Centenary Review Article

Indian J Med Res 137, April 2013, pp 643-658

Rheumatic fever & rheumatic heart disease: The last 50 years

R. Krishna Kumar & R. Tandon*

Division of Pediatric Cardiology, Amrita Institute of Medical Sciences & Research Centre,
Kochi & *Sitaram Bhartia Institute of Science & Research, New Delhi, India

Received December 19, 2012

Rheumatic fever (RF) and rheumatic heart disease (RHD) continue to be a major health hazard in
most developing countries as well as sporadically in developed economies. Despite reservations about
the utility, echocardiographic and Doppler (E&D) studies have identified a massive burden of RHD
suggesting the inadequacy of the Jones’ criteria updated by the American Heart Association in 1992.
Subclinical carditis has been recognized by E&D in patients with acute RF without clinical carditis as
well as by follow up of RHD patients presenting as isolated chorea or those without clinical evidence of
carditis. Over the years, the medical management of RF has not changed. Paediatric and juvenile mitral
stenosis (MS), upto the age of 12 and 20 yr respectively, severe enough to require operative treatement
was documented. These negate the belief that patients of RHD become symptomatic ≥20 years after RF
as well as the fact that congestive cardiac failure in childhood indicates active carditis and RF. Non-
surgical balloon mitral valvotomy for MS has been initiated. Mitral and/or aortic valve replacement
during active RF in patients not responding to medical treatment has been found to be life saving as
well as confirming that congestive heart failure in acute RF is due to an acute haemodynamic overload.
Pathogenesis as well as susceptibility to RF continue to be elusive. Prevention of RF morbidity depends
on secondary prophylaxis which cannot reduce the burden of diseases. Primary prophylaxis is not
feasible in the absence of a suitable vaccine. Attempts to design an antistreptococcal vaccine utilizing
the M-protein has not succeeded in the last 40 years. Besides pathogenesis many other questions remain
unanswered.

Key words Antistreptococcal vaccine - heart disease - myocarditis - rheumatic fever - rheumatic heart disease - streptococcal infections -
subclinical carditis

Rheumatic heart disease (RHD) follows rheumatic highlights the changes that have occurred in the area of
fever (RF), as a non-suppurative manifestation of group RF and RHD in the last 50 years.
A beta haemolytic streptococcal (GAS) pharyngitis. Historical perspective
RF is widely accepted as an immunological disorder
following GAS infection. Although the burden has About 100 years back RF/RHD was believed to be
come down in developed countries, RHD continues a disease of “temperate climate”. In 1835, Malcomson
to be a prominent cause of morbidity and mortality observed that rheumatism was prevalent among
in developing countries of the world. This review sepoys1 and in 1870 Moore2 reported numerous cases

643
644 INDIAN J MED RES, APRIL 2013

of rheumatism in Rajasthan. Rogers3 indicated absence

Table I. Percentage of RHD patients in hospital admission
of RF in India as except one possible case he did not
find RHD in 4800 postmortem records in 37 years in Author Place Year (%)
Calcutta (Kolkata) inspite of 25 cases of mitral stenosis Kutumbiah13 Madras (Chennai) 1941 39.5
which he labelled as non rheumatic. Megaw4 reported Bannerjea 14
Calcutta (Kolkata) 1965 44.6
RHD from plains of India but felt that it was less Sanjeevi 15
Madras (Chennai) 1946 46.8
common than seen in colder climates. Clark5 reported Vakil16 Bombay (Mumbai) 1954 24.7
absence of haemolytic streptococcal infections and Padmawati 17
Delhi 1958 39.1
low prevalence of RF/RHD in tropics. Keats6 did not
Devichand18 Shimla 1959 50.6
find a single case of RHD in 600 autopsies in Amritsar.
Drury7 found mitral valve disease in 62 per cent and Mathur 19
Agra 1960 35.1
mitral stenosis in 10 per cent in an analysis of 319 Malhotra20 Punjab 1963 27.6
clinically diagnosed cases of heart disease admitted
to the Medical College Hospital in Calcutta (Kolkata).
Basu8 found 8.3 per cent cases of rheumatic carditis and hospital admissions are largely represented by CAD
pericarditis in 446 patients of acquired heart disease. patients in most hospitals.
Hughes and Yusuf9 referred to mitral stenosis in an Population based surveys for prevalence are
article on heart disease in Punjab9. Hodge reported on very few and scattered. (Table II). In a study in rural
rheumatism and indicated that it was not rare in India. Haryana prevalence of RHD was found to be 2.2/1000
The first clinical evidence of RF came from Punjab in 5 to 30 year old subjects23. Mathur in a study of the
by Wig in 193511 and on rheumatism in childhood urban population of Agra found RHD in 1.8/1000 in the
and adolescence by Kutumbiah in 194012. This was same age group24. Berry25 studied the urban population
followed by a large number of hospital-based surveys of Chandigarh and found RHD in 1.23/1000 male and
for the relatively “new” disease accounting for 20 to 50 2.07/1000 in the female population of all age groups.
per cent admissions in hospitals in various parts of the A recent Indian Council of Medical Research (ICMR)
country (Table I). With the results, rheumatic fever was study (between 2000 and 2010) in 10 different, mostly
labelled as severe or malignant in India with multivalve urban, locations of the country found the prevalence
involvement and congestive cardiac failure even in the to range from 0.2 to 1.1/1000 for RHD and 0.0007 to
initial attack of RF21. Roy delineated the features of RF 0.2 /1000 for RF26. The data were based on registration
and compared with features seen in Boston (USA)22. of all cases in one million population by approaching
The presence of RF/RHD was not only established but hospitals, private practitioners and extensive advertising
also considered to be the commonest heart disease in for establishing a registry of all known cases. The
the country by mid 1950s. recent registry data suggests decline but registries are
able to collect about 50 to 70 per cent cases. Hence,
Burden of the disease in India
overall decline is debatable.
The information regarding the burden of disease
ICMR has conducted three school-based surveys in
comes from hospital data, population based studies and
children 5 to 14 yr in age over a 40-year period between
school surveys. Hospital based data between 1945 and
1970 and 2010. The first survey from 1972 to 1975
1963 indicated that anywhere from 20 to 50 per cent
was in schools at Agra, Alleppy, Bombay (Mumbai),
hospital admissions for cardiac patients were for RHD
Delhi and Hyderabad. The second from 1984 to 1987
(Table I). Since the hospital-based data do not represent
included schools at Delhi, Varanasi and Vellore.
the population of the region, there is a bias towards
the worst affected and those seeking admission for
procedures. Additional bias may be introduced through Table II. Prevalence of RHD in population surveys
changes in the population served by the hospital over
Age group (yr) N Prevalence/1000
many years. With increasing marginalization of the
poorer sections of the society some hospitals may no Roy 23
5-30 4847 2.2
longer be serving those who are worst affected with Mathur et al24 5-30 7953 1.8
RHD. Perhaps the most important source of bias is in Berry 25
5-30 19768 1.87
the preference of the admitting units. With emergence All ages 33361 1.55
of the epidemic of coronary artery disease (CAD),
 KRISHNA KUMAR & TANDON: RHEUMATIC FEVER & HEART DISEASE 645

