ACUTE RHEUMATIC FEVER AND RHEUMATIC HEART DISEASES

1. ACUTE RHEUMATIC FEVER
IN THE PAST AND PRESENT
MURTAZA KAMAL
20/11+06/12/2018
murtaza.vmmc@gmail.com
1

2. RF LICKS AT THE JOINTS BUT BITES AT
THE HEART
• French physician
• 1884
• Ernest-Charles Lasègue
2

3. THOMAS DUCKETT JONES
• US physician
• 1944: The famous criteria
3

4. Alexander Fleming
• Scottish physician
• 1929: The wonder drug
4

5. SCOPE OF THE TALK
• Epidemiology
• Pathogenesis
• Clinical features
• Diagnosis
• Treatment
• Prevention
• Future prospective
5

6. INTRODUCTION
• Leading cause of acquired ht disease in kids/ young adults
• Pharyngeal infection with GAS 2-3 weeks latency Acute inflammation
• Damage to CT ground substance+ collagen fibrils FIBRINOID
DEGENERATION Hence CTD/ Collagen vascular ds
• RHD: Destructive effect on heart valves Chronic sequelae
• Almost all cases: Entirely preventable
6

7. EPIDEMIOLOGY
7
CIRCULATION. 1985;72:1155-62
PRINCIPALS OF MEDICINE IN AFRICA. 3RD ED. CAMBRIDGE: CAMBRIDGE
UNIVERSITY PRESS; 2004, p 861

8. EPIDEMIOLOGY CONT…
• RF Hot spot: 543/1L population per year??
•KYRGYZSTAN
• High incidence among indigenous population of developed countries:
Australia/ New Zealand
8

9. EPIDEMIOLOGY CONT…
9
LANCET INFECT DIS.
2005;5:685-94

10. EPIDEMIOLOGICAL METHODS FOR
RF/ RHD
10CSI TEXTBOOK OF CARDIOLOGY. 1st ed .2018

11. Status of our country
11
CSI TEXTBOOK OF CARDIOLOGY. 1st ed .2018

12. Changing profile of ARF: Indian scenario
12
Vijayalakshmi IB, Vishnuprabhu RO, Chitra N, Rajasri R, Anuradha TV. The efficacy of echocardiographic criterions
for the diagnosisof carditis in acute rheumatic fever. Cardiol Young 2008:18: 586–592.

13. PATHOGENESIS
• Multifactorial ds
• Different theories…
13

14. THEORY OF MOLECULAR MIMICRY
14
LANCET 2005;366:155

15. THEORY OF MOLECULAR MIMICRY
Cont…
• GAS pharyngitis AI response to epitopes in organism (Group A
carbohydrates/ N- acetyl –B-D- glucosamine/ laminin) Cross reacts with
similar epitopes in heart (Laminar basement membrane) / brain/ joints/
skin Repeated episodes of RF Leading to RHD
• T cells in peripheral blood+ heart valves cross reacts with streptococcal M
protein+ cardiac myosin
• Autoantibodies against GAS carbohydrate epitope GLcNAc+ cardiac
myosin Appear during RHD progression
15

16. THEORY OF MOLECULAR MIMICRY
Cont…
• Autoantibodies against collagen that are not cross reactive May form due
to release of collagen from damaged valves
• Streptococcal skin infection Doesn’t cause
• 3%: Incidence of ARF in untreated GAS pharyngitis epidemics
• 0.3%: Incidence of ARF in population
16

17. THE THEORY CONTINUES…
• Antibody attack of valve epithelium facilitates extravasation of t- cells
through activated epithelium into valve tissue Formation of
granulomatous tissue ASCHOFF BODIES (Characteristic of rheumatic
myocarditis)
• Area of central necrosis Surrounded by a ring of plump histiocytes
Anitschkow cells
17

18. ASCHOFF- GEIPEL BODIES
18
DIAGNOSTIC PEDIATRIC SURGICAL PATHOLOGY.
LONDON. CHURCHILL LIVINGSTONE;2010

19. The theory continues…
• Sydenham chorea: Human monoclonal Abs derived from patients with
disease target GLcNAc, gangliosides+ dopa receptors Found on surface
of neuronal cells in brain
• mABs+ autoantibodies Activates Ca- calmodulin dependent PK-II in
neuronal cells+ recognize intracellular protein biomarker Tubulin
19

