Rheumatic fever

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RHEUMATIC FEVER V medical unit Prof Dr. M.Natarajan M.D Asst prof Dr.G.Selvarani M.D Dr.K.Muralitharan M.D

Introduction :

Introduction Acute rheumatic fever is a multisystem disease resulting from autoimmune reaction to infection with Group A Beta hemolytic streptococcus (GABHS) in the children aged between 5-15 years Continues to be a problem worldwide: „ sporadic outbreaks in developed countries frequent occurrences in developing countries Still gaining understanding of etiology „ link between genetic predisposition and clinical manifestations best prevention still correct use of antibiotics

Acute Rheumatic Fever :

Acute Rheumatic Fever Epidemiology Pathogenesis Clinical features Diagnosis Treatment Future treatments


EPIDEMIOLOGY It is estimated that 3.37 million patients have RHD in India (2008) 44000 Pts are added each year At least 1/3 rd of whom are children It accounts for 20-30% of cardiology admissions in Indian hospitals


Incidence The incidence of RF in Developing countries is 27-100/1 lac /yr In developed countries is <5/ 1lac/yr ( G.S.Sainani Japi 2006) The incidence of rheumatic fever (RF) varies from 0.2 to 0.75/1000/ year in schoolchildren 5–15 years of age (2001 Govt Census) Anil Grover,padamavati S et al, etal INJ 2002

Epidemiology (continued):

Epidemiology (continued) Usually occurs in people between 5 and 15 years old „ Males and females equally affected „ ARF and RHD are considered as diseases of poverty„ Virulence of strain is important „ In tropics/subtropics: year-round incidence with peak in colder months

Area Prevalence/1000:

Area Prevalence/1000 US 0.3 Japan 0.3 India 2.2 Africa 5.7 South america 1.3


Pathogenesis RF occurs 1-5wks after streptococcal throat infection , avg is 3 wks AGENT Streptococci-GABHS Gram positive cocci occuring in chains Capsulated with fimbria


STREPTOCOCCI Streptococci pyogenes Beta Haemolytic -Complete heamolysis on blood agar Lancefield groups 19 –according to carbohydrate antigen ( A to U except I,J) Surface M protein -80 serotypes T,R proteins.

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GABHS Rheumatogenic serotypes 1, 3,5,6,14, 12 ,18,19,24 ,27,29 Nephritogenic serotypes 12 & 49


structure capsule hyaluronic acid cellwall outer – fimbria+lipoteichoic acid+m protein middle-carbohydrate inner- peptidoglycan layer cytoplasmic membrane

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Autoimmune disease Antigenic mimicry Antibodies against these antigens result in a hyperactive immune response M protein helical protein-constant ,variable and highly variable region N-terminal C & B repeat regions

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Crossreactivity - cytoskeleton, tropomyosin and myosin. M protein of GABHS virulence factor -> ability to resist phagocytosis specific immunity against M protein

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Group specific polysaccharide wall -> glycoprotein of cardiac valves Antibodies to the streptococcal peptidoglycan complexes have been implicated in rheumatic arthritis Somatic antigens of the cell wall & cell membrane -> myocardial sarcolemma ,vascular initima and skin

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In Sydenham chorea, antibodies directed against the cell membrane cross react with tissues in the caudate nucleus of the brain Role of fimbrial & lipoteichoic proteins is uncertain.


TOXINS Streptolysin ( Heamolysin ) O and S Erythrogenic toxin Streptokinase DNAase NADase Hyaluronidase protinase

Immune response:

Immune response RF develops following streptococcal tonsillopharyngeal infection only, but not after infection at other sites Exotoxin C, mitogenic factor and M protein. T cell immunity.

Immune response:

Immune response HLA class I A,B,C HLA class II DP,DQ,DR Present on monocytes ,macrophages and present antigen to CD4 cells Exaggerated resonse Release of cytokines


HOST Genetic susceptibility Presence of specific B cell alloantigen D8/17 RF risk has been associated with increased prevalence of HLA DR3 & DQw2 in India, HLA DR4 in USA This may help in identifying susceptible groups


PATHOLOGY RF is a multisystem connective tissue disease Inflammatory lesions in the heart, joints & subcutaneous tissue Microscopy Aschoff granuloma is the pathological hallmark of RF. It consists of central fibrinoid necrosis surrounded by histiocytes ( Anitschkow cells) with a typical “owl-eye” nucleus.

Aschoff nodule and Anitschkow cell:

Aschoff nodule and Anitschkow cell

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Seen in 30-40% biopsies Fibrinoid necrosis of valve leaflets, cellular infiltrates neovascularization of valves Monocytic infiltration of myocardium Myocarditis with scattered aschoffs nodules Myocardial necrosis uncommon

Gross appearance:

Gross appearance Valves appear dull & thickened Verucous pinhead vegetations on the atrial surface of the mitral valve, chords, ventricular surface of aortic valve with edema or hemorrhage in the leaflet tissue Vegetations are composed of fibrin

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Small 1-2 mm verruce along the line of closure of valves Serofibrinous pericarditis bread and butter appearance Scar in LA – McCallums patch due to regurgitation jet.



Natural History:

Natural History

Spectrum of RHD in INDIA:

Spectrum of RHD in INDIA Younger age group Multivalvular involvement Multiple recrudance of RF Rapid progression of disease Higher incidence of complications such as AF, embolism, CCF, Problems associated prophylaxsis and treatment

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India western Onset Symptoms from initial attack 3- 11 yrs 19 yrs Severe valve lesion from initial attack 5 – 20 yrs 31 yrs Age at the time of intervention 2 or 3 th decade 4 or 5 th decade

Clinical Features:

Clinical Features Following upper airway infection with GAS Silent period of 2 - 6 weeks Sudden onset of fever, pallor, malaise, fatigue

Diagnosis of rheumatic fever:

Diagnosis of rheumatic fever Sir T . Duckett Jones 1944 Modified in 1956,1965,1984 and 1992

Jones criteria 1944:

Jones criteria 1944 Major criteria- Carditis Arthralgia Chorea Subcutaneous nodules History of previous rheumatic fever or RHD

Minor Criteria:

Minor Criteria Fever abdominal pain precordial pain epistaxis pulmonary findings -rheumatic intersitial pneumonitis , pleurisy Electrocardiographic abnormalities, Erythema marginatum microcytic anaemia, Elevated total leucocyte count, Raised ESR

Jones criteria 1965:

Jones criteria 1965 Major criteria- Carditis polyarthritis Chorea Erythema marginatum Subcutaneous nodules Minor Criteria H/O rheumatic fever or RHD Arthralgia Fever Raised ESR,CRP Leucocyctosis PR interval Plus evidence of strep infection rising ASLO titre , positive culture ,or recent scarlet fever

Amended Jones criteria 1984:

Amended Jones criteria 1984 Polyarthralgia was taken as major criteria if ASLO > 400 units and raised ESR


JONES CRITERIA 1992 MAJOR MANIFESTATIONS Carditis Polyarthritis Chorea Erythema marginatum Subcutaneous nodules


MINOR MANIFESTATIONS Previous RF or RHD Clinical findings Athralgia Fever Lab findings Raised ESR >30mm/hr Elevated C-reactive protein >8mg/dl Prolonged PR interval

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Supporting evidence of antecedent GABHS infection Positive throat culture or Rapid streptococcal antigen test Elevated or rising streptococcal antibody titer

Diagnosis of Rheumatic Fever:

Diagnosis of Rheumatic Fever Two major manifestations OR One major & Two minor manifestations if supported by evidence of preceding GABHS infection indicate a high probability of Acute RF Sensitivity 77%, Specificity 97%

In 3 special categories listed below,:

In 3 special categories listed below, diagnosis of RF is acceptable without Jones criteria Only in (1) & (2) conditions the requirement for evidence of a recent streptococcal infection can be ignored Chorea if other causes are excluded Insidious or late onset carditis with no explanation Rheumatic recurrence (a new episode of Rh.fever occuring after another GABHS infection , occuring > 6-8wks following stopping treatment)

World Health Association for Diagnosis of Acute Rheumatic Fever :

World Health Association for Diagnosis of Acute Rheumatic Fever First episode- same as the Jones criteria Recurrent episode in a patient without established RHD- same as for first episode Recurrent episode in a patient with established RHD- requires 2 minor Jones criteria manifestations and evidence of an antecedent group A streptococcus infection

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05/05/1999 Dr.Said Alavi 44 Recommendations of the American Heart Association


Carditis Seen in 42% of patients with acute RF 80% of patients who develop carditis within the first 2 wks of onset of RF Rheumatic carditis is a pancarditis affecting the endocardium , myocardium & pericardium to various degrees Predominant effect is scarring of the heart valves

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In one study, clinical carditis was seen in 72% whereas ECHO detected carditis was seen in 91% Mitral regurgitation is the hallmark of rheumatic carditis Aortic regurgitation is less common Pulmonic & tricuspid valves are rarely involved Patients who have significant arthritis less commonly have severe carditis


Endocarditis Most commonly effects mitral & aortic valves Mitral valve disease 70-75% pts of RHD Mitral + Aortic valve disease 20-25% Isolated Aortic valve disease 5-8% Isolated Aortic stenosis is rare 3-4 %

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Isolated tricuspid & Pulmonary valve is never involved Tricuspid valve along with Mitral & Aortic valve is involved in 11.8% of RHD patients Rheumatic Pulmonary valve is very rare , if present it is quadrivalve involvement

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Most common in carditis is MR (GR I –IV), causes blowing pansystolic murmur radiating to axilla associated with mid diastolic murmur (Carey Coombs murmur) without presystolic accentuation. Caused by valvulitis ,valve prolapse , annular dysfunction. Severity of MR has prognostic significance AR is mild to moderate


Myocarditis Due to severe myocardial inflammation Clinically- Soft S1, gallop sounds, murmur, cardiomegaly , CCF,prolonged PR interval CCF is mostly due to severe MR Myocardial necrosis is rare.


Pericarditis Occurs in 6-15% pts of RF Indicates carditis Clinically frictional pericardial rub Always associated with valvulitis Often associated with serosanguinous effusion Effusion always resolves without any sequelae

Silent carditis:

Silent carditis Occurs in 2-8% of ARF No clinical evidence of carditis Only have histological evidence of carditis Recently Echocardiographic evidence of valvular nodules has been proposed to diagnose silent carditis TEE is more sensitive

Scheme for diagnosis of Acute Rheumatic Carditis:

Scheme for diagnosis of Acute Rheumatic Carditis First attacks Recurrences Valvulitis New murmur Changed murmur Apical systolic New murmur Carey coombs Aortic regurgitation Myocarditis Unexp Cardio- megaly,CHF Worsening cardio - megaly

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Pericarditis Pericardial rubs -----do---- Effusion Misc Conduction disturbances Unexp tachycardia ECHO imaging Morphologic evidence Histologic evidence at biopsy


POLYARTHRITIS Incidence > 2/3 rd of patients Asymmetric, migratory involving large joints- knees, ankles, elbows & wrists Axial joints are rarely involved Swelling, redness ,hot, severe pain, limitation of joint movements are the main symptoms

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Physical findings disproptionate to symptoms Joints are involved at various intervals lasts for 4-5 days Arthritis resolves by 3 to 4 wks without any permanent damage Joint aspirate >10000 WBCs/cu.mm Dramatic response to aspirin –improves within 48hrs

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Jaccoud’s arthritis- Involves small joints & causes correctable deformities, was thought to be due to RF but has never been proved