The third study included children from 10 centres in decline in prevalence is a difficult question to answer.
the country located at Shimla, Jammu, Chandigarh, At the same time, addition of echocardiographic RHD
Jodhpur, Indore, Kochi, Wayanad, Mumbai, Vellore surveys of normal children have introduced a new
and Dibrugarh. It has a wider coverage but not of the dimension to the assessment of disease burden. Most
whole country. In the first study (1972-1975), 1,33,000 available echocardiographic evaluation studies for the
children were evaluated and the prevalence of RHD presence of RHD in school children suggest more than
varied from 0.8 to 11/1000, overall 5.3/1000. The 10 to 20 times higher prevalence of clinically “silent”
second study (1984-1987) included 53,786 children RHD (Table IV). The reliability or acceptability of the
and the prevalence ranged from 1.0 to 5.6/1000 overall prevalence data based on clinical evaluation alone is
2.9/1000. The third and the largest study included not known with certainty. Further, echocardiographic
1,76,904 school children with a prevalence varying diagnosis has fallacies and follow up studies of the
from 0.13 to 1.5/1000 (overall 0.9/1000) in the 5 to 14 clinically silent or subclinical (SC) RHD are required to
yr age range26. The data suggest a progressive decline establish the significance of disease identified through
in RHD from 5.3 to 2.9 to below 1.0/1000 between echocardiography alone. Is this “subclinical” valve
1970 to 2010. In the last study echocardiographic disease really silent RHD? A long-term follow up of
evaluation was performed in all children clinically the patients is required to establish the natural history
diagnosed to have a heart murmur and children with of disease identified through echocardiography alone.
congenital heart disease could be excluded. In a study
An analysis of the shortcomings associated with the
on 1,18,212 school children 4-18 yr in age a heart
estimation of the prevalence of RF/RHD in our country
murmur was found in 389 normal children. Echo
has been discussed earlier38. The overall prevalence
evaluation identified 61 children with RHD giving a
estimated to be about 1.5-2/1000 in all age groups, in
prevalence of 0.5/1000 children in Uttar Pradesh27.
India (total population about 1.3 billion) suggests that
Studies from Punjab, Gujarat, Rajasthan, Uttar Pradesh
there are about 2.0 to 2.5 million patients of RHD in
and Tamil Nadu have found the prevalence to range
the country.
from 0.67 to 4.54/1000 children (Table III). The figures
are variable but suggest a decline in the prevalence of Global and Asian burden of RF/RHD
RHD over time, however, whether they identify a real The burden of RF/ RHD has been described in detail
by Carapetis and colleagues39,40. Excluding developed
economies, the global burden of RHD in the 5 to 14 yr
Table III. Prevalence of rheumatic heart disease (RHD) in old children was estimated to be 0.8 - 5.7/1000 with a
school surveys median of 1.3/1000. The estimated number of children
Place Year Age (yr) Prevalence/1000 would be about 2.4 million (Table V). Subsequent
Punjab28 1988-91 5-15 2.1 data from studies in Asia suggested that the number of
Gujarat 29
1986 8-18 2.03 children with RHD in Asia could be between 1.96 to
Punjab30 1987 6-16 1.3 2.21 million. The findings were extrapolated to include
Uttar Pradesh 31
2000 7-15 4.54
all ages and estimated that globally there were 15.6 -
19.6 million patients. In the study of Asian countries the
Tamil Nadu32 2001-2 5-18 0.68
burden of RHD was estimated to be 10.8 - 15.9 million
Rajasthan 33
2006 5-14 0.67 patients. The estimates of RHD in Asian countries

Table IV. Prevalence of subclinical carditis in echo studies of school children

Place n Clinical Echo Subclinical
Nicaragua 34
3150 13 (4) 150 (48) 137 (44)
Tonga35 5053 78 (15.4) 169 (33.4) 91 (18)
Cambodia 36
3677 8 (2.2) 79 (21.5) 71 (19.3)
Mozambique36 2170 5 (2.3) 66 (30.4) 61 (28.1)
India 37
6270 5 (0.8) 128 (20.4) 123 (19.6)
Tonga auscultation positive 46% silent 54 % (figures calculated)
Figures in parenthesis are per 1000
646 INDIAN J MED RES, APRIL 2013

