1. Rheumatic fever in children
Dr.Mohd.Arif
Pediatric resident,
IOM
1

2. INDEX
1. Introduction
2. Problem statement
3. Incidence and prevalence (worldwide & Nepal)
4. Pathogenesis
5. Diagnosis
6. Treatment
7. Rheumatic heart disease
8. Vaccine status
2

3. Introduction
• Rheumatic fever and rheumatic heart disease
are the non suppuartive complications of
Group-A Streptococcal infection due to a
delayed immune response.
• Most children developed at least one episode
of pharygitis per year
• 15-20% of which are cause by group-A
streptococci
3

4. • Group –A has been linked to the
etiopathogenesis of rheumatic fever and
rheumatic heart disease.
• Group C and D ,can produce extra cellular
antigens ( streptolysin-O)
• Group E & G may also cause rheumatic fever
4

5. Problem statement
• 20 million cases of rheumatic heart disease
world wide
• 500000 deaths each year due to acute
rheumatic fever and rheumatic heart disease
• Mainly in adolescents and young adults
( Carapetis JR, Steer AC, Mullholand EK et al, The global burden of group –A
strepptococcal disease, Lancet Infect Dis 2005)
• Disability adjusted life years ( DALYs) for south
east Asia region is 173.4 /100000 population
5

6. • Congestive heart failure- 3 millions
• Valve surgery required- 1 million
• Annual incidence of rheumatic fever- 0.5/
million
• Number of RHD cases added- 300000/year
• Estimated deaths from RHD- 200000/year
(WHO tech series923;2004)
6

7. • Rheumatic heart disease is a major cause of
morbidity and mortality in low and middle
income countries and among underprivileged
communities in high income countries
(Carapetis JR, Steer AC, Mulholland EK, Weber M. The global burden of group
A streptococcal diseases. Lancet Infect Dis. 2005;5:685–694)
• 15 million cases of RHD worldwide, with
282,000 new cases and 233,000 deaths
annually.
(Review article by Michael D seckeler, Tracy R hoke,dept.of pediatrics,
university of Viginia,US
Clinical epidemiology 2011)
7

8. Incidence worldwide( First attack)
• Review of ten prospective studies
• Five of them were using active surveillance while
other five were using passive surveillance
• Overall mean incidence rate 19/ 100000
population
• India (51/100000)
• Maori community of New Zealand
( >80/100000)
( K B Tibazarwa ,J A Wolmink, BM Mayosi, Heart 2008:94)
8

9. • Highest incidence among the indigenous
population of Australia and New Zealand.
• Annual number of cases in aged 5-14 years is
374/100000 population.
• 60% of these developed rheumatic heart
disease
• Rheumatic heart disease in school children
,sub Sahran Africa 5.7/1000, Indigenous
population of Australia and New Zealand
3.5/1000 while south central Asia is 2.2/1000.
9

10. Acute rheumatic fever in Nepal
• 9420 school students ,4466 male & 4956 females
between 4-14 years.
• 83 children suspected to have heart disease
• 23 were confirmed cases on clinical examination
• 11 rheumatic heart disease & 12 congenital heart
disease were found
• Prevalence 1.2 &1.3 respectively, Mitral
regurgitation and ASD most common lesion
identified
(Bahadur KC, Sharma D, Shrestha MP, Gurung S, Rajbhandari S, Malla
R, Rajbhandari R, Limbu YR,
Regmi SR, Koirala B,Department of Cardiology, Shahid Gangalal
National Heart Center, Bansbari, Kathmandu
Indian Heart Journal 2003, nov:dec) 10

11. Rural community-Hill region
• 5-16 years, 20-25 km outside Kathmandu valley
• 4816 school children were interviewed
• WHO expert committee criteria (1966) was used
• Chest X-ray ,ECG, Echocardiography, Doppler
study was done in all suspected cases
• 1 mitral stenosis, 3 mitral regurgitation and 2
combined MS & MR
• Prevalence 1.35/1000 children
(Shrestha UK, Bhattarai TN, Pandey MR,Department of Medicine, Bir
Hospital, Kathmandu, Nepal,
Indian heart journal 1991,jan:fab)
11

12. Acute rheumatic fever -Nepal
• Prevalence of rheumatic heart disease in
school children is 1.2/1000 population
(Prakash RR et al, Prevalence of rheumatic fever and rheumatic
heart disease in school children of Kathmandu city, Indian
Heart journal 1997,49:518-520)
12

13. Acute Rheumatic fever-TUTH
• Total admitted case between 10/67 to 09/68
1106
• Rheumatic fever / rheumatic heart disease
17
• Prevalence= 1.53
13

14. Acute rheumatic fever- Kanti children
hospital
• Total number of case = 6334
• Rheumatic fever/ rheumatic heart disease =
26
• Prevalence= 0.7
14

15. Etiology
• Group –A streptococcus
• 66% Patients have history of upper respiratory
tract infection
• Closed communities like boarding schools and
military bases
• M strain (type-1,3,5,6,18.24) is commonly
associated with ARF
• Type-4 , not associated with recurrence
• Mucoid strain are commonly isolated during
outbreaks
15

16. • Almost, always have raised ASO titre
• N-acetyl glucosamine ,cell wall carbohydrate
also present in human tissue
• Streptolysin hylauronidase,erythrogenic toxin,
streptokinase and deoxyribonuclease
• M1,M5,M6 & M19 share epitopes with human
myosin and tropomyosin
16

17. Pathogenesis of rheumatic fever
IMMUNOLOGICAL THEORY
• HLA molecules process antigen within a host cell
and present them on the cell surface to T-cells
• T-cells either attack the antigen or activate B-cells
to produce antibodies.
• If HLA molecule present antigen resembles both
streptococcus and human tissue ,host cells can be
attacked.
• No universal association between HLA allele &
ARF
• HLA-DR7 most frequently associated
• HLA-DR3 in south east Asia
17

18. • IN ARF & RHD ,foreign antigen is M-protein,
cross reacts with cardiac myosin
• T-cells mediated attack on heart tissue and
valve
• In Saydenham chorea ,carbohydrate
component of streptococcal cell wall cross
reacts with gangliosides in the cell
membrane of neurons in basal ganglion
• Damage neuron ,hampered cell signaling
,unable to stop motor impulses
18

19. Streptococcal M-Protein
• Two region
 Hypervariable N terminal
 Conserved C-terminal ( A,B & C
repeat)
• Class- I (1,3,5,6,14,18,19 & 24)
• ( 2,49,57,60 & 61 )
• Class-II Non reacting M protein
19

20. Streptococcal superantigens
• M protein fragments (PeP M5)
• Erythrogenic toxin
• GRAB ( alpha-2 macroglobin binding protein)
• sfb1 ( streptococcal fibronectin binding
protein)
• SCPA- Streptococcal C5a peptidase
20

21. • TUMOR NECROSIS FACTOR-α
 Also located on chromosome-6 ,near HLA
allele
 TNF- α is upregulated in patients with
increase susceptibility to ARF
 Increased inflammatory response & ARF
• MANNOSE BINDING LACTIN-
MBL helps to mark foreign cells to eliminate
 High level of MBL in mitral valve damage
 Low level in aortic valve involvement
21

22. Cytotoxic theory
• Gas toxin directly involved
• Anti steptolysin –O has direct effect on
mammalian cells in tissue culture
• Can not explain latent period
22

23. Risk factors
• Age- 5-15 years, high risk of developing GAS
pharyngitis
• Previous attack of rheumatic fever is risk factor
• Seasonal variation- winter and autumn months
• Closed communities- boarding schools
• Heredity- mataanalysis of six studies,435 twin
pair were included .concordance risk in
monozygotic twins is 44% while in dizygotic twin
is 12%,with 60% heritability in all studies
( Mark E Engel, Raphaella Stander,Jonathan Vogel,Adebowale
A,Bongani Mayosi, Deparment of medicine,Groot Schuur
hospital,Univery of capetown ,RSA,2011)
23

24. Jones’s criteria
• Major criteria
 Carditis
 Migratory polyarthritis
 Sydenham chorea
 Erythema marginatum
 Subcutaneous nodule
• Minor criteria
 Fever
 Arthralgia
 Previous rheumatic fever
or rheumatic heart
disease
 Leukocytosis, raised ESR
or elevated CRP
 Prolonged PR interval
Essential criteria
 Recent staph. Infection with
culture positivity or Rapid testing,
DNAase-B, ASO title or
streptokinase, recent scarlet fever 24

25. WHO criteria (2002-03)
• Chorea and indolent carditis do not require
evidence of antecedent group –A streptococcus
infection
• First episode should be diagnose as per Jones
criteria
Recurrent episode
• In a patient without established RHD- as per first
episode
• In a patient with established RHD- two minor
manifestation plus evidence of antecedent group-
A streptococcal infection with addition of recent
scarlet fever 25