Differential diagnosis:

Differential diagnosis Post streptococcal reactive arthritis Septic arthritis Gonococcal arthritis SABE Juvenile rheumatoid arthritis Tuberculosis arthritis Hepatitis B Henoch scholein purpura Serum sickness

Post streptococcal reactive arthritis (PSRA):

Post streptococcal reactive arthritis (PSRA) ) Arthritis following acute streptococcal pharyngitis but does not fulfill Jones criteria Small joint involvement,symmetric Short latent period (usually <1week) Occassional causation by non GABHS Absence of other features like carditis PSRA does not respond dramatically to anti-inflammatory agents This condition should be treated as ARF.

CHOREA (St.Vitus dance):

CHOREA ( St.Vitus dance) It is a series of jerky, nonrepeatative , q ausipurposive involuntary movements involving the face & extremities with emotional lability . Movements disappear during sleep Due to rheumatic inflammation of basal ganglia & caudate nucleus Late manifestation after several weeks (3mths or longer) after RF

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These pts do not fulfill Jones criteria Incidence 20% Common in children 7 to 14 yrs Common in females Lasts from weeks to months Self limiting No relapses High incidence of chronic RHD(22%) Secondary prophylaxis is must


SKIN MANIFESTATIONS Subcutaneous nodules(1 to 21%) Late manifestation of RF Indicate presence of underlying carditis Firm, painless, moveable 0.5 to 3cm in size On bony prominence, extensor tendons (elbows ,knees , wrists,ankles ), vertebral spinous process,suboccipital region,medial border of scapulae Appear in crops, disappear in 8 to 12wks



Erythema Marginatum:

Erythema Marginatum Early or late manifestation Incidence 10-15 % Indicate presence of underlying carditis On trunk & proximal extremities Serpigenious erythrematous macular/ papular nonpuritic rash Rash extends outwards with central clearing No residual scarring May appear or disappear in mins -hrs

Erythema Marginatum:

Erythema Marginatum


Arthralgia Joint pain without objective signs of inflammation Common in rheumatic recurrences & in patients with RHD in developing countries Migratory polyarthralgia

Laboratory Diagnosis:

Laboratory Diagnosis Throat Culture Positive in only 11% cases of ARF Streptococcal Antibody Tests ASLO Titer Slide agglutination test Elevated in 80% patients with ARF Reach a maximum level 2-3wks after infection, plateau for 3-6mths & disappear in the next 6-12mths

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Adults /preschool children < 85 todd units School age = 170 todd units Titers alter with age, geographical area ASO titer >250 Todd units in adults >333 Todd units in children is used for diagnosis,

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Rising titer is more specific ,second sample 7 to 10 days. Specificity is 93% Results alter with antibiotics,steriods liver disease & bacterial contamination

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AntiDNAse B/ Antihyaluronidase test Done when ASO is nondiagnostic Levels remain elevated for several mths Less affected by antibiotics and steriods . DNA ase 6-12 mths Titre > 300 IU/dl


normal values Anti DNase B titer 1:60 unit in preschool, 1:480 units in –  school children & 1:340 in adults) Antihyaluronidase > 200 IU/dl Streptozyme test – 5 antigens Rapid slide agglutination test Not fully accepted

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Acute phase reactants Raised ESR Elevated CRP ECG Prolonged PR interval Tachycardia AV block QRS-T changes s/o Myocarditis


Echocardiography Helpful to diagnose silent carditis More sensitive than clinical examination In Utah(1987)EPIDEMIC cardiac involvement was diagnosed in 47% of cardiac asymptomatic patients Abernathy(1994) found 30% cardiac involvement in patients without clinical carditis

Is ECHO of clinical benefit:

Is ECHO of clinical benefit Vasan et al –circulation 1996 -108 pts of acute RF ARF without clinical carditis - echo trivial MR 29% trivial AR 7%,trivial PR 21% none of them developed residual RHD on follow up ECHO ARF with clinical carditis = 69% had valvular regurgitation at 6 mths.

