Rheumatic silent carditis: Echocardiographic diagnosis and prognosis of long-term follow up

1

This article is protected by copyright. All rights reserved.

‘Rheumatic Silent Carditis: Echocardiographic diagnosis and prognosis of long term follow-

up’1

Running Title: ‘ Echocardiographic diagnosis of silent carditis’

Esra Pekpak1, Semra Atalay2, Cem Karadeniz2, Fikri Demir2, Ercan Tutar2, Tayfun Uçar2

1 Department of Pediatrics, Ankara University Faculty of Medicine, Cebeci, Ankara,

TURKEY

2 Pediatric Cardiology Unit, Department of Pediatrics, Ankara University Faculty of Medicine,

Cebeci, Ankara, TURKEY

Correspondence: Cem Karadeniz

Address: Pediatric Cardiology Unit, Department of Pediatrics,

Ankara University Faculty of Medicine,

Cebeci, 06100, Ankara, TURKEY

Business phone: +90 (312) 595 61 00

Fax number: +90 (312) 319 14 40

E-mail: [email protected]

Main text: 10 pages (p: 1-10), References: 3 pages (p:11-13), Tables: 5 pages

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/ped.12163 Acc

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Abstract

Background: Rheumatic fever and Rheumatic heart disease continue to be an important public

health problem in the developing countries. Doppler echocardiography is now widely used for

early detection and recurrences of clinical evident carditis (CC) and silent (subclinical) carditis

(SC). The aim of the study is to determine the frequency of silent carditis and to compare

clinical and echocardiographic features of the patients with silent and clinical carditis.

Methods: 156 consecutive patients, diagnosed with acute rheumatic fever were included into

study. The patients without clinical evidence but with echocardiographic findings of carditis

were diagnosed as SC.

Results: Acute rheumatic fever was diagnosed in 156 patients and 103 (66%) of them had

carditis. The ratio of SC was 28.2% among these 103 patients. Seventy-four of the patients with

carditis were followed up more than one year and 20 of those had SC. Valvular regurgitation

disappeared completely in 18.5% and improved in 45.5% of the patients with CC. The recovery

and improvement rates in SC group were 15% and 30%, respectively.

Conclusion: We suggest that Doppler echocardiography should be performed in all patients

with suspected acute rheumatic fever for early detection of SC. Echocardiographic examination

should be taken as a diagnostic criterion in order not to miss the diagnosis of SC.

Key words: carditis, echocardiography, patients, rheumatic fever, rheumatic heart disease

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Introduction

Rheumatic fever (RF) is an inflammatory disease caused by autoimmune response to a

preceding group A streptococcal infection. It is an important public health problem associated

with poor living conditions and reduced access to appropriate health care services throughout

developing countries.1

Immune-mediated damage of RF occurs most prominently in the heart, joints, brain, skin and

subcutaneous tissues. It is the leading cause of acquired heart disease in children and young

adults worldwide and carditis is the most important manifestation of RF that may result in

significant morbidity, even mortality.2 Because there is no spesific diagnostic test for this

disease, a combination of clinical and laboratory findings, called Jones criteria (JC) were used

as a guide for the diagnosis.3

Echocardiography along with colour Doppler imaging is now worldwide used for early

detection of cardiac involvement even in the absence of clinical evidence.4,5 This entity, called

silent carditis (SC) was reported to cause similar consequences to clinically evident carditis.6

However, JC seems inadequate in the diagnosis of this silent but potentially harmful carditis

which necessitates secondary antibiotic prophylaxis in order to avoid recurrences. These

observations have led to thought that echocardiographic examination should be included into

JC.5,7

In this study, we aimed to determine the frequency of silent carditis and to compare clinical and

echocardiographic features of the patients with silent and clinically evident carditis. We also

investigated to compare permanent valvular regurgitation rates and accuracy of

echocardiography for assesment and follow-up patients with silent and clinical carditis.

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Methods

The patients, diagnosed with RF in Ankara University Faculty of Medicine, Department of

Pediatric Cardiology between the years 2003 and 2009 were enrolled into study. The patients

were followed-up until 2012. The personal data, a detailed medical history, and the findings of

physical examination were recorded. An electrocardiogram, a chest x ray, quantification of

complete blood count, erythrocyte sedimentation rate, C-reactive protein, and anti-streptolysin

O titers, and a throat swab culture were obtained from all the patients. All the participants

underwent echocardiographic examination which was performed by a pediatric cardiologist

experienced in rheumatic heart disease (The author,SA). Follow-up data was also obtained.