20. Do not blame the pathogen alone…
HOST FACTORS
• 3-6%: Lifetime cumulative incidence of RF in populations exposed to
rheumatogenic GAS infection regardless of geography/ ethnicity
• Familial aggregation: 5X risk (RR 2.93 in kids raised separately from parents with
RHD)
• Monozygotic twins: 6X than dizygotic twins
• Heritability of RF: 60%
• HLA-DR (Susceptible: 7, 4; Protection: 5,6,51,52)
• B-Cell Ag-883 20

21. The age old culprit… ENVIRONMENT
• Low SE strata
• Overcrowding
• Poor housing + nutritional conditions
• Parental unemployment
• Access to heath care
21

22. CLINICAL FEATURES
22

23. CLINICAL FEATURES
• Streptococcal pharangitis 2-3 weeks latent period RF
• Latent period: No clinical/ lab evidence of active inflammation
• 33% patients: Develop RF after asymptomatic GAS pharyngitis
• 58% patients: Have no symptoms of pharyngitis in outbreaks
• 4-15 years
• India/ Saudi Arabia: Juvenile MS: 3-5 years
• Illness begins with high fever
23

24. MAJOR MANIFESTATIONS OF RF
24
Moss & Adam’s 9TH ed.

25. ARTHRITIS
• Young adults (almost 100%)> Teens (82%)> Children (66%)
• Typically: Migratory (Sometimes additive)
• 6-16 joints involved in untreated patients
• Duration:
• Single joint: Few days to 1 week
• Polyarthritis severe for 1 week (2/3rds ), another 1-2 weeks (1/3rd)
• If > 4 weeks: Other diagnosis (JIA/ SLE)
25

26. ARTHRITIS
• Usually affects LL f/b UL
• 17-25%: Monoarthritis
• MC: Knees/ Ankles/ Elbows / Wrist
• LC: Hip/ Shoulders/ Small joints
• Sinovial fluid: Sterile inflammatory fluid
• Decreased complements: C1q, C3, C4: Consumption by immune complexes
• X-Ray: Joint effusion
• Dramatic response to NSAIDs (Cause of apparent fall in incidence)
26

27. JACCOUD ARTHRITIS/ ARTHROPATHY
• Chronic post RF arthropathy
• Rare manifestation
• Deformities of fingers/ toes
• May occur after repeated attacks of RF:
Recurrent inflammation of fibrous
articular capsule
• Ulnar deviation of fingers, flexion at
MCP joints, hyperextension of PIP
joints SWAN NECK DEFORMITY
• Painless/ No signs of inflammation
• Usually correctable
• X-Ray: No true erosions
• RH Factor: -ve
27

28. JACCOUD ARTHRITIS/ ARTHROPATHY
28
BEST PRAC RES CLIN RHEUMATOL 2011;25: 715

29. POLYARTHRITIS+ FEVER D/Ds
29NJEM. 1994;330:769-774

30. IMP D/D
POST STREPTOCOCCAL REACTIVE ARTHRITIS
• Arthritis not typical of RF, but evidence of recent streptoccoal infection
• Shorter latent period than RF, less NSAID responsive, ± renal
manifestations, carditis- Usually not seen
• Distinction: Unclear Recommended that a diagnosis of PSRA not be
made in population with high incidence of RF
• In such populations: Even if diagnosis of PSRA made Appropriate to
offer a period of secondary penicillin prophylaxis
30

31. CARDITIS
• Most serious manifestation
• Chronic RHD (AF/ stroke/ HF/ IE/ death)
• Incidence during initial attack: 40-91%
• Incidence with 1st attack varies with age:
• 90-92%: < 3 yrs
• 50%: 3-6 yrs
• 32%: Teens 14-17 yrs
• 15%: Adults
31

32. CARDITIS
• Pancarditis
• Endocarditis: Organic murmur not present previously
• Myocarditis: Cardiomegaly/ CHF
• Pericarditis: Pericardial rub/ PE
32

33. MYOCARDITIS
• Myocarditis in absence of valvulitis: Unlikely to be of rheumatic origin
• To be accompanied by apical systolic/ basal diastolic murmur
• Cardiomegaly/ CHF/ Varying degree of ht blocks
• CHF:
• May be caused by myocarditis or severe involvement of 1 or more valves
• 5-10% during initial episodes
• More frequent during recurrences
33

34. PERICARDITIS
• Anterior chest pain/ Pericardial rub
• 10% cases: Pericarditis detected clinically
• PE: May be large
• CT: Rare
• CP: Does not occur
34

35. ENDOCARDITIS
• In ARF:
• Mitral: 70-75%
• Mitral+ Aortic: 20-25%
• Isolated aortic: 5%
• In chronic RHD (Indian data):
• MS+MR: 46%
• MS+AR: 26%
• MR+AR: 23%
• MS+AS: 2.4%
• MR+AS: 0.3%
• IHJ 2014: 320-326
35

36. ROLE OF ECHO IN CARDITIS: Steinfield
(1986)
36

37. Clinical & Echo comparison of valve
regurgitation
37
Vijayalakshmi IB, Vishnuprabhu RO, Chitra N, Rajasri R, Anuradha TV. The efficacy of echocardiographic criterions for the diagnosis of carditis in acute rheumatic fever. Cardiol Young 2008;
18: 586–592.

38. Incidence of various ECHO features
38
Vijayalakshmi IB, Mithravinda J, Deva AN. The role of echocardiographyin diagnosing carditis in the setting of acute rheumaticfever. Cardiol Young 2005; 15: 583–588.

39. 2012 WORLD HEART FEDARATION
minimum Echo criteria for diagnosis of
pathological valvular regurgitation
• Pathological mitral regurgitation (all
4 criteria met)
• Seen in at least 2 views
• Jet length ≥2 cm in at least 1 view
• Peak velocity >3 m/s
• Pansystolic jet in at least 1 envelope
• Pathological aortic regurgitation (all
4 criteria met)
• Seen in at least 2 views
• Jet length ≥1 cm in at least 1 view
• Peak velocity >3 m/s
• Pan diastolic jet in at least 1 envelope
39

40. D/D OF RHEUMATIC CARDITIS
• Innocent murmur
• MVP
• Congenital MV disease (with
regurgitation)
• Congenital AV disease (With
regurgitation)
• IE
• Moss & Adams’ 9th edition
• Non infective endocarditis
(Autoimmune)
• Myocarditis
• Pericarditis
40

41. SYDENHAM CHOREA
• May be only presenting manifestation: 15% cases
• Females: MC (Increases after puberty)
• Latent period: 6-8 weeks
• Involuntary, purposeless, jerky movements of hands,
arms, shoulders, feet, legs, face and trunk associated
with hypotonia + weakness
• Interfere with voluntary activity
• Disappears during sleep 41

42. SYDENHAM CHOREA Cont…
• Motor impersistence:
• Jack in the box tongue:
Intermittently, involuntarily
withdrawing tongue when
attempted to protrude it for
30 sec
• Milking sign: Repetitive,
irregular squeezes of
examiner’s hand
• Emotional lability:
• Personality changes
• Inappropriate behaviour
• Restlessness
• Outbursts of anger/ cry
• Learning difficulties
42

43. SYDENHAM CHOREA Cont…
• Duration: 8-15 weeks
• ESR/ CRP/ ASLO: May be normal (Long latent period+ resolution of
original infection)
• Does not occur simultaneously with arthritis/ May co-exist with carditis
• Due to immune mediated reaction to auto-antibodies of basal ganglia
43

44. D/D OF CHOREA
44
Moss & Adams’- 9th edition

45. SYDENHAM CHOREA Cont…
• SC with motor tics May overlap with involuntary jerks of Tourette syndrome
• PANDAS: Children with tic or OCD triggered by GAS infection with no associated
cardiac valve damage
• Recommended that in populations at high risk of RF: Clinicians should rarely make
diagnosis of PANDAS; prefer RF and give secondary prophylaxis
• LINK: https://www.youtube.com/watch?v=-Os3T6Yz7w0
45

46. SUBCUTANEOUS NODULES
• 0%-10%
• Resemble nodules of rheumatoid arthritis
• Occiput,elbows,knees, ankles, achilles tendon
• Nodules tend to occur over olecranon,
whereas rheumatoid nodules tend to occur
more distally along extensor aspect of upper
forearm
• Firm, painless, freely mobile over
subcutaneous tissue
• 0.5- 2 cm, in crops
• Usually smaller, more discrete and less
persistent than rheumatoid
• Usually seen in kids with prolonged
active carditis rather than in early stages
• Few week, Never >1 month
• Multiple crops- May be related to severity
of rheumatic carditis
46

47. SUBCUTANEOUS NODULES
47
CIRCULATION. (2010;121:946-47)

48. ERYTHEMA MARGINATUM
• < 5%, Upper arms/ trunk (Not on face)
• Not pathognomonic of disease
• Evanescent, pink, non pruritic
• Irregular, serpiginous borders
• Extends centrifugally while skin at centre returns to normal
• Hot shower
• Usually in patients of carditis, may occur early/ late in course of disease
48

49. ERYTHEMA MARGINATUM Cont…
49
INFECTIOUS DISEASES. 2ND ED. ST LOUIS: MOSBY; 2004

50. OTHER MANIFESTATIONS
• Fever
• When temperature used as minor
criteria: Cut off >37.5 deg C Will
allow diagnosis in 90% in endemic
rheumatic fever zone
• 1 week usual, > 4 wks: Rare
• Abdo pain: Severe
• Epistaxis: Past
• Rapid sleeping PR, Tachycardia out
of proportion to fever, malaise,
anemia
• Rheumatic pneumonia: Rare
50

51. DIAGNOSIS
51

52. Evolution of diagnostic criteria over years
52
Journal, Indian academy of clinical
Medicine. Vol 11, No2, April-June.2010

53. List of studies reporting subclinical carditis
53
DOI: 10.1161/CIR.0000000000000205

54. 2015 AHA-Revised John’s criteria
• Low-risk populations
• Those with ARF incidence ≤2 per 100 000 school-aged children or
• All-age RHD prevalence of ≤1 per 1000 population per year
• Moderate- high risk populations
54

55. 2015 AHA-Revised John’s criteria
55

56. 2015 AHA-Revised John’s criteria:
ESSENTIAL CRITERIA
• Evidence of preceding GAS infection:
• Throat swab culture (+ve in only 11%/ Do not differentiate b/w
recent throat infection+ ch. pharyngeal carrier)
• +ve rapid gr A carb Ag test
• Rising titre of ASLO/ anti- DNAse- B
56

57. DIAGNOSIS
• For all patient populations with evidence of preceding GAS infection:
• Diagnosis: Initial ARF:
•2 Major manifestations or
•1 major+ 2 minor
• Diagnosis: Recurrent ARF:
•2 Major or
•1 major+ 2 minor or
•3 minor 57

58. ECHO Criteria in rheumatic valvulitis
58

59. VIJAYA’S ECHO SCORE
• >6/16
• Sn: 81%/ Sp: 93%
59

60. Streptococcal Ab tests
• Most reliable lab test for recent infection
• Onset of clinical manifestations coincides with peak of streptoccoal Ab
response
• ASLO:
• Increased 80% cases of ARF; 20% of normal individuals; 67% of
isolated chorea patients
• Kids: 333 Todd units, Adults: 250 Todd units
• Use local data 60

61. Streptococcal Ab tests
• Rising titre more important
• Anti DNAse-B
• Streptozyme test:
• Simple agglutination test
• Less standardised and less reproducible
• Not to be used as a definitive test
61

62. ULN for serum streptococcal Ab titers
AGE GROUP ULN (U/ml) TODD U ULN (U/ml) TODD U
YEARS ASLO TIT ANTI DNAse-B TIT
1-4 170 366
5-14 276 499
15-24 238 473
25-34 177 390
≥35 127 265
62
Reproduced from Australian Guidelines

63. POSSIBLE RF
• Appropriate to apply clinical judgment in parts of world where RF common and
• It is not possible to fulfill Jones criteria because of lack of laboratory facilities
• When a diagnosis of possible RF is made in a high-incidence setting: Reasonable to
consider offering 12 months of secondary prophylaxis, followed by reevaluation based on history,
physical examination, and repeat echocardiogram
63

64. Investigations in suspected RF
• Recommended for all cases:
• TLC/ ESR or CRP
• Throat swab before giving antibiotics
• Blood culture, if febrile
• Antistreptococcal serology: Both ASO+ anti-
DNase B titers (repeat after 10 to 14 days if first
test is not confirmatory)
• ECG/ CXR/ ECHO
• From Australian guidelines
• Tests for alternative diagnosis:
• Repeated blood cultures with temperature spikes
if IE suspected
• Joint aspirate for possible septic arthritis
• Cu, ceruloplasmin, ANA and drug screen for
choreiform movements
• Serology and autoimmune markers for arboviral,
autoimmune, or reactive arthritis
• PS for SCD
64

65. Diagnosis strategies for ARF
65
DOI: 10.1161/CIR.0000000000000205

66. Diagnosis strategies for ARF
66
DOI: 10.1161/CIR.0000000000000205

67. TREATMENT
67

68. AIM OF TREATMENT
• 1. Suppression of inflammatory response Minimise effects of
inflammation on heart/ joints
• 2. Eradication of GAS from pharynx
• 3. Symptomatic relief
• 4. Commence secondary prophylaxis
68

69. What to do??
69
MOSS & ADAMS’- 9TH ED.

70. Story of the wonder drug…
• In March 1942, a 33-year-old woman in the USA was hospitalized for a month
with a life-threatening streptococcal infection at a New Haven, Connecticut,
hospital. She had streptococcal septicemia from childbirth. She was delirious
and her temperature reached almost 107°F (41.6°C). Treatments with sulfa
drugs, blood transfusions, and surgery had no effect. As a last resort, her
doctors injected her with a tiny amount of an obscure experimental drug
called penicillin. Her hospital chart, now at the Smithsonian Institution,
indicates a sharp overnight drop in temperature; by the next day, she was no
longer delirious. She survived to marry, raise a family, and meet Sir Alexander
Fleming, the scientist who discovered penicillin. The patient died in June 1999
at the age of 90 years
70

71. PRIMARY PREVENTION OF RF
• Benzathine benzylpenicillin: Single
IM 1.2 million units; 50% if <30
kg DOC
• Phenoxymethylpenicillin (Penicillin
VK): Oral for 10 days: 250-500 mg
TID
• Erythromycin ethylsuccinate: Oral
for 10 days
• WHO:2004
71

72. SECONDARY PREVENTION OF RF
• Benzathine benzylpenicillin:
• Single IM every 3-4 weeks ≥30 kg: 1.2M units
• <30 kg in weight: 0.6M units
• Penicillin V: Oral 250 mg BD
• Sulfonamide: Oral
• ≥30 kg : 1 g OD
• <30 kg : 500 mg OD
• Erythromycin: Oral 250 mg BD 72
WHO 2004

73. RF recurrence rate using drugs
• 3 weekly benzathine penicillin: 0.25/100 person years
• 4 weekly benzathine penicillin: 1.29/100 person years
• Sulphonamides: 2.8/100 person years
• Oral penicillin: 5.5/ 100 person years (So, preferred in those who have
reached young adulthood and remained free for rheumatic attacks for 5
years)
73

74. Duration of secondary prophylaxis
• Patient without proven carditis: 5 years after last attack or until 18 years of
age (whichever is longer)
• Patient with carditis (mild mitral regurgitation or healed carditis): For 10
years after last attack or at least until 25 years of age (whichever is longer)
• More severe valvular disease: Lifelong
• After valve surgery: Lifelong
• WHO: 2004
74

75. Anti- inflammatory drugs
• Salicylates/ Steroids
• No significant difference in risk of cardiac disease at 1 year between
corticosteroid treated and aspirin-treated groups (six studies, 907 participants;
relative risk [RR], 0.87; 95% confidence interval [CI] 0.66 to 1.15)
• Use of prednisone compared to aspirin did not reduce risk of developing heart
disease after 1 year (two studies, 212 participants; RR, 1.13; 95% CI 0.52 to 2.45)
• 3 studies reporting adverse events all found substantial adverse events
• Thus, there is little evidence of benefit from using corticosteroids or IV
immunoglobulins to reduce risk of heart valve lesions in patients with ARF
• Cilliers A, Manyemba J, Adler AJ, Saloojee H. Anti-inflammatory treatment for carditis in acuterheumatic fever. Cochrane Database Syst Rev. 2012;(6) [CD003176]. 75

76. Anti- inflammatory drugs
76
Park- Pediatric cardiology for practitioners: 2014

77. Rest & Indoor ambulation
Arthritis alone Mild carditis Moderate carditis Severe carditis
Bed rest 1-2 wks 3-4 wks 4-6 wks As long as CHF is
present
Indoor ambulation 1-2 wks 3-4 wks 4-6 wks 2-3 months
77Park- Pediatric cardiology for practitioners: 2014

78. Treatment of chorea
• Phenobarbitone: 15-30 mg QID
• Haloperidol: 2 mg TID
• Valparin: 20mg/kg/day in divided dosage
78

79. Future Prospective
• Key challenge to control of RF: Identification and removal of barriers to
translation of existing knowledge into policy, programs and practice
• Efforts to prevent and control facilitated by:
• Improvement of access to and development of better penicillin
formulation
• Identification of 3-5% individuals with genetic susceptibility
• Development of effective vaccine
79

80. Issues in development of GAS vaccine
80
CSI TEXTBOOK OF CARDIOLOGY. 1st ed .2018

81. TAKE HOME MESSAGE
• ARF/ RHD: Major PH problem in our country
• Early diagnosis+ proper treatment: Prevent marked disability left behind by
disease
• Active role of us clinicians needed to prevent this disease from our country
81

82. THANKS FOR YOUR
PATIENCE
82