1. Rheumatic Fever and Rheumatic Heart Disease
DR.ABDUL GHAFFAR MEMON
Associate Professor Cardiology
LUMHS HYD/JAMSHORO

2. Learning Objectives:
To understand the pathogenesis of acute rheumatic fever and rheumatic heart disease
To appreciate the burden of disease
To recognize the features of a streptococcal sore throat
To know the treatment regimens of a streptococcal sore throat
To be aware of secondary prevention measures

3. Examine the burden of disease within own communities
Performance Objectives:
Examine the burden of disease within own communities
Timely recognition of a streptococcal sore throat with correct treatment
Institute secondary prevention programme
Join the global community fighting Rheumatic fever and rheumatic heart disease

4. What is the incidence of acute rheumatic fever and rheumatic heart disease?

5. Epidemiology 20 % bacterial 80 % viral 15% GABHS 5% other bact.
ARF is a disease of child age group 6 – 15 yrs.
ARF uncommon < 5 yrs. And recurrence very rare after 34 yrs.
Pharyngitis
20 % bacterial
80 % viral
15% GABHS
5% other bact.
.3 – 3 % ARF

6. Incidence of ARF: Population-based Studies
Incidence of acute rheumatic fever in the world: a systematic review of population-based studies.
Tibazarwa KB, Volmink JA, Mayosi BM.
Heart Dec;94(12): Epub 2008 Jul 31. Review.

7. What is the prevalence of rheumatic heart disease?

8. According to the WHO, 15.6 million people worldwide are living with RHD. Of the who develop ARF each year, go on to develop RHD and deaths are attributable each year to ARF/RHD. The are conservative estimates and the true burden of disease is thought to be even greater. This mortality rates are higher than those of rotaviruses, meningitis and hepatitis B and half of those with malaria.
Rheumatic fever: neglected again.
Watkins DA, Zuhlke LJ, Engel ME, Mayosi BM.
Science Apr 3;324(5923):37. No abstract available.

9. Pathobiology environ-ment agent host -GABHS
->100 subtype of M protein
Heart-myosin
Heart valve- laminin
Synovia- vimentin
Skin-keratin
Brain- lysoganglioside
-Extent of immune response to pharyngitis
-Genetic susceptibility
-Prior history of RF
-Over crowding
-low socioeconomic status

10. The pathogenic pathway for rheumatic heart disease starts with the susceptible individual. Twin studies have demonstrated that a genetic component may exist. ( add link)(Repeated streptococcal infections are thought to prime a susceptible individual resulting in a heightened response to an infection with rheumatogenic streptococcus. This results in acute rheumatic fever usually 3 weeks after the initial tonsilllopharyngeal infection. The precise pathogenetic mechanism has not yet been defined, yet strong evidence exists that an autoimmune response mediates the development of RF/RHD in a susceptible host. Genetically determined host factors interacting with the molecular similarity of the streptococcal antigens and host tissues results in the involvement of brain, joints, tissues and heart. The pathogenesis of RF/RHD is a complex maze of events involving major histocompatibility antigens, potential tissue-specific antigens, antibodies and superantigenic activation . However it remains clear that environmental factors such as overcrowding, poor living conditions and poor access to health care is the most significant determinant of disease distribution.
Lancet Jul 9-15;366(9480):
Acute rheumatic fever.
Carapetis JR, McDonald M, Wilson NJ.
Carapetis. Lancet 2005;366:155

11. What is the pathogenesis of acute rheumatic fever?

12. ACUTE RHEUMATIC FEVER
Autoimmune consequence of infection with Group A streptococcal infection
Results in a generalised inflammatory response affecting brains, joints, skin, subcutaneous tissues and the heart.
RF is a delayed autoimmune response to Group A streptococcal pharyngitis. The clinical manifestation of the response and its severity in an individual is determined by host genetic susceptibility, the virulence of the infecting pathogen and a conducive environment. RF is thought to occur only after GAS infection of the upper respiratory tract although this thinking has been challenged by those working in tropical areas where skin infections are rife.
(Low rates of streptococcal pharyngitis and high rates of pyoderma in Australian aboriginal communities where acute rheumatic fever is hyperendemic.McDonald MI, Towers RJ, Andrews RM, Benger N, Currie BJ, Carapetis JR.Clin Infect Dis Sep 15;43(6): Epub 2006 Aug 9.
(The challenge of acute rheumatic fever diagnosis in a high-incidence population: a prospective study and proposed guidelines for diagnosis in Australia's Northern Territory.
Ralph A, Jacups S, McGough K, McDonald M, Currie BJ.
Heart Lung Circ Apr;15(2): Epub 2005 Oct 27.)

