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Year : 2017  |  Volume : 5  |  Issue : 4  |  Page : 152-156

Prevalence of subclinical myocardial involvement among acute rheumatic fever patients without overt clinical carditis in Northern India: An evidence from plasma N-terminal pro-brain natriuretic peptide assessment

1 Department of Cardiology, LPS Institute, Kanpur, Uttar Pradesh, India
2 Department of Cardiology, King George Medical University, Lucknow, Uttar Pradesh, India

Date of Web Publication28-Dec-2017

Correspondence Address:
Gaurav kumar Chaudhary
Department of Cardiology, King George Medical University, Chowk, Lucknow - 226 003, Uttar Pradesh
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/heartindia.heartindia_31_17

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Objectives: It is important to diagnose subclinical carditis in acute rheumatic fever (ARF) since it has a bearing on prognosis and duration of prophylaxis. Plasma N-terminal pro-brain natriuretic peptide (NT pro-BNP) has been used as both diagnostic and prognostic tools, and it was hypothesized that it may prove useful in ARF without overt carditis. The study was undertaken to measure the plasma levels of NT pro-BNP in patients of ARF who did not have overt clinical carditis and to correlate the same with echocardiographic (ECHO) parameters of subclinical myocardial involvement.
Materials and Methods: A total of 27 ARF patients without overt clinical carditis were enrolled in this prospective follow-up study. Plasma NT pro-BNP levels of these patients were assessed on day 1 of presentation and then after 6 weeks. ECHO was performed and patients were divided into two groups: group I, patients with subclinical carditis (n = 18) and group II, patients without subclinical carditis (n = 9).
Results: The mean plasma NT pro-BNP levels were significantly higher in patients with subclinical carditis (509.16 ± 282.9 pg/ml) compared to those without subclinical carditis (109.33 ± 82.95 pg/ml) (P < 0.001). A cutoff value of 134 pg/ml of NT pro-BNP had a sensitivity of 94.4% and specificity of 88.9% for detecting subclinical rheumatic carditis in ARF.
Conclusions: The present study suggests that elevated levels of NT pro-BNP may be used to diagnose subclinical myocardial involvement in patients of ARF without overt clinical carditis.

Keywords: N-terminal pro-brain natriuretic peptide, rheumatic fever, subclinical carditis

How to cite this article:
Mehrotra A, Narain VS, Sethi R, Dwivedi Sk, Chandra S, Chaudhary Gk. Prevalence of subclinical myocardial involvement among acute rheumatic fever patients without overt clinical carditis in Northern India: An evidence from plasma N-terminal pro-brain natriuretic peptide assessment. Heart India 2017;5:152-6

How to cite this URL:
Mehrotra A, Narain VS, Sethi R, Dwivedi Sk, Chandra S, Chaudhary Gk. Prevalence of subclinical myocardial involvement among acute rheumatic fever patients without overt clinical carditis in Northern India: An evidence from plasma N-terminal pro-brain natriuretic peptide assessment. Heart India [serial online] 2017 [cited 2021 Dec 2];5:152-6. Available from: https://www.heartindia.net/text.asp?2017/5/4/152/221866

  Introduction Top

Acute rheumatic fever (ARF), a complication of group A streptococcal infection, is an acute immunologically mediated, multisystem inflammatory disorder. More than one-third of affected children develop carditis. Recurrent episodes can result in permanent valvular lesions and rheumatic disease (RHD) over a period of time.

RHD is quite prevalent in developing countries, whereas in developed countries, its incidence is minimal. This can be attributed to better living conditions and penicillin use, ultimately leading to reduction in group A streptococci transmission.[1],[2],[3]

The estimated burden of RHD in school-going children based on auscultatory confirmations has clearly underestimated the prevalence of the disease, as it is unable to detect early-stage RHD cases, cardiac auscultation being unremarkable in one-third of the patients.[4] Being apparently normal, these children still present with significant features of RHD on echocardiography (ECHO).

Systematic use of ECHO may be 10 times more sensitive in detecting subclinical form of carditis than traditional surveys based on cardiac auscultation.[5],[6] However, due to logistics and workforce, the implementation of this specialized technique is a challenging task in developing countries and there is a need to look for other simple biochemical markers which would be able to predict subclinical carditis at a much earlier stage.

Detection of subclinical carditis in children with ARF is vital because it defines the duration of penicillin prophylaxis, prevent recurrent episodes and progression to valvular disease all of which, will reduce the burden of RHD in the population.

A large number of studies have shown that plasma brain natriuretic peptide (BNP) and N-terminal pro-BNP (NT pro-BNP) levels provide information regarding cardiovascular risk in addition to those provided by conventional risk factors. NT pro-BNP also indicates cardiac dysfunction and predicts cardiovascular events.[7],[8],[9],[10]

The present study was carried out to see whether plasma NT pro-BNP is a useful marker in predicting subclinical carditis in patients with ARF, in reference to ECHO findings.

  Materials and Methods Top

In this prospective follow-up study, 27 patients of both sexes aged between 6 and 15 years, diagnosed with ARF as per the 2002–2003 World Health Organization (WHO) guidelines[11] and who were referred to a tertiary care hospital, were included. Patients with established rheumatic heart disease, clinical heart failure, cirrhosis, renal dysfunction, sepsis, hyperthyroidism, acute coronary syndromes, pulmonary embolism, pulmonary hypertension, and severe lung disease were excluded.

Subclinical carditis was confirmed when there was no murmur or only a soft 1–2/6 innocent short duration systolic murmur along with pathological mitral or aortic insufficiency on ECHO along with historical or clinical findings compatible with rheumatic fever. Based on the presence or absence of subclinical carditis, the participants were divided into two groups: group I (n = 18) with carditis and group II (n = 19) without carditis. Follow-up of all the patients was done for a period of 6 weeks.

For blood investigations, venous blood samples were taken with the patient resting quietly in semi-recumbent position. The erythrocyte sedimentation rate was determined by Westergren's method. Antistreptolysin O (Rapitex ASL) and C-reactive protein titers were determined using standard reagents on Beckman-Coulter DXC 800 systems analyzer. Antistreptolysin O titer was considered to be elevated if it was >320 Todd units/ml. C-reactive protein >5 mg/l was considered raised.

Plasma NT pro-BNP was measured by the commercially available method from Roche Diagnostics utilizing a two-site sandwich principle and detection by chemiluminescence. Levels were measured at the time of presentation and after 6 weeks of the acute attack and compared between both groups, both in the acute and in the convalescent phase.

Transthoracic ECHO was performed in all cases using GE medical system, VIVID7 Dimension (N-3190, Horten, Norway) with the patient in the supine left lateral decubitus position. Parasternal long axis, parasternal short axis, apical four-chamber, subcostal frontal, caval, and suprasternal views were obtained to evaluate the cardiac valves and chambers. Color, pulsed wave, and continuous wave Doppler ECHO was done to evaluate the mitral and aortic insufficiency.

Pathological mitral regurgitation was diagnosed by two views seen in jet length ≥2 cm at a velocity of ≥3 m/s for one complete envelope with pansystolic jet in at least one envelope. Pathological aortic regurgitation was diagnosed on a jet length ≥1 cm at a velocity of ≥3 m/s in early diastole with pandiastolic jet in at least one envelope.[12] ECHO evaluation was done by an observer who was blinded to the clinical features. The study protocol was approved by the institutional ethics committee, and informed consent was obtained from all the children and their parents/guardians before the enrollment.

