 consecutive patients fulfilling the revised Jones criteria for rheumatic fever. Clini-cal and echocardiographic examination was repeated in 32 patients after one year and in 17 afterfive years. Ten patients had subclinical carditis on admission, six of whom were followed for fiveyears.Main outcome measures—Auscultatory and echocardiographic evidence of mitral or aorticregurgitation during the acute attack or at follow up.Results—Mitral or aortic regurgitation was detected by Doppler echocardiographic imaging in25/35 rheumatic fever patients as opposed to 5/35 by clinical examination (p = 0.03). Dopplerechocardiography revealed acute valvar lesions in 10 of 20 rheumatic fever patients who had noauscultatory evidence of rheumatic carditis (subclinical carditis). Three of these subclinicallesions and three of the clinical or auscultatory lesions detected on admission were still presentafter five years of follow up, emphasising that subclinical lesions are not necessarily transient.Conclusions—Doppler echocardiographic imaging improves the detection of rheumaticcarditis. Subclinical valve lesions, detected only by Doppler imaging, can persist. Echocardio-graphic findings should be accepted as a major criterion for the diagnosis of rheumatic fever.(Heart 2001;85:407–410)

Keywords: rheumatic heart disease; rheumatic fever; echocardiography; carditis

Acute rheumatic fever and rheumatic heartdisease continue to be a major health problemin developing countries, and rheumatic fever isthe leading cause of acquired heart disease inchildren and young adults worldwide.1 2 Withthe recent advent of cross sectional echocardio-graphy and colour flow Doppler imaging, it hasbeen claimed that mitral and aortic valve insuf-ficiency can be detected in up to 90% of rheu-matic fever patients who have no clinicalevidence of carditis.3 4 Nonetheless, the 1992update of the Jones criteria excludes the use ofechocardiography, including Doppler, to docu-ment valve disease in the absence of ausculta-tory signs of carditis.5 One concern has beenthe finding of silent mitral regurgitation in nor-mal subjects, which may be a cause ofoverdiagnosis of rheumatic fever.6 Severalinvestigators have addressed this point,3 7 andtwo groups have carried out blinded tests oftheir ability to distinguish physiological frompathological patterns of regurgitation in rheu-matic fever patients and controls.4 8

A remaining issue relating to colour flowDoppler echocardiography in rheumatic fever

has been uncertainty over the long termsignificance of abnormal regurgitant flowpatterns when carditis is not clinically appar-ent.3 9 Few studies have addressed this problemprospectively, and follow up has been of limitedduration.3 10 11 We therefore conducted a pro-spective multicentre clinical and Dopplerechocardiographic survey of a cohort of 35rheumatic fever patients fulfilling the Jonesdiagnostic criteria.12 We now report ourfindings, including those cases with clinicallysilent (subclinical) rheumatic carditis, whowere followed with repeat examinations over aperiod of five years.

MethodsFrom February 1992 to December 1993 weenrolled prospectively 35 consecutive patientsfulfilling the revised Jones criteria for rheu-matic fever.12 These where admitted to theCatholic University hospital in Santiago(n = 4), the Sótero del Río hospital in the southeast metropolitan area of Santiago (n = 17), orthe regional hospital of Temuco in Chile’sninth region (n = 14).

Heart 2001;85:407–410 407

Facultad de Medicina,Universidad de losAndes, Avenida SanCarlos de Apoquindo2200, Santiago deChile, ChileF E FigueroaP ValdésF CarriónF Valdés

Facultad de Medicina,Pontificia UniversidadCatólica de Chile,Santiago de ChileM Soledad FernándezC WilsonX Berríos

Facultad de Medicina,Universidad de laFrontera, Santiago deChileF Lanas

Correspondence to:Dr FigueroaYguero@uandes.cl

Accepted 5 December 2000

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On entry, patients underwent a standardisedexamination protocol consisting of a detailedmedical history recorded by a physician, andgeneral and specific laboratory tests, includingan ECG, a chest x ray, throat swab cultures,and quantification of anti-streptolysin O(ASO) and anti-DNAse-B (ADB). All patientswere examined on repeated occasions through-out the investigation by one or two of theinvestigators (MF, CW, or FL—all cardiolo-gists experienced in the care of patients withrheumatic fever). These investigators bothcompleted the standardised protocol andperformed the Doppler echocardiographystudies, thus enabling the additional infor-mation provided by echocardiography to beevaluated in clinical practice.

As our main purpose was to compare thelong term outcome of clinical and subclinicalvalvar lesions, blinding of clinicians to theechocardiographic studies was not considerednecessary. Disease manifestations and auscul-tatory findings were evaluated according to cri-teria published by the World Health Organiza-tion13 and by Taranta and Markowitz,14 asdescribed elsewhere.15 Cross sectional echo-cardiography and colour Doppler evaluationwas performed within five days of admission,on discharge, and at three months, 12 months,and five years from entry to the study. We ini-tially employed an Aloka SSD-870 (Aloka CoLtd, Mure, Mitaki-shi, Tokyo, Japan) and thena Hewlett-Packard 1000 or 1500 ultrasoundsystem, with 2.7 and 3.5 MHz transducers forpulsed and continuous wave Doppler and col-our flow imaging (Hewlett-Packard Inc, Ando-ver, Massachusetts, USA). A 1.9 MHz image-less pencil-type probe was also employed for

continuous Doppler. Multiple cross sectionalviews were taken from parasternal, apical, andsubcostal positions according to the recom-mendations of the American Society of Echo-cardiography.16

Criteria for pathological mitral regurgita-tion, previously agreed upon by the authors,were as follows:x colour jet identified in at least two planes;x mosaic colour jet;x persistence of the jet throughout systole.

The length of the colour jet was notnecessarily > 1 cm in all cases. Clinical,echocardiographic, and laboratory data on theevolution of each episode were collected inspecially designed computerised data collec-tion forms.

One patient refused follow up after the firstweek and one was lost after three months. Anadditional patient was excluded from finalanalysis because he required valve surgery after10 months. The remaining 32 patients areincluded in our one year follow up report. Sev-enteen of these patients were evaluated again atfive years after entry to the study, with an aver-age follow up of five years and seven months.

STATISTICS

Data from the groups were compared by t test.When data were not normally distributed, thenon-parametric Mann–Whitney U test, the ÷2

test, and the Fisher exact test were used. Prob-ability values of p < 0.05 were consideredsignificant.

ResultsThe baseline features of this group of 35 rheu-matic fever patients are shown in table 1.Fifteen patients (43%) had clinical evidence ofcarditis according to classical criteria.14 15 Ful-filment of the revised Jones criteria12 was a pre-requisite for enrolment, but in retrospectpatients also satisfied the 1992 updated Jonescriteria.5

A comparison of clinical and echocardio-graphic diagnosis of rheumatic carditis is givenin table 2. During the rheumatic fever episodeand also during follow up, Doppler echocardio-graphy detected more valvar lesions than clini-cal examination. This diVerence was significantfor all lesions (mitral or aortic) during the acuteepisode (p = 0.03) and for aortic lesions, bothduring the acute attack (p = 0.01) and one yearlater (p = 0.025). Doppler echocardiographydetected aortic regurgitation in 11 morepatients (31%) than clinical examination, andit detected mitral regurgitation in five morepatients (15%) than clinical examination.

At entry, 25 patients had echocardiographicevidence of valvar (mitral or aortic) incompe-tence (table 2). Among these cases, we found10 individuals with no auscultatory or clinicalfindings suggesting acute rheumatic carditis, inspite of repeated examinations (fig 1). These 10individuals constitute our group of rheumaticfever patients with subclinical carditis. Theyrepresent almost 30% (10 of 35) of all therheumatic fever patients entering the study (fig1). Purely echocardiographic evidence of acuterheumatic carditis (that is, subclinical carditis)

Table 1 Baseline characteristics and major Jones criteriaof patients with acute rheumatic fever on entry to the study

Total number of ARF patients 35

SexMale 21 (60)Female 14 (40)

Age (years) (mean (range)) 15 (5–34)First ARF episode 29 (83)Polyarthritis 28 (80)Carditis 15 (43)Chorea 4 (11)Erythema marginatum 1 (3)Subcutaneous nodules 0

Values are n or n (%) unless stated otherwise.Raised anti-streptolysin O and/or anti-DNAse-B titres werepresent in all patients.ARF, acute rheumatic fever.