Informed verbal consent was taken from the parents and the ethical committee of our university

approved the study. The diagnosis of RF was established when the JC were fulfilled for acute

cases.3 However, silent and significant mitral and/or aortic regurgitation were accepted as

probable chronic rheumatic valvular disease in accordance with the recommendation of the

World Health Organization even in the absence of any symptom or inflammatory sign.8

A Vivid 7 Pro Ultrasound System (GE Medical Systems, Vingmed Ultrasound AS, N- 3190

Horten, Norway), with 3 MHz transducers was used for 2-D, M-mode, and colour flow Doppler

imaging echocardiography. Any valvular incompetence, thickening, vegetation, prolapse or

nodular appearence; annular and/or cordal pathologies, and pericardial effusion were recorded.

Mitral and aortic valve regurgitation were assessed by color Doppler echocardiography from

apical and parasternal long axis views. Pathological valve regurgitation was defined according

to the following criteria. 9,10

1) Regurgitation color jet should be seen in at least two planes.

2) For pathological mitral valve regurgitation; mosaic posterolateral color jet must extend

longer than 1 cm into the left atrium, and should be seen in at least two planes.

3) For pathologic aortic valve regurtation; color jet must be longer than 1 cm and it must

extend at least 1 cm beyond the aortic valve into the left ventricle. Acc

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4) In continuous wave and pulsed wave Doppler examinations, regurgitant flow must be

holosystolic for mitral valve and holodiastolic for aortic valve and peak velocities

should be higher than 2.5 m/sec.

The patients without clinical evidence or valvular regurgitation murmur but with

echocardiographic findings of carditis were diagnosed as silent carditis. The features of those

patients were compared with clinically evident carditis group. The severity of carditis was

evaluated in terms of JC.3 Arthritis were treated with aspirin or non-steroidal anti-inflammatory

drugs. Silent and mild carditis were treated with aspirin. Patients with moderate to severe

carditis were given prednisolone for 2-4 weeks, followed by aspirin for 4-8 weeks. All the

patients were advised bed rest during inflammation period and were given benzathine penicillin

prophylaxis every three weeks for lifelong.

Data was analyzed and processed with SPSS 15.0 statistical package programme (SPSS Inc.,

Chicago, Illinois, USA). The distribution pattern of data was assessed by the Shapiro-Wilk test.

Qualitative variables were shown as number and percentage. Quantitative variables were

demonstrated as mean ± standard deviation for normally distributed data or as median and

interquartile range for the others. The Chi-square test or Fisher’s exact test were used to

compare the qualitative data. The differences between the quantitative groups with normal

distribution were evaluated with Student’s t-test. The Mann-Whitney U test was used for

abnormally distributed data. P value of < 0.05 was considered as statistically significant.

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Results

One hundred and fifty-six patients were diagnosed with rheumatic fever between the years 2003

and 2009. The characteristics of those patients were summarized in Table 1. The murmur was

the most frequent cause of referral to our clinic and the heart was the most commonly involved

organ. Sixty patients (38.5%) were presented with arthritis, nineteen of whom had monoarthritis

(31.7%) and the rest had migratory polyarthritis. Knee was the most frequently involved joint.

The frequency of carditis was 89.5 % in patients with chorea and seen more commonly in

females (female/male ratio:2.16).

Carditis was diagnosed in 66% of the cases with rheumatic fever. The majority of the patients

(71.8%) had clinically evident and the remaining 28.2% had silent carditis. The features of the

patients with carditis were shown in Table 2. Arthralgia was the most common symptom in both

the silent and clinically evident carditis group. However, the murmur was the most frequent

finding and reason for referral to cardiologists before the diagnosis of CC.

Isolated mitral regurgitation was present in almost all (93.2%) of the cases with carditis and

aortic regurgitation (AR) was determined in 1/3 of those patients. The frequency and severity of

valvular involvement in relation to type of carditis were shown in Table 3 and 4, respectively.

Mitral valvulitis was associated with leaflet prolapse in six of the patients and only one patient

had pericardial effusion together with carditis. The 66 of 74 patients with clinically evident

carditis had mild involvement. Four had moderate and another four had severe carditis. All the

patients with silent carditis had mild disease.