Statistical analysis

All results are expressed as mean ± 2 SD. Student's t-test was done for comparison between two groups. The performance of NT pro-BNP as a predictor of acute rheumatic carditis and the optimal cutoff level was assessed by the receiver-operating characteristic (ROC) curve. P < 0.05 was considered statistically significant. The data were analyzed using XLSTAT version-

  Results Top

The demographic, clinical, and laboratory data of the study group are shown in [Table 1]. Mean age in group I was 11.27 ± 2.05 years (6–15 years); of them, 11 were boys and 7 were girls. The mean age in group II was 10.9 ± 1.76 years (7–14 years); of them, 6 were boys and 3 were girls. Polyarthritis was seen in 4 and 14 patients in groups I and II, respectively. None of the patients had erythema marginatum, chorea, or subcutaneous nodules.
Table 1: Demographic, clinical, and laboratory data of the study group

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NT pro-BNP levels were significantly higher in patients with subclinical carditis, group I (509.16 ± 282.9 pg/ml), when compared to those without subclinical carditis, group II (109.33 ± 82.95 pg/ml) (P < 0.001) [Figure 1]. In those with subclinical carditis, there was a marked significant difference in the NT pro-BNP levels between acute (509.16 ± 282.9 pg/ml) and convalescent phase (127.8 ± 62.43 pg/ml) (P < 0.001) as compared to patients of ARF without subclinical carditis where difference was not statistically significant, acute phase (109.33 ± 82.9 pg/ml) and convalescent phase (74.0 ± 12.73 pg/ml) (P = 0.24) [Figure 2] and [Figure 3].
Figure 1: Plasma levels of N-terminal pro-brain natriuretic peptide in patients with subclinical carditis and without subclinical carditis

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Figure 2: Plasma levels of N-terminal pro-brain natriuretic peptide during acute and convalescent phase of acute rheumatic fever in patients with subclinical carditis

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Figure 3: Plasma levels of N-terminal pro-brain natriuretic peptide during acute and convalescent phase of acute rheumatic fever in patients without subclinical carditis

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Based on the presence and absence of subclinical carditis on ECHO and NT pro-BNP levels in plasma, a 2 × 2 table was made for sensitivity and specificity calculation. Seventeen patients were true positive and 8 patients were true negative [Table 2]. A NT pro-BNP plasma level of 134 pg/ml had an acceptable sensitivity (94.4%) and specificity (88.9%) for detecting subclinical carditis in ARF patients using ROC curve. The area under the curve was 0.957 [Figure 4].
Table 2: 2×2 based on the presence and absence of subclinical carditis on echocardiography and N-terminal pro-brain natriuretic peptide levels

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Figure 4: Receiver-operating characteristic curve for plasma N-terminal pro-brain natriuretic peptide in the diagnosis of acute rheumatic carditis. Area under the curve was 0.957. A cutoff level of 134 pg/ml has sensitivity (94.4%) and specificity (88.9%) for detecting subclinical carditis in the setting of acute rheumatic fever

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  Discussion Top

Carditis in ARF can cause permanent functional and morphological impairment. Recurrent episodes of carditis result in extensive cardiac injury and thus increase morbidity and mortality. Several reports have suggested that valvular deficit may be seen in as many as 90% of the patients even in the absence of clinical signs of carditis.[13],[14],[15]

Depending only on auscultation in individuals with arthritis or arthralgia, or in individuals with typical or atypical signs and symptoms of ARF, a diagnosis of such subclinical carditis can go unnoticed, leading to recurrences or perhaps severe cardiac involvement in young patients due to lack of long-term secondary prophylaxis.[16]

Studies have found ECHO as a useful test for making the diagnosis of subclinical carditis and confirming auscultation findings, which subsequently allows for estimation of the severity of myocarditis, pericarditis, and valvular regurgitation.[17] However, practical implementation of ECHO evaluation in developing countries and a strong possibility of overdiagnosis by way of not being able to differentiate between physiological and pathological valvar leaks in those untrained at the peripheral level evokes a need to look for a simple biochemical marker for predicting subclinical carditis and additionally for ruling out false positives of ECHO.

Cardiac natriuretic peptides, atrial natriuretic factor, and BNP are polypeptide hormones secreted by the heart. Their presence is unique in assessing longitudinal changes in these prohormone levels in children with subclinical rheumatic carditis.

Our study prospectively evaluated the longitudinal changes in the plasma concentrations of NT pro-BNP hormone in children with subclinical rheumatic carditis. Plasma NT pro-BNP levels were significantly increased in acute subclinical carditis as diagnosed by ECHO in contrast to those without carditis. There was also a significant decrease in plasma NT pro-BNP levels following anti-inflammatory therapy. NT pro-BNP could thus serve not only as a marker in identifying and supporting the diagnosis of subclinical carditis but also to rule out false-positive cases by ECHO.

