Acute Rheumatic Fever (Licks the Joints and Bites the Heart) Etiology: Group A beta hemolytic streptococci (GABS) Serotypes (M protein..,3,18) Rheumatogenicity

Epidemiology: 5-15 y/o Developing or underdeveloped countries New outbreaks Crowding Low sanitary Season Pharyngitis but not impetigo

Pharyngitis by History in Recent Reports of ARF

Pathogenesis: Unknown Toxic effect Abnormal immune response Genetic influence (alloantigen on surface of non T-lymphocytes in 99% of ARF but 13% of controls)

Pathogenesis: Abnormal immune response Alteration in helper and suppressor T cells Anti heart antibodies IgG, IgM, C3 deposition in pericard

Streptococcal and Human Tissue Immunologic Cross Reactivity Capsule Hyaluronic acid Cell wall M – protein Group carbohydrate Rhamnose N-acetyl glucosamine Protoplast membrane Protein, lipid, glucose Joint Myocardium Valves Myoc.Sarcolemma, Subthalamic & Caudate nuclei

Frequency of Major Manifestations of ARF in Recent Reports No. of cases Carditis % Arthritis Chorea Erythema Marginatum 40 50 65 18 13 59 58 76 3 74 91 46 31 17 47 30 23 78 9 26 73 4 43 49 42 2 All 22

Clinical manifestations: Polyarthritis: The most common Migratory polyarthritis Tenderness Large joints Duration Joint effusion and analysis Response to ASA There is often an inverse relationship between the severity of arthritis and the severity of cardiac involvement.

Poststreptococcal Reactive Arthritis: Arthritis and recent evidence for GABS infection but do not fulfill the Jones criteria Arthritis course & response to Rx. like JRA About 5% acquire valvular disease without secondary prophylaxis

Clinical manifestations: Carditis: 40-80% Mitral valve (the most common) Pancarditis Pericarditis Arrhythmia CHF

Subclinical Carditis: >90% ? Over diagnosis

The Incidence of Carditis Depends on Age: < 3 Y/O 90% 3-6 Y/O 50% 14-17 Y/O 32% > 25 Y/O Rare  

Chance of Having Normal Heart in Follow Up: Initial Attack 5 Year Follow Up 10 Year Follow Up No Carditis 96% 94% CHF 40% 30%

Carditis: Isolated Mitral valve disease has 76% rheumatic etiology Isolated Aortic valve disease has 13% rheumatic etiology Combined Mitral and Aortic valve disease has 97% rheumatic etiology Roberts: in Moss & Adams textbook, 2001 edition

First streptococcal pharyngitis attack cause ARF in: Epidemic = 3%, Endemic = 0.3% Second attack cause ARF in 11- 65% (after 10 years 4-8%) RHD and cardiomegaly has 43% recurrence rate RHD and no cardiomegaly has 27% recurrence rate Normal heart has 10% recurrence rate < 5% have chronic active carditis for > 6 months duration Rheumatic activity may be prolonged with rebound

Clinical manifestations: Sydenham chorea: Deterioration of handwriting Emotional instability Milkmaid’s, silk fork and bag of worm signs Late presentation Disappear with sleep

Clinical manifestations: Subcutaneous nodule: Not tender Extensor surface Associated with severe carditis (MS)

Clinical manifestations: Erythema Marginatum: Not pathognomonic Non tender No itching Associated with chronic carditis

Erythema Marginatum:

Minor Manifestations: Fever Arthralgia

Modified Jones Criteria: Major Minor Carditis Fever Polyarthritis, migratory Arthralgia Erythema marginatum ESR, CRP Chorea Prolonged PR interval Subcutaneous nodule ? Previous Hx. of ARF Plus: Evidence of preceding streptococcal infection Except: Chorea, insidious or late onset carditis

Modified Jones criteria: 2 major or one major and 2 minor criteria plus evidence for recent streptococcal infection. Recurrence of ARF: Only one major criteria or fever, arthralgia, and elevated acute phase reactants

Lab findings: ASO titer (acute and convalescent sera) ADB AH Throat culture ECG Echocardiography

Frequency of Elevated Antibody Titer (%) in Patients With ARF ASO Anti-Dnase B ASO & Anti Dnase B Normal Controls 19 30 ARF 83 82 92

ASO Titers in Children in Tropical Countries Country % ASO titer Over 200 units Thailand 17.7 Pakistan 18.4 Burma 37.2 Mongolia 52.3 Algeria 36.4 Kenya 40.6 Nigeria 53.3

Antibody response: Anti-A carbohydrate test reaches a peak 1 month after GABS infection and declines to normal levels about 2 years thereafter, except in patient with persistent rheumatic MR which will be maintained for several years.

Frequency of Positive Throat Culture Following Untreated Streptococcal Pharyngitis

Differential diagnosis: JRA SBE Connective tissue disorders

Differential diagnosis: >7 days, at least 6 weeks arthritis ARF JRA Large joints Small joints Migratory arthritis Additive arthritis <7 days, Max 6 weeks arthritis >7 days, at least 6 weeks arthritis Very tender Painful Red joints Pallor over the joints ASA effective in 24-48 hr ASA effective in 5-7 days No damage (? Jaccoud’s) Joint damage possible Synovial fluid <10000 WBC Synovial fluid >20000 WBC > Endocarditis > Pericarditis

Treatment: Penicillin ASA (first sign of toxicity is hyperventilation) Prednisolone Rx. For CHF Bed rest Rx. Of Chorea (Phenobarbital (is choice) 16-32 mg every 6-8 hr PO, chlorpromazine 0.5 mg/kg every 4-6 hr PO, diazepam, haloperidol 0.01-0.03 mg/kg/24 hr divided bid PO, valproate, vitamine E 50 mg/2 wk) SBE prophylaxis (not penicillin)

Patients with typical migratory polyarthritis and those with carditis without cardiomegaly or congestive heart failure should be treated with oral salicylates. The usual dose of aspirin is 100 mg/kg/day in 4 divided doses PO for 3-5 days, followed by 75 mg/kg/day in 4 divided doses PO for 4 wk. There is no evidence that nonsteroidal antiinflammatory agents are any more effective than salicylates.

Patients with carditis and cardiomegaly or congestive heart failure should receive corticosteroids. The usual dose of prednisone is 2 mg/kg/day in 4 divided doses for 2-3 wk followed by a tapering of the dose that reduces the dose by 5 mg/24 hr every 2-3 days. At the beginning of the tapering of the prednisone dose, aspirin should be started at 75 mg/kg/day in 4 divided doses for 6 wk. Supportive therapies for patients with moderate to severe carditis include digoxin, fluid and salt restriction, diuretics, and oxygen. The cardiac toxicity of digoxin is enhanced with myocarditis.

Surgical Treatment: MR: AI: Functional class III or IV LVSD >26 mm/m2 LVDD >40 mm/m2 SF < 31% AI: LVSD >55 mm lower limit of normal SF & EF

Prevention: Primary prophylaxis Secondary prophylaxis 3 or 4 weeks 600.000-1.200.000 units Benzathine Penicillin No vaccine available

Duration of secondary prophylaxis? AHA 2009 Rheumatic fever without carditis 5 yr or until 21 yr of age, whichever is longer. Rheumatic fever with carditis but without residual heart disease (no valvular disease) 10 yr or until 21 yr of age, whichever is longer. Rheumatic fever with carditis and residual heart disease (persistent valvular disease) 10 yr or until 40 yr of age, whichever is longer, sometimes lifelong prophylaxis

Immunologic Factors in Patients With Acute Rheumatic Fever Compared to Patients With Rheumatic Heart Disease and Healthy Individuals. Sabri MR, Zohouri D, et al, IJMC; 2001; 26(3,4) :116-119

