Rheumatic Fever 2023 May.pdf

History
4
1886 Cheadle ARF
1904 Aschoff Nodule
1931 Cobun Strep-RF
1944 Jones Criteria For Diagnosis
1951 Wannamaker Primary prophylaxis
1954 Stollerman Secondary Prophylaxis
1955 AHA Guideline
2015 AHA High /Low risk group
Doppler ECHO
Diagnosis of recurrence

5
Rheumatic heart disease (RHD) is still a major health
problem in several countries due to the heart lesions that
follow a rheumatic fever (RF) episode in 30-45% of
patients. The incidence of acute RF (ARF) in some
developing countries exceeds 50 per 100,000 children. The
worldwide prevalence of RHD is at least 15.6 million cases,
and this disease is responsible for around 233,000
deaths/year. (Carapetis JR, Steer AC, Mulholland EK, Weber M. The global burden of
group A streptococcal disease. Lancet Infect Dis 2005;5:685-94)
RHD results from autoimmune reactions triggered by an
untreated S. pyogenes throat infection leading to severe
valvular damage in genetically susceptible individuals.
Recurrences of ARF play an important role in the worsening
of valvular lesions. (Mota CC, Aiello DV, Anderson RH. Chronic rheumatic heart disease. In:
Anderson RH, Baker EJ, Penny DJ, editors. Pediatric Cardiology. 3 rd ed. Philadelphia: Churchill
Livingstone/Elsevier; 2009. p. 1091-133.
Bland EF, Duckett Jones T. Rheumatic fever and rheumatic heart disease: A 20 years report on 1000 patients followed
since childhood. Circulation 1951;4:836-43.)

Is it rheumatic fever ?
Migratory -Sore knees ankles wrists elbows
Heart murmur
Hard to breath
Jerking twitching movements of the body
Fever - Hot person
Recent sore throat or skin sores- impetigo

Definition
7
Rheumatic fever (RF) is an inflammatory disease that can
involve the heart, joints, skin, and brain. he disease typically
develops two to four weeks after a streptococcal throat
infection. Signs and symptoms include fever, multiple painful
joints, involuntary muscle movements, and occasionally a
characteristic non-itchy rash known as erythema Marginatum.
The heart is involved in about half of cases.
Damage to the heart valves, known as rheumatic heart
disease (RHD), usually occurs after repeated attacks but can
sometimes occur after one episode. The damaged valves may
result in heart failure, atrial fibrillation and infection of the
valves

8
Rheumatic fever is an inflammatory disease that
can develop as a complication of inadequately
treated strep throat or scarlet fever.
Strep throat and scarlet fever are caused by an
infection with streptococcus bacteria.
Group A streptococcus infections of the skin or
other parts of the body rarely trigger
rheumatic fever. The available data support the
hypothesis that group A streptococcal impetigo
plays a role in the pathogenesis of RHD.
(Curr Opin Infect Dis. 2012 Apr;25(2):145-53.)
Etiology

9
The similarity between antigens of Streptococcus
pyogenes and multiple cardiac proteins can cause a life-
threatening type II hypersensitivity reaction. Usually, self
reactive B cells remain anergic in the periphery without T
cell co-stimulation.
During a streptococcal infection, mature antigen-presenting
cells such as B cells present the bacterial antigen to CD4+T
cells which differentiate into helper T2 cells.
Helper T2 cells subsequently activate the B cells to
become plasma cells and induce the production of antibodies
against the cell wall of Streptococcus. However the
antibodies may also react against the myocardium and joints,

10
T cell activation is triggered by the presentation of bacterial
antigens. In RHD, molecular mimicry results in incorrect T cell
activation, and these T lymphocytes can go on to activate B
cells, which will begin to produce self-antigen-specific
antibodies. This leads to an immune response attack mounted
against tissues in the heart that have been misidentified as
pathogens.
Rheumatic valves display increased expression of VCAM-1, a
protein that mediates the adhesion of lymphocytes.
Self-antigen-specific antibodies generated via molecular
mimicry between human proteins and streptococcal antigens
up-regulate VCAM-1 after binding to the valvular endothelium.
This leads to the inflammation and valve scarring observed in
rheumatic valvulitis, mainly due to CD4+ T cell infiltration.

Etiology
l Acute rheumatic fever is a systemic
disease of childhood, Often recurrent
that follows group A beta hemolytic
streptococcal infection.
l It is a delayed non-suppurative sequelae
to URTI with GABH streptococci.
11

Risk factors
Factors that can increase the risk of rheumatic fever are:
Family history. Some people carry a gene or genes that
might make them more likely to develop rheumatic fever.
Type of strep bacteria. Certain strains of strep bacteria
are more likely to contribute to rheumatic fever than are
other strains.
Environmental factors. A greater risk of rheumatic fever
is associated with overcrowding, poor sanitation and other
conditions that can easily result in the rapid transmission
or multiple exposures to strep bacteria.

Epidemiology
l Ages 5-15 years are most susceptible
l Rare <3 years
l Girls>boys
l Common in 3rd world countries
l Environmental factors--over crowding,
poor sanitation, poverty,
l Incidence more during fall, winter &
early spring
13

Epidemiology
l Females are affected more frequently than are males by a
ratio of 2:1. Chorea appears to be less common in adults,
particularly men.
l SC appears to have a familial predisposition, as illustrated
by the following observations:
A family history of rheumatic fever occurs in up to 30
percent of families with a history of chorea and in an
older study, SC occurred in 3.5 percent of families with
rheumatic fever and 2.1 percent of siblings in the same
family.
The Indian Council of Medical Research (ICMR) data
suggest a progressive decline in RHD from 5.3 to 2.9 to
below 1.0/1000 from 1970 to 2010.
In addition, the hospital admission rate has declined by
5-26%. (Ann Pediatr Cardiol. 2016 May-Aug; 9(2): 164–166.)

GABHS STRIKE RATE
15
THE STRIKE RATE IS 3/1000
It means 997 children out of 1000 infected
do not develop ARF
Susceptibility is linked to –
HLA : Human leukocyte antigen (HLA) class II allele DR7
(HLA-DR7) is most often associated with RHD, and its
combination with certain DQ alleles is seemingly associated
with the development of valvular lesions.
B cell allo Ag
Cytokine genes

Pathogenesis
16
GABS
SUSCEPTIBLE HOST
IMMUNE INJURY
RF
T Cell
CD4+
CD8+
BREACH IN ENDOTHELIAL
CONTINUITY
SUB ENDOTHELIAL
DAMAGE
RF Initial insult
RHD Chronic insult
Genetic
B Cell
CROSS
REACTING
ANTIBODY
Virus ?
ENVIRONMENT

17
It is believed to be caused by antibody cross-reactivity against M
protein, a virulence factor that is highly antigenic.
This cross-reactivity is a type II hypersensitivity reaction and is
t e r m e d m o l e c u l a r m i m i c r y . U s u a l l y , s e l f r e a c t i v e B
cells remain anergic in the periphery without T cell co-stimulation.
This causes an autoimmune reaction against native tissues in the heart
that are incorrectly recognized as "foreign" due to the cross-reactivity
of antibodies generated as a result of epitope sharing
During a streptococcal infection, mature antigen-presenting cells such
as B cells present the bacterial antigen to CD4+T cells which
differentiate into helper T2 cells. Helper T2 cells subsequently activate
the B cells to become plasma cells and induce the production of
antibodies against the cell wall of Streptococcus. However the
antibodies may also react against the myocardium and joints, producing
the symptoms of rheumatic fever.

18
Several genes controlling innate and/or adaptive immune
responses are involved with the development of the
Rheumatic fever and Rheumatic Heart disease
Role of genetics in ARF & RHD

19
Role of genetics in ARF & RHD
Cytokines seem to play a pivotal role in the activation of immunological
and inflammatory responses in RF. It has been shown that peripheral
blood mononuclear cells (PBMC) from children with RF produce more
TNF-α than healthy controls. (Miller LC, Gray ED, Mansour M, Abdin ZH, Kamel R, Zaher S, et al. Cytokines and
immunoglobulin in rheumatic heart disease: Production by blood and tonsillar mononuclear cells. J Rheumatol 1989;16:1436-42.)
Moreover, interleukin-6 (IL-6) and TNF-α are considered inducers of
the acute phase of RF and are strongly correlated with C-reactive
protein. (Yeðin O, Coþkun M, Ertuð H. Cytokines in acute rheumatic fever. Eur J Pediatr 1997;156:25-9. )

20
Innate and Adaptive Immune Responses
Protection against pathogens in the humans relies on
complex interactions between innate and adaptive immunity.
Most of the pathogens that enter the body are recognized
initially by the innate immune system. The complement
system is part of the innate immune system and consists of
many proteins involved in a cascade of proteolysis and
protein complex assembly that culminates in the elimination
of invading pathogens. Several components of the bacterial
cell surface combine with Pattern Recognizing Receptors
such as Ficolin family of proteins, or Mannan binding lectins
(MBL). These complexes, in turn combine with serine
proteases and lead to complement activation via lectin
pathway resulting in opsono-phagocytosis of the invading
pathogen, apoptosis, or modulation of inflammation. The
molecules produced during the innate immune response act
as signals to activate adaptive immune responses.