Table 2 Clinical (auscultatory) and echo Doppler detection of valve lesions in patientswith acute rheumatic fever during the acute episode and during follow up

Valve involvement

ARF at entry (n=35)

Follow up

1 year (n=32) 5 years (n=17)

Clinical 2D-echo-D Clinical 2D-echo-D Clinical 2D-echo-D

Mitral 15 (42%) 20 (75%) 7 (22%) 12 (32%) 3 (18%) 5 (29%)Aortic 6 (17%) 17 (48%)* 2 (6%) 9 (28%)† 0 (0%) 3 (18%)Mitral and/or aortic 5 (43%) 25 (71%)** 8 (25%) 15 (47%) 3 (18%) 7 (41%)Not detected 20 (57%) 10 (29%) 24 (75%) 17 (53%) 14 (82%) 10 (59%)

*Clinical v 2D-echo-D at entry, p = 0.01 (÷2).**Clinical v 2D-echo-D at entry, p = 0.03 (÷2).†Clinical v 2D-echo-D at 1 year, p = 0.025 (Fisher’s exact test).ARF, acute rheumatic fever; 2D-echo-D, cross sectional echocardiography and colour flow Dop-pler imaging.

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was found in 10 of the 20 rheumatic feverpatients who had no clinical signs or ausculta-tory evidence of acute rheumatic carditis atentry (table 2 and fig 1). Five of these cases hadaortic regurgitation, four had mitral insuY-ciency, and one had mitral–aortic disease. Thislast case was classified as moderate,14 while allthe other cases were considered mild. Nonehad annular dilatation, elongation of chordaeto the anterior leaflet, valve prolapse, thicken-ing, focal nodularities, or limitation of aper-ture. Nine of the patients had polyarthritis andone had Sydenham’s chorea as major Jones cri-teria. Six had systolic murmurs of typicallyinnocent quality; such murmurs were alsofound in a similar proportion in the groupwithout carditis.

As the high sensitivity of ultrasound indetecting mitral and aortic regurgitation is wellknown,3 4 our main objective was rather toassess the long term significance of subclinicalvalve disease in rheumatic fever. We thereforesought to compare how often the finding of aclinical or a subclinical valve lesion, detected atentry to the study, would persist after one orfive years of follow up.

Figure 1 shows the percentage of rheumaticfever patients who were found to have subclini-cal valve disease (subclinical), clinically evidentor auscultatory disease (clinical), or no detect-able valve lesions, either clinical or echocardio-graphic (no rheumatic heart disease) during theacute episode (fig 1A) and after one year (fig1B) and five years (fig 1C) of follow up. Asexpected, in the group of 32 rheumatic fevercases with repeat examination at one year andin the 17 cases re-examined at five years, thepercentage of individuals with subclinical valvelesions, as well as those with clinical lesions,decreased with time. Nonetheless, some sub-clinical valve lesions were found to persist afterfive years of follow up (3/17; 18%) (fig 1C). Infact, as shown in table 3, half (three of six) ofour cases of subclinical carditis who werefollowed for five years still had valvar incompe-tence, detected only by Doppler echocardio-graphy, at the end of the study. Furthermore,when we compared the percentage of clinical orsubclinical valve lesions that persisted through-out follow up, we found no significant diVer-ences after one year (57% v 44%) or five years

(60% v 50%) (table 3), suggesting that acutevalve lesions induced by subclinical rheumaticcarditis persist to about the same extent as thelesions in clinically evident acute rheumaticheart disease.

No individual with subclinical carditis devel-oped a clinically detectable or auscultatorylesion during follow up; however, one case wasof special interest as his subclinical mitral–aortic disease initially resolved during followup but reappeared again after five years, withno evidence of recurrence of rheumatic fever.

DiscussionClinically manifest mitral or aortic regurgita-tion is still considered the diagnostic hallmarkof acute rheumatic carditis.6 7 However, ourfindings confirm previous reports that Dopplerechocardiography can detect significant valvarincompetence in the absence of auscultatoryfindings, during both the acute and thequiescent phases of the disease.3 4 7 17 18 In thewell known recent outbreak of rheumatic feverin the USA, carditis was diagnosed by auscul-tation in 53 of the 74 patients (72%), whileDoppler echocardiography detected mitralregurgitation in an additional 14 patients(19%).19 The same group also detected sub-clinical carditis in 47% of rheumatic feverpatients presenting with polyarthritis and 57%of patients with “pure” chorea,7 as we did in50% of our own cases with no clinical evidenceof rheumatic heart disease. Similar findingshave been reported by Folger and colleagues inthe Middle East3 and by Abernethy and associ-ates in New Zealand.4 In our series, roughlyone third of rheumatic fever patients hadsubclinical carditis, in spite of being repeatedly

Figure 1 Subclinical and clinical valve lesions in rheumatic fever patients at entry (A) and at one year (B) and fiveyears (C) follow up. ARF, acute rheumatic fever; No RHD, no clinical or echocardiographic evidence of rheumatic heartdisease.

