New1Acute Rheumatic Fever ARF Amira.pptx

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1. Pathogenesis and diagnosis of Acute Rheumatic fever Presenter: Dr Amira (IMR1) Moderator: Dr Chala Fekadu ( MD, Internist, consultant cardiologist)

2. Outlines Introduction Epidemiology Pathogenesis Diagnosis Overview of Management

3. Introduction Acute rheumatic fever is a non suppurative complication of GAS pharyngeal infection involving multiple systems. Follows streptococcal pharyngitis two-four weeks. Clinical feature includes acute inflammation of the heart, joints, skin, subcutaneous tissue and CNS.

4. Cont. No single diagnostic tool or laboratory test . Diagnosis is based on clinical features and diagnostic criteria.

5. Epidemiology In 2005 471,000 new cases of ARF each year 15.6-19.6 million prevalent cases of RHD 350,000 annual death from ARF and RHD. Recent studies show 19 million cases of RHD worldwide and 250,000 annual death and 95% of death occur in developing countries. Is associated with poverty and economic disadvantage. Leading cause of cardiovascular death in the first 5 decades of life.

6. Cont Sub Saharan Africa and south central Asia account for most of the cases. Highest incidence in Kyrgyzstan 543/100,000 cases. Australia and new Zealand 162/100,000 in males and 228/100,000 in females. US- <10 cases/100,000 population

7. Cont. Suppurative pharyngitis is the only well established prequel for ARF. This could be due to large repository of lymphoid tissue. In tropical countries GAS pyoderma may complicate with ARF. The burden of ARF worldwide has shown multiple changing pattern.

8. Epidemiology of ARF and RHD in Ethiopia In 1990’s survey conducted based on auscultatory findings showed prevalence of RHD 4.6/1000 in rural and 6.4/1000 in urban areas. In 2016 study based on echocardiography based screening prevalence of RHD among school children in Ethiopia was 19 cases/1000 (13.9-23.4,95% CI).

9. Cont. Study conducted in harari among 1739 school children with mean age of 11.5 years(6-9), 21 had ARF. 2weeks prevalence of ARF and tonsilopharyngitis were 21/1739(1.2%) and 231/1739 (13.2%) respectively.

10. GAS pharyngitis and ARF Accounts for 20-40% of exudative pharyngitis in children Common age group is between 6 and 15 years. GABHS was the cause of bacterial pharyngitis in 75% of children with severe symptoms. Recurrence occurs in adolescents and young adults and it is rare after the age of 34.

11. Roles of streptococcus pyogenes Out breaks of ARF closely follow streptococcal pharyngitis . Adequate treatment of pharyngitis significantly decrease ARF incidence by 70%. Appropriate antimicrobial treatment decreases recurrence. Elevated antibody titers to streptococcal antigens in patients with ARF.

12. Cont. 0.3-3% of patients develop ARF after Untreated GABHS. No predilection based on sex but MS and chorea are more commonly seen in Females.

13. Pathogenesis Development of ARF following GAS phayngitis depends on the bacterial strains, susceptible host and socioeconomic status..

14. Bacterial strain specificity GABHS has more than 100 subtypes 5 chromosome patterns of emm genes , A-E that code for M and M like cell surface protein M protein on surface molecule define the subtypes. Pharyngitis strains have typical pattern of A-C and impetigo strains have D-E but there are reported cases of ARF following infection with D-E strains. emm types (3,5,6,14,18,19,24, and 29) are termed as rheumatogenic strains.

15. Pathogenesis T and B cell mediated autoimmunity is triggered by M-protein and streptococcal toxins causing production of IgG and IgM and activation of CD4+ T cells. Activation of both cellular and humoral immune system leads to clinical features of ARF like transient arthritis and chorea.

16. Molecular mimicry Structural similarity between exogenous agent and human proteins. M-protein, N-Acetyl beta D-glucosamine and other epitopes mimic myocardium(myosin and topomycin ) Heart valves( laminin ) synovia ( vimentin ), skin (keratin), subthalamic and caudate nuclei in the brain ( lysoganglioside )

17. Cont. Evidences show presence of cross reactive auto antibodies targeting GlcNAc , laminin and laminar BM of heart valve endothelium. T-cells in patients with RHD also cross react with M-protein and cardiac myocin .