21
Several alleles of the HLA class II genes appear to be the dominant
contributors to the development of RF and RHD. Polymorphisms (SNPs
and variable number of tandem repeat sequences of nucleotides) in
genes involved with inflammatory responses and host defenses against
pathogens that are associated with disease probably contribute to the
development of valvular lesions and can determine the type of rheumatic
valvular lesions stenosis, regurgitation, or both that occur in RHD patients.
( L Guilherme, KF Köhler, E Postol, J Kalil Genes, autoimmunity and pathogenesis of rheumatic heart disease 2011 | Volume : 4 | Issue : 1
| Page : 13-21)

Pathogenesis
l Delayed immune response to
infection with group.
A beta hemolytic streptococci.
l After a latent period of 1-3 weeks,
antibody induced immunological damage
occur to heart valves, joints,
subcutaneous tissue & basal
ganglia of brain
22

23
l Strains responsible for rheumatic fever are
M types l, 3, 5, 6,18 & 24.
l Pharyngitis- produced by GABHS can lead to
- acute rheumatic fever, rheumatic heart
disease and post strept. Glomerulonephritis.
l Skin infection- produced by GABHS leads to
post streptococcal glomerulonephritis only.
It rarely result in Rheumatic fever.
Group A Beta Hemolytic Streptococcus

24
Diagrammatic structure of the group A
beta hemolytic streptococcus
Capsule
Cell wall
Protein antigens
Group carbohydrate
Peptidoglycan
Cyto.membrane
Cytoplasm
……………………………………………
……...
Antigen of outer
protein cell wall
of GABHS
induces antibody
response in
victim which
result in
autoimmune
damage to heart
valves,
sub cutaneous
tissue,tendons,
joints & basal
ganglia of brain

25
The M protein is the most important antigenic structure of
the S. pyogenes and shares structural homology with a-
helical coiled-coil human proteins such as cardiac myosin,
tropomyosin, keratin, laminin, vimentin and several valvular
proteins. Among these human proteins, cardiac myosin and
vimentin seem to be the major targets of cross-reactive
reactions, along with other intracellular valvular proteins.
Cunningham MW. Pathogenesis of group A streptococcal infections. Clin Microbiol Rev 2000;13:470-511.
Pathophysiology

26
N-acetyl ß-D-glucosamine, a polysaccharide present in streptococcal
cell wall, induces cross-reactivity against laminin, an extracellular
matrix alpha helical coiled-coil protein present in the valves. By
using affinity purified anti-myosin antibodies, Cunningham΄s group
identified a five amino acid (Gln-Lys-Ser-Lys-Gln) epitope of the N-
terminal M proteins of serotypes 5 and 6 (M5, M6) as being cross-
reactive with cardiac myosin.
Cunningham MW. Pathogenesis of group A streptococcal infections. Clin Microbiol Rev 2000;13:470-511.

28
Molecular mimicry between streptococcal antigens and
human proteins, including cardiac myosin epitopes, vimentin
and other intracellular proteins is central to the
pathogenesis of RHD.
Autoreactive T cells migrate from the peripheral blood to
the heart and proliferate in the valves in response to
stimulation with specific cytokines. The types of cells
involved in the inflammation as well as different cytokine
profiles in these patients are being investigated. High TNF
alpha, interferon gamma, and low IL4 are found in the
rheumatic valve suggesting an imbalance between Th1 and
Th2 cytokines and probably contributing to the progressive
and permanent valve damage.
(Genes, autoimmunity and pathogenesis of rheumatic heart disease L Guilherme, KF Köhler, E Postol, J Kalil Annals
of Pediatric Cardiology, Year 2011, Volume 4, Issue 1 p. 13-21)

29
GAS infection results in suppurative and non-suppurative disease manifestations.
The two non - suppurative manifestations are acute RF and acute
Glomerulonephritis (GN). An immunological basis for pathogenesis has been widely
accepted for both non - suppurative manifestations.

Pathophysiology
Aschoff nodules
Aschoff Nondule(AN) which are the hallmark of rheumatic pathology are
not secondary to myocardial damage and are derived from mesenchymal
tissue.
A typical AN measures upto 10.68 ± 0.06 × 10−2 mm 2 (mean area 9.43 ±
0.87 × 10−2 mm 2 ). AN contain 21% T lymphocytes, 13% macrophages,
four% "β" cells, fibroblasts, and giant cells.
Of the T lymphocytes, CD4+ cells and CD8+ cells are in a ratio of 2.0.
CD4+ cells could be from 70% to 100% and the CD8+ cells from 0% to 30%.
The dominant infiltrative cells are the T lymphocytes and the macrophages.
The macrophages are not of muscle origin since they do not stain with
HHF-35 monoclonal antibodies (mabs) specific for actin.

Pathophysiology
Aschoff nodules
The giant cells - owl eye and the Anitschkow - are negative for myosin,
myoglobin, and desmin.
The giant cells are positive for the presence of vimentin which is of
mesenchymal origin.
The macrophages express MHC antigens (HIA-DR+).
Cytokine studies indicate the production of tumor necrosis factor and
interleukin-1.
Thus, the presence of AN is useful in identifying rheumatic inflammatory
pathology but does not indicate the presence of rheumatic myocarditis.

32
Perivascular AN in left ventricular myocardium. The myocardium
and the interstitial tissues are unaffected except in the
perivascular area

Pathologic Lesions
l Fibrinoid degeneration of connective tissue,
inflammatory edema, inflammatory cell
infiltration & proliferation of specific cells
resulting in formation of Ashcoff nodules,
resulting in-
-Pancarditis in the heart
-Arthritis in the joints
-Ashcoff nodules in the
subcutaneous tissue
-Basal gangliar lesions resulting in
chorea
33

34
Heart is the most extensively studied organ and the findings
have been summarized by Virmani et al. There is evidence
for inflammation which is confined to the sub-epicardial,
sub-endocardial, and perivascular connective tissue of the
heart in addition to a generalized vasculitis throughout the
body. There is little myocyte disruption and the
intermyocardial connective tissue is not damaged. The
hallmark of RF carditis is the Aschoff nodule (AN). The AN
is strictly peri-vascular in location with minimal surrounding
myocyte and connective tissue damage. The AN contains
lymphocytes, macrophages, β cells, and giant cells.
Immunopathology of the AN indicates that it does not have
any cells of myocardial origin. Therefore, it can safely be
concluded that the AN, the hallmark of rheumatic carditis,
is not derived from myocardial damage. Except the
perivascular area, the rest of the myocardium and the
interstitial tissue are normal.

days
penicillin
concentration
in
blood
GAS
exposure
GAS
exposure
Joint/
carditis
ARF
Chorea
ARF
2-3 weeks
6-9
weeks
Peak in
ASOT
Peak in antiDNAseB
days at
risk
Days at risk

Clinical Features
l In children below 5 yrs arthritis usually mild
but cardiac involvement is more prominent
38
1.Arthritis 80%
Clinically individual joints have evidence for inflammation
lasting 1-7 days.
"The synovial membrane is reddened and thickened and
covered with fibrinous exudates. Histologically there is
marked edema, engorgement, and dilation of blood vessels
and diffuse and focal infiltrates of lymphocytes and
polymorphs. Fibrinoid and histiocytic granulomas are formed."
Arthritis has a limited duration of 2−3 weeks and heals without
residual damage. Similar to other organs, arthritis can also be ascribed
to endothelial inflammation.

39
Rheumatic arthritis is an asymmetric, migratory / fleeting
polyarthritis with predominant involvement of large joints
of lower limbs and migrates to the upper limb.
Commonly involved joints- knee, ankle, elbow & wrist, in 80%.
Classically the joints are red, tender, swollen and the child
cannot tolerate any movement about the joint.
If untreated, then symptoms subside in about a week
without residual damage followed by affection of other
joint.
The child responds dramatically to aspirin. Rheumatic
arthritis is treated with aspirin in doses of 90-120
mg/kg/day in four divided doses for 12 weeks.

40
Small joints involvement (metacarpophalangeal,
interphalangeal) was reported in 2-8% by Terreri et al.
Terreri MT, Caldas AM, Len CA, Ultchak F, Hilario MO. Clinical and demographic features of 193 patients with rheumatic fever. Rev
Bras Reumatol. 2006;46:385–90.
while in Lin Chen and Robazzi et al. study it constituted
18% and 38.7% of their cases, respectively. Robazzi TC, de Araújo SR, Costa
Sde A, de Oliveira Júnior AB, Nunes LS, Guimarães I. Articular manifestations in patients with atypical rheumatic fever. Rev Bras
Reumatol. 2014;54:268–72.
Pileggi et al. described involvement of cervical spine and
lumbar spine in 26% and 4%, respectively. Pileggi GC, Ferriani VP. Atypical
arthritis in children with rheumatic fever. J Pediatr (Rio J) 2000;76:49–54
The involvement of small joints of feet and hands and axial
skeleton (spine and sacroiliac and hip joints) may cause
diagnostic difficulties with post-streptococcal reactive
arthritis (PSRA),

Jaccoud’s arthritis
41
Jaccoud’s arthritis, which is a progressive deformity
of the hands and feet in young adults following
recurrent rheumatic fever .
In Jaccoud’s arthritis; Subluxation of the proximal
phalanges may cause a hook-like deformity of the
metacarpal heads. The toes may also be affected.

42
Comparison of Post-Streptococcal Reactive Arthritis (PSRA) and Acute
Rheumatic Fever (ARF)
PSRA ARF
Age Bimodal: 8-14 years and
21-37 years
5-15 years with peaking
around 12 years
Disease onset following
streptococcal infection
7-10 days (short) 10-28 days (longer)
Joint involvement Additive and persistent;
large, small and axial
joints
Migratory, transient; large
joints
Acute phase reactants Moderate elevation Marked elevation
Response of arthritis to
aspirin
Poor to moderate Dramatic
Carditis Conflicting reports, but
uncommon
Major diagnostic criterion,
between 60-70%
Antibiotic prophylaxis For one year if
echocardiogram is normal
Long-term secondary
antibiotic prophylaxis

Heart 40-50%
l Manifest as pancarditis (endocarditis and
pericarditis)
l occur in 40-50% of cases.
l Inflammation of Valve is the only
manifestation of rheumatic fever that leaves
a sequelae & permanent damage to the organ
l Inflammation of Valve occur in acute phase
l In Chronic phase- fibrosis, calcification &
stenosis of heart valves occur (fish mouth
valves)
43

44
Rheumatic carditis has been described as a pancarditis
involving the pericardium, the myocardium, and the
endocardium.
Recent studies indicate that RF does not cause myocardial
damage.
Oran et al. ( Indian J Pediatr 2001;68:943-4. ) found that the creatine kinase MB,
myoglobin, and troponin-I in patients with acute RF with active
carditis with or without cardiomegaly or congestive failure remain
normal on the 3 rd , 7 th , 14 th and 21 st day indicating an absence of
significant myocardial damage.
Kamblock and associates(Europ Ht J 2003;24:855-62. ) estimated cardiac
troponin-I (cTnl) levels and studied the left ventricular function in 95
consecutive patients of acute RF. They concluded that there was no
cTnI elevations or echocardiographic abnormalities suggesting
significant myocardial involvement during RF. Congestive heart
failure was always associated to severe valvar regurgitation

45
Radhakrishnan and associates (Thesis submitted to All India Institute of Medical Sciences 1986)
used technetium 99m stannous pyrophosphate scan in 12
patients of acute RF. Myocardial staining was uniformly absent
in all. They concluded that the technique was insensitive for the
diagnosis of myocarditis in acute RF.
Narula et al.( Lea and Febiger; 1994. p. 109-17 ) used indium 111 -labeled
antimyosin fab in patients with acute RF to identify the
presence of myocardial damage. Except in the presence of
pericarditis or congestive failure there was very poor staining
indicating the absence of significant myosin damage.
Further, Narula et al. (Circulation 1993;88:2198-205) used myocardial
biopsy in 89 patients of acute RF and chronic rheumatic heart
disease to identify the presence of active myocarditis. They
concluded that myocardial biopsy performed during acute RF
does not add to the clinically obvious myocarditis due to paucity
of myocardial damage.

46
Histopathological findings of carditis, summarized by
Virmani et al.,(Rheumatic fever. Washington DC: Amer Reg Path AFIP; 1999. p. 217-34. ) indicate
inflammatory changes in the sub-epicardial, sub-endocardial,
and perivascular interstitial tissue with little myocyte
disruption.
Aschoff nodules (AN) are strictly perivascular in location.
The rest of the myocardium and the interstitial tissue is
normal.
Aschoff Nodule contain lymphocytes, macrophages, β cells, and giant
cells. Immunopathology of AN, studied by Gulizia and
associates(Rheumatic fever. Washington DC: Amer Reg Path AFIP; 1999. p. 235-44.) , indicates that
it does not have any cells of myocardial origin. Therefore, Aschoff
nodule, the hallmark of rheumatic carditis, is not derived from
myocardial damage.

47
Thus, the absence of myocarditis has been demonstrated
and documented by –
(1) the absence of increase in markers of myocardial
damage (CK-MB, Troponin-I),
(2) echocardiographic left ventricular function studies,
(3) radionuclide imaging (technetium pyrophosphate,
indium 111 , antimyosin fab)
(4) myocardial biopsy studies
(5) surgical management during active carditis
(6) histopathology and immunopathology.

48
The pathological findings of RF provide clues to the
pathophysiology of RF.
"RF is characterized by proliferative and exudative
inflammation involving primarily collagen tissue or its ground
substance. There is a pronounced tendency to affect tissues
lined by endothelium, including blood vessels, endocardium,
pericardium, and synovia.“(Rheumatic fever. In: Friedberg CK (Ed.). Diseases of the heart.
3 rd ed. Philadelphia: W.B. Saunders; 1966. p. 1322. )
Pathological findings indicate that RF predominantly
damages the endothelium, selectively throughout the body.
However, due to its proximate location to endothelium,
inflammation progresses to the sub-endothelial layer.

49
The sub-epicardial, sub-endothelial, and perivascular
inflammatory deposits which are frequently observed are
directly related to and under the endothelium.
"Microscopically pericardial lesions are found in 100 percent
of active cases; however, there is no residual damage."
Gross evidence of active pericarditis was found in 46% while
operating for aortic valve replacement during acute RF.
The inflammation is strictly related to and localized to the
endothelium, the underlying basement membrane, and the
subendothelial tissue. There is no evidence for the cardiac
muscle or intermyocardial connective tissue damage.

50
Kinsley and associates replaced mitral and/or the aortic
valve in patients of acute RF, with deterioration despite
anti-congestive measures (Kinsley RH, Girdwood RW, Milner S. Surgical treatment during the
acute phase of rheumatic carditis. In: Nyhus LM, editor. Surgery annual v.13. New York: Appleton-Century-Crofts; 1981. p.
299-323.).
Following mitral or aortic valve replacement, the left
ventricular size and function returned to normal and
congestive cardiac failure subsided, with clinically ongoing
carditis.
Thus they concluded that congestive cardiac failure was
the result of an acute volume overload secondary to mitral
and/or aortic valve regurgitation and not due to
myocarditis per se.

51
The cardiac valves - mitral, aortic, tricuspid, and pulmonary -
histologically consist of a connective tissue core covered on
both sides by the endothelium. There is no muscle tissue and
there are no blood vessels in the valves. The absence of blood
vessels is important since blood vessels have some muscle
tissue in their walls and are lined by endothelium.
Since the valves structurally consist of a connective tissue
core covered by a reduplicated endothelium, the damage to
endothelium initiates an inflammatory damage to the
underlying connective tissue of the valve. The mitral, aortic,
and less commonly the tricuspid and pulmonary valves are
involved. "The tricuspid and pulmonary valves may disclose
distinct microscopic lesions when they appear normal on gross
examination. The atrial surface of the mitral and tricuspid
valves may show gross vascularization."

55
Rheumatic
heart
disease.
Abnormal
mitral
valve.
Thick,
fused
chordae

56
Thick and
fused mitral
valves in
Rheumatic
heart disease

57
Arteries
"Lesions of the vascular compartment, including the coronary
arteries, represent a fundamental features of the pathology
of RF. The pulmonary artery, aorta, coronary vessels, small and
large muscular arteries including the vasa-vasorum are
involved." They have edema of intima and media, fibrinoid
thickening, and at times thrombosis. Intima and media have
histiocytic and inflammatory cell infiltration. Aschoff bodies
are perivascular in location and related to adventitia. Gross
evaluation, while operating on active cases, has shown aortitis
"characterized by macroscopic edema of the aortic adventitia
in 43 percent." The adventitia had an "acute inflammatory cell
infiltration." ( Nyhus LM, editor. Surgery annual v.13. New York: Appleton-Century-Crofts; 1981.
p. 299-323. )

58
"Occasionally there are macroscopic brownish ridges or
plaques on the inner surface of the aorta. The usual lesions at
the root of aorta are microscopic and situated chiefly in the
outer portion of the media and adventitia, following the course
of vasa-vasorum." There is infiltration with lymphocytes,
neutrophils and Aschoff bodies, edema, pronounced
capillarization, scarring, and disruption of elastica.
Similar lesions are found in the pulmonary artery and arteries
elsewhere in the body

59
High pulse
rate
Hemodynamic
over load
Murmur
Valve &
endocardium
involvement
Pericardial
rub
pericarditis
Cardiomegaly
And failure
Valvulitis and
volume over
load
Prolong PR
interval
Involvement
of conducting
system

Sydenham Chorea
5-10%
60
l Occur in 5-10% of cases
l Mainly in girls of 1-15 years age
l May appear even 6/12 after the attack of
rheumatic fever
l Clinically manifest as-clumsiness,
deterioration of hand writing, emotional
labiality or grimacing of face
l Clinical signs- pronator sign, jack in the
box sign , milking sign of hands

61
Disseminated meningo-encephalitis affecting the basal
ganglia, caudate nucleus, putamen in corpus striatum,
cortex, internal capsule, and cerebellum is present.
There is an obliterating arteritis involving the small
meningeal and cortical vessels with infarction and softening
of cerebral tissue. Perivascular round cell infiltration,
petechial hemorrhages, and hyalinization of small blood
vessels are present. Aschoff Nodule are not formed.
The central nervous system changes are present with or
without the patient presenting as chorea.
The pathological changes are, therefore, strictly a vascular
pathology with a limited perivascular disease, with the
central nervous system otherwise remaining normal.

