1. Acute Rheumatic Fever comprehensive Notes .pptx

Notes from Harrison and Nelson

1. Acute Rheumatic Fever Brook A. June/2016 Harrison’s, Nelson’s Newzealand 2014 guideline

2. Acute Rheumatic Fever Acute rheumatic fever (ARF) is a multisystem disease resulting from an autoimmune reaction to infection with group A streptococcus. Although many parts of the body may be affected, almost all of the manifestations resolve completely. The exception is cardiac valvular damage [rheumatic heart disease (RHD)], which may persist after the other features have disappeared .

3. Acute Rheumatic Fever ARF and RHD are diseases of poverty. It has been estimated that between 15 and 19 million people worldwide are affected by RHD, with approximately one-quarter of a million deaths occurring each year. Some 95% of ARF cases and RHD deaths now occur in developing countries .

4. Acute Rheumatic Fever Although ARF and RHD are relatively common in all developing countries, they occur at particularly elevated rates in certain regions. These "hot spots" are sub-Saharan Africa, Pacific nations, Australasia, and the Indian subcontinent ARF is mainly a disease of children aged 5–14 years. Initial episodes become less common in older adolescents and young adults and are rare in persons aged >30 years.

5. Epidemiology By contrast, recurrent episodes of ARF remain relatively common in adolescents and young adults. This pattern contrasts with the prevalence of RHD, which peaks between 25 and 40 years. There is no clear gender association for ARF, but RHD more commonly affects females, sometimes up to twice as frequently as males.

6. Pathogenesis Based on currently available evidence, ARF is exclusively caused by infection of the upper respiratory tract with group A streptococci C lassically , certain M-serotypes (particularly types 1, 3, 5, 6, 14, 18, 19, 24, 27, and 29) were associated with ARF (“ Rheumatogenic ”) In high-incidence regions, however, it is now thought that any strain of group A streptococcus has the potential to cause ARF. Evidences for the mentioned and other atypical strains (see next slide)

7. Pathogenesis Do GAS skin infections ( pyoderma / impetigo ) cause ARF ?

8. Pathogenesis Do GAS skin infections (pyoderma/ impetigo) cause ARF?

9. Can some GAS strains cause both acute post streptococcal glomerulonephritis (APSGN) and ARF

10. Pathogenesis Genetic Susceptibility It is likely that 3–5% of people in any population have an inherent susceptibility to ARF, although the basis of this susceptibility is unknown And this proportion does not vary dramatically between populations. Findings of familial clustering of cases and concordance in monozygotic twins—particularly for chorea—confirm that susceptibility to ARF is an inherited characteristic *

11. Pathogenesis Genetic Susceptibility Associations have also been described with high levels of circulating mannose-binding lectin and polymorphisms of transforming growth factor  β 1  gene and immunoglobulin genes. High-level expression of a particular alloantigen present on B cells, D8-17, has been found in patients with a history of ARF in many populations With intermediate-level expression in first-degree family members, suggesting that this may be a marker of inherited susceptibility

12. Pathogenesis Genetic Susceptibility- Any Evidence? Evidences for familial clustring * 1937: Wilson and Schweitzer proposed that susceptibility to ARF was transmitted in an autosomal recessive fashion Stevenson & Cheeseman (1953) and Uchida (1953 )- both failed to confirm this As did reanalysis of the data by Elandt -Johnson (1970 ) Sit (1990) has also re- analysed these data sets and supports Wilson and Schweitzer’s conclusion of classical Mendelian recessive transmission, with the caveat that effective antibiotic treatment is able to prevent the expression of disease susceptibility

13. Pathogenesis Genetic Susceptibility- Any Evidence?

14. Pathogenesis Association with HLA Major histocompatability complex (MHC) class II antigens are present on antigen presenting cells and B lymphocytes, where they function as antigen receptors. Carlquist et al- Meta-analysis of studies of HLA DR frequencies in RHD This supported an association between class II alleles and the risk for RHD but concluded that considerable heterogeneity existed between different ethnic and racial groups.

15. Pathogenesis Association with HLA Subsequent studies support the observation that associations with HLA DR and DQ loci are stronger and more consistent in groups homogeneous for ethnicity and with respect to manifestations of rheumatic fever. 37-43

16. Pathogenesis Historically there have been three major categories of hypotheses Direct infection (for example , by the group A streptococcus ); Effects of a streptococcal toxin ( streptolysin O has been among the most commonly discussed); and Most feasibly, the concept of antigenic mimicry in association with an abnormal immune response. During the past half century, it is the concept of antigenic mimicry and/or an abnormal immune response to group A streptococcal extracellular or somatic antigens which has been most interesting

17. Pathogenesis When a susceptible host encounters a group A streptococcus, an autoimmune reaction results, which leads to damage to human tissues as a result of cross-reactivity between epitopes on the organism and the host Cross-reactive epitopes are present in the streptococcal M protein and the N- acetylglucosamine of group A streptococcal carbohydrate and are immunologically similar to molecules in human myosin, tropomyosin , keratin, actin, laminin , vimentin , and N- acetylglucosamine .

18. Pathogenesis It is currently thought that the initial damage is due to cross-reactive antibodies attaching at the cardiac valve endothelium, allowing the entry of primed CD4+ T cells, leading to subsequent T cell-mediated inflammation The only recognised natural host (and reservoir) for group A streptococci is the human , and an appropriate animal model has not been identified in half a century *

19. Pathogenesis In a New Zealand study of primary prevention the attack rate after culture proven GAS pharyngitis was 0.2%.

20. Do recurrent sore throats increase the risk of a patient progressing to ARF?

21. Do recurrent sore throats increase the risk of a patient progressing to ARF?

22. Pathogenesis Unanswered questions Why is Mitral valve (and aortic valve) preferred if it is true antigen mimicry? Why does one present with arthritis while another develop carditis …? Why does one patient with rheumatic carditis develop RHD while another do not?

23. Clinical Features There is a latent period of ~3 weeks (1–5 weeks) between the precipitating group A streptococcal infection and the appearance of the clinical features of ARF. The exceptions are chorea and indolent carditis , which may follow prolonged latent periods lasting up to 6 months. Although many patients report a prior sore throat, the preceding group A streptococcal infection is commonly subclinical In these cases it can only be confirmed using streptococcal antibody testing. The most common clinical presentation of ARF is polyarthritis and fever.

24. Clinical Features Polyarthritis is present in 60–75% of cases and carditis in 50–60%. The prevalence of chorea in ARF varies substantially between populations, ranging from <2% to 30%. Erythema marginatum and subcutaneous nodules are now rare, being found in <5% of cases .

25. Clinical Features Arthritis The typical arthritis is migratory, moving from one joint to another over a period of hours. ARF almost always affects the large joints—most commonly the knees, ankles, hips, and elbows—and is asymmetric. The pain is severe and usually disabling until anti-inflammatory medication is commenced.

26. Clinical Features Arthritis Less severe joint involvement is also relatively common but qualifies only as a minor manifestation . Arthralgia without objective joint inflammation usually affects large joints in the same migratory pattern as polyarthritis. In some populations, aseptic monoarthritis may be a presenting feature of ARF. This may occur because of early commencement of anti-inflammatory medication before the typical migratory pattern is established .

27. Clinical Features Arthritis The joint manifestations of ARF are highly responsive to salicylates and other nonsteroidal anti-inflammatory drugs (NSAIDs). Indeed , joint involvement that persists more than 1 or 2 days after starting salicylates is unlikely to be due to ARF. Conversely , if salicylates are commenced early in the illness, before fever and migratory polyarthritis have become manifest, it may be difficult to make a diagnosis of ARF. For this reason, salicylates and other NSAIDs should be withheld—and pain managed with acetaminophen or codeine—until the diagnosis is confirmed .

28. Clinical Features Carditis Up to 60% of patients with ARF carditis progress to RHD. The endocardium, pericardium, or myocardium may be affected. Valvular damage is the hallmark of rheumatic carditis . The mitral valve is almost always affected, sometimes together with the aortic valve; Isolated aortic valve involvement is rare.

29. Clinical Features Carditis Early valvular damage leads to regurgitation. Over ensuing years, usually as a result of recurrent episodes, leaflet thickening, scarring, calcification, and valvular stenosis may develop Therefore the characteristic manifestation of carditis in previously unaffected individuals is mitral regurgitation, sometimes accompanied by aortic regurgitation.

30. Clinical Features Carditis Myocardial inflammation may affect electrical conduction pathways, leading to P-R interval prolongation (first-degree AV block or rarely higher-level block) and softening of the first heart sound To qualify as a major manifestation, joint involvement in ARF must be arthritic, i.e., objective evidence of inflammation, with hot, swollen, red and/or tender joints, and involvement of more than one joint (i.e., polyarthritis).

31. Clinical Features Indolent Carditis First described in the USA in earlier decades and sometimes called insidious onset carditis Characterised by a subacute illness of several weeks or months with severe cardiac involvement and little or no joint symptoms. This is a rare scenario and is recognised in about two to three children per year in New Zealand . The usual case would have a modest elevation of inflammatory markers ( ESR and CRP).

32. Clinical Features Indolent Carditis Evidence of a streptococcal infection is not required. Younger children especially may have cardiac cachexia with weight loss. Another subset of older children present with ARF severe chronic rheumatic valve disease and impaired ventricular function to the extent that heart valve surgery is contraindicated. The only option for these children and young adults is cardiac transplantation.

33. Clinical Features Sydenham's chorea Commonly occurs in the absence of other manifestations, follows a prolonged latent period after group A streptococcal infection, and is found mainly in females. The three major clinical manifestations of Sydenham chorea include chorea , hypotonia , and emotional lability .

34. Clinical Features Sydenham’s Chorea The chorea is usually symmetric, although children may have the choreic movements limited to one side of the body. The movements, which are rapid and jerky, are prominent in the face, trunk, and distal extremities and dart from one muscle group to another; they are increased by stress and disappear during sleep. The onset may be abrupt, but the chorea typically has a slowly progressive course.

35. Clinical Features Sydenham’s Chorea Hypotonia may be a prominent sign, and when combined with severe chorea, the patient may be incapable of feeding, dressing, or walking. The speech is often involved and is sometimes unintelligible. Periods of uncontrollable crying and extreme mood swings are characteristic, perhaps in part as a result of the motor handicap and feelings of helplessness.

36. Clinical Features Sydenham’s Chorea Several typical signs are associated with Sydenham chorea The “milkmaid's grip ”- relaxing and tightening hand shake T he “ choreic hand ”- spooning of the extended hand by flexion at the wrist and extension of the fingers The “darting tongue ”- the tongue cannot be protruded for longer than a few seconds, and T he “pronator sign ”- the arms and palms turn outward when held above the head

37. Clinical Features Sydenham’s Chorea The chorea varies in severity. In mild cases it may be evident only on careful examination, while in the most severe cases the affected individuals are unable to perform activities of daily living and are at risk of injuring themselves. Chorea eventually resolves completely, usually within 6 weeks .

38. Clinical Features Sydenham’s Chorea ‡ During recent outbreaks of ARF in the USA, up to 71% of patients with chorea had carditis. 89 Even though clinically evident carditis increases the risk of later development of RHD, prior to cardiac echocardiography approximately 25% of patients with “pure” chorea also eventually developed RHD. 87,90 This is explained by the finding that over 50% of patients with chorea, but without cardiac murmurs, have echocardiographic evidence of mitral regurgitation.

39. Clinical Features Erythema marginatum The classic rash of ARF is erythema marginatum , which begins as pink macules that clear centrally, leaving a serpiginous , spreading edge. The rash is evanescent, appearing and disappearing before the examiner's eyes. It occurs usually on the trunk, sometimes on the limbs, but almost never on the face.

40. Clinical Features

41. Clinical Features Subcutaneous nodules Occur as painless, small (0.5–2 cm), mobile lumps beneath the skin overlying bony prominences, particularly of the hands, feet, elbows, occiput, and occasionally the vertebrae. They are a delayed manifestation, appearing 2–3 weeks after the onset of disease, last for just a few days up to 3 weeks, and are commonly associated with carditis

42. Clinical Features

43. Clinical Features Fever occurs in most cases of ARF, although rarely in cases of pure chorea. Although high-grade fever ( > 39°C ) is the rule, lower grade temperature elevations are not uncommon. Elevated acute-phase reactants are also present in most cases. C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are often dramatically elevated. Occasionally the peripheral leukocyte count is mildly elevated.

44. Clinical Features Other Less Common Clinical Features These include epistaxis, abdominal pain, rheumatic pneumonia (pulmonary infiltrates in patients with acute carditis ), mild elevations of plasma transaminase levels and microscopic haematuria , pyuria or proteinuria . None is specific for ARF but epistaxis and abdominal pain occur commonly.

45. Evidence of a Preceding GAS Infection With the exception of chorea and low-grade carditis , both of which may become manifest many months later, evidence of a preceding group A streptococcal infection is essential in making the diagnosis of ARF. As most cases do not have a positive throat swab culture or rapid antigen test, serologic evidence is usually needed.

46. Evidence of a Preceding GAS Infection The most common serologic tests are the anti- streptolysin O (ASO) and anti- DNase B (ADB) titers. Where possible, age-specific reference ranges should be determined in a local population of healthy people without a recent group A streptococcal infection .

47. Evidence of a Preceding GAS Infection A positive throat culture or rapid antigen test for GAS alone is less secure as 50% of those with a positive throat culture will be carriers only* Therefore, a positive culture alone demotes a case to probable or possible ARF. The most commonly used tests are the plasma antistreptolysin O (ASO) and the antideoxyribonuclease B (anti- DNase B) titres

48. Evidence of a Preceding GAS Infection S erum ASO titre reaches a maximum at about three to six weeks after infection and the serum anti- DNase B titre can take up to six to eight weeks to reach a maximum. The rate of decline of these antibodies varies considerably ASO titre starting to fall six to eight weeks and the anti- DNase B titre three months after infection. In the absence of reinfection, the ASO titre usually approaches preinfection levels after six to 12 months , whereas the anti- DNase B titre tends to remain elevated for longer.

49. Evidence of a Preceding GAS Infection The reference range for these antibody titres varies with age and geographical location. Ideally this should be determined for each geographic location. In a population with a high rate of streptococcal infections, many children will have high background streptococcal titres . The upper limit of normal approach attempts to determine a raised titre over and above this background, and therefore select out those children who have had a recent streptococcal infection

50. Evidence of a Preceding GAS Infection In New Zealand, an ASO titre of greater than or equal to 480 and/or an anti DNase B titre of greater than or equal to 680 is accepted as significant All cases of suspected ARF (chorea is an exception) should have elevated serum streptococcal serology demonstrated. If the initial titre is below the upper limit of normal, testing should be repeated 10 to 14 days later

51. Laboratory Tests Recommended Tests in Cases of Possible Acute Rheumatic Fever Recommended for all cases     White blood cell count     Erythrocyte sedimentation rate     C-reactive protein     Blood cultures if febrile      Electrocardiogram (repeat in 2 weeks and 2 months if prolonged P-R interval or other rhythm abnormality)     Chest x-ray if clinical or echocardiographic evidence of carditis      Echocardiogram (consider repeating after 1 month if negative)     Throat swab (preferably before giving antibiotics)–culture for group A streptococcus     Anti-streptococcal serology: both anti- streptolysin O and anti- DNase B titres , if available (repeat 10–14 days later if 1st test not confirmatory)

52. Laboratory Tests Recommended Tests in Cases of Possible Acute Rheumatic Fever Tests for alternative diagnoses, depending on clinical features     Repeated blood cultures if possible endocarditis     Joint aspirate (microscopy and culture) for possible septic arthritis     Copper, ceruloplasmin , anti-nuclear antibody, drug screen for choreiform movements     Serology and auto-immune markers for arboviral , auto-immune or reactive arthriti

53. Acute Rheumatic Fever Diagnosis Because there is no definitive test, the diagnosis of ARF relies on the presence of a combination of typical clinical features together with evidence of the precipitating group A streptococcal infection, and the exclusion of other diagnoses. This uncertainty led Dr. T. Duckett Jones in 1944 to develop a set of criteria (subsequently known as the Jones criteria* ) to aid in the diagnosis.

54. 2002-3 WHO (Revised John’s) Criteria Major manifestations Carditis Polyarthritis Chorea Erythema marginatum Subcutaneous nodules Minor manifestations Clinical : Fever , Polyarthralgia Laboratory : Elevated ESR or leukocyte count * ECG : Prolonged P-R interval Evidence of a preceding streptococcal infection within the last 45 days Elevated or rising ASO or other streptococcal antibody, or A positive throat culture, or Rapid antigen test for GAS, or Recent scarlet fever *

55. New Zealand 2014 criteria ‡ Acceptance of echocardiographic evidence of carditis as a major criterion was the New Zealand modification to the Jones (1992) update § When carditis is present as a major manifestation (clinical and/or echocardiographic), a prolonged P-R interval cannot be considered an additional minor manifestation in the same person

56. Diagnostic Groups Criteria Primary episode of rheumatic fever * Two major OR One major & two minor manifestations plus evidence of preceding GAS infection Recurrent attack of rheumatic fever in a patient without established rheumatic heart disease Two major OR One major & two minor manifestations plus evidence of preceding GAS infection Recurrent attack of rheumatic fever in a patient with established rheumatic heart disease ^ Two minor manifestations plus evidence of preceding GAS infection ^ Rheumatic chorea Insidious onset rheumatic carditis ^ Other major manifestations OR evidence of GAS infection NOT REQUIRED Chronic valve lesions of rheumatic heart disease (patients presenting for the first time with pure mitral stenosis or mixed mitral valve disease and/or aortic valve disease) d Do not require any other criteria to be diagnosed as having rheumatic heart disease

57. Echocardiography for ARF All patients with suspected or definite ARF should undergo echocardiography, to identify sub clinical carditis and to assess the severity of regurgitation and left ventricular size and function on those with clinical carditis (Grade C). The use of colour -Doppler echocardiography, permitting definitions of echocardiographic findings as a major criterion for ARF diagnosis, has evolved over the past two decades.

58. Echocardiography for ARF These criteria further evolved as part of the development of both the New Zealand and the Australian guidelines on rheumatic fever diagnosis (2006) and the WHO working groups . The minimal colour -Doppler criteria for valvulitis of ARF is the same as the minimal colour -Doppler requirement for the diagnosis of rheumatic mitral regurgitation and aortic regurgitation . As there is no differentiation of the colour -Doppler findings of acute carditis and that of chronic rheumatic valve regurgitation we recommend the same criteria for defining the acute phase and the chronic phase .

59. Echocardiography for ARF

60. Echocardiography for ARF

61. Differential Diagnosis

62. * The substantive change for the New Zealand Criteria from 2006 to 2014 is that aseptic monoarthritis is accepted as a major criteria even when NSAID have been used. Data from Auckland since 2006 has shown that even in the absence of NSAID use, monoarthritis is a frequent presenting symptom in patients with ARF 70 Importantly 29 of 34 (85%) of cases of monoarthritis with ARF had echocardiographic changes supporting the probability that the monoarthritis was due to ARF. Of these , 25 of the 34 cases had echocardiographic changes on admission and four developed mild regurgitation on follow up echocardiography. Thus monoarthritis is now included as a major criterion even in the absence of NSAID use in this 2014 guideline

63. Treatment Echocardiography should be performed on all possible cases to aid in making the diagnosis and to determine the severity at baseline of any carditis . There is no treatment for ARF that has been proven to alter the likelihood of developing, or the severity of, RHD. With the exception of treatment of heart failure, which may be life-saving in cases of severe carditis , the treatment of ARF is symptomatic .

64. Treatment Antibiotics All patients with ARF should receive antibiotics sufficient to treat the precipitating group A streptococcal infection Penicillin is the drug of choice can be given as follows Orally [as phenoxymethyl penicillin, 500 mg (250 mg for children < 27 kg) PO twice daily, or amoxicillin 50 mg/kg (max 1 g) daily, for 10 days] or as A single dose of 1.2 million units (600,000 units for children < 27 kg) IM benzathine penicillin G .

65. Treatment

66. Treatment Salicylates and NSAIDs These may be used for the treatment of arthritis, arthralgia, and fever, once the diagnosis is confirmed. They are of no proven value in the treatment of carditis or chorea . Aspirin is the drug of choice. An initial dose of 80–100 mg/kg per day in children (4–8 g/d in adults) in 4–5 divided doses is often needed for the first few days up to 2 weeks. A lower dose should be used if symptoms of salicylate toxicity emerge, such as nausea, vomiting, or tinnitus. When the acute symptoms are substantially resolved, the dose can be reduced to 60–70 mg/kg per day for a further 2–4 weeks.

67. Treatment Salicylates and NSAIDs Fever, joint manifestations, and elevated acute-phase reactants sometimes recur up to 3 weeks after the medication is discontinued. This does not indicate a recurrence and can be managed by recommencing salicylates for a brief period. Although less well studied, naproxen at a dose of 10–20 mg/kg per day has been reported to lead to good symptomatic response .

68. Treatment

69. Treatment Glucocorticoids The use of glucocorticoids in ARF remains controversial * However , the potential benefits of this treatment should be balanced against the possible adverse effects, including gastrointestinal bleeding and fluid retention. If used, prednisone or prednisolone are recommended at doses of 1–2 mg/kg per day (maximum, 80 mg). Glucocorticoids are often only required for a few days or up to a maximum of 3 weeks .

70. Treatment Manage Heart Failure Bed Rest Traditional recommendations for long-term bed rest, once the cornerstone of management, are no longer widely practiced. Instead , bed rest should be prescribed as needed while arthritis and arthralgia are present, and for patients with heart failure . Once symptoms are well controlled, gradual mobilization can commence as tolerated .

71. Treatment Chorea Medications to control the abnormal movements do not alter the duration or outcome of chorea. Milder cases can usually be managed by providing a calm environment. In patients with severe chorea, carbamazepine or sodium valproate are preferred to haloperidol. A response may not be seen for 1–2 weeks, and a successful response may only be to reduce rather than resolve the abnormal movements. Medication should be continued for 1–2 weeks after symptoms subside .

72. Treatment Chorea- Intravenous Immunoglobulin ( Ivig ) Small studies have suggested that IVIg may lead to more rapid resolution of chorea but has shown no benefit on the short- or long-term outcome of carditis in ARF without chorea. In the absence of better data, IVIg is not recommended except in cases of severe chorea refractory to other treatments .

73. Timing of Discharge The duration of treatment is dictated by the clinical response and improvement in inflammatory markers (ESR and CRP). Most ARF patients without severe carditis can be discharged from hospital after approximately two weeks. The length of admission will partly depend on the social and home circumstances*

74. ARF Recurrence Etiology Most recurrences occur due to programme failure of delivery of secondary prophylaxis i.e. the person has stopped benzathine penicillin (for a variety of reasons). True penicillin failure in patients on four weekly penicillin can occur 30 although this appears to be uncommon

75. ARF Recurrence Management  Benzathine penicillin should be recommenced four weekly if patient not already on benzathine penicillin  If there is a failure of benzathine penicillin on four weekly regimen, then this should be administered three weekly  There is no proven data that severity of RHD should influence the frequency of benzathine penicillin regimen  There can be difficulty deciding if there is new onset carditis in those with previous severe RHD; in these cases the minor criteria plus evidence of recent GAS pharyngitis allow a diagnosis of recurrent ARF or not  It has been suggested that ‘root-cause analysis’ of ARF at the time of hospital admissions may reveal a higher proportion of missed opportunity cases of previous ARF but this is unproven as of 2014  Those with recurrences of ARF are at risk of other poor health outcomes.74

76. Acute Rheumatic Fever Prognosis Untreated, ARF lasts on average 12 weeks. With treatment, patients are usually discharged from hospital within 1–2 weeks. Inflammatory markers should be monitored every 1–2 weeks until they have normalized (usually within 4–6 weeks) An echocardiogram should be performed after 1 month to determine if there has been progression of carditis . Cases with more severe carditis need close clinical and echocardiographic monitoring in the longer term .

77. Primary Prevention Ideally, primary prevention would entail elimination of the major risk factors for streptococcal infection, particularly overcrowded housing. This is difficult to achieve in most places where ARF is common. Therefore, the mainstay of primary prevention for ARF remains primary prophylaxis (i.e., the timely and complete treatment of group A streptococcal sore throat with antibiotics).

78. Primary Prevention What’s the Evidence for Penicillin? There is good evidence from RCTs that treating GAS sore throats with antibiotics reduces the likelihood of developing ARF (see next slides)

79. Primary Prevention What’s the Evidence for Penicillin? If commenced within 9 days of sore throat onset, a course of penicillin (as outlined above for treatment of ARF) will prevent almost all cases of ARF that would otherwise have developed.

80. Primary Prevention Seasonal Prophylactic Treatment? There is limited evidence from two RCTs that this may be effective in a circumscribed community No recommendation can be give though*

81. Primary Prevention Treating GAS skin infection? Current data is insufficient to suggest or refute that treating GAS skin infection can prevent Arf No conclusions or recommendations are able to be made

82. Secondary Prevention The mainstay of controlling ARF and RHD is secondary prevention. Patients with ARF are at dramatically higher risk than the general population of developing a further episode of ARF after a GAS infection, they should receive long-term penicillin prophylaxis to prevent recurrences. The regular administration of antibiotics to prevent infection with GAS and recurrent ARF is recommended for all people with a history of ARF or RHD

83. Secondary Prevention What’s the Evidence? This strategy has been proven in RCTs to prevent recurrence of ARF. Manyemba et al 2002 152 : A Cochrane meta-analysis Use of penicillin (compared to no therapy) is beneficial in the prevention of recurrent ARF And that intramuscular benzathine penicillin is superior to oral penicillin in the reduction of both recurrent ARF (87-96% reduction) (Level I) There is strong evidence that secondary prophylaxis reduces the severity of RHD by preventing disease progression. 153,154,155,156

84. Secondary Prevention Which Agent? In early studies of ARF prophylaxis using sulphonamides , 1.5% of treated cases developed ARF recurrences , compared to 20% of untreated cases. Subsequently , penicillin was found to be more efficacious than sulphonamides (Level I). 60,123 Secondary prophylaxis also reduces the severity of RHD. It is associated with regression of heart disease in approximately 50-70% of those with adequate adherence over a decade (Level III 2 ), 90,157,158 and reduces mortality (Level III 2) 159

85. Secondary Prevention Penicillin Dose & Frequency The best antibiotic for secondary prophylaxis is benzathine penicillin G (1.2 million units, or 600,000 units if <27 kg) While benzathine penicillin is usually administered every four weeks (28 days), serum penicillin levels may be low or undetectable 28 days following a dose of 1,200,000 U. Fewer streptococcal infections and ARF recurrences occurred among those receiving three weekly BPG (Level I ). 152,163,164 Moreover, the three-weekly regimen resulted in greater resolution of mitral regurgitation in a long-term randomised study in Taiwan (66% vs 46%) (Level II). 165

86. Secondary Prevention Penicillin Dose & Frequency Prospective data from New Zealand however, showed that recurrences were rare among people who were fully adherent to a four-weekly benzathine penicillin regimen

87. Secondary Prevention Penicillin Dose & Frequency An audit of practice in the Auckland region 29,30 (1993 to 1999) showed that Of 360 ARF patients, there were 20 recurrences in 19 patients (median age 21 years). The rate of recurrence in fully adherent individuals on a 28 day regime was 0.07 per 100 patient years . Failure on the prophylaxis programme ( i.e. including those who were less than fully adherent) was 1.4 per patient years . Patient nonadherence accounted for 55% of recurrences. Two recurrences were following discharge from prophylaxis as per the New Zealand guideline, occurring three and 13 years later.

88. Secondary Prevention Penicillin Dose & Frequency Administration three days early and up to five days late is considered reasonable (i.e. 25-33 days following the previous injection). Dose intervals can be adjusted for individual circumstances. Intramuscular benzathine penicillin injections can cause local pain and discomfort. This can lead to poor compliance in those requiring ongoing prophylaxis Amir et al demonstