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

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

4. Pharyngitis by History in Recent Reports of ARF

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

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

7. 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

8. 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

9. 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.

10. 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

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

12. Subclinical Carditis:
>90%
? Over diagnosis

13. 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

14. 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%

15. 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

16. First streptococcal pharyngitis attack cause ARF in: Epidemic = 3%, Endemic = 0.3%
Second attack cause ARF in % (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

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

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

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

20. Erythema Marginatum:

21. Minor Manifestations:
Fever
Arthralgia

22. 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

23. 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

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

25. 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

26. 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

27. 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.

28. Frequency of Positive Throat Culture Following Untreated Streptococcal Pharyngitis

29. Differential diagnosis:
JRA
SBE
Connective tissue disorders

30. 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 hr
ASA effective in 5-7 days
No damage (? Jaccoud’s)
Joint damage possible
Synovial fluid <10000 WBC
Synovial fluid >20000 WBC
> Endocarditis
> Pericarditis

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

32. 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.

33. 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.

34. 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

35. Prevention: Primary prophylaxis Secondary prophylaxis
3 or 4 weeks units Benzathine Penicillin
No vaccine available

36. 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

37. 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) :

38. 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.

39. 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.

40. 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.

41. 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

42. 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%

43. 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 -

44. 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).

45. 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 Shiraz-Iran

46. 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.

47. 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).

48. 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.

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

50. 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

51. 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 = ± 4.87 kg), with p value <
There was no significant differences in mean SPL between boys and girls (p = 0.145).

52. 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.

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

54. 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

55. 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%.

56. Review of Journals

57. Treatment of rheumatic carditis with intravenous gammaglobulin: is there a beneficial effect?
SO: Cardiol-Young 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

58. 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

59. 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.

60. 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):

61. 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

62. 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

63. 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

64. Thank You