Table V. Global and Asian magnitude of RF/RHD (Excluding

the same time it is well known that recurrences of RHD
developed economies) have mimetic features and the subclinical disease may
become a clinically obvious disease in recurrences in
RHD Age (yr) No. of patients
(Million) the absence of secondary prophylaxis43. The magnitude
of subclinical carditis, 10 to 20 times higher than
Global 5-14 2.4
manifest RHD, indicates the difficulties regarding
Asia 5-14 01.96 - 2.2 secondary prophylaxis. Secondary prophylaxis is
Global all ages 15.6 - 19.6 ethically mandatory in this age group. Can we identify
Asia all ages 10.8 - 15.9 children with subclinical carditis and not put them on
secondary prophylaxis ?
Acute RF n / year
Global 5-14 336000 Diagnosis of RF
All ages 471000 The criteria for the diagnosis enunciated by Dr
If 282 60% have RHD 282000 new cases T. Duckett Jones’ have been modified, revised and
188.4 40% potential RHD 189000 updated by the American Heart Association (AHA)44.
Rate/year n / year The diagnostic criteria consist of major manifestations
Estimated deaths carditis, arthritis, subcutaneous nodules, erythema
(%)
Global 1.5 233000 - 294000
marginatum and chorea. Rheumatic carditis resulting
in a more or less permanent damage to the heart is the
Asia 3.3 356000 - 524000
main virulent manifestation of RF.
Source: Refs 39, 40
The minor manifestations consist of fever,
arthralgia, elevated sedimentation rate, C-reactive
indicate that the global burden is significantly higher
protein (CRP) and prolonged PR interval in the
than the earlier estimates for children as well as all age
electrocardiogram. Presence of two major or one
groups.
major and two minor manifestations with an evidence
On the basis of 1.5 per cent mortality per year, for recent GAS infection (essential criterion) indicate
global deaths from RHD were estimated to be 233,000 acute RF. Evidence for recent GAS infection can be
- 294,000/year. The mortality in Asian countries was in the form of a positive throat culture, elevated anti-
calculated on the basis of a study showing 3.3 per streptococcal, antibodies or presence of features for
cent per year mortality41. As such the mortality in Asia recent scarlet fever, rare in our country.
accounts for 356,000 to 524,000 deaths/year suggesting
The components of major, minor and essential
that the global mortality must be higher.
criteria for the diagnosis remain more or less as before
For acute RF a global estimate in the 5-14 yr in AHA guidelines44. The updated criteria emphasize
age group suggested 336000 new cases per year. the value of indolent carditis and chorea to be accepted
Extrapolating to all ages it indicated that about 471,000/ as evidence of RF and have removed previous RF or
year get RF. Calculating on the basis of 60 per cent presence of RHD as a minor manifestation to simplify
patients of RF getting carditis, about 282,000 new cases the diagnosis of first attack of RF. In the presence of
of RF are added each year with the remaining 40 per previous history of RF/RHD one major or more than
cent or 189,000/year having a potential for subclinical one minor criterion is acceptable for the diagnosis
RHD (Table V). A review of the incidence of acute RF, of recurrent RF. Additionally echocardiogram based
in population based studies in the world has estimated diagnosis of carditis has been questioned in the absence
that the overall incidence varies from 5 to 51/100,000 of clinical findings to indicate cardiac involvement.
population with a mean of 19/100, 00042. The clinical manifestations of RF, except for minor
differences in frequency, is the same all over the world.
These estimates do not take into account subclinical
In our country erythema marginatum is not recognized
carditis identified on the basis of echocardiography
possibly because of the darker skin complexion (Table
and Doppler studies in surveys of school children
VI)22,45-48.
(Table IV). Although the exact significance of the
subclinical carditis in terms of morbidity has not been It needs to be emphasized that the diagnostic
established, it cannot be disregarded. Studies suggest criteria are guidelines that help in the identification
that subclinical RHD can progress to clinical RHD. At of RF. However, physicians have a right to make a
 KRISHNA KUMAR & TANDON: RHEUMATIC FEVER & HEART DISEASE 647

Table VI. Major manifestations of acute RF

Roy 22
Padmawati & Sanyal et al46 Agarwal & Vaishnava et al48
Arora45 Agarwal47
Delhi Boston Delhi Delhi Allahabad Vellore
N 113 490 - 102 100 166
Carditis 46 53 14 33 51 97
Arthritis 32 58 36 67 68 2.4
Chorea 5 19 4 21 16 5.4
SC nod 3 12 1 2 5 1.2
E. marg 0 11 0 2 0 0
Figures indicate percentage of patients
SC nod, subcutaneous nodules; E. marg, erythema marginatum

diagnosis of RF on the basis of clinical judgment even mitral valve obstruction (MS). Similarly, Aron et al51
if the updated criteria are not satisfied. This may be in a 30-year follow up of 50 patients of pure chorea
due to (i) absence of history suggestive of RF in almost ended up with RHD, predominantly MS, in 34 per cent
50 per cent patients of RHD, and (ii) identification patients. Roy et al52 drew attention towards the onset
of subclinical carditis by echocardiographic studies, of symptomatic severe MS below the age of 20 yr and
indicating inadequacy of clinical diagnosis. designated it as juvenile MS in India. In our evaluation
of children below 12 yr of age who have been operated
Identification of RF for MS 57 per cent gave history consistent with RF,
RHD can occur only after a patient has had RF. haemodynamic studies in 29 and operation in 35 of the
Evaluation of data indicates that about 65 per cent 42 patients indicated moderately severe to severe MS
patients get clinically recognizable RHD following requiring operative treatment below the age of 12 yr53.
RF. In the global estimate a conservative figure of The assessment of the exact time of RF and the interval
60 per cent carditis has been used for calculating the between RF and onset of symptoms of MS could be
burden of RHD39. This suggests that at least 40 per cent fallacious since it was dependent entirely on the past
patients who have had RF could be potentially patients history of arthritis and arthralgia. Nine patients became
of subclinical carditis. On the basis of Utah study, 27 symptomatic, within a year and five within two years,
per cent patients had subclinical carditis49. Hence, the all below 12 yr in age. The youngest patient was six
actual estimated burden could be much more than years old at the time of operation without a history
the actual burden. Secondly, most prevalence figures suggestive of RF53. In a subsequent evaluation of 125
indicate that the prevalence of RF in surveys is about children below of the age of 12 yr with isolated mitral
one tenth or even less than that of RHD (0.1/1000 vs stenosis, past history of rheumatic fever was available
1/1000)26. The inference could be that the diagnosis in 54 (51%)54.
of RF is being missed more often than desirable or These studies indicate that MS can occur very
acceptable. Less than half of all RHD patients give quickly following RF. Secondly 43-50 per cent
history of past RF. Unfortunately, diagnosis of past RF developed significant mitral obstruction without a
is not possible unless patients give history of arthritis, history to suggest RF indicating that acute RF is not
arthralgia, chorea or have established RHD. Hence, being recognized, possibly because RF is occurring
retrospective diagnosis or identification of past RF is with subclinical carditis but without arthritis, arthralgia,
missed or not available in almost 50 per cent patients subcutaneous nodules, and chorea. Missing a clinical
with RHD. diagnosis of acute RF in children less than 12 yr of age
Follow up of patients with pure chorea without is most disturbing since the time available to forget the
manifestation of acute RF is very short if we accept
RHD or of patients who have had RF but no clinical
that RF must have occurred beyond the age of 2 to 3 yr
evidence of carditis indicates that RHD can develop
in most.
over a period of time. Bland50 in a 20 year follow up of
patients with isolated chorea found 23 per cent patients Presence of subclinical carditis diagnosed using
without clinical carditis to develop RHD predominantly echocardiography in surveys of 5-14 yr old children
648 INDIAN J MED RES, APRIL 2013