13. The clinical presentation can be vague and difficult to diagnose.
ACUTE RHEUMATIC FEVER
The clinical presentation can be vague and difficult to diagnose.
Currently the modified Duckett-Jones criteria form the basis of the diagnosis of the condition.
Acute rheumatic fever is a systemic inflammatory disease occurring as a sequel to beta haemolytic streptococcal infection. The clinical presentation can be vague, complex and difficult to diagnose. The modified Duckett-Jones criteria to establish the diagnosis arose from research in North America and Europe during the first part of the 20th century and may not apply in other parts of the world.
It is thought that % of untreated group A beta haemolytic streptococcal infection progress to develop acute rheumatic fever.
Prevention of rheumatic fever and diagnosis and treatment of acute Streptococcal pharyngitis: a scientific statement from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee of the Council on Cardiovascular Disease in the Young, the Interdisciplinary Council on Functional Genomics and Translational Biology, and the Interdisciplinary Council on Quality of Care and Outcomes Research: endorsed by the American Academy of Pediatrics.
Gerber MA, Baltimore RS, Eaton CB, Gewitz M, Rowley AH, Shulman ST, Taubert KA.
Circulation Mar 24;119(11): Epub 2009 Feb 26

14. The Jones criteria were introduced in 1944 as a set of clinical guidelines for the diagnosis of RHF. They have subsequently undergone significant modifications ,the final ones published in
These revised WHO criteria speak to the diagnosis of :
a primary episode of RF
recurrent attacks of RF in patients without RHD
recurrent attacks of RF with RHD
rheumatic chorea
insidious onset rheumatic carditis
chronic RHD
It is important to note that in the context of a preceding streptococcal infection, 2 major criteria, or a combination of one major and 2 minor, provide reasonable evidence for a diagnosis of RF.
Major criteria: carditis, arthritis, chorea, subcutaneous nodules, erythema marginatum.
Minor criteria:
Clinical: fever, polyarthralgia
Lab: elevated acute phase reactants ESR/CRP
This little cartoon character demonstrates the features of acute rheumatic fever.
Chorea (St Vitus dance)
Flitting polyarthritis- it is important to be aware that monoarthritis is an important presenting complaint in patients from developing countries WEBLINK
Erythema marginatum and subcutaneous nodules are the dermatological manifestations of ARF.
The only manifestation of ARF with potentially life-threatening and permanent sequelae is the carditis- as evident either as valvulitis( the precursor to rheumatic heart disease) pericarditis and myocarditis.ie a pancarditis.
Histologically Aschoff nodules is the hallmark pathognomonic feature and on special investigations the minor criteria such as high ESR or CRP is noted. Evidence of previous infection with GAS either via ASOT/anti-DNAse B titres or with precious evidence of streptococcus being cultured from the throat is an important adjunct to this diagnosis.
Currently carditis as diagnosed by echo alone is not included in the major criteria despite repeated calls for its inclusion. It is currently recommended that all patients with the clinical diagnosis of ARF even those without clinical evidence of carditis be referred for an echocardiogram( if available)

15. RHEUMATIC HEART DISEASE
Rheumatic Heart Disease is the permanent heart valve damage resulting from one or more attacks of ARF.
It is thought that 40-60% of patients with ARF will go on to developing RHD.
Prevention of infective endocarditis: guidelines from the American Heart Association: a guideline from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group.
Wilson W, Taubert KA, Gewitz M, Lockhart PB, Baddour LM, Levison M, Bolger A, Cabell CH, Takahashi M, Baltimore RS, Newburger JW, Strom BL, Tani LY, Gerber M, Bonow RO, Pallasch T, Shulman ST, Rowley AH, Burns JC, Ferrieri P, Gardner T, Goff D, Durack DT; American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee; American Heart Association Council on Cardiovascular Disease in the Young; American Heart Association Council on Clinical Cardiology; American Heart Association Council on Cardiovascular Surgery and Anesthesia; Quality of Care and Outcomes Research Interdisciplinary Working Group.
Circulation Oct 9;116(15): Epub 2007 Apr 19. Erratum in: Circulation Oct 9;116(15):e376-7.

16. RHEUMATIC HEART DISEASE
The commonest valves affecting are the mitral and aortic, in that order. However all four valves can be affected.
It is important to note that the natural history of valve disease can differ in the developed and developing world with the progression to mitral valve stenosis(for example) having a latency period of several decades as opposed to the early and aggressive presentation of the same lesion in developing countries.