Aim: To clarify the state of different immunologic factors in patients with ARF and RHD in compare to the healthy individuals. Patients and Methods: ARF (21 patients), RHD (19 Patients), and. healthy children as the control group (20 children) were studied. All patients were evaluated and followed for the presence and the severity of carditis, heart failure, and valvular involvement with echocardiography. ASO titer, ESR, serum C3 and C4, IgA, IgM, and IgG, IgM Rheumatoid Factor (RF), IgM and IgG anti-cardiolipin antibody (ACLA), and IgM and IgG anti-M group A streptococcal protein (AMP) were compared.

Results: 1) A significant difference for IgG and IgM ACLA between groups. These significances were shown to reflect the difference between patients with ARF and the other two groups. 2) A significant difference for IgG AMP between ARF and RHD groups. 3) A significant difference for IgM RF between ARF and RHD groups. 4) A significant difference for serum IgG between groups. This significance was shown to reflect the difference between patients with ARF and the two other groups. 5) Serum IgG was significantly lower in patients with than in patients without aortic valve involvement. Similarly, Serum IgG was significantly lower in patients with pericardial effusion.

Conclusion: There are significant differences for IgG and IgM ACLA and IgG AMP and serum IgG levels and IgM RF between ARF patients and the other two groups. The reproducibility of finding as well as whether IgG has a “protective effect” in patients with ARF preventing them from developing pericardial effusion, aortic valve involvement, or other complications are notable questions that must be answered in larger studies.

Correlation Between The Severity of Carditis And The Level of Acute Phase Reactants and Anti Streptolysin O Titer In Acute Rheumatic Fever, A Retrospective Study In Shiraz, Iran. SABRI MR, KADIVAR MR; MJIRI, 1999; 13 (1); 11-14

Frequency of the Observed Symptoms and Signs in the Study Group (104 Patients). Symptoms or Signs Frequency(%) Arthralgia 95.2% Signs of CHF 6.7% Fever 85.5% Chorea 3.8% Arthritis 81.7% Erythema Marginatum 0% Heart Murmur 76.0% Subcutaneous Nodule 0.9%

Frequency of the Echocardiographic Findings in the Study Patients Isolated MR. 40.3% MR,AR,TR,PR 1.9% MR & AR 26.9% MR, AR, PR MR,AR,TR 5.7% Pericardial effusion 3.8% Isolated AR 2.9% Normal 17.5% MR,TR -

Results: Conclusion: The ESR was 20 Wintrobe unit in 98.0%. The CRP was elevated in 83.0%. The ASO titer was 400 Todd unit in 91.0% of patients. Conclusion: There was no significant statistical difference between those patients with mild and severe carditis for the level of ESR, CRP, and ASO titer. There was also no significant statistical difference between the level of these parameters and the presence or absence of carditis, and the patient’s age (8 years or >8 years old).

A Prospective One Year Follow Up of Patients With Acute Rheumatic Fever And Evaluation of Valvular Regurgitation SABRI MR, REZAIE M, 13 th International Congress Of Geographic Medicine and the Congress of cardiovascular diseases , 2-5 Oct. 2000 Shiraz-Iran

Introduction: Patients and methods: Initial carditis, cardiomegaly, CHF, moderate or severe degrees of valvar regurgitation and recurrence of ARF significantly increase the risk of subsequent rheumatic heart disease. Patients and methods: In this study, 80 children with first attack or recurrence of ARF associated with carditis were visited a by pediatric cardiologist and echo was done for them. 64 patients had regular follow up for one year.

Results: Valvular regurgitation disappeared in seven patients (11%) at the end of follow up. Severity of MR and AI decreased in 74% and 61% of patients respectively after one year. In isolated MR, the regurgitation decreased in severity in 53.3% of patients and there was no significant statistical difference between this group and those who had 2 or more valvar regurgitation ((p=0.37). 4) There was no significant statistical differences between two sexes (p=0.40), in different age groups (p>0.30) and type of presentation at the initial attack of ARF (carditis+arthritis or chorea or both with p>0.70).