when combined with the findings of the children units or more whereas in non-endemic areas it could
with MS suggests that RF is being missed more often be as low as 50 Todd units. Increasing titres indicate
than desirable. Some patients have only one clinical recent GAS infection. Using two antibody titres, that
manifestation - fever with valvulitis during the episode is, ASLO combined with deoxyribonuclease B titres
of RF and the diagnosis of RF is being missed since increases the specificity of diagnosis to 90 per cent56.
the carditis is asymptomatic, mild and not associated
Presence of GAS in throat culture with low values
with any murmurs (subclinical). The findings suggest
of ASLO suggests a carrier state. As such a positive
that the diagnosis of RF based on the 1992 guidelines
throat culture for GAS cannot be taken as recent
of AHA are necessary but insufficient in identifying RF
infection unless the antibody titres are elevated.
in a fairly large number of patients44.
Presence of active vs. inactive RF in recurrences: Two
Diagnostic tests in RF/RHD
investigations have been tried to assess the presence
The diagnostic tests can be considered as those or absence of active RF in patients with recurrences
meant for (i) diagnosis of RF, (ii) presence of active vs. besides ESR, CRP and evidence for recent GAS
inactive RF in recurrences, and (iii) identification of infection.
carditis and valve damage in RHD.
(i) Induced subcutaneous nodules (SCN): Massell et
Diagnosis of RF: al57 tried inducing SCN by injecting five dl autologous
blood drawn from a vein and injecting over the
(1) The diagnosis of RF is dependent on some
olecranon process of one elbow and saline in the other
laboratory tests included as minor criteria and
elbow. Frictional pressure was applied to the injected
consist of the following:
sites. Appearance of a SCN in 5 to 10 days was
(i) Acute phase reactants (leukocytosis, elevated accepted as indicating active RF. Vasan modified this
sedimentation rate and presence of C reactive test and used concentrated leukocyte injection instead
protein CRP). of whole blood with 86 per cent sensitivity and 94 per
cent specifically to identify active RF. The test offers
(ii) Prolonged PR interval in the electrocardiogram.
the advantage of being cheap and easily available
(2) The diagnosis requires presence of essential criteria everywhere. The potential utility of the test lies in
in the form of evidence for recent GAS infection identifying active RF. However, additional validation
and consists of: studies are perhaps needed.
(i) elevated antistreptococcal antibodies, (ii) Myocardial biopsy: A study of myocardial histology
to identify active vs. inactive RF was utilized in
(ii) positive throat culture for GAS, and
patients of RF59. Myocardial biopsies were performed
(iii) evidence for recent scarlet fever- rare in India. in 89 patients of active RF and chronic RHD to identify
Elevated erythrocyte sedimentation rate (ESR) active carditis Myocardial biopsies failed to improve on
is a nonspecific evidence for an active disease. It is clinically assessed presence of active RF. Myocardial
elevated in acute RF but can be normal if the patient biopsy was felt to be insensitive for identifying presence
has congestive failure and can be high in the presence of active carditis58.
of anaemia. Normal CRP is against the diagnosis of Rheumatic carditis and valve damage
active RF. Prolonged PR interval can be seen in the
The virulence of RF is related to its capacity to
electrocardiograms in patients with active RF. Prolonged
cause cardiac damage. Clinically carditis has been
PR interval is a non specific finding and does not indicate
reported by several investigators in the initial attack
the presence of myocarditis. Elevated antistreptococcal
in India (Table VI)22,45-48. Rheumatic carditis has been
antibodies identify recent streptococcal infection. A
considered to be a pancarditis causing pericardial,
fair amount of confusion exists about the exact level
myocardial and endocardial disease.
of antibodies to be considered as high. Generally
antistreptolysin O (ASLO) is the commonest antibody Pericarditis occurs in about 15 per cent cases. It is
measured. It appears in about 7 to 10 days and peaks in identified by the presence of a pericardial friction rub
2 to 3 wk55. It is considered high if the figure is more and may be associated with precordial chest pain. It
than the baseline value present in the community. In can be evanescent and may appear for a brief period.
endemic areas the baseline ASLO could be 250 Todd An echocardiogram can identify the effusion, which
 KRISHNA KUMAR & TANDON: RHEUMATIC FEVER & HEART DISEASE 649