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Focal nodules 25% - disappeared on follow up Regurgitation lesions disappeared in 22% of cases at 6 mth Pts without echo evidence of carditis did not develop regurgitation on follow up. No incremental diagnostic utility of echocardiography in rheumatic fever without clinical evidence of carditis

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Role of Echocardiography remains controversial as 28 % of normal population has trivial MR But can diagnose Valvulitis –thickening of valve, nodular structure on valve. TEE is more sensitive.

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Many have proposed Echocardiographic Valvulitis should be major Jones criteria Diagnose subclinical carditis Has prognostic significance Sensivity increases in serial follow up Echocardiography Can guide for duration of secondary prophylaxsis . Jagat Narula , Y. Chandrasekhar, Shahbudin Rahimtoola , curculation 1999.

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Even though Echocardiography can overdiagnose carditis , its better to treat the patient Disadvantages Echocardiographic facilities are limited Costly Cannot be recommended as a routine mode of investigation in developing countries.

Artificial subcutaneous nodule test:

Artificial subcutaneous nodule test 1.5 ml subcut inj of autologous blood on elbow – subcutaneous nodule 4-7 days – active carditis ( Massel et al 1937) Bhattacharya et al.1987 replicated this study specificity 100% sensitivity 29%

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Vasan modified the test and used only the white cell concentrate Centrifuged 3 ml of venous blood in sterile tubes and obtained buffy coat by removing plasma sensitivity 86% and specificity 94%, It is a simple, inexpensive, safe, and sensitive investigation Raj Tandon dec 2005 IHJ

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No single symptom ,sign or lab test is diagnostic of rheumatic fever Jones criteria assist and are not substitute to clinical judgement

Diffferential diagnosis:

Diffferential diagnosis Juvenile rh.arthiritis SLE Other CTD- vasculitis Bacterial endocarditis Reactive arthiritis Seronegative spondyloarthiritis Infections ( hansen’s,lyme,yersinia ) Leukemias Antiphospholipid antibody syndrome Sarcoidosis Sickle cell anaemia & other HB disorder

TREATMENT Acute Rheumatic fever:

TREATMENT Acute Rheumatic fever Inj. Benzathine Penicillin 12 lac units i.m single dose OR Erythromycin 40mg/kg/day in 2-4 divided doses for 10days Aspirin 100mg/kg/day in 4-5 divided doses for 3-4 wks, dose is gradually tapered depending upon ESR & CRP levels. Indian Authors JAPI June2006 Sainani,padamavati S recommend Aspirin for 6 wks

Treatment of Rheumatic Carditis:

Treatment of Rheumatic Carditis Without Failure Same as ARF With Failure/severe carditis Prednisone 1-2mg/kg/day for minimum of 2 wks & then tapered for next 2 wks When to switch Aspirin to Steroids No response to aspirin within 3-4 days New cardiac findings develops Child develops CCF Child intolerant to aspirin

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Aspirin is started during the tapering course of Corticosteroids and is continued for 4 wks or until there is sufficient clinical &laboratory evidence of reduced rheumatic activity IAP ,IJOP 2002 Saxena A recommend aspirin for minimum 12 wks It is given to reduce the rebound activity after stopping of steroids. 5% of patients of ARF continue to have rheumatic activity for >6mths


SEVERE CASES Anti failure therapy SURGICAL THERAPY Mitral valve repair Mitral valve replacement

Prevention of RF :

Prevention of RF PRIMODIAL PREVENTION Involves measures to prevent the occurrence of a GABHS sore throat Clean & Healthy environment. Mass chemoprophylaxis can work in some high risk situations Vaccines are in experimental phase Not feasible in all situations