Results: Mitral valve involvement in patients with CHF was more severe than in patients without it. Decrease in the severity of valvular disease was more significant in patients without CHF. There were no statistical difference between patients with respect to initial ASO titer, ESR and CRP level. There were no statistical difference between patients who received anti-inflammatory medication during acute phase of disease, comparing with those who didn’t (all p>0.05). 5) Six patients had recurrence of ARF and all of them had no change in valvular involvement at the end of one year follow up.

Serum Penicillin Level After Intramuscular Injection of 1. 200 Serum Penicillin Level After Intramuscular Injection of 1.200.000 Units of Benzathine Penicillin G, in Children With Rheumatic Fever. SABRI MR, KADIVAR MR, BORZOUEE M; MJIRI; 2000; 14 (1); 23-26

Patients and Methods: 42 patients with RF Mean age ± SD = 14.8 ± 11.9 years SPL was determined by disk agar diffusion method The minimum accepted SPL to be effective against group A  hemolytic streptococci was 0.02 µg/ml

Results: The mean SPL decreased to <0.02 µg/ml at the end of third week (mean ± SD = 2.35 ± 1.3 weeks in 46% of patients). The mean SPL were significantly higher in patients who weighed <45 kg (mean ± SD = 38.6 ± 4.3 kg) in comparison with those who weighed 45 kg (mean ± SD = 54.25 ± 4.87 kg), with p value <0.0001. There was no significant differences in mean SPL between boys and girls (p = 0.145).

Conclusion: Although in this study the mean SPL was <0.02 µg/ml in 46% of patients at the end of third week, we could not recommend every 3 weekly injection of BPG in all patients, except in: High risk patients and situations as recommended by WHO: 1) Living in crowded areas 2) Recurrence of ARF despite regular 4 weeks BPG injection 3) Heart failure or severe valvular disease in first attack. This suggestion may be helpful specially in the first 5 years after initial attack of rheumatic fever. And also in those patients who weighed 45 kg.

Serum Penicillin Level After Intramuscular Injection of 1. 800 Serum Penicillin Level After Intramuscular Injection of 1.800.000 Units of Benzathine Penicillin G, in Children With Rheumatic Fever. Ajami GH, SABRI MR, KADIVAR MR,

Patients and Methods: 16 patients with RF Mean age ± SD = 13.6 ± 3.8 years SPL was determined by disk agar diffusion method The minimum accepted SPL to be effective against group A  hemolytic streptococci was 0.02 µg/ml

Results: The mean SPL decreased to <0.02 µg/ml at the end of third week (mean ± SD = 3.6 ± 0.83 weeks). In comparison with the first study of us (2.35 ± 1.3 weeks ) the p value was 0.001 The percentage of patients with acceptable SPL on days 7, 14, 21, 28 after BPG injection were 100%, 93.3%, 85.1%, and 73.3%.

Review of Journals

Treatment of rheumatic carditis with intravenous gammaglobulin: is there a beneficial effect? SO: Cardiol-Young. 2001 Sep; 11(5): 565-7 Serum cardiac troponin-I in active rheumatic carditis.(CONCLUSIONS:did not gain clinical use) SO:Indian-J-Pediatr.2001 Oct;68(10):943-4 Prospective comparison of clinical and echo diagnosis of rheumatic carditis: long term (5 years) FU of patients with subclinical disease. (CONCLUSIONS: Doppler echo imaging improves the detection of rheumatic carditis. Subclinical lesions, detected only by Doppler, can persist. Echo findings should be accepted as a major criterion for the diagnosis of rheumatic fever). SO: Heart.2001 Apr;85(4):407-10