never results in tamponade and subsides without any

Table VII. Frequency of subclinical (SC) carditis in acute RF
sequelae.
Studies N RHD SC (%) Carditis (%)
Studies strongly suggest that RF does not cause Lanna et al 72
40 28 02 (5) 30 (75)
myocarditis. Absence of myocarditis has been
Hilario et al73 22 08 05 (22.7) 13 (59)
documented by (i) absence of increase in markers of
myocardial damage - MB fraction of creatinine kinase Figuero et al 74
35 15 10 (28.6) 25 (71)
(CK-MB), troponin I & T and myoglobin60-62, (ii) Araujo et al75 462 258 72 (15.6) 330 (71)
normal left ventricular systolic function and myocardial SC, subclinical carditis
contractility by echocardiographic studies62,63, (iii)
radionuclide studies using technetium pyrophosphate and aortic valve disease. Clinically carditis has been
scanning and indiumIII labelled anticardiac myocin found in anywhere between 14 to 97 per cent patients
Fab (FAB) do not indicate presence of myocardial (Table VI). The commonest clinical finding is the
damage64,65, (iv) myocardial biopsy studies have not presence of mitral regurgitation with or without aortic
been able to identify the presence of myocarditis59, regurgitation.
(v) normalization of heart size and disappearance of
congestive failure following surgical mitral and/or aortic More recent studies on patients with acute RF
valve replacement in patients deteriorating in spite of utilizing echocardiography have brought out the
aggressive medical management66, (vi) histopathology shortcomings of auscultation in identifying valve
of the left ventricular myocardium showing absence disease which does not result in haemodynamic
of myocardial or inter-myocardial connective tissue abnormalities consisting of regurgitant systolic (mitral)
damage67 and (vii) immunopathology of Ashoff nodule or diastolic (aortic) murmurs. This has resulted in the
(AN), the diagnostic marker of rheumatic pathology, identification of sub-clinical carditis (SC). Data for SC
being derived from mesenchymal cells, complete are now available from a number of studies. However,
absence of cells of myocardial origin in AN and absence follow up data are insufficient. Subclinical carditis
of actin, myosin and desmin (of myocardial origin) in has been assessed by echocardiographic and Doppler
the AN indicating that AN is not of myocardial origin68. (E&D) studies in (i) patients with acute RF, (ii) follow
Hence, congestive cardiac failure in acute RF is due up of patients with past RF who were clinically judged
to an acute volume overload from mitral and/or aortic not to have carditis (NHD), and (iii) evaluation of
regurgitation but not due to myocarditis per se. normal children. SC has been found in 5 to 29 per cent
patients of acute RF (Table VII)73-76 by E&D studies. In
Rheumatic endocarditis represented by cardiac the Utah epidemic of acute RF clinically identifiable
valve involvement results in the only permanent carditis was present in 64 per cent whereas SC
damage from RF. Pathological evaluation of the valves diagnosed by E&D was found in 27 per cent resulting
of patients dying from acute RF indicates microscopic in an overall prevalence of 91 per cent49. Although the
disease in each of the four cardiac valves69. However, American Heart Association (AHA) has not accepted
clinically mitral valve involvement occurs in 90 to 95 E&D studies for the identification of carditis, many
per cent of whom in 20 to 25 per cent, it is associated clinicians feel that E&D studies are necessary for the
with aortic valve disease as well. Clinically isolated care of patients with acute RF since SC cannot be
aortic valve involvement has been reported in less disregarded. Follow up data on patients of acute RF with
than five to eight per cent cases70,71. Tricuspid valve SC are unsatisfactory. Available follow up E&D studies
involvement in acute RF is uncommon and the indicate that the SC can worsen to become clinically
pulmonary valve involvement very rare. Tricuspid obvious RHD, improve or remain unchanged. Lanna et
valve disease has been found to occur in up to 30 to al73 reported an 8-year follow up on 40 patients of RF.
50 per cent in necropsy studies72. Since pericarditis Initially they found two patients with SC but after eight
subsides without sequelae and myocarditis does not years six lost clinical evidence of mitral regurgitation
occur, the morbidity and mortality of RF is determined resulting in eight patients (20%) having SC. Araujo et
by valvulitis the cause of permanent cardiac damage in al76 followed 462 patients for 2 to 23 yr (mean 13.6 yr).
RF. Initial evaluation indicated that 258 (56%) had carditis
In an evaluation of patients with RF the final and 204 without clinical evidence for heart disease.
diagnosis regarding the presence or absence of carditis E&D studies identified 72 (16%) with SC. At the end
is determined by clinical findings related to the mitral of follow up (13.6 yr) the number with clinical carditis
650 INDIAN J MED RES, APRIL 2013

went up to 298 (65 from 56%)76. The E&D studies thus that WHO guidelines are insufficient81. Logically
indicate that patients identified as SC could improve diagnosis of SC should be based on changes of valve
and lose features of SC or become worse and develop damage as well as the haemodynamic consequences of
clinical carditis (RHD). valve damage. We believe that morphological changes
A review of SC involving more than 1700 patients indicating valve damage should be considered more
found overall prevalence to be 16.8 per cent77. WHO important and essential rather than the presence of
criteria for the identification of SC by E&D were valve regurgitation alone, since it is the rheumatic valve
satisfied by 10 studies which gave a prevalence of 18.1 damage which is responsible for the haemodynamic
per cent. Of the 99 patients whose follow up of up to 2 changes in RHD.
years was available, 48 per cent showed improvement At present we need to (i) establish E&D guidelines
and 52 per cent either no change or became worse for identification of SC, (ii) identify the magnitude of
indicating variable course of SC77. SC in apparently “healthy” children, and (iii) follow
In one of the largest study of 1000 patients of acute up studies of SC in apparently healthy children to
RF with a 100 per cent 20 year follow up, 154 (15%) decide the line of management. If follow up studies
patients developed RHD out of 347 (35%) patients indicate that SC can deteriorate to RHD in the absence
initially diagnosed as NHD (labeled as potential of secondary prophylaxis those identified as having SC
RHD), indicating the presence of SC in retrospect78. will have to be put on secondary prophylaxis. In the
In the same study 32 (20%) of the 157 children with absence of long term follow up it is desirable to evaluate
pure chorea (NHD) developed RHD, predominantly adults 20 to 35 yr in age to find out the prevalence of
mitral stenosis in 20 years identifying the presence of SC. This should help in defining the course of SC to
SC. Bland and Jones78 in their study made two crucial some extent. The study from Nicaragua of 376 adults
statements while detailing the delayed appearance of identifying 23/1000 with SC is useful but too small for
RHD. Both statements are sharp clinical judgments any conclusion34.
(in 1951) in the absence of investigative facilities for Pathogenesis of RF
identification of carditis.
It is well established that RF causes permanent
“It may be that minimally scarred valves (initially damage only to the cardiac valves. Clinically the mitral
silent as far as physical signs are concerned) provide aortic, tricuspid and pulmonary valves are involved in
a locus for ------------------- deformed and stenotic order of frequency. Mitral valve involvement is the
orifice”78. commonest and the pulmonary valve involvement is
“In an occasional instance a blowing diastolic rare. However, pathological evaluation of valves from
murmur (slight aortic regurgitation) of grade 1to 2 patients dying of acute RF indicates that microscopic
intensity has been observed to disappear. We suspect involvement of tricuspid and pulmonary valves occurs
that minimal scarring persists in spite of the absence of in almost 100 per cent cases69. The cardiac valve damage
murmurs or enlargement. Postmortem examination in is the basic reason why RF needs to be controlled to
one instance following accidental death supports this reduce the morbidity and mortality related to RF.
suspicion, as well as the insidious appearance of mitral Cardiac valves are derived from the ventricular
stenosis in a few patients 10 to 20 years later78”. myocardium by a process of undermining. The valves
A large amount of data is now accumulating and are composed of a central core of connective tissue
identifying SC by E&D studies of normal children covered on both sides by endothelium. The central core
(Table IV). The exact significance of SC identified of connective tissue is derived from the ventricular
in apparently normal school children needs to be myocardium - muscle and inter-myocardial connective
established. The criteria for identifying SC by E&D tissue. Histopathology indicates absence of myocardial
studies need careful definition. Presently WHO and connective tissue damage in carditis due to acute
and World Heart Federation (WHF) guidelines are RF. Immuno-histopathology excludes myocardial
available79,80. WHO has used only Doppler based damage in RF. Hence, the site of damage in the valves
guidelines identifying the presence and severity of derived from the ventricular myocardium has to be
valve regurgitation. WHF has used changes in valve the valve endothelium82. Endothelium per se consists
morphology as well as Doppler estimation of valve of two components – the endothelial cells and the
regurgitation. At least one study has already indicated basement membrane to which the cells are attached. By
 KRISHNA KUMAR & TANDON: RHEUMATIC FEVER & HEART DISEASE 651