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PRIMARY PREVENTION Involves effective recognition & treatment of GABHS sore throat & in turn prevent the development of RF Detection of Streptococcal sore throat Sore throat with fever Painful deglutition Headache,abd pain,nausea,vomiting Definitive diagnosis Throat culture

Canadian Physician group:

Canadian Physician group Tonsillar exudate Swollen ant cervical nodes H/O fever >38˚C Lack of cough Is used to stratify risk of Streptococcal throat infection. Sensitivity 82% specificity 42%

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Primary prophylaxis Benzathine penicillin G <27kg 0.6 MU IM Once >27kg 1.2 MU PenicillinV Children 250mg bd / tid PO 10days Adults 500mg bd / tid Penicillin allergy Erythromycin 250mg qid PO 10days Azithromycin 500mg PO 1 day 250mg OD 4 days Others – nafcillin , ampicillin , amoxycillin , clindamycin , cephalexin




SECONDARY PREVENTION Involves prevention of streptococcal sore throat in patients with previous episodes of RF & thereby prevent recurrent cardiac damage RF is a recurrent disease Recurrence per infection - 40-60% Permanent cardiac damage increases with Recurrences

Duration of secondary prophylaxis:

Duration of secondary prophylaxis Category Duration RF with carditis & residual valvular lifelong RF with carditis 10yrs or well into but no residual adulthood,whichever valvular dis is longer RF without 5yrs or until age 21 carditis whichever is longer


TERTIARY PREVENTION Valvotomy Valve replacement

Rheumatic recurrence despite prophylaxis:

Rheumatic recurrence despite prophylaxis Penicillin 0.45% Penicillin(oral) 5.5% Sulfa drugs 2.8% Control 15% All in terms of 100 pts years


chorea Haloperidol -0.25 – 0.5mg/kg/d Diazepam -0.25 – 0.5mg/kg/d Valproate -15mg/kg/d IVIG can be tried in refractory chorea,not responding to other drugs

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Streptococcal vaccine May prove to be the most effective way to reduce global RF burden Still in experimental stage M proteins are type specific & Antibodies to them effectively confer immunity to that strain Setbacks- Changes in the streptococcal strain in different communities Number of bacteria are not M typeable

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First vaccine 1969 with 3 M proteins-Failed multivalent N-terminal vaccine Strategy Dr Jim Dale & Canadian biotechnology company ID Biomedical.- StreptAvax The vaccine - sequence of short peptides from the N terminal region of 26 different GAS emm type strains Only vaccine in phase II trial 3 doses.

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Professor Michael Good’s team in Australia Identified a 20 amino acid peptide, peptide145, located within C-repeat region of the M protein Seven type-specific determinants on a polymer backbone Phase I clinical trial

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Professor Vince Fischetti’s team in New York Vaccine contains recombinant streptococcal protein fragments linked to E.coli labile toxin likely to prevent mucosal colonization due to the formation of IgA antibodies Phase I human trial

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Streptococcal C5a peptidase (SCPA) vaccine -Dr Pat Cleary and colleagues. Streptococcal cysteine protease, also known as Streptococcal pyrogenic exotoxin B vaccine -Professor Musser Professor Singh Chhatwal’s group in Germany intranasal spray vaccine The streptococcal adhesin , fibronectin -binding protein 1 (Sfb1) GAS vaccine

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ICMR is working actively to produce RF vaccine. ICMR has initiated Jal Vigyan Mission Mode Project at Chandigarh and Vellore where the development of RF vaccine is in progress. Vaccine is being prepared using Indian strains of A streptococci.

Streptococcal vaccine:

Streptococcal vaccine The 26-valent vaccine - four different recombinant proteins, each containing six or seven N-terminal M protein Developed by Centers for Disease Control and Prevention, Atlanta, Georgia 5 Clinical trial 2005


CONCERNS It is now 100yrs that we know about RHD,still it continues to be a major problem in developing countries Eradication of RF is still a distant dream In future an effective antistreptococcal vaccine may alter the epidemiology of RF/RHD

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