The value of echo in the diagnosis and FU of rheumatic carditis in children and adolescents: a 2 year prospective study.(CONCLUSION: This blind study suggests the existence of asymptomatic carditis in some patients with rheumatic fever and the role of ECHO/Doppler). SO:J-Rheumatol.2000 Apr;27(4):1082-6 Evidence against a myocardial factor as the cause of LV dilation in active rheumatic carditis. (CONCLUSIONS: LV dilation and heart failure in patients with rheumatic carditis rarely occur in the absence of hemodynamically significant regurgitant valve lesions). SO:J-Am-Coll-Cardiol.1993 Sep;22(3):826-9

Doppler echo distinguishes between physiologic and pathologic "silent" MR in patients with ARF. SO:Clin-Cardiol.1997 Nov;20(11):924-6 Pathologic MR was defined as meeting the following four criteria: (1)length of color jet > 1 cm (2)color jet in at least two planes (3)mosaic color jet (4)persistence of jet throughout systole. CONCLUSION: Pathologic "silent" MR of ARF can be distinguished from physiologic MR using strict Doppler criteria, particularly when the jet is directed posteriorly. These data support the use of Doppler echo as a minor criterion for evaluating patients with suspected ARF.

Poststreptococcal reactive arthritis (PSRA). SO:Curr-Opin-Rheumatol.2002 Sep;14(5):562 PSRA refers to a condition that does not fulfill the Jones Criteria for diagnosis of ARF. Clinical features include additive arthritis that responds poorly to ASA and nonsteroidals; persistence for mean of 2 months; elevated acute phase reactants; and laboratory evidence of recent GABS infection. PSRA is not associated with HLA-B27 but rather with HLA-DRB1*01. Up to 6% of PSRA patients develop mitral valve disease. Give prophylaxis for 1 year and then discontinue if there is no evidence of cardiac involvement. PSRA (recommend prophylaxy for a minimum period of 5 years or until the age of 21 years, whichever is longer). SO:Curr-Opin-Rheumatol.2000 Jul;12(4):306-10 PSRA in adults: a case series. (there is no evidence to support the use of penicillin prophylaxis at this time).  SO:Mayo-Clin-Proc.2000 Feb;75(2):144-7 1

Rheumatic fever in children: a 15-year experience in a developing country.(carditis (93%), arthritis (39%), Sydenham's chorea (2%), erythema marginatum (4%), subcutaneous nodules (1%), fever (62%), arthralgia (55%), and acute congestive heart failure (CHF) on initial presentation (44%). Pericardial effusion occurred in 11%). SO:Pediatr-Cardiol.2000Mar-Apr;21(2):119-22 Prophylactic efficiency of 3-weekly BPG in rheumatic fever. (conclusion: 3-weekly BPG regimen was satisfactory for secondary prophylaxis in RF, even though serum penicillin level was inadequate during the third week in some of the patients). SO:Indian-J-Pediatr.2000 Mar;67(3):163-7

Cardiac involvement in Sydenham's chorea: clinical and Doppler echocardiographic findings. (conclusion: colour Doppler echo may be useful in detecting silent valvular regurgitation and in deciding the duration of prophylaxis). SO:Acta-Paediatr.1999 Oct;88(10):1074-7 Lidocaine as a diluent for administration of benzathine penicillin G. SO:Pediatr-Infect-Dis-J.1998Oct;17(10):890-3

Three- versus 4-week administration of BPG: effects on incidence of streptococcal infections and recurrences of ARF. CONCLUSIONS. This 12-year prospective and controlled study documented that streptococcal infections and RF recurrences occurred more often in the 4-week program than in the 3-week program. The risk of prophylaxis failure was fivefold greater in the 4-week program than in the 3-week program SO:Pediatrics.1996 Jun;97(6 Pt 2):984-8 Are the currently recommended doses of benzathine penicillin G adequate for secondary prophylaxis of rheumatic fever? SO:Pediatrics.1996 Jun;97(6 Pt 2):989-91

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