exclusion the findings suggest that the valve damage is active or inactive at the time a patient presents as
related to the valve endothelium- the endothelial cells, chorea? Hence high or normal ESR and CRP do not
the basement membrane and the substance binding identify active or inactive rheumatic process. Why
these together82. should chorea occur three to six months after the CNS
It is well established that RF follows GAS infection damage that occurs during acute RF? What is the
of the tonsillopharynx and does not follow skin duration of active rheumatic inflammation in RF? The
infection. Mesothelium and endothelium are derived damage resulting from active rheumatic process has
from mesenchymal cells. Mesothelial cells cover to be separated from the residual effect of the damage
tonsillopharyngeal region whereas ectodermal cells, caused by the rheumatic disease. The duration of the
which are completely different in composition from disease in acute glomerulonephritis, the other non-
mesothelial cells, cover skin. Why should RF follow suppurative manifestation of GAS infection, is less than
pharyngeal infection but not dermal infection? Is it seven to ten days85. Majority of patients recover within
because the GAS infection affecting the pharyngeal that time. Urinalysis continues to show microscopic
mesothelial cells sensitizes the cells in a way which haematuria for several months in spite of clinical
later manifests as endothelial cell damage of the valve recovery. Unfortunately there are no investigations,
tissue and mesothelial cell damage elsewhere (arthritis, which can identify active rheumatic disease process
etc.) later on ? itself.
Pathogenesis of RF is not known. Research to Management
elucidate the pathogenesis has been directed almost There has been no significant change in the
exclusively toward myocarditis and myosin for the last management of acute RF in the last 50 years. Patients
more than 60 years without any breakthrough83,84. An need penicillin to eradicate GAS present in throat. Anti
alternative approach with endothelium as the target inflammatory agents - aspirin or steroids - are used to
of rheumatic damage as well as guidelines for further control rheumatic activity. Aspirin or steroids do not
research have been suggested in the hope that these may
cure RF. These suppress the inflammatory response
help in identifying the GAS antigen (s) responsible for
which lasts for about 12 wk in more than 80 per cent
RF82.
patients. Hence, the standard dose of aspirin (90-120
Acute RF: duration of disease mg/kg/day) is given for ten weeks and tapered in the
A combination of some clinical manifestations next two weeks. The dose of prednisone 60 mg/day
and laboratory tests put together by Jones, revised and above 20 kg and 40 mg /day below 20 kg in weight
modified from time to time by the AHA, identify the is given for three weeks and tapered in the next nine
syndrome of RF. Elevated ESR and CRP are nonspecific weeks. The standard 12 week course can be reduced to
and identify the presence of an active inflammatory four to eight weeks depending on the patient’s response.
disease. Elevated anti-streptococcal antibodies indicate Patients without carditis can have weekly follow up of
streptococcal infection. Thus there is no specific ESR and CRP. If they normalize, the course can be
investigation, which is diagnostic for RF. Of the reduced to a shorter period. Aspirin is preferred over
clinical manifestations arthritis, erythema marginatum steroids as long as the carditis is mild and the patient is
and carditis suggest acute and active RF. Subcutaneous not in congestive failure. However, with severe carditis
nodules and chorea are late manifestations and indicate and congestive failure steroid is the drug of choice
past RF not active RF. because of the more potent suppressive effect.
The inference that RF lasts 10 to 12 wk in about 80 Non-steroidal anti-inflammatory drugs (NSAIDs)
per cent patients was dependent on the elevated ESR have not been systematically utilized to establish their
and CRP. As of today we do not know the duration of usefulness. Immunosuppressive agents like azathioprine
active rheumatic “process” per se. Arthritis suggests and cyclosporine A have also been considered for acute
active RF, however, if the rheumatic process is active rheumatic fever. Despite of the concerns of side effects,
why should arthritis subside without treatment? The toxicity and late onset of lymphomas with the use of
central nervous system (CNS) damage occurs with these immunosuppressive it is possible to argue that a
acute RF. At the time patients present with chorea the short course of 6 to 8 wk may result in a greater benefit
ESR and CRP may be normal indicating absence of an than harm. However, most ethics committees will
active disease process. Is the rheumatic inflammation hesitate to permit systematic testing of these agents.
652 INDIAN J MED RES, APRIL 2013

It is now well accepted that rheumatic endocarditis with acute RF, without additional risk and acceptable
involving heart valves is the main cause of morbidity results. In the presence of acute RF restenosis rate was,
and mortality in RF. Surgical management consisting however, 40 per cent compared to 10 per cent in those
of mitral and /or aortic valve replacement in patients without active RF88,89.
whose congestive failure cannot be controlled by
aggressive medical treatment during acute RF, is life Prevention of RF and RHD
saving. It the congestive failure cannot be controlled A disease which follows a bacterial infection
with maximal medical therapy and the patient is should, theoretically, be preventable if the organism
deteriorating due to mitral regurgitation, mitral valve does not become resistant to antibiotics. GAS have
replacement during active RF is indicated. In spite of remained sensitive to penicillin and should have
clinical evidence for active RF, the heart size returns to been eradicated. Unfortunately despite a decline in
normal and congestive failure disappears, confirming prevalence, RF continues to occur in socioeconomically
that rheumatic myocarditis plays little or no role in the disadvantaged populations and even developed
mortality of RF66. countries have witnessed resurgences in localized
Management of chorea: It has a self limiting course, areas49,90. Steps in the development of RF consist
hence parents need reassurance. The children could be of GAS pharyngitis, which should be symptomatic
treated with sedatives like phenobarbitone 30 mg thrice enough to require medical attention, throat culture
daily. chlorpromazine, valium, diphendydramine or to confirm the diagnosis and ensuring that the course
promethazine can be used as sedatives. Haloperidol 5 to of penicillin treatment has been completed. The last
10 mg twice daily has been used effectively. Although epidemic of RF in Utah area in USA occurred in well
aspirin and steroids are not supposed to have a place to do middle class families, absence of overcrowding
in the treatment of chorea, some patients have shown and with access to good medical care. The findings of
dramatic response to steroids, if they do not show the epidemic indicated that the preceding pharyngitis
adequate response to sedatives86,87. Since, long term was asymptomatic in 78 per cent, 18 per cent obtained
follow up of chorea patients have identified subclinical medical help and the 10 day course of oral penicillin
carditis in 20 to 30 per cent patients, penicillin was not completed by patients49,90.
prophylaxis is essential and should be continued on a
long term basis50,51. Prevalence of RF/RHD has been attributed to
overcrowding and unhygienic living related to low
Rheumatic heart disease: Surgical management socio-economic status. Unhygienic living results in
of valve disease was the standard approach till persistent GAS in the environment. Since GAS spreads
balloon mitral valvotomy was introduced in 1985. by droplet dissemination, overcrowding causes cross
Mitral stenosis could be corrected surgically either infection from person to person. Low socio-economic
by closed valvotomy, open commissurotomy or by status may undermine nutrition and seriously limit
valve replacement if the valve was calcified. Balloon access to medical treatment. Poor nutritional status is
valvotomy provides results as good as surgical believed to contribute to a decreased immune response.
valvotomy and has become the treatment of choice in The result is not only endemic RF but also a more
spite of being more expensive. For mitral regurgitation
severe or virulent disease (Fig. 1).
the choice of treatment would be valve repair especially
in younger patients to avoid long-term anti-coagulant It is possible at the same time that the initial
therapy. Most patients with mitral or aortic valve attack of RF is mild and results in mild carditis, which
regurgitation end up with valve replacement. Hence, remains subclinical, undiagnosed, and as such the
although surgical help is very useful it is expensive patient does not get prophylaxis to prevent recurrences.
and requires prolonged care with anticoagulant therapy In low socio-economic settings, recurrences causing
with the associated complications of valve thrombosis further cardiac damage result in symptomatic RHD
and systemic embolic disasters especially in the low- with multivalve involvement and congestive failure
income population of the country. Over a long follow up identified as the first attack of severe (malignant) RF
period relatively few patients remain free of events. (Fig. 2). The high prevalence of subclinical carditis
Balloon mitral valvotomy has been utilized in the found by echocardiographic studies suggests that the
paediatric patients below 12 yr in age with acceptable initial attack of RF is probably relatively mild and in the
results. It has been extended to patients of mitral stenosis absence of secondary prophylaxis it is the recurrences,
 KRISHNA KUMAR & TANDON: RHEUMATIC FEVER & HEART DISEASE 653

the risk of RF from sore throat specially below the age

of 15 yr.
Low socio-economic status Improvement in nutrition improves immune
response and the capacity of individuals to resist and
fight infection. Public education is the most important
component for primordial prevention. Unless parents
know that a sore throat can cause RF and RHD, it is
GAS GAS most unlikely to be seen by a physician and treated.
Improvement in socio-economic status and preventing
overcrowding cannot be relied upon to reduce the
burden of RHD.
Primary prevention: Primary prevention is theoretically
feasible but practically extremely difficult to achieve.
Primary prevention requires identification of (GAS)
sore throat and use of penicillin to eradicate the
Fig. 1. Relationship of low socio-economic status to rheumatic streptococci. The requirement for primary prevention
fever (RF). consist of (i) public awareness regarding danger of
RF from sore throat (ii) identification of sore throat as
being due to GAS infection, and (iii) use of injectable
which are responsible for patients presenting with penicillin to cure the infection.
severe disease being labelled as the first attack of RF.
It is important to know that oral penicillin may not
The strategies for prevention consist of primordial be effective in preventing RF. RF occurred in 15 to 48
prevention, primary prevention and secondary per cent children given oral penicillin for 10 days in an
prevention. earlier epidemic in USA90. Compliance of a 10 day oral
Primordial prevention: It requires, preventing the treatment even in educated families is not certain. It
development of ‘risk factors’ in the community to is, therefore, essential that injectable penicillin is used
prevent the disease in the population and thus protect to prevent RF. The recommended dose of penicillin
individuals. Requirements for primordial prevention in is 400,000 units of procaine penicillin twice daily for
relation with RF and RHD consist of (i) improvement in ten days. Although recommended, one injection of 1.2
socio-economic status, (ii) prevention of overcrowding, mega units of benzathine penicillin may not be enough
(iii) improving nutritional status, (iv) availability of to eradicate GAS infection especially in endemic
prompt medical care, and (v) public education regarding areas91. Since GAS infection spreads through droplets
from person to person, eradication of GAS even in one
individual will reduce the total burden of the organism
in the community. The inability to utilize primary
prevention at the community level is due to the large
number of sore throats requiring treatment to prevent a
single episode of RF.
Community level management requires a
sledgehammer approach, that is, each sore throat must
be treated. At present, bacteriological facilities required
to identify GAS sore throat at the community level for
the whole country, would be expensive, do not exist
and are not likely in the near future. Hence, each sore
throat will need to be treated to reduce the cost. Treating
each sore throat is logistically not feasible. Anywhere
from 3 to 20 per cent of sore throats can be due to GAS
Fig. 2. Possible mechanism to explain why RF appears to be severe infection, the rest being viral infections, which do not
in the initial attack. require treatment. About 0.3 per cent of streptococcal
654 INDIAN J MED RES, APRIL 2013