Seventy-four of the 103 patients with carditis were followed up more than one year. Most of

those 74 cases had clinically evident carditis (73%). Fourty-six of 74 patients had had signs of

active cardiac inflammation at initial evaluation, whereas the rest had been diagnosed after the

inflammation subsided. The characteristics of regularly followed up patient group were

summarized in Table 5. The frequency of active carditis was significantly higher in CC group. Acc

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Valvular involvement disappeared in 10 patients (18.5%) with clinical carditis, 3 patients (15%)

with silent carditis. And valvular involvement improved 25 patients (45.5%) in clinical carditis,

6 patients (30%) in silent carditis. The murmur of MR was able to heard several months after

the diagnosis in one patient with SC. No new valvular lesion was observed but one patient with

MR developed valvular stenosis during follow-up period. Although 89.2% of the patients were

compliant with penicillin prophylaxis, rheumatic fever activation was observed in nine cases

(12.2%). Five of those patients received prophylaxis regularly. Two patients with severe mitral

insufficiency underwent valve replacement surgery. Infective endocarditis was not observed in

any of the patients.

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Discussion

Mitral and aortic valve insufficiency is the most important finding of the rheumatic carditis,

sometimes that may be present without clinical evidence, called silent carditis. Jones criteria

themselves may be incapable of the diagnosis of silent carditis so that Doppler

echocardiography can detect valvar insufficiency during both acute and chronic phases of the

disease. The observation that SC may also result in significant morbidity enhanced the value of

echocardiographic examination in rheumatic heart disease.1-3,11

The frequency of carditis in our study population was found as 66% which was parallel with

earlier investigations that reported the rates of 40 % to 80%.12-16 Mitral valve was the most

commonly involved valve (93.2%) and it was followed by aortic valvulitis in 32% of the cases.

These was concordant with other studies,14,17-19 few authors stated that aortic involvement was

the commonest.13 Tutar et al.15 found that MR was more prevalent in CC group but isolated AR

was more common in SC group. The valvulitis of SC was usually thought to be milder form of

valvular involvement seen in CC.4,20,21 Although we did not determine any difference between

the groups by frequency of MR or AR , it was observed that valvular dysfunction was more

severe in CC group and two cases had mitral valve replacement. Furthermore, all the patients in

SC group had first and second degree regurgitation only.

The patient with any finding that may be associated with RF should undergo echocardiographic

examination even in the absence of clinical signs of carditis. Otherwise the existing clinical

features may be inadequate to fulfill the JC and to diagnose RF. Therefore penicillin

prophylaxis with crucial importance can not be carried out and the reccurence of the previously

undiagnosed SC may result in severe carditis.1,16 Carapetis et al.22 found that 54% of RF

diagnosis were missed unless echocardiography was performed in the cases with normal

auscultatory findings. In accordance with this report, in our study, echocardiography of chorea

patients with normal cardiac examination revealed SC in 47.4% of them. Although the Acc

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incidence of SC was usually determined between 14 and 25%, quite variable results were also

reported.23-25 We found relatively higher rate of SC (28.2%) than the others including two

previous reports from our country.13,15 When the findings of the current study and an earlier one

from our clinic 15 were assessed, it was observed that the frequency of SC was increased 6% in

six years. The reason for this increase can be explained with echocardiographic assessment of

all patients admitted to our clinic with mono or polyarthritis and polyarthralgia.

The most common complaint of the cases with SC was arthralgia (38%). It was emphasized

earlier that arthritis and chorea were two major findings that necessisated an echocardiographic

examination and not rarely resulted in the diagnosis of SC. The incidence of arthritis and chorea

were found as 50% to 66% and %34 to 50%, respectively among the SC patients in those

studies.14,15 The frequencies of chorea and arthritis were relatively lower in our SC group than

previously reported rates.

Seventy-four of carditis patients (72%) have obeyed regular clinic visits for more than one year.

Mean follow up period was 45.6±21.6 and 43.4±25 months in clinical and silent carditis

respectively. The majority of them (62.2%) had inflammatory signs of active carditis at referral,

whereas the inflammation was not detected in the remainder. Active carditis was seen more

frequently in CC group. As the patients with SC had no symptom or sign of cardiac disease,

they could just be diagnosed incidentally after the inflammation subsided.

Figuero et al.21 reported persistence of valvular involvement in 60% of SC patients beyond five

years of follow-up despite regular penicillin prophylaxis. Some others also stated the persistence

of valvular regurgitations of SC,14,26 whereas Ozkutlu et al.27 found that 23 out of 40 (%57.5)

patients with carditis valvular insufficiency improved after 18.1±13.9 months follow-up and

they were emphasized that with the use of prednisolone in silent carditis patients improvement

of the valvular damage was accelerated. In the current study, the valvular regurgitation did not

change in 27.8 % of CC and 55 % of SC groups, whereas it disappeared in 18.5% of CC and Acc

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15% of SC groups. The improvement of valvular lesion was observed in only 42% of all cases

and it was relatively rarer when compared with the study of Carapetis et al.24 In the light of

current and previous studies, it was thought that valvulitis of SC followed a similar course with

CC. Therefore, we think that long-term penicillin prophylaxis is necessary for patients

diagnosed with silent carditis.