Subclinicaln = 10 (29%)

Subclinicaln = 4(13%)

Subclinicaln = 3(18%)

No RHDn = 10 (29%)

No RHDn = 20 (62%)

No RHDn = 11 (65%)

Clinicaln = 15 (42%)

A ARF B 1 year C 5 years

n = 35 n = 32 n = 17

Clinicaln = 8 (25%)

Clinicaln = 3 (17%)

Table 3 Persistence of valvar lesions in patients who hadsubclinical (only echocardiographic) or clinical(auscultatory) carditis at entry, when re-examined one andfive years after the episode of acute rheumatic fever (ARF)

Valve involvement during ARFepisode

Persisting lesions

After 1 year After 5 years

Clinical (n=15) 8/14 3/5Subclinical (n=10) 4/9 3/6

The percentage of clinical and subclinical valve lesions stilldetectable after follow up was not diVerent after one year (p =0.68) or five years (p = 1.0).

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examined by cardiologists experienced inrheumatic fever. Several reports suggest thatactive rheumatic carditis may be clinicallysilent or unsuspected; for example, 30–40% ofadults with mitral stenosis cannot recall an ill-ness suggesting rheumatic fever.20 On the otherhand, studies of patients with isolated choreasuggest that subclinical rheumatic heart diseasemay lead to irreversible sequelae. Carapetisand Currie recently reported that the majority(68%) of people with chorea who developchronic rheumatic heart disease have noevidence of carditis at the time of their initialattack of rheumatic fever.21 Also, follow up ofpatients with isolated chorea for 20 yearsshowed that 23% developed mitral stenosis.22

Only one prospective study from India hasfailed to find evidence of Doppler regurgitationin rheumatic fever patients without clinical evi-dence of carditis.10 This discrepancy has beenattributed to the presumption that in develop-ing countries patients may seek medical atten-tion only in a late phase of the disease, whenclinical valvar involvement is evident. Thiswould be concordant with the findings from astudy in New Zealand, where all patients withsubclinical carditis developed an audible mur-mur within the next two weeks.4 In contrast,none of our patients with only Dopplerevidence of carditis developed new murmursduring follow up. This does not imply that thefinding of subclinical carditis is irrelevant.Veasy and colleagues reported a case ofinfective endocarditis in a patient with subclini-cal carditis,7 and Folger and associates foundthat four of six patients with only Doppler evi-dence of valve involvement continued to showvalvar regurgitation 18–36 months later.3 Inone or our cases, subclinical valvar diseasebecame evident again, after initial resolution,with no known recurrence of rheumatic fever.

Except for the data from our present report,there is no available information on the longterm evolution of subclinical carditis in rheu-matic fever patients.23 In this regard, our mostimportant observation is that clinically silentcarditis is not necessarily a benign or transiententity, because at least in 60% of cases, valvardisease persisted after five years of follow up inspite of continuous penicillin prophylaxis andno evidence of recurrent disease. As seen intable 3, the persistence of subclinical valvelesions was similar to that found in the caseswith clinical or auscultatory carditis. As all ourpatients fulfilled the Jones diagnostic criteria asa prerequisite for entry to the study and no caseof subclinical carditis was severe, the contribu-tion of Doppler echocardiography in thesecases did not alter the management of the epi-sode of rheumatic fever. However, thesefindings could be important with respect tolong term prognosis and the development oflate cardiovascular sequelae, and therefore maybe relevant to decisions regarding penicillinprophylaxis.

CONCLUSIONS

These findings confirm that Doppler echo-cardiography improves the detection of rheu-matic carditis and chronic rheumatic heart dis-ease and show that subclinical valve lesions canpersist. They lend support to the view thatechocardiographic findings should be acceptedas a major criterion for the diagnosis ofrheumatic fever.24

This work was funded by grant No 1960117 from FondoNacional de Desarrollo Científico y Tecnológico (Fondecyt),Chile. The study was presented at the annual meeting of theAmerican College of Rheumatology, Boston, Massachusetts,November 13–17, 1999.

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