sore throats result in RF92. Recent data suggest that Secondary prevention has been found to help in
almost 90 per cent of those who get RF develop RHD49. disappearance of clinical findings of RHD. However,
Hence if 10,000 sore throats were treated by the disappearance of murmurs does not indicate that the
sledgehammer approach, anywhere between 300-2000 heart disease has disappeared. Recurrence of RF results
GAS sore throats would be treated (assuming 3 to 20% not only in appearance of murmurs but also the valve
are due to GAS). This would result in preventing RF in damage is worse than before.
one to six children (0.3% GAS throats cause RF), and Anti-streptococcal vaccine
RHD in either five or six children. Therefore, 10,000
sore throats need to be treated to prevent RHD in five Availability of a vaccine, which could prevent
to six children. A community level primary prevention streptococcal infection, is essential for primary
by sledge-hammer approach is not feasible. prevention of RF. It is at present not available. GAS
infection results in suppurative and non-suppurative
Another problem in sledgehammer approach is the manifestations. Suppurative diseases like toxic shock
identification of sore throat and its treatment. The data syndrome and necrotizing fasciitis could be lethal. The
from resurgence of RF in USA indicate that as much as two non-suppurative manifestations are acute RF and
78 per cent of GAS sore throats may be asymptomatic, acute glomerulonephritis (GN). Several GAS protein
ten day oral penicillin treatment was not followed by and polysaccharide components have been considered
well educated families and 48 per cent of those given in developing a vaccine. Most work has been in relation
oral penicillin developed RF49,90. Unless a sore throat with the M- protein, considered to be the virulence
is symptomatic, it would not be treated and could still factor of the GAS83,84. Other components of GAS being
result in RF. Even an individual patient cannot be tried for preparing a vaccine are GAS C5a peptidase,
protected if the preceding sore throat is asymptomatic. a major surface virulence factor; fibronectin binding
This makes primary prevention based on the diagnosis protein sfb1, and the chimeric peptide J8 from the
of GAS sore throat and use of oral penicillin inadequate conserved region of the M- protein93.
to reduce the burden of RHD in the country. The amount
M- protein has been found to be strain-specific,
of penicillin required for sledgehammer approach is
that is, each strain has its specific characteristics and
not available in the country.
protective against only that particular strain. Since
As of today there are no markers that can be used more than 250 different strains have been identified, it
to identify susceptibility to RF. Studies on HLA and the is essential that the vaccine must be polyvalent, that is,
B-lymphocyte antigen, D8/17 have not given results incorporate all the strains present in the community94.
which can be used to identify the susceptible people in GAS has a strong tendency for mutation and the
the population to practice primary prevention92. vaccine may not be effective if the infection is due to an
organism, which has mutated after being incorporated
Primary prevention is possible if an anti- in the vaccine95. Virulent GAS infection causing
streptococcal vaccine becomes available. death from toxic shock syndrome is now known not
Secondary prevention: Secondary prevention to express M-protein96. Hence, M-protein cannot be
requires identification of those with RF or RHD and the chief virulence factor of GAS. Vaccine based on
maintenance of a registry. Once identified, the patient M-protein is unlikely to succeed because:
needs injections of benzathine penicillin, given once On the basis of emm typing of M-protein more than
in two to three weeks, depending on age, body size 250 strains of GAS can cause infection and provide only
and muscle mass. Benzathine penicillin is painful, may strain-specific immunity. Hence, the anti GAS vaccine
result in fever and very rarely in anaphylactic reactions. has to include all the strains in the community94.
Most physicians are very reluctant to give penicillin
injections. The necessity of penicillin prophylaxis is Heterogeneous distribution of strains varies
due to the fact that RF has a tendency for recurrences from place to place and keeps changing even within
in those who have had RF in the past. Each new attack a closed community in a short period. Vaccine based
causes further damage to the valve tissue making the on M-protein made in Delhi may not be effective in
disease worse than before43. Secondary prevention can Chandigarh, Chennai or Mumbai or even in Delhi after
a few months97.
reduce the damage of recurrences but cannot prevent
the initial damage. Further, secondary prevention GAS mutation alters the emm gene sequence of
cannot reduce the burden of RHD in the community. the M-protein. Mutation can occur in a few weeks.
 KRISHNA KUMAR & TANDON: RHEUMATIC FEVER & HEART DISEASE 655

The vaccine may not be effective against infection by The answer to the question “Is it possible to
a strain that has mutated after being incorporated in the prevent rheumatic fever”? has to be “No”, for primary
vaccine even in a very short time95. prevention at the community level. Primary prevention
will have to wait till a safe and effective GAS vaccine
GAS infection has resulted in lethal toxic shock becomes available.
syndrome without expressing M-protein, electron
microscopy failing to identify M-protein fibrils on the In our country the health of the child generally
surface of the organism and the isolate failing to resist remains a priority responsibility of the parents even
phagocytosis, suggesting the absence of “functional when the child becomes an adult. Hence, prevention
M-protein”96. of RF and RHD is possible to a large extent if we
can provide the message, in local languages, to the
M-protein has been excluded as the antigen population (parents) that sore throats should not
responsible for acute GN the other non suppurative be neglected; that sore throats should be shown to a
manifestation of GAS infection85. doctor for treatment to prevent RF and RHD. Radio
The surface M-protein of GAS was designated and television are available for reaching each corner
as the virulence factor of GAS. The similarity in the of the country and should be utilized for this purpose.
structure of M-protein and the human tropomyosin If education can be made compulsory till the age of
has resulted in accepting, without proof, that it is 15 yr, school health education and school health care
facilities can be utilized to control RF.
responsible for RF. There is no evidence to indicate
that M-protein is the antigen responsible for [Link] RF and RHD continue to be an undesirable burden.
is no information regarding the role M-protein plays in RF occurring at a young age results in morbidity as
the suppurative diseases due to GAS infection. well as mortality in adolescents and young adults, and
also becomes one of the major causes of loss of the
Toxic shock syndrome occurred in the absence of
most productive years of life in our country. With the
functional M-protein and the paediatric nephrologists
identification of subclinical carditis in normal children,
have excluded M-protein as being responsible for the total burden of RHD is much higher than that
acute GN. Therefore, there is evidence that at least estimated in various studies. Although the disease (RF)
two, one suppurative and one non-suppurative of the follows a bacterial (GAS) infection, the pathogenesis
various GAS related manifestations are unlikely to has not been worked out in more than 60 years. Duration
be prevented by a vaccine based on M-protein The of the disease, specific medical treatment to control or
vaccine if and when available is expected to prevent prevent cardiac damage and primary prevention of
GAS infection. This will prevent GAS infection related RF continue to be elusive. Primary prevention has to
diseases - necrotizing fasciitis, toxic shock syndrome, depend on designing a vaccine to prevent GAS infection
acute glomerulonephritis, rheumatic fever, pyoderma related suppurative as well as non-suppurative disease
and septic arthritis, etc. manifestations.
Unfortunately in spite of extensive evaluation
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New Delhi 110 016, India
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