Secondary antibiotic prophylaxis was long known to decrease the recurrence risk of RF and

approximately 10% of the cases had recurrence within five years after initial attack in the

absence of prophylaxis.24,28 Most of our cases were compliant with penicillin porphylaxis

(89.2%). However, the recurrence of RF was observed in nine (12%) of the patients. The

frequency of second attack was found as 7.3% in an investigation conducted in our country.13 It

was learned that four of those cases with recurrence did not receive recommended prophylaxis.

Seven of them were in CC group and the remainder had SC. Recurrences were usually in the

form of carditis.

In conclusion, RF is still an important health problem with significant morbidity even mortality

especially in underdeveloped countries. According to the results of our study, silent carditis

should be considered as mild carditis. JC themselves may be insufficient to diagnose SC so that,

echocardiography should be included into JC as a major finding and long-term penicillin

prophylaxis should be given for these patients. As in order to establish this, we need more

studies with longer follow-up duration that will completely reveal clinical and particularly

prognostic features of SC.

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with up to 60 months of follow-up evaluation. Pediatr. Cardiol. 2008; 29: 1048-53.

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using auscultation and portable echocardiography to detect asymptomatic rheumatic

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Table 1 The characteristics of 156 patients with rheumatic fever

Features Value

Age (mean ± SD years) 10.8 ± 2.6

Gender (%female/%male) 49.4 / 50.6

Referral symptoms and signs (number (%))

Murmurs 74 (47.4) Arhtralgia 67 (43) Arhtritis 60 (38.5) Fever 26 (16.7) Chorea 19 (12.1) Chest pain 13 (8.3) Fatigabilty 5 (3.2) Abdominal pain 2 (1.3) More than one of the above 95 (60.8) Jones major clinical findings (number (%))

Carditis 103 (66) Arthritis 60 (38.5) Chorea 19 (12.1) Erythema marginatum 4 (2.6) Subcutaneous nodules 2 (1.3) Carditis + arthritis 33 (21.2) Carditis + chorea 17 (10.9)

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Table 2 The features of the patients with carditis CC (n:74) SC (n:29) P value

Age (mean ± SD) 11.16 ± 2.46 years 11.14 ± 2.40 years NS

Gender (%female/%male) 51.4 / 48.6 44.8 / 55.2 NS

Arthralgia* 29 (39.2) 11 (37.9) NS

Fever* 14 (18.9) 2 (6.9) NS

Polyarthritis* 17 (23) 2(6.9) NS

Monoarthritis* 10 (13.3) 4 (14.3) NS

Chorea* 8 (10.8) 9 (31) 0.019

*: shown as number (%)

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Table 3 The frequency of valvular involvement

Valvular involvement* CC (n:74) SC (n:29) P value

Isolated MR 49 (66.2) 21 (72.4) NS

Isolated AR 4 (5.4) 1 (3.4) NS

MR + AR 21 (28.4) 7 (24.2) NS

*All the involvements were shown as number (%).

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Table 4 The severity of valvular involvement

Degree of regurgitation

CC (n:74) SC (n:29)

MR* AR* MR* AR*

1st 39 (52.7) 22 (29.7) 26 (89.7) 8 (27.6)

2nd 20 (27.0) 3 (4.1) 2 (6.9) 0 (0)

3rd 9 (12.2) 0 (0) 0 (0) 0 (0)

4th 2 (2.7) 0 (0) 0 (0) 0 (0)

*All the valvular involvements were shown as number (%).

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Table 5 The characteristics of followed up patients

CC (n:54) SC (n:20) P value

Follow up period (months) 45.6±21.6 § 43.4±25 § NS

Signs of inflammation at referral* 39 (72.2) 7 (35) 0.003

Disapperance of valvular regurgitation* 10 (18.5) 3 (15) NS

İmprovement of valvular regurgitation* 25(45.5) 6 (30) NS

Deterioration of valvular regurgitation* 4 (7.4) 0 (0) NS

Unchanged valvular status* 15 (27.8) 11 (55) 0.029

Compliance with penicilin prophylaxis* 48 (88.9) 18 (90) NS

Rebound or recurrence* 7 (13) 2 (10) NS

*: parameters, shown as number (%), §: parameters, shown as mean ± SD

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Rheumatic silent carditis: Echocardiographic diagnosis and prognosis of long-term follow up