We found a NT pro-BNP cutoff level of 134 pg/mL as having a high sensitivity of 94.4% and specificity of 88.9% for detecting subclinical carditis in the setting of ARF and as suggestive of cardiac involvement in patients without overt carditis but presenting with only one of the major noncardiac criteria of rheumatic fever. To the best of our knowledge, this is the first study which has looked into NT pro-BNP in patients of ARF with subclinical carditis.

Till additional scientific studies are done to determine the importance of subclinical carditis, physicians will need to make management decisions which are not evidence based. By presuming subclinical carditis as a benign condition, which it may not be, several affected individuals who meet poor prognostic criteria in ARF will probably be missed; secondary prophylaxis will not be prescribed and thus will have a higher risk of developing recurrent ARF and more severe RHD.

It may be discussed that the simple assumption that subclinical carditis provides prognostic information similar to mild clinical RHD, individuals devoid of ARF will probably be misdiagnosed as having this condition and therefore inappropriately receive antibiotic prophylaxis for several years. However, within settings where ARF and RHD are usually endemic, the possibility of ARF recurrences is actually high; we believe that it is much more important to risk overdiagnosis in a few cases associated with ARF to prevent the actual devastating outcomes of underdiagnosis. This is recognized by the WHO recommendations that advocate individuals with silent, but significant, mitral and/or aortic regurgitation being labeled as “probable RHD” and that they be placed on secondary prophylaxis.

Subclinical carditis is considered a major diagnostic criterion by some authors.[16],[17],[18] Inclusion of subclinical carditis as a major criteria is expected to result in an 11%–16% increase in the diagnosis of ARF.[16] Inclusion of monoarthritis and subclinical carditis as major criteria and mild fever as a minor criterion in the current diagnostic criteria has been reported to cause an increase in the number of ARF diagnoses.[19]

The Task Force on Rheumatic Fever has declared that subclinical carditis on the basis of ECHO should not be considered as major diagnostic criteria for ARF due to the possibility of “overdiagnosis;” this is based on the presumption that subclinical carditis could be very easily confused with physiological mitral and aortic insufficiency. Our study findings suggest that in addition to making a diagnosis of carditis in the absence of ECHO, NT pro-BNP rise may supplement the diagnosis of carditis by ruling out the false positives of ECHO; if put to use to screen subclinical carditis, then it may alleviate the need for ECHO examination.

Given the paucity of investigations that can detect subclinical carditis in and the potential value of treatment of subclinical rheumatic carditis, the NT pro-BNP which is a simple, widely available, bedside standardized test can prove to be of considerable value even as an objective adjunct to the Jones criteria.

This study has the limitation of being small in size and needs further validation from larger number of patients with ARF.