Chorea
l The onset of chorea usually occurs one to eight
months after the inciting infection, in contrast to
inflammation of valve and arthritis, which typically
present within 21 days.
l The onset is typically insidious but may be abrupt.
Emotional changes, such as easy crying or
ina ppropria te la ughing, m a y pre c e d e t h e
development of chorea and, in some cases,
regression in school performance is the initial
concern.

Erythema Marginatum
l Occur in <5%.
l Unique, transient, serpiginous-looking
lesions of 1-2 inches in size
l Pale center with red irregular margin
l More on trunks & limbs & non-itchy
l Worsens with application of heat
l Often associated with chronic
carditis
63

Subcutaneous nodules
l Occur in 10%
l Painless, pea-sized, palpable nodules
l Mainly over extensor surfaces of joints,
spine, scapulae & scalp
l Associated with strong sero-positivity
l Always associated with severe carditis
64

65
Pleura, pericardium, and the peritoneum are lined by a
single layer of mesothelium. Mesothelium and endothelium
are derived from mesenchymal cells. They differ from the
epithelium since they contain vimentin whereas epithelium
contains keratin.
Serofibrinous exudates occur over the pleura, pericardium,
and the peritoneum and extend to underlying tissue.
Abdominal pain could be due to necrotizing arteritis of
visceral arteries or other vascular lesions. Healing occurs
without residual damage.

66
"Despite the diffuse collagen - vascular involvement, one of the
mysteries of the pathology of RF is the remarkable tendency for the
disease to heal rather than to scar the tissues it affects with the
exception of cardiac valves (Stollerman GH. Rheumatic fever and streptococcal infection. New
York: Grune & Stratton; 1975. ).
Since the endothelium repairs itself very fast, evidence for its
damage will be lost very quickly.
The subendothelial damage is limited to a very little depth hence
scarring does not occur.". Except the cardiac valves all other
manifestations - arthritis, subcutaneous nodules, and chorea - heal
with no evidence for residual disease.

Clinical Features
l Fever-(up to 101 degree F) > 38.5 c
l Arthralgia
l Pallor
l Anorexia
l Loss of weight
68
Other features (Minor features)

Tests for rheumatic fever
Throat swab : Throat culture-GAB H streptococci
Blood tests :
l High ESR
l Anemia, leukocytosis
l Elevated C-reactive protein
l ASO titer >200 Todd units.
(Peak value attained at 3 weeks,then
comes down to normal by 6 weeks)
l Anti-DNAse B test
l
Upper limit of normal for serum
streptococcal antibody titres
Age group ULN (U/mL)
(years) ASO titre Anti-DNase B titre
1-4 170 366
5-14 276 499
15-24 238 473
25-34 177 390
≥35 127 265
Anti-DNase, antideoxyribonuclease B;
ASO, antistreptolysin O; ULN,
upper limit of normal.

Tests for rheumatic fever
ECG – PR interval
Upper limits of normal of P-R interval
Age group (years) Sec
3–12 0.16
12–16 0.18
17+ 0.20
Source: Adapted from Park MK, Pediatric cardiology for
practitioners,
2nd edn. Chicago: Year Book Medical; 1998.

E C G
l Prolonged atrio-ventricular conduction, i.e., first degree
heart block, is a well-recognized feature of acute
rheumatic fever, occurring in about one-fifth to three-
fifths of patients (Clarke M., Keith J.D. Atrioventricular conduction in acute rheumatic fever. Br Heart
J. 1972;34:472–479.) and is considered a minor criterion in the
diagnosis of this condition.
l Higher degrees of heart block, however, are not usual
features of acute rheumatic fever - 2nd or 3rd degree
blocks, ST depression, T inversion
71

Laboratory Findings
l 2D and Color Doppler Echo Cardiography-
l Valve thickness, beading, mitral(prolapse) regurgitation, LA
& LV dilatation, pericardial effusion, decreased
contractility, MR &AR jet
72

Diagnosis
l Rheumatic fever is mainly a clinical
diagnosis
l No single diagnostic sign or specific
laboratory test available for diagnosis
l Diagnosis most of the time is based on
“MODIFIED JONES CRITERIA “
73

T. Duckett Jones Criteria – Evolution
The Original Jones Criteria – 1944*
Major Manifestations Minor Manifestations
1. Carditis 1. Fever
2. Arthralgia 2. Abdominal pain
3. Chorea 3. Precordial pain
4. Subcutaneous 4. Rashes (erythema
nodules marginatum)
5. History of previous 5. Epistaxis
definite rheumatic 6. Pulmonary findings
fever or rheumatic 7. Laboratory findings
heart disease a. Electrocardiographic
abnormalities
b. Microcytic anemia
c. Elevated total leukocyte
count
d. Elevated erythrocyte
sedimentation rate
I

The Modified Jones Criteria – 1956*
2. Polyarthritis 2. Arthralgia
3. Chorea 3. Prolonged PR interval
4. Subcutaneous nodules 4. Increased erythrocyte
5. Erythema Marginatum sedimention rate,
presence of C-reactive
protein or leukocytosis
5. Previous history of
rheumatic fever or the
presence of inactive
rheumatic heart disease
6. Evidence of preceding
beta hemolytic
streptococcal infection
II

The Revised Jones Criteria – 1965*
3. Chorea 3. Previous rheumatic fever or
rheumatic heart disease.
4.Erythema marginatum 4. Elevated erythrocyte sedi-
mentation rate, positive C-
reactive protein, leukocytosis
5.Subcutaneous nodules 5. Prolonged PR interval
Plus supporting evidence of preceding streptococcal infection :
history of recent scarlet fever; positive throat culture for group
A streptococcus; increased ASO titer or other streptococcal
antibodies:
III

The Jones Criteria Update – 1992*
1. Carditis 1. Clinical findings
3. Chorea 3. Fever
4. Erythema marginatum 4. Laboratory findings
5. Subcutaneous nodules Elevated acute phase
reactants, erythrocyte
sedimentation rate, C-reactive
protein
5. Prolonged PR interval
Supporting Evidence of Antecedent Group A Streptococcal Infection
Positive throat culture or rapid streptococcal antigen test
Elevated or rising streptococcal antibody titer
IF supported by evidence of preceding group A streptococcal
infection, the presence of two major manifestations or one major and
two minor manifestations indicates a high probability of acute
rheumatic fever.
IV

78
JonesCriteria(Revised) for Guidanceinthe
Diagnosisof RheumaticFever*
Major Manifestation Minor
Manifestations
Supporting Evidence
of Streptococal Infection
Clinical Laboratory
Carditis
Polyarthritis
Chorea
Erythema Marginatum
Subcutaneous Nodules
Previous
rheumatic
fever or
rheumatic
heart disease
Arthralgia
Fever
Acutephase
reactants:
Erythrocyte
sedimentation
rate,
C-reactive
protein,
leukocytosis
Prolonged P-
Rinterval
Increased Titer of Anti-
Streptococcal Antibodies ASO
(anti-streptolysin O),
others
PositiveThroat Culture
for Group AStreptococcus
Recent Scarlet Fever
*The presenceof twomajor criteria, or of one major andtwominor criteria,
indicates a highprobabilityof acuterheumatic fever, if supportedby evidenceof
GroupAstreptococcal nfection.
Recommendations of the American Heart Association

Pit falls of Jones criteria
79
1. It is difficult to diagnose ARF when Carditis is the only
manifestation of the disease particularly in a
recurrence.
2. When patient has sub clinical Carditis the clinicians fail
to detect clinically
3. Clinically apparent Carditis is present but supportive
minor criteria are not fulfilled.
4. When previous cardiac status is unknown it is not
possible to know in a new case whether the findings are
due to acute carditis or it is recrudescence or it is
established old case of RHD.
5. In cases of polyarthralgia, which is a minor criterion, if
the patient is neglected and not evaluated for ARF, they
would go undiagnosed, and could end up with RHD, allegedly
without any past history of ARF, as the patient and the
parents would have long forgotten the joint pain.