26. Changes in New Zealand Guidelines
2010
• Acceptance of echo-cardigraphic finding as a
major criteria
• When carditis is present as a major criteria,
prolonged P-R interval can not be considered
as minor criteria in the same patient.
• If polyarthritis is present as a major criteria ,
arthralgia can not be taken as minor criteria in
same patient
26

27. Carditis
• First layer to involve is endocardium
• Presence of pericardium and myocardium is
variable
• Isolated mitral valve involvement or mixed mitral
and aortic disease
• Valvular insufficiency
• Stenosis appear later
• Tachycardia /murmurs
• Present in 50-60% cases
• Carey coomb’s murmur
27

28. Arthritis
• 75% of patients
• Migratory in nature
• Involve larger joints
• NSAIDS
• Dramatic response to salicylates
• Non deforming
• Earliest manifestation
• Inverse relationship with cardiac involvement
• Synovial fluid aspiration
28

29. Chorea
• 10-15%
• Occasionally unilateral (16%)
• Latent period can be in months
• Milkmaid’s grip
• Pronation sign
• Handwriting
29

30. Erythema marginatum
• < 3%
• Serpiginous ,macular lesions with pale centers
• Non pruritic
• Trunk and extremities
30

31. Subcutneous nodule
• <1%
• firm nodule
• 1 cm in diameter
• extensor surface of tendon near bony
prominence
• Directly proportional to cardiac involvement
31

32. Lab parameters
• Anti streptolysin O titre > 480
• Anti DNAase-B > 680
• Lower level in very young and those who are
above 15 years.
• Two fold rise in level within 10-14 days is
diagnostic
• Leukocytes count-10000-15000/cu.mm
• ESR- 4-10 weeks, upto 12 weeks
32

33. Role of echocardiography
• Controversial- 80% of murmurs can be
ausculatated ,remaining 20% likely to heal
without permanent squealae.
• Silent MR has good prognosis
33

34. Role of echocardiography
• Early detection of milder lesion in
asymptomatic children can prevent severe
valvular lesion by instituting secondary
prophylaxis
( Narijon E et al, New England jour .of med 2007,357;470-6)
• Prevalence of rheumatic heart disease by
echo doppler is 20/1000 children
(Anita saxena, S.ramakrisnan, A roy, A krishnan,All India
institute of medical sciences ,New Delhi & India –U.K.
education reserch initiative,2010)
34

35. Echocardiography
• Prospective cross sectional study over 2years in KCH,
under 14 years of age with the diagnosis of RF as per
jones criteria( carditis 92%,arthritis33%, Chorea8%,
subcutaneous nodule 4%, fever 51%, raised ASO titre
94%, raised CRP 78%,Prolonged PR interval 45% ,
pericardial effusion 22% & cardiac failure 28%)
• Total 51 patients with male :female ratio was 1.6:1
• murmer was audible in 78.4% patients while diseased
valve on echocardiography seen in 88.2 %)
• Mitral regurgitation 24% is most common lesion
(Rayamajhi A, Sharma D, Shakya U.Cardiology Unit, Department
of Paediatrics, National Academy of Medical Sciences, Kanti
Children's Hospital, Kathmandu, Nepal
Ann Trop Paediatr. 2007 Sep;27(3):169-77) 35

36. Echocardiography
• In 51 patients ( 25 first episode ,26 recurrent
rheumatic fever),arthritis occur in higher number in
first episode( p= 0.047) while cardiac symptoms viz
SOB (p= 0.003), palpitation (p=0.034),aortic
regurgitation (p =0.001)
• Audible murmur with corresponding echo finding were
present in all cases of recurrent rheumatic fever
• In first episode audible murmur in 61.5% while echo
shows 81% regurgitation
(Rayamajhi A, Sharma D, Shakya U.
Department of Pediatrics, Cardiology Unit, National Academy of
Medical Sciences, Kanti Children's Hospital, Kathmandu, Nepal
Pediatr Int. 2009 Apr;51(2):269-75)
36

37. Right ventricular endomyocardial
biopsy
• Diagnostic sensitivity is only 27%
• Can be beneficial in pts when unexplained
heart failure in pre existing RHD with high ASO
titre
• No role in chronic heart disease
37

38. Radionucliotide imaging
• Simple, non invasive
• Gallium-67, radiolabelled leukocytes,
radiolabelled antimyosin antibody
• Myocardial inflammation
• Infiltrative carditis
38