17. RHEUMATIC HEART DISEASE
Sadly, RHD can go undetected with the result that patients present with debilitating heart failure.
At this stage surgery is the only possible treatment option.
It has been suggested that the medical management of RHD must defer to operative intervention according to echocardiographic and clinical guidelines. The absence of access to cardiac surgery, a reality for many parts of Africa, India and Pacific Islands, implies that patients present in advanced stages of the disease, with cardiac failure and with significant complications.
Cardiovasc J Afr Sep-Oct;18(5): Epub 2007 Oct 22.
Prevalence and pattern of rheumatic heart disease in the Nigerian savannah: an echocardiographic study.

18. RHEUMATIC HEART DISEASE
Patients living in poor countries have limited or no access to expensive heart surgery.
Prosthetic valves themselves are costly and associated with a not insignificant morbidity and mortality.
In 2000, the average cost of surgery for RHD in Africa was around US$5000;in low income countries of sub-Saharan Africa with a GDP per capita of less than US$500, such as Ghana, the cost of surgery is therefore prohibitive and would also adversely affect any poverty reduction strategies.
Rheumatic and nonrheumatic valvular heart disease: epidemiology, management, and prevention in Africa.
Essop MR, Nkomo VT.
Circulation Dec 6;112(23): Review

19. What are the clinical features of strep sore throat?

21. Hallmarks of STREP sore throat
Tender lymph nodes
Close contact with infected person
Scarlet fever rash
Excoriated nares( crusted lesions) in infants
Tonsillar exudates in older children
Abdominal pain
GOLD STANDARD: POSITIVE THROAT CULTURE
Management of group A beta-hemolytic streptococcal pharyngotonsillitis in children.
Brook I, Dohar JE.
J Fam Pract Dec;55(12):S1-11; quiz S12. Review.

22. Hallmarks of VIRAL sore throat
Coryza: runny nose or mouth ulcers
Other family with COLD symptoms
Evidence of another viral infection
Itchy watery eyes
Hoarseness and cough: non-specific
Fever: not specific
Red Throat: not specific

24. 2002-03 WHO criteria for the diagnosis of RF and RHF
Diagnostic Categories
Criteria
Primary episode of rheumatic fever
Recurrent attack of RF in a pt. without stablished RHD
Recurrent attack of RF in a pt. with stablished RHD
Rheumatic chorea OR insidious onset rheumatic carditis.
2 major or 1 major plus 2 minor plus evidence of GAS Infection.
Same as above
2minor manifestation plus evidence of GAS infection.
No other major manifestations or evidence of GAS infection

25. Continue…. Diagnostic categories Criteria
Chronic valve lesion of RHD (pts presenting for first time with pure MS or mixed mitral valve disease and/or aortic valve disease.)
Do not require any other criteria to be diagnose as having RHD

26. Arthritis
Manifest in the 60 – 75% of pt.
Painful, migratory, and limited to the major joint of extremities
Inflammation in 1 joint lasts for 1-2 week and polyarthritis as whole resolve in 1 month or less.
Tenderness out of proportion to other findings.
JACCOUD Arthropathy can be occur.
Arthritis can overlap carditis but both manifestation
inversely related in severity.
Very good response to salicylates.

27. Carditis
Manifest as valvulitis – (MR and/or AR) myocarditis or pericarditis or both.
40 – 60% result in RHD
Soft blowing pansystolic murmur of MR is hallmark of carditis in RF.
HF due to the MR not due to myocardial involvement.
Pericarditis cause friction rub and sometime pleuritic chest pain.
Myocardial inflammation can cause conduction defect and heart block.
There is a linear relationship b/w severity of MR during the first episode of RF and subsequent RHD.

28. Continue…… In the setting of LV dysfunction or/and pericarditis
myocarditis without valvular involvement path-
ology is unlikely to rheumatic in origin.

29. Sydenham's chorea Purposeless, rapid, involuntary, nonrepetitive,
jerky dance like movements.
Milk maid grip.
Lizard tongue.
Raising of hand above the head.
5 – 35% pt. of RF
Prior to puberty F>>>M, after puberty no male
involvement.
Risk of developing subsequent RHD is 50%.

30. Sydenham chorea
No residual neurological deficit per se, psychiatric disturbances occur in a small no. of pts.
Recurrence are common.
PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection) also a manifestation GABHS but not associated with other features of RF.