83
1. Echocardiography with Doppler should be performed in all cases of
confirmed and suspected ARF (Class I; Level of Evidence B).
2. It is reasonable to consider performing serial
echocardiography/Doppler studies in any patient with diagnosed or
suspected ARF even if documented carditis is not present on
diagnosis (Class IIa; Level of Evidence C).
3. Echocardiography/Doppler testing should be performed (strictly
fulfilling the findings noted in Tables 2 and 3) to assess whether
carditis is present in the absence of auscultatory findings,
particularly in moderate- to high-risk
populations and when ARF is considered likely (Class I; Level of
Evidence B).
4. Echocardiography/Doppler findings not consistent with carditis
should exclude that diagnosis in patients with a heart murmur
otherwise thought to indicate rheumatic carditis (Class I; Level of
Evidence B).

Keywords in the revision 2015 AHA
84
• SUBCLINICAL CARDITIS (echocardiography as a way to diagnose carditis
• even in the absence of overt clinical findings “subclinical carditis”)
• ECHO CRITERIA
• TEMPERATURE
• 1992 CRITERIA MISSES MANY CASES IN
MODERATE TO HIGH RISK AREA
• CREITERIAOF DIAGNOSIS OF ARF ON EXISTING CRDH

85
Diagnosis: initial ARF: 2 Major manifestations or 1 major plus 2
minor manifestations
Diagnosis: recurrent ARF: 2 Major or 1 major and 2 minor or 3
minor

86
M-mode interrogation •
Dimensions of left atrium, aorta and their ratio
• Left ventricular dimension in diastole and systole
Cross-sectional interrogation in long axis, four-chamber, five-
chamber and short axis
• Thickness of the valves, with less than 3 millimetres taken as
normal, and more than 4 millimetres as thickened
• Beaded appearance, especially of mitral, tricuspid and aortic valves
• Prolapse of mitral valve, particularly the aortic leaflet
• Decreased or increased mobility of the valves
• Hyperechogenicity of the thickened submitral apparatus
• Chordal tears to mitral leaflets
• Pericardial effusion
• End diastolic volume, end systolic volume and ejection Fraction

The guideline recommendations for diagnosing rheumatic
fever recurrences are:
1. With a reliable past history of ARF or established RHD,
and in the face of documented group A st
infection, 2 major or 1 major and 2 minor or 3
may
(Cla
ss
be
IIb
;
sufficient
Level
for
of
a presumptive
gnosis Evidence C).
. When
exclusion
nor manifestations alone
cause
s
are present,
of other more likely of the clinical
presentation
ARF recurrence is made (Class I; Level of Evidence C).
107

.“Possible” Rheumatic Fever
In some circumstances, a given clinical presentation may not fulfill these updated
Jones criteria, but the clinician may still have good reason to suspect
the
This may occur in high-incidence settings. In such situations the cli
that ARF is
diagnosis.
should
use their discretion and clinical acumen to make the diagnosis that they
most likely and manage the patient accordingly.
sider
1. Where
nths
history
there is genuine uncertainty, it is reasonable to consider offering 12
of secondary prophylaxis followed by reevaluation to include a careful
and physical examination in addition to a repeat echocardiogram (Class
; Level of ce C).
2. a patient with recurrent symptoms (particularly involving the joints) who has
been adherent to prophylaxis recommendations but lacks serological evidence
of
group A streptococcal infection and lacks echocardiographic evidence of
valvulitis, it is reasonable to conclude that the recurrent symptoms are
not likely related to ARF, and discontinuation of antibiotic prophylaxis may be
appropriate (Class IIa; Level of Evidence C).
108

91
Differentiation of physiological and pathological regurgitation
Colour jet in two planes extending well beyond valvar leaflets,
with pulsed
Doppler confirming the velocity signal, holosystolic for mitral
regurgitation and holo-diastolic for aortic regurgitation, was taken as
indicative of pathological regurgitation

92
Morphological Findings on Echocardiogram
in Rheumatic Valvulitis
Acute mitral valve changes
1.Annular dilation
2.Chordal elongation
3.Chordal rupture resulting in
flail leaflet with severe mitral
regurgitation Anterior
(or less commonly posterior)
leaflet tip prolapse
4.Beading/nodularity of leaflet tips
1
2
3
4

93
Chronic mitral valve changes: not seen in acute carditis
Leaflet thickening
Chordal thickening and fusion
Restricted leaflet motion
Calcification

94
Aortic valve changes in either acute or chronic carditis
Irregular or focal leaflet thickening
Coaptation defect
Leaflet prolapse

95
Specific Doppler criteria for diagnosis of rheumatic
Valvulitis
Pathological mitral regurgitation (all 4 criteria met)
1.Seen in at least 2 views
2.Jet length ≥2 cm in at least 1 view
3.Peak velocity >3 m/s
4.Pansystolic jet in at least 1 envelope
Pathological aortic regurgitation (all 4 criteria met)
1.Seen in at least 2 views
2.Jet length ≥1 cm in at least 1 view
3.Peak velocity >3 m/s
4.Pan diastolic jet in at least 1 envelope

Specific criteria exist for Doppler findings in rheumatic
valvulitis:
1) Mitral regurgitation (all four): seen in ≥2 views, jet
length ≥2 cm, peak velocity >3 m/s, pansystolic
2) Aortic regurgitation (all four):
length ≥1 cm, peak velocity
>3
seen in ≥2
m/s, pandiastolic. –
See more at: http://www.acc.org/latest-
in-
cardiology/ten-points-to -
5/05/08/15/22/revision-of-the-jones-
criteria-
fever#sthash.yZOeermJ.dpuf
92

‘Vijaya’s ECHO criteria’ proposed for the precise diagnosis of both
‘clinical carditis’ and ‘sub clinical valvulitis’ has 81% sensitivity with
93% specificity
An Echo score of >6 out of 16 were taken as ECHO positive, so as to
avoid over diagnosis of MR. Score of > 6 is diagnostic of rheumatic
carditis
94

95
IVC
IVC
RV
LV
LV
RV
RA AML
PROLAPSE
LA
LA
RA

96
ARF
RV
AO
LV
LA
AO
RV
LA
AO
LV
RV
LA
AO
EFF
LA

118
Course of Rheumatic Heart disease

119
Specific criteria exist for Doppler findings in
rheumatic valvulitis:
1)Mitral regurgitation (all four): seen in ≥2 views,
jet length ≥2 cm, peak velocity >3 m/s,
pansystolic; and
2) Aortic regurgitation (all four): seen in ≥2
views, jet length ≥1 cm, peak velocity >3 m/s,
pandiastolic. –
See more at: http://www.acc.org/latest-in-
cardiology/ten-points-to -
remember/2015/05/08/15/22/revision-of-
the-jones-criteria-for-the-diagnosis-of-acute-
rheumatic-fever#sthash.yZOeermJ.dpuf

120
The guideline recommendations for diagnosing rheumatic
fever recurrences are:
1. With a reliable past history of ARF or established RHD,
and in the face of documented group A streptococcal
infection, 2 major or 1 major and 2 minor or 3 minor
manifestations may be sufficient for a presumptive
d i a g n o s i s ( C l a s s I I b ; L e v e l o f E v i d e n c e C ) .
2. When minor manifestations alone are present,
the exclusion of other more likely causes of the clinical
presentation is recommended before a diagnosis of an
ARF recurrence is made (Class I; Level of Evidence C).

121
.“Possible” Rheumatic Fever
In some circumstances, a given clinical presentation may not fulfill these updated
Jones criteria, but the clinician may still have good reason to suspect that ARF is
t h e d i a g n o s i s .
This may occur in high-incidence settings. In such situations the clinicians should
use their discretion and clinical acumen to make the diagnosis that they consider
most likely and manage the patient accordingly.
1. Where there is genuine uncertainty, it is reasonable to consider offering 12
months of secondary prophylaxis followed by reevaluation to include a careful
history and physical examination in addition to a repeat echocardiogram (Class
IIa; Level of Evidence C).
2. In a patient with recurrent symptoms (particularly involving the joints) who has
been adherent to prophylaxis recommendations but lacks serological evidence of
group A streptococcal infection and lacks echocardiographic evidence of
valvulitis, it is reasonable to conclude that the recurrent symptoms are
not likely related to ARF, and discontinuation of antibiotic prophylaxis may be
appropriate (Class IIa; Level of Evidence C).

122
Border line R H D
(1) 2 morphological features of RHD of MV without pathological MR or MS
Ø AML thickening >3, > 4mm aged 21-40 and > 5 mm over age 40yrs
Ø Chordal thickening
Ø Restricted leaflet motion
Ø Excessive leaflet tip motion during systole
Features in the Av
Irregular or focal thickening
Coaptation defect
prolapse
(2) Pathological MR
(3) Pathological AR

123
Border line R H D
Rémond et al. ( Int J Cardiol 2015;198:117-22.) examined Australian
children using the WHF criteria in a prospective follow-up
study after 2.5–5 years and found that individuals with
borderline RHD were 8.8 times more likely to develop ARF,
over eight times more likely to experience echocardiographic
progression of valve lesions, and that 1 in 6 progressed to
definite RHD.
However, one-third of these children were receiving
secondary prophylaxis, which may have altered the natural
course of the disease.