  Conclusions Top

Raised NT pro-BNP in those patients with ARF (both in acute and convalescent stages) who have no cardiac signs and/or symptoms indicates subclinical carditis and can be a useful biochemical investigation to guide treatment with reference to prophylaxis. Furthermore, it may help in those where it is difficult to decide whether ECHO Doppler detected regurgitant lesion is pathological or physiological.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Carapetis JR, McDonald M, Wilson NJ. Acute rheumatic fever. Lancet 2005;366:155-68.  Back to cited text no. 1
McDonald M, Currie BJ, Carapetis JR. Acute rheumatic fever: A chink in the chain that links the heart to the throat? Lancet Infect Dis 2004;4:240-5.  Back to cited text no. 2
Carapetis JR, Steer AC, Mulholland EK, Weber M. The global burden of group A streptococcal diseases. Lancet Infect Dis 2005;5:685-94.  Back to cited text no. 3
Meira ZM, Goulart EM, Colosimo EA, Mota CC. Long term follow up of rheumatic fever and predictors of severe rheumatic valvar disease in Brazilian children and adolescents. Heart 2005;91:1019-22.  Back to cited text no. 4
Marijon E, Ou P, Celermajer DS, Ferreira B, Mocumbi AO, Jani D, et al. Prevalence of rheumatic heart disease detected by echocardiographic screening. N Engl J Med 2007;357:470-6.  Back to cited text no. 5
Carapetis JR, Hardy M, Fakakovikaetau T, Taib R, Wilkinson L, Penny DJ, et al. Evaluation of a screening protocol using auscultation and portable echocardiography to detect asymptomatic rheumatic heart disease in Tongan schoolchildren. Nat Clin Pract Cardiovasc Med 2008;5:411-7.  Back to cited text no. 6
Sutton TM, Stewart RA, Gerber IL, West TM, Richards AM, Yandle TG, et al. Plasma natriuretic peptide levels increase with symptoms and severity of mitral regurgitation. J Am Coll Cardiol 2003;41:2280-7.  Back to cited text no. 7
Gerber IL, Stewart RA, Legget ME, West TM, French RL, Sutton TM, et al. Increased plasma natriuretic peptide levels reflect symptom onset in aortic stenosis. Circulation 2003;107:1884-90.  Back to cited text no. 8
Seino Y, Ogawa A, Yamashita T, Fukushima M, Ogata K, Fukumoto H, et al. Application of NT-proBNP and BNP measurements in cardiac care: A more discerning marker for the detection and evaluation of heart failure. Eur J Heart Fail 2004;6:295-300.  Back to cited text no. 9
Davutoglu V, Celik A, Aksoy M, Sezen Y, Soydinc S, Gunay N, et al. Plasma NT-proBNP is a potential marker of disease severity and correlates with symptoms in patients with chronic rheumatic valve disease. Eur J Heart Fail 2005;7:532-6.  Back to cited text no. 10
WHO. Rheumatic Fever and Rheumatic Heart Disease: Report of a WHO Expert Consultation, Geneva, 29 October–1 November 2001. Geneva: World Health Organization; 2004.  Back to cited text no. 11
Reményi B, Wilson N, Steer A, Ferreira B, Kado J, Kumar K, et al. World heart federation criteria for echocardiographic diagnosis of rheumatic heart disease – An evidence-based guideline. Nat Rev Cardiol 2012;9:297-309.  Back to cited text no. 12
Abernethy M, Bass N, Sharpe N, Grant C, Neutze J, Clarkson P, et al. Doppler echocardiography and the early diagnosis of carditis in acute rheumatic fever. Aust N Z J Med 1994;24:530-5.  Back to cited text no. 13
Folger GM Jr. Hajar R, Robida A, Hajar HA. Occurrence of valvar heart disease in acute rheumatic fever without evident carditis: Colour-flow Doppler identification. Br Heart J 1992;67:434-8.  Back to cited text no. 14
Ozkutlu S, Ayabakan C, Saraçlar M. Can subclinical valvitis detected by echocardiography be accepted as evidence of carditis in the diagnosis of acute rheumatic fever? Cardiol Young 2001;11:255-60.  Back to cited text no. 15
Wilson N. Echocardiography and subclinical carditis: Guidelines that increase sensitivity for acute rheumatic fever. Cardiol Young 2008;18:565-8.  Back to cited text no. 16
Vijayalakshmi IB, Vishnuprabhu RO, Chitra N, Rajasri R, Anuradha TV. The efficacy of echocardiographic criterions for the diagnosis of carditis in acute rheumatic fever. Cardiol Young 2008;18:586-92.  Back to cited text no. 17
Mota CC. Doppler echocardiographic assessment of subclinical valvitis in the diagnosis of acute rheumatic fever. Cardiol Young 2001;11:251-4.  Back to cited text no. 18
Cann MP, Sive AA, Norton RE, McBride WJ, Ketheesan N. Clinical presentation of rheumatic fever in an endemic area. Arch Dis Child 2010;95:455-7.  Back to cited text no. 19


  [Figure 1], [Figure 2], [Figure 3], [Figure 4]

  [Table 1], [Table 2]


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