31. Erythema marginatum 5 – 13% of RF
Begin 1-3 cm, pink to red, nonpruritic, macule or
papule.
Trunk and proximal limb but never on face.
Central clearing in serpegious fashion
Exacerbate by heat.
Also can seen in sepsis, drug reaction,
glomerulonephritis, JRA, Lyme disease.
Occur in conjunction with milder form of carditis.
May lasts for months or years.

32. Closer view of erythema marginatum in the same patient

33. Subcutaneous nodules 0 – 8% of pt. of RF
External surface of elbow, knee, ankles, knuckles, scalp and spinal process.
Firm, nontender, free from attachment of underlying skin.
Strongly support the severity of carditis
Resolve within weeks to 1 or 2 months.
Not diagnostic for rheumatic fever can seen with other
autoimmune disorder.

35. Recommended test in case of possible acute rheumatic fever..
CBC
ESR
CRP
BLOOD CULTURE
ECG
X-RAY CHEST PA VIEW
2D-ECHO
THROAT SWAB CULTURE FOR GAS (gold standard)
ASO TITRE (rising) much specific for RF

36. What are the treatment regimens of streptococcal sore throat?

37. Treatment of ARF First line of symptomatic therapy is antiinflammatory
agent ranging from salicylates to steroid.
Naproxen can be alternative for Aspirin.
Bed rest in carditis pts.
Effective antibiotic treatment acutely (starting less than
10 days.)almost completely eliminates risk of the dis.

38. Treatment
Drug Name :Aspirin -- Begin administration immediately after diagnosis of RF. Initiation of therapy may mask manifestations of disease.
Adult Dose: 4-8 g/d PO divided q4-6h; maintain aspirin levels in mg/dL range until all symptoms have resolved and APRs have returned to normal

39. Treatment
Drug Name: Prednisone -- Used in carditis and CHF. High-dose prednisone is administered for 2-3 wk, then tapered over 3 wk. IV corticosteroids are reserved for fulminant cases.
Adult Dose :40-60 mg PO qd for 2-3 wk initially, then discontinue by gradual taper over 3 wk

40. Treatment
Pediatric Dose : mg/kg PO qd for 2-3 wk initially, then discontinue by gradual taper over 3 wk
Contraindications
Documented hypersensitivity; viral infection; peptic ulcer disease; hepatic dysfunction; connective tissue infections; fungal or tubercular skin infections; GI disease

41. Treatment of GABHS Infection
Benzathine million U. One time Acutely
penicillin G IM one
Penicillin V mg oral BD days
Amoxicillin mg oral TDS days
Erythromycin mg oral BD days

42. Antibiotics
The roles for antibiotics are to (1)initially treat GAS pharyngitis,
(2) prevent recurrent streptococcal pharyngitis, RF, and RHD, and
(3) provide prophylaxis against bacterial endocarditis.

43. Treatment
Drug Name: Penicillin V -- DOC for treatment of GAS pharyngitis.
Do not use tetracycline and sulfonamides to treat GAS pharyngitis. For recurrent GAS pharyngitis, a second 10-d course of same antibiotic may be repeated.

44. Treatment
Drug Name: Benzathine /procaine penicillin -- Adult Dose: Eradication: 1.2 million U of benzathine penicillin G or a combination of 900,000 U of benzathine penicillin G with 300,000 U of procaine penicillin G IM as a single dose

45. Treatment
Erythromycin -- Used for patients who are allergic to penicillin.
Other options include clarithromycin, azithromycin, or a narrow-spectrum cephalosporin (ie, cephalexin).
As many as 15% of penicillin-allergic patients also are allergic to cephalosporins.

46. Treatment
Drug Name: Clarithromycin -- Alternate antibiotic for treating GAS pharyngitis in patients allergic to penicillin.
Adult Dose: mg PO bid for 10d
Pediatric Dose: 7.5 mg/kg PO bid for 10 d

47. Treatment
Drug Name: Azithromycin -- Alternate antibiotic for treating GAS pharyngitis in patients allergic to penicillin.
Adult Dose :12 mg/kg (not to exceed 500 mg) PO qd for 5 d
Pediatric Dose :Administer as in adults

48. Treatment
Cephalexin -- Alternate antibiotic for treating GAS pharyngitis in patients allergic to penicillin.
Adult Dose: mg PO qid for 10d
Pediatric Dose: mg/kg/d PO divided qid for 10 d

49. Primordial prevention
1. Improvements in socioeconomic status.
2. Prevention of overcrowding.
3. Prevention of under nutrition and malnutrition.

50. Primary prevention

51. Effective eradication of GABHS from the pharynx define the role of primary prevention.
Antibiotic
Administration
Dose
Benzathine benzyl penicillin
Single IM injection
1.2 MU > 30kg
U < 30 kg
Phenoxymethyl penicillin
(Pen VK)
PO for 10 days
mg qds for 10 days
125mg qds X 10 if <30 kg
Erythromycin ethylsuccinate
Use same dose as above.
Oral penicillin is less efficacious than Penicillin IMI
Anaphylaxis is extremely unusual

52. Secondary Prevention Stops sore throat, prevents recurrences of ARF and aids in regression of RHD
Antibiotic
Administration
Dose
Benzathine benzyl penicillin
Single IM injection
monthly
1.2 MU > 30kg
U < 30 kg
Phenoxymethyl penicillin
(Pen VK)
BD PO daily
mg bd
Erythromycin ethylsuccinate
BD po daily
Use same dose as above.
There is evidence to suggest that oral penicillin results in poorer rates of adherence and serum penicillin concentration may also be less predictable compared to intramuscular penicillin. The rate of anaphylactic reactions is about 0.2% with fatalities being extremely rare.
Oral penicillin has been shown to be less effective than Penicillin IMI
Anaphylaxis is extremely unusual

53. During an episode of ARF, valve changes can be minor and are still able to regress.
After recurrent episodes of ARF, thickening of subvalvar apparatus, chordal thickening and shortening and progression to permanent valve damage is evident.
This long axis parasternal images demonstrates the progression of valvular disease in the period between ARF and RHD. It is important to remember that timeous diagnosis, treatment and secondary prevention may in cases prevent this progression.
The efficacy of echocardiographic criterions for the diagnosis of carditis in acute rheumatic fever.
Vijayalakshmi IB, Vishnuprabhu RO, Chitra N, Rajasri R, Anuradha TV.
Cardiol Young Dec;18(6): Epub 2008 Oct 10

54. Secondary prevention: Duration
CATEGORY
DURATION OF PROPHYLAXIS
All persons with ARF with no or mild carditis
MINIMUM 10 years after most recent episode or age 21
All persons with ARF and moderate carditis
MINIMUM 10 years after most recent episode or age 35
All persons with ARF and severe carditis
MINIMUM 10 years after most recent episode or age 35 and then specialist review for need to continue. Post surgical cases definitely lifelong.
Awareness ♦ Surveillance ♦ Advocacy ♦ Prevention

55. Secondary prevention: specifics
PENCILLIN
Secondary prophylaxis also reduces the severity of RHD.
It is associated with regression of heart disease in approximately 50-70% of those with good adherence over a decade and reduces mortality.
Route:
BPG is most effective when given as a deep intramuscular injection.
Rheumatic fever diagnosis, management, and secondary prevention: a New Zealand guideline.
Atatoa-Carr P, Lennon D, Wilson N; New Zealand Rheumatic Fever Guidelines Writing Group.
N Z Med J Apr 4;121(1271): Review.

56. Secondary prevention: Adherence
How can we reduce the pain associated with IM Penicillin?
Use a 23-gauge needle- deeper is better
Local pressure to area for 10 secs
Warm syringe to room temperature
First allow alcohol to dry or use ethylchloride spray .

57. Secondary prevention: Adherence
Deliver injection very slowly(over 2-3mins)
Distraction techniques
Good rapport with the case, is a significant aid to injection comfort, compliance and understanding.
Use 0.5-1ml of 1% lignocaine. Reduces pain significantly and excellent for younger patients.

58. Ensuring that patients understand their disease, are informed regarding their future and receive secondary prophylaxis
EDUCATION
Health education is critical at all levels
Lack of parental awareness of the causes and consequences of ARF/RHD is a key contributor to poor adherence amongst children on long-term prophylaxis.

59. A.S.A.P. Programme for the Control of RHD in Africa: Focus areas for action
Awareness raising: public, healthcare workers
Surveillance: incidence, prevalence, temporal trends
Advocacy: appropriate funding of the treatment and prevention programmes
Prevention: application of existing knowledge in primary & secondary prevention
Robertson KA et al SAMJ 2006:96:241-5
The PASCAR-driven( Pan-African Society of Cardiology) ASAP programme was launched in 2005 at a meeting in the Drakensberg and the Drakensberg declaration was published in This meeting brought together interested cardiologists and physicians from all over Africa dealing with rheumatic heart disease on a daily basis in an attempt to develop a method to eradicate rheumatic fever and rheumatic heart disease using a multi-pronged approach.

60. Summary
Rheumatic heart disease is the only truly preventable chronic heart condition
Primary prevention:
Penicillin for suspected strep sore throat
Secondary prevention
Penicillin prophylaxis