124
Border line R H D
Removing the morphological criteria entirely and measuring
MR jet length only, is a strategy that researchers have
recently begun to employ.
Since 2012, several studies have examined the performance of
MR jet length as the single echocardiographic criterion
against a reference approach .
The definition of pathological MR varied (≥1.5–2.0 cm) between
different studies and some included the presence of any
degree of AR as a marker of RHD.
Sensitivity for borderline plus define RHD varied from 73%
to 78.9% and specificity 82.4%–87.3%. Sensitivity for definite
RHD was much better, ranging between 97.8% and 97.9%
between studies.
Pediatrics 2015;135:e939-44. Eur Heart J Cardiovasc Imaging 2015;16:475-82.

Exceptions to Jones Criteria
 Chorea alone, if other causes have
been excluded
 Insidious or late-onset carditis with
no other explanation
 Patients with documented RHD or
prior rheumatic fever, one major
criterion, or of fever, arthralgia or
high CRP suggests recurrence
129

Differential Diagnosis
l Juvenile Rheumatoid Arthritis
l Septic arthritis
l Sickle-cell Arthropathy
l Kawasaki disease
l Myocarditis
l Scarlet fever
l Leukemia
130

Management
Of Rheumatic Heart Fever &
disease
TREATMENT PLANNING

132
Latent RHD All cases of RHD diagnosed through echocardiographic
screening, to include previously unrecognized clinical
RHD and subclinical RHD
Clinical RHD All cases of RHD that have clinical signs or symptoms
including pathological heart murmur* diagnosed either
through echocardiographic screening or clinical evaluation.
Clinical RHD is typically more advanced than subclinical
RHD.
Subclinical RHD All cases of RHD that do not have clinical signs or symptoms
including heart murmur.* Subclinical RHD is only diagnosed
by echocardiography and is typically less advanced than
clinical RHD.

Tertiary
Secondary
Primary
Primordial
Prevention of further ARF episodes
• in people who have already had ARF &/or have already developed RHD using
an antibiotic to prevent streptococcal infection for minimum of 10 years
Improving living
condition &
access to health
care
Treatment of
GAS pharyngitis
Surveillance
GAS vaccine
Management of exiting RHD by
Valve repair or replacement
Preventing infection, care during
pregnancy and Rx of arrhythmia
Regular
prevention of
ARF after 1st
Episode

134
T
e
r
t
i
a
r
y
P
r
e
v
e
n
t
i
o
n
M
a
n
a
g
e
m
e
n
t
o
f
e
x
i
t
i
n
g
R
H
D
b
y
V
a
l
v
e
r
e
p
a
i
r
o
r
r
e
p
l
a
c
e
m
e
n
t
P
r
e
v
e
n
t
i
n
g
i
n
f
e
c
t
i
o
n
,
c
a
r
e
d
u
r
i
n
g
p
r
e
g
n
a
n
c
y
a
n
d
R
x
o
f
a
r
r
h
y
t
h
m
i
a

Primordial prevention
135
Preventing the development of risk factors in the community
to prevent the disease in the population
Measures to prevent RF and RHD consist of -
1.Improvement in socio-economic status.
2.Peventionof overcrowding
3.Prevention of under nutrition & malnutrition
4. Public education regarding RF following sore throat, particularly
between age 4-15 years.

1. Register with RHD program
2. Establish or continue secondary prophylaxis
3. Disease education and self-management support
4. Regular clinical review and echocardiogram
5. Regular dental care
Tertiary prophylaxis
6. Management of cardiac symptoms
7. Infective endocarditis prevention
8. Family planning
9. Well-planned surgery
10. Management of pregnancy
Ten-point management plan

Treatment
l Step I - Primary prevention
(eradication of streptococci)
l Step II - Anti inflammatory treatment
(aspirin, steroids)
l Step III- Supportive management &
management of complications
l Step IV- Secondary prevention
(prevention of recurrent attacks)
l Step V – Tertiary prevention
137

Treatment
l Primary prophylaxis
l Timely diagnosis of GAS pharyngitis and
appropriate treatment. Treatment of
choice is still Penicillin as all GAS is
susceptible.
l Treatment administered within 10 days
of onset of illness has been shown to
prevent ARF.
l Alternatives – amoxicillin, erythromycin,
1st generation cephalosporin

139
STEP I: Primary Prevention of Rheumatic Fever
(Treatment of Streptococcal Tonsillopharyngitis)
Agent Dose Mode Duration
Benzathine penicillin G 600 000 U for patients Intramuscular Once
27 kg (60 lb)
1 200 000 U for patients >27 kg
or
Penicillin V Children: 250 mg 2-3 times daily Oral 1 0D
(phenoxymethyl penicillin) Adolescents and adults:
500 mg 2-3 times daily
For individuals allergic to penicillin
Erythromycin: 20-40 mg/kg/d 2-4 times daily Oral 1 0D
Estolate (maximum 1 g/d)
or
Ethylsuccinate 40 mg/kg/d 2-4 times daily Oral 1 0D
(maximum 1 g/d)
Recommendations of American Heart Association

140
Step II: Anti inflammatory treatment
Clinical condition Drugs
Prednisolone :
Taper 5mg/day
Every 3-5days

141
l Bed rest
l Treatment of congestive cardiac
failure: -Digitalis, diuretics, Enalapril
l Treatment of chorea:
-Diazepam or haloperidol
l Rest to joints & supportive splinting
3.Step III: Supportive management &
management of
complications

Treatment of chorea
l Previously recommendation was prednisone +
AEDs +/- plasmapheresis.
l However… most new studies have shown to
benefit from immunomodulation.
l “The best small study comparing plasmapheresis,
prednisone and IVIG conducted at the National
Institute of Mental Health as referenced in the
"Journal of Child Neurology," volume 20, #5,
pages 424-429, by Dr. Garvey, et. al., suggests.
l IVIG at 1 gram per kg over a 2-day course
appear better than plasmapheresis and
prednisone”

Step IV
l Secondary prophylaxis
l Patient’s diagnosed with ARF need to undergo
secondary prophylaxis to prevent relapses.
l Prophylaxis regimens include oral
l Pen VK BID
l Pen G IM q month
l Oral sufisoxazole q day,
l Oral erythromycin BID.

144
STEP IV : Secondary Prevention of Rheumatic Fever
(Prevention of Recurrent Attacks)
Agent Dose
Mode
Benzathine penicillin G 1 200 000 U every 4 weeks*
Intramuscular
or
Penicillin V 250 mg twice daily
Oral
or
Sulfadiazine 0.5 g once daily for patients 27 kg (60 lb
Oral
1.0 g once daily for patients >27 kg (60 lb)
For individuals allergic to penicillin and sulfadiazine
Erythromycin 250 mg twice daily
Oral

145
Duration of Secondary Rheumatic Fever
Prophylaxis
Category Duration
Rheumatic fever with carditis and At least 10 y since last
residual heart disease episode and at
least until (persistent valvular disease*) age 40 y,
sometimes lifelong prophylaxis
Rheumatic fever with carditis 10 y
or well into adulthood, but no residual heart disease
whichever is longer (no valvular disease*)
Rheumatic fever without carditis 5 y or until age 21 y,
whichever is longer
*Clinical or echocardiography evidence.

