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Acute rheumatic fever in children

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  • 1. Rheumatic fever in children Dr.Mohd.Arif Pediatric resident, IOM 1
  • 2. INDEX 1. 2. 3. 4. 5. 6. 7. 8. Introduction Problem statement Incidence and prevalence (worldwide & Nepal) Pathogenesis Diagnosis Treatment Rheumatic heart disease 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 groupA 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 35 Ann Trop Paediatr. 2007 Sep;27(3):169-77)
  • 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

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