39. Differential diagnosis
Arthritis-
• Reactive arthritis
• Sickle cell disease
• Systemic lupus erythromatosus
• Lyme disease
• Gout
• Bacterial endocarditis
39

40. Carditis
• Viral myocarditis
• Infective endocarditis
• Kawasaki disease
• Congenital heart dieses
• Innocent murmur
40

41. Chorea
• Huntingson chorea
• Wilson’s disease
• Tics
• Cerebral palsy
• Systemic lupus erythromatosus
• Cerebrovascular accidents
41

42. Treatment
• General Measurements-
 Hospital admission may be helpful
 Bed Rest- carditis & chorea
 Diet-
42

43. Suppression of the inflammatory
process
• Aspirin -100-125 mg/kg/day ,in 4-5 equal
doses
• 60-70 mg/kg/day after two weeks (3-4 weeks)
• Naproxen 10-20 mg/kg/day
• Steroids
 prednisone
 methyl-prednisolone
43

44. • Salicylates-
 Rapid resolution of fever, arthritis & arthralgia
 Should not be used in treatment of carditis
 Do not decrease the incident of residual RHD
• Steroids-
Decreases fever and acute phase reactants
No superiority over salicylates in reducing
incidence of residual RHD and vice versa
44

45. Management of heart failure
• Diuretics
• Angiotensin converting enzyme inhibitors
• Digoxin
45

46. Management of chorea
• Rest in quite room
• Haloperidol
• Valproate
46

47. Intravenous immunoglobins-
• Do not alter the clinical course or reduction in
RHD
• May hasten recovery in chorea
47

48. Antibiotics
• Benzathine penicillin (i.m./single)
• Oral penicillin/erythromycin (10 days)
( Nelson’s text book of pediatrics)
• Procaine penicillin-400000 units,I.m., twice
daily for 10 days
• Followed by Benzathine penicillin 1.2 million
units every 21 days OR 0.6 million units every
15 days
48

49. Primary prevention
• Adequate antibiotic therapy for group-A
streptococcal infection
49

50. Secondary prevention
Benzathine
penicillin
1.2 million units,
every 4 weekly
intramuscular
Penicillin V 250 mg, twice a day oral
Sulfadiazine or
sulfasoxazole
0.5 mg once a day
for <27kg
1.0 mg once a day
for >27kg
oral
Erythromycin 250 mg ,twice daily oral
50

51. Duration of prophylaxis
Rheumatic fever without
carditis
5 yr or untill age of
21yrs,whichever is longer
Rheumatic fever with carditis
without residual valve disease
10yr or well into adulthood
,whichever is longer
Rheumatic fever with carditis
with residual heart disease
At least 10 yrs since last
episode ,atleast 40 yr of age,
consider prophylaxis
51

52. Mitral regurgitation
• Most common lesion
• Fatigue is most common symptom
• Systolic thrill is present in <10 % of patients
• Third heart sound may be present
• Diastolic murmur/thrill (more common, no
attenuation)
• Sinus tachycardia
• Left ventricular hypertrophy
52

53. Treatment of Mitral regurgitation
• Mile to moderate- medical management
• Severe regurgitation- surgical repair
53

54. Mitral stenosis & Tricuspid
Regurgitation
• 10 % off all rheumatic mitral stenosis
• Dyspnea –most common symptom
• Dyspnea on exertion, Paroxysmal nocturnal
dyspnea, atypical angina
• Small volume pulse , engorged neck veins,
tender liver
• Diastolic thrill(late attenuation)
• Opening snap
54

55. Aortic regurgitation
• Pure aortic regurgitation in 5-8% patients
• Main symptom- Palpitation
• Corrigan’s sign
• Dancing peripheral arteries
• Visible pulsation of abdominal aorta
• de Musset’s sign
• Hill’s sign
55

56. Prognosis
• Clinical manifestation at the time of initial
episode
• Severity of initial episode
• Recurrence of the disease
• Presence of Carditis
• Presence of Chorea
56

57. Streptococcal vaccine
• Multiplicity of M protein serotypes
• Toxicity of M protein preparation
• Cross reaction with human tissue
• Antibodies against synthetic agent are
opsonic but does not cross react with human
tissue
• Phase -1 trial are in progress for this synthetic
vaccine
57

58. Thank you 58

59. References
• Nelson’s text book of pediatrics 19th edition
• WHO guideline for diagnosis & treatment of
ARF 2004
• Essential pediatrics- OP Ghai 7th edition
59