146
Priorities for Defining Minimum Duration of
Secondary Prophylaxis

147
Category Definition Comments
Possible
(uncertain) ARF
Normal echocardiogram Reassess in 12 mo. If ARF remains
uncertain, consider ceasing; if
highly suspected or definite ARF,
continue as indicated
Probable (highly
suspected) and
definite ARF
Normal echocardiogram Abbreviated prophylaxis (5 y
after last episode or 21 y of
age) as per standard
recommendation
Borderline RHD Borderline RHD detected on
echocardiography without a history
of ARF
In some cases, based on
nonechocardiographic risk factors
such as family history of RHD,
individuals may opt to commence
secondary prophylaxis to reduce
risk of ARF; in these cases, it
should be prescribed as per mild
RHD
Mild RHD May or may not be associated with
a cardiac murmur
Risk of recurrence is extremely low
in people aged >40 y. In some
cases (eg, when the patient decides
they want to reduce even a minimal
risk of recurrence), prophylaxis may
be continued beyond the age of 40
y, or even for life. Lifelong
prophylaxis is preferable for
patients who have had cardiac
valve surgery
Moderate RHD Moderate RHD (asymptomatic) with
normal left ventricular function
Severe RHD Severe RHD, previous valve repairs or
prosthetic valves, or symptomatic
moderate RHD

148
American (AHA 2009)60 ARF with carditis and residual heart disease: until age 40 y
or for 10 y after last ARF (whichever is longer).
lifetime prophylaxis may be needed ARF with carditis but
no residual heart disease: until age 21 y or for 10 y after
last ARF (whichever is longer)
ARF without carditis: until age 21 y or for 5 y after last ARF
(whichever is longer)
WHO Expert Consultation
Geneva (2004)
Lifelong if severe valvular disease or after valve surgery For 10
y after last ARF or until age 25 y.
In patients with previous diagnosis of carditis For 5 y after last
ARF or until age 18 y
In patients without proven carditis
Indian (2008) Lifelong in severe disease or post intervention patients; may opt
for secondary prophylaxis until age 40 y
ARF with healed, mild, or moderate carditis: until age 25 y or for
10 y after last ARF (whichever is longer)
ARF without carditis: until age 18 y or for 5 y after last ARF
(whichever is longer)

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28
days
days
penicillin
concentration
in
blood
Concentration of penicillin in bloodstream
over time, after a single injection
Potential risk of acquiring
new strep infection when
penicillin levels are low
Definite risk of
acquiring new strep
infection if next dose
not given on time

150
The above mentioned Cochrane review concluded that on the basis of studies
that 2 or 3 weekly injections were more effective than 4 weekly. there are
supporting pharmacokinetic studies that have demonstrated that penicillin
injections given IM every two or three weeks ensure serum penicillin levels
remain above the minimum inhibitory concentration. (Manyemba J, Mayosi BM. Penicillin
for secondary prevention of rheumatic fever. Cochrane Database Syst Rev. 2002(3):CD002227. )
Serum concentrations of penicillin were measured in children with rheumatic
fever. The adequacy of the values after administration of 1.2 million units of
benzathine penicillin G every 2 or 3 weeks was confirmed; the adequacy of a
4-week regimen was questionable. The administration of 0.6 million units every
3 weeks was found to be inadequate to maintain serum levels high enough for
the secondary prophylaxis of rheumatic fever. (Meira ZM, Mota Cde C, Tonelli E, Nunan
EA, Mitre AM, Moreira NS. Evaluation of secondary prophylactic schemes, based on benzathine penicillin G, for
rheumatic fever in children. J Pediatr. 1993 Jul;123(1):156-8. )
Article on acute rheumatic fever in the Lancet in 2005,14 Carapetis et al
promote the 4-weekly regimen. They and others raise the concern of patient
acceptance of twice-weekly IM injections versus four-weekly, and thus the
issue of adherence.(Carapetis J, McDonald M, Wilson N. Acute rheumatic fever (author's reply). Lancet.
2005 October;366(9494):1355-6. )

151
l Recurrence of Streptococcal infection with :
l parenterally injected penicillin was, 7%,
orally administered penicillin was 20% and
sulfadiazine was 24%.
l Acute Rheumatic fever recurrence -
With parenterally injected penicillin was –
none, oral penicillin was 4.8% and
sulfadiazine was 2.7%.
Alvan R. Feinstein, Harrison F. Wood, et al N Engl J Med 1959; 260:697-702

Medicine
A needle every 28 days or full moon for many
years to stop the strep germ

Needles
Remember your needles use the
Full Moon Needle Calendar

Needles
Don’t miss any needles you can get
Rheumatic Fever again.
Every time you get Rheumatic Fever your heart
can get damaged more.
You might have to go to “Tertiary care centre”
for an intervention ( balloon dilatation) or
operation.

Prognosis
l Rheumatic fever can recur whenever the
individual experience new GABH
streptococcal infection, if not on
prophylactic medicines
l Good prognosis for older age group & if no
Carditis during the initial attack
l Bad prognosis for younger children & those
with carditis with valvular lesions – may
develop critical MS, at early age. May be
within 9 months after initial episodes.
155

Aortic Valve 25%
Mitral Valve 65-70%
Tricuspid Valve 10%
Pulmonic Valve – rarely involved
} }

Tertiary prevention of RHD
Prevention of morbidity and mortality of RHD patient :
l Prevention of acute rheumatic fever recurrence
l - 3-4 weekly Benzathine Penicillin G
l Modification of environment
l Heart failure management
l Valve repair
l Valve replacement
l Heart failure medication
l Anticoagulation management
l Dilated left atrium
l Atrial fibrillation
l Mechanical valve
l Arrhythmia management
l Ablation
l Medication – digoxin
l Anticoagulation
l Endocarditis prevention
l Prevention of pregnancy related complications
STEP V -

1. Prevention of acute rheumatic fever recurrence
l 3-4 weekly Benzathine Penicillin G
l Modification of environment
l Secondary prophylaxis plus

2. Treatment of heart failure:
l Heart failure - medication
l Valve repair
l Valve replacement
1. Medications 2. Repair 3. Replacement

l The Australian experience with mitral valve repair
Mitral Valve
repair
0%
20%
40%
60%
80%
100%
0 5 10 15
Probability
of
survival
Post operative years
Survival probability following mitral
valve repair
Australian paediatric cohort – RCH
Melbourne

l
Mitral Valve
replacement

3. Prevention of stroke - anticoagulation
l Anticoagulation management
l Dilated left atrium
l Atrial fibrillation
l Mechanical valve
l Options: Claxane / Warfarin

Dose of warfarin
A: Loading dose:
Initial day I: Days 2-4: Maintenance dose (day 5 and
beyond)
0.2 mg/kg (max 10 mg) INR 1.1–1.3, repeat loading dose INR 1.1–1.4, increase dose by 20%
of previous dose
0.1 mg/kg, if there is evidence of
hepatic dysfunction
INR 1.4–1.9, give 50% of initial
loading dose
INR 1.5–1.9, increase dose by 10%
of previous dose
loading dose
INR 2.0–3.0, no change
loading dose
INR 3.1–3.5, decrease dose by
10% of previous dose
INR >3.5, hold until <3.5, restart
at 50% of previous dose
INR >3.5, hold until <3.5, restart
at 20% less than last dose

Complication associated with warfarin therapy
The risk of serious bleeding in children receiving VKA for mechanical prosthetic
valves is approximately 3.2% per patient-year.
(Monagle P, Michelson AD, Bovill E, Andrew M. Antithrombotic therapy in children. Chest. 2001;119:344S–70S)
Most cases of bleeding can be treated with vitamin K administration (30 mcg/kg).
(Bolton-Maggs P, Brook L. The use of vitamin K for reversal of over-warfarinization in children. Br J Haematol. 2002;118:924.)
In life-threatening bleeding complications, fresh frozen plasma should be used.
Other adverse effects of warfarin include skin necrosis, gangrene, osteoporosis,
fever, hair loss and tracheal calcification.

4. Management of arrhythmias
l Arrhythmia management
l Ablation
l Medication – digoxin
l Anticoagulation

5. Prevention of endocarditis
l Brushing teeth twice daily
l Dental review 6 monthly
l Endocarditis prophylaxis at time of dental procedures

Gastrointestinal & Genito-
urinary procedure
168

Why does RHD get worse in pregnancy ?
l Normal pregnancy:
l 30-50% increase in blood volume
l Increase in heart rate by 10-15 beats per
minute
l therefore ‘hyperdynamic circulation’; major extra
cardiac work needed.
l Labour – further major increase in cardiac
work needed
l If heart capacity is reduced due to RHD,
then breathlessness and heart failure can
occur
6. Prevention of pregnancy related complications

Pregnancy:
Careful planning, careful management
l Contraception to allow for careful planning
l Education: risks for mother / risk for baby
l Advice / decision on anticoagulation
Warfarin - tablets Clexane injection Heparin infusion
Safest for mother Safest for baby Not an option to stay on
infusion for 40 weeks
Miscarriage, late foetal loss
-30%
Embryopathy- birth defects
– 8%
-greatest risk 6-12 weeks
20% risk of valve
blockage
Peri-partum
haemorrhage
Option1:
1. Clexane 0- 13 weeks
2. Warfarin 14-36 weeks
3. Then Clexane
Option 2:
1. Warfarin until 36 weeks
2. Then Clexane

Basic care plan for Mild (Priority 3) RHD

Basic care plan for Moderate ( Priority 2) RHD

Basic care plan for Severe (Priority 1) RHD

Mitral valve
The normal atrioventricular filling occurs through a valve
orifice of approximately 3 cm2.
Mildest degrees of valve obstruction (between
cm2) are virtually unmeasurable. Mild mitral
2 and 3
sis (a
applied to valve areas between 2 and 1.4
cm2) seldom produces symptoms.
Moderate (in the range between 1.4 and 0.9 cm2)
severe st (less than 0.9 cm2)
Natural History of Mitral Stenosis: A Review. Circulation,
Volume XLV, April 1972
156