18. Cont. Two hit hypothesis proposes that antibody attack facilitates extravasations of T cells through activated epithelium into valve tissue leading to formation of granulomatous nodules called Aschoff bodies. In sydenham chorea human monoclonal antibodies( mAbs ) and auto antibodies target lysoganglioside and dopamine receptors

19. Cont. An alternative hypothesis - initial damage is due to streptococcal invasion of epithelial surfaces, with binding of M protein to type IV collagen.

20. Genetic susceptibility 3-6% of the population is susceptible for ARF Associated with HLA (HLA-DR7 and HLA-DR4 associated with susceptibility), B-cell allo antigens, polymorphism TNF-a gene mannose-binding lectin Toll like receptor

21. Cont. The result shows susceptibility to acute rheumatic fever is an inherited characteristics concordance was 12% in dizygotic twins and 44% In monozygotic twins. Estimated heritability reaches up to 60%.

22. Clinical features Five major clinical manifestations Arthritis 60-80% Carditis and valvulitis 50-80% Central nervous system involvement 10-30% Subcutaneous nodule 0-10% Erythema marginatum < 6%

23. Cont. minor manifestations Arthralgia Fever Elevated acute phase reactants Prolonged PR interval

24. Arthritis Most common and usually the earliest manifestation of ARF. It is more common and severe in teenagers ( 82%) and children (66%). pain is mostly transient (days-1 week) and more prominent than physical findings of arthritis. Typically has migratory pattern but can also have additive pattern. Monoarthritis seen in 17-25% of patients. Mostly involve knee, ankle, elbows and wrists.

25. Cont. Hip, shoulder and small joint involvement not common. Arthritis resolves without treatment in approximately 4 weeks long term joint deformity is rare. Arthritis subsides quickly with NSAIDs and glucocorticoids . Radiography is usually unremarkable or shows slight effusion. Analysis - sterile inflammatory fluid.

26. carditis On average 3 weeks after GAS infection. ARF causes Pancarditis but endocarditis with valvulitis is more common. Incidence of carditis in ARF varies based on age and is more common in children especially age<3. Mitral and aortic valve usually involved and involvement of tricuspid is not common. Valvuitis is the predominant feature and in abscense of valvulitis myocarditis and pericarditis alone make the diagnosis of ARF unlikely.

27. Cont. Clinical feature Clinically new onset murmur on auscultation or echocardiographic evidence of AR or MR. Transient apical mid systolic murmur could be present ( carey-coombs ). Chest pain and friction rub in pericarditis and may have pericardial effusion. In 10% of patients carditis is severe and cause acute heart failure.

28. Cont. Mechanism of MR in ARF is due to annulitis with annular dilatation, chorditis with chordal elongation, Valvulitis with anterior mitral leaflet prolapse and pathologic MR. Chordal rupture may occur

29. Cont. Pericarditis occur in 10% of patients and resolves without sequelae . Subclinical carditis 53% of rheumatic carditis Echocardiography/ doppler shows AR or MR in the absence of auscultatory findings. ECG- AV block CxR - Cardiomegaly 40-60% of patients complicate with RHD.

30. Sydenham chorea AKA chorea minor or St Vitus dance Abrupt non-rhythmic involuntary movements musclar weakness and emotional disturbances. Involves hand shoulder, face feet leg and trunk. Choriform movements more on one side that subside with sleep. Motor impersistence evidenced on tounge protrusion and milk maid’s sign diffuse hypotonia may occur.

31. Cont Emotional disturbance- outbursts of crying inappropriate behavior, halted speech, restlessness and learning difficulties. OCD and rarely transient psychosis is reported. Longer latent period 1-8 months. May occur as an isolated finding or may have concomitant carditis . Recurrence may occur but almost all patients recover 6weeks-6months. Diagnosis is clinical but CSF analysis and MRI can be done to exclude differential diagnosis.

32. Erythema marginatum Evanescent non pruritic pink or faintly red rash with irregular boarder involving the limbs and trunk but not the face. Commonly occurs early in ARF Extends centrifugally Mostly occurs in patients with acute carditis .

33. Subcutaneous nodule Firm, painless, mobile lesions located over boy prominence or near tendons. Resemble subcutaneous nodules of RA but smaller and present for shorter period. Appear after the first weeks of illness Average of 3-4 nodules with variable size Rare as solitary manifestation of ARF. Overlying skin is not inflamed.

34. Clinical features cont. Other features include Abdominal and precordial pain Epistaxis Malaise Tachycardia NC NC anemia Normal complement levels

35. RHD Most common cause of acquired valvular disease in the world. 50% of patients with carditis 10-20 years after initial illness. Mitral valve most commonly affected followed by aortic valve.

36. Jaccoud arthropathy AKA chronic post rheumatic fever arthropathy . A rare painless benign arthropathy causing deformity of fingers and toes. Occurs after repeated attacks of ARF Is due to recurrent inflammation of the fibrous articular capsule. Initially correctable deformity but later becomes fixed.

37. Diagnosis of ARF 2015 jones criteria Differ for low risk or moderate-high risk population low risk population those with rheumatic fever incidence <=2 per 100,000school aged children per year or all age RHD prevalence <=1per 1000 population

38. 2015 Jones criteria cont. Initial ARF Two major or one major and two minor criteria and in a patient with evidence of preceding GAS infection. For recurrence Two major or one major and two minor criteria Three minor required Exceptions Chorea as the only manifestation Indolent carditis as the only manifestation

39. Cont. For moderate and high risk population Major criteria includes monoarthritis or polyatrthralgia For minor monoarthralgia rather than polyarthralgia Fever >=38 ESR >= 30

40. Evidence of preceding GAS infection Historical evidence of pharyngitis has age related variability and is unreliable. Positive throat culture for GAS Positive rapid streptococcal antigen test Elevated or rising anti streptococcal antibody titers ASO Antideoxyribonuclease B (ADB)

41. Cont. Positive throat culture Negative in 75% of patients by the time they have ARF. Rapid streptococcal antigen test ASO and ADB More helpful ASO more sensitive (73%) ASO Peaks 3-5 weeks following ARF and ADB at 6-8 weeks.

42. Cont. Other laboratory studies CRP ESR CBC with differential Blood culture CXR Echocardiography ECG

43. Management Goal of treatment Symptomatic relief of acute disease manifestations Eradication of GAS Secondary Prophylaxis suppressing inflammation Preventing progression to a cardiac disease Patient education

44. Cont. Treatment consists of Anti- inflammatory treatment Antibiotics Management of Heart failure

45. management of arthritis Bed rest Anti inflammatory agents( salicyclates NSAIDS, Glucocorticoids , immunoglobulins ) NSAIDs prevents new joint involvement. Aspirin 80-100 mg/kg per day in children and 4-8 gm/day in adults. Naproxen(10-20mg/kg/day) is currently replacing aspirin. Continued until inflamation has subsided both clinically or on laboratory evidence but mostly given 1-2 weeks. Low dose glucocorticoids reserved for patients who do not tolerate aspirin or naproxen.

46. Carditis management Early diagnosis and assessment of severity (significant cardiomegaly , CHF, and 3 rd degree heart block) Management of heart failure Secondary prophylaxis. Steroids help in treatment of carditis but no evidence of benefit in preventing it’s chronic complications. Surgery for severe valve insufficiency

47. Chorea management Symptomatic treatment for those with moderate to severe symptoms interfering with normal activity especially gait disturbance. Dopamin 2 receptor blockers Haloperidol, fluphenazine , pimozide Mild cases can be treated with carbamazepine , levetiracetam clonidine and valporic acid, phenobarbital .

48. Cont. Immune modulation Predinsone 1-2mg/kg/day-shorten course symptos . IV immunoglobulins Plasmapharesis

49. Prevention Primordial prevention socioeconomic, environmental, behavioral and cultural changes. Primary prevention

50. Antibiotics Other alternative drugs cephalosporins Macrolids Incosamides

51. Secondary prophylaxis

52. Secondary prophylaxis

53. Cont. Household contacts Throat cultures or evaluation for pyoderma If results are positive antibiotic therapy.

54. References Braunwald's Cardiovascular Medicine 11th Edition 2019 Uptodate online Harrison’s Principles of Internal Medicine, 20th Edition Acute rheumatic fever and rheumatic heart disease guideline- Nature Reviews

55. Thank you!