Mitral valve
157
Mitral valve pathology
Grade Valve Sub-valvular
structure
Mobility Thickening Calcification
1. Highly mobile valve, only
tip is restricted
Thickness 4-
5mm
Single area of
increase
brightness
Minimal
thickness below
mitral valve
2. Mid & base of valve have
normal mobility
Margin 5-8mm Scattered area
of brightness at
margin
1/3 length of
chordae are
thick
3. Valve move forward in
diastole from the base
Entire leaflet is
thick 5-8mm
Calcification
from margin to
mid portion of
leaflet
Chordal
thickness
extending to
distal 1/3 of
chods
4. No or minimal forward
movement of leaflet in
diastole
All leaflets are
thick >8-10mm
Extensive
brightness
throughout
leaflet
Extensive
thickening &
shortening of all
chordal
structure down
to the papillary
muscle

Stage of Mitral valve stenosis
exercise
158
Stage Definition Valve anatomy Valve
haemodynamic
Haemodynamic
consequence
symptoms
A at risk MS Mild valve doming during
diastole
Normal trans
mitral velocity
None None
B Progressive MS Commissural fusion &
diastolic doming of leaflet
Planimeter MVA >
1.5sqcm
Increased trans
mitral velocity
MVA > 1.5 sqcm
Diastolic PH1/2
<150msec
Mild to moderate
LA enlargement
PA pressure
normal at rest
none
C Asymptomatic
MS
Commissural fusion &
diastolic doming of leaflet
Planimeter MVA < 1.5
sqcm
MVA <1sqcm with very
severe MS
Diastolic PH1/2
>150msec
Diastolic PH1/2
<220msec
Severe LA
enlargement
Elevated PASP >
30mm Hg
none
D Symptomatic
MS
- DO - - DO - - DO - Decrease
tolerance
Exertional
dyspnea

Mitral valve stenosis severity
recommendations for clinical practice
* BJA Education, Volume 17, Issue 1, January 2017, Pages 1–9,
160
Mild Moderate severe
Valve area sq cm >1.5 1-1.5 <1 (specific)
*Pressure ½ time ms 139 140-219 >220
Trans valvular gradient <5 5-10 >10
PA pressure mmHg <30 30-50 >50

161
Stage of Mitral valve regurgitation
Stage Definition Valve anatomy Valve haemodynamic Haemodynamic
consequence
symptom
s
A at risk MR Mild valve prolapse
with normal coaptation
Mild valve thickening &
leaflet restriction
No MR jet or jet area
<20 of LA
Vena contract < 3 mm
None None
B Progressive
MR
Severe valve prolapse
Mild valve thickening ,
leaflet restriction & loss of
central coaptation
Prior IE
jet area <20 -40% of LA
or late systolic eccentric
jet
regurgitant volume
60mm
ERO < 0.4 sqcm
Angiography grade 1-2
Mild t LA
enlargement No
LV
enlargement
normal
PA pressure
none
C Asymptomatic
MR
Severe valve prolapse
Mild valve thicking ,
leaflet restriction & loss of
central coaptation Prior
IE
jet area <20 -40% of LA
or late systolic eccentric
jet
Regurgitant volume
60mm
ERO < 0.4 sqcm
Angiography grade 3-4
Moderate to
severe LA
enlargement
LV enlargement
PA hypertension
at rest or
exercise C1 EF
>60% LVSED
<40mm
C2EF<60%
LVESD >40
mm
none
Symptomatic - DO - - DO - - DO - Decreas

Stage of Aortic valve stenosis
163
Aortic Mild Moderate Severe
sclerosis
Aortic jet
velocity m/s
<2.5 2.6-2.9 3-4 >4
Mean gradient <20 20-40 >40
AVA sq cm >1.5 1-1.5 <1
Index valve
area sqcm/sqm
>0.85 0.60-0.85 <0.6
Velocity ratio 0.50 0.25-0.50 <0.25

Tricuspid valve stenosis severity
165
Specific
Mean pressure gradient >5 mm Hg
Flow velocity >60cm/sec
T 1/2 >190 ms
Valve area <1 sq cm
Supportive
Enlargement of RA Moderate
IVC Dilated

Pulmonary valve stenosis severity
166
Mild Moderate severe
Peak velocity M/S <3 3-4 >4
Peak pressure <36 36-64 >64 gradient

182
RATIONALE FOR RHEUMATIC HEART DISEASE
SCREENING
RHD often presents with moderate-to-severe multivalvular
disease (63.9%), heart failure (33.4%), pulmonary
hypertension (28.8%), atrial fibrillation (21.8%), stroke
(7.1%), and infective endocarditis (4%). Eur Heart J. 2015;36:1115–22a.
Treating sore throats with penicillin to prevent ARF
(primary prophylaxis) and treating episodes of ARF with
long-term penicillin (2–4 weekly intramuscular benzathine
penicillin G, [BPG]) to prevent further episodes of ARF
(secondary prophylaxis) may not be reliable approaches to
disease control on a population scale.
Primordial prophylaxis (strategies to avoid GAS infection,
e.g., improve housing) and a GAS vaccine that would prevent
ARF are potential options too but with significant barriers.

183
Auscultation for a pathological murmur has been the
traditional approach to screening school-aged children for
RHD. However, it is neither sensitive nor specific as
demonstrated in the seminal paper by Marijon et al. in
2007,(N Engl J Med. 2007;357:470–6.) who showed that ten times
more cases of RHD were detected using echocardiography
compared with auscultation. Subsequent studies have also
shown a significant (5–50-fold) increase in RHD detection by
echocardiography versus auscultation.
(Echocardiography. 2010;27:448–53. Heart. 2011;97:2018–22.)
The advent of echocardiography thus heralded a new era,
revolutionizing RHD screening in the process.
The high sensitivity of echocardiography meant researchers
were discovering early morphological valvular changes before
any clinically detectable functional lesion had developed and
the term “subclinical RHD” (or latent RHD) subsequently
emerged, recognizing that RHD could be clinically silent.

184
The abridged World Heart
Federation diagnostic screening
criteria for rheumatic heart disease

185
Prospective Vaccines against S. Pyogenes
Many studies have focused on developing a vaccine against
S. pyogenes in order to prevent infection and its complications.
There are four anti-group A streptococci (GAS) vaccine
candidates based on the M protein and eight more candidates
based on other streptococci antigens, including group A CHO,
C5a peptidase (SCPA), cysteine protease (Spe B), binding
proteins similar to fibronectin, opacity factor, lipoproteins,
Spes (super antigens) and streptococcal pili. (Steer AC, Batzloff MR,
Mulholland, Carapetis JR. Group A streptococcal vaccines: facts versus fantasy. Curr Opin Infect Dis 2009;22:544-
52. )

186
Prospective Vaccines against S.Pyogenes
A multivalent vaccine, currently under phase II clinical trials,
combines the amino acid sequences of the N-terminal portion
of the M protein from the 26 most common strains of GAS in
the US as a recombinant protein.
Because the C-terminal portion of the M protein is conserved
among the 200 strains identified by their emm-types, vaccines
based on this region are expected to provide broad coverage.
The first attempt to develop a vaccine based on the C-
terminal portion of the M protein was performed by Fischetti
et al. (Bessen D, Fischetti VA. Passive acquired mucosal immunity to group A streptococci by secretory
immunoglobulin A. J Exp Med 1988;167:1945-50.). This vaccine was able to induce
protection against S. pyogenes containing homologous (M6) and
heterologous (M14) M protein, demonstrating that the use of
conserved region-derived peptides could induce protection
against different serotypes.

Cardiac conditions associated risk of endocarditis are -
1.Prosthetic cardiac valve or prosthetic material used for cardiac valve
repair.
2 Previous infective endocarditis
3.Congenital heart disease (CHD)* - Unrepaired cyanotic CHD,
including palliative shunts and conduits Completely repaired
congenital heart defect with prosthetic material or device, whether
placed by surgery or by catheter intervention, during the first six
months after the procedure†
4.Repaired CHD with residual defects at the site or adjacent to the site
of a prosthetic patch or prosthetic device (which inhibit
endothelialization)
5.Cardiac transplantation recipients who develop cardiac valvulopathy
All these need antibiotic prophylaxis before dental and endoscopic
procedures.
* Except for the conditions listed above, antibiotic prophylaxis is no longer recommended for
any other form of CHD. † Prophylaxis is reasonable because endothelialization of prosthetic
material occurs within six months after the procedure.

190
: Epidemiological definitions
Endemic: Usual prevalence of a disease in a population within a
geographic area
Hyperendemic: Constantly high incidence or prevalence of disease
rate in a population within a geographic area Importantly, there is no
current consensus definition for endemic or hyper endemic incidence
or prevalence of ARF or RHD
Control: A reduction in the incidence, prevalence, morbidity, or
mortality of a disease to a locally acceptable level. Continual
interventions required
Elimination: Reduction to zero (or very low target rate) the incidence
of a disease within a defined geographical area. Continual
interventions required
Eradication: Permanent reduction to zero of the worldwide incidence
of the disease. Control interventions no longer required
ARF: Acute rheumatic fever, RHD: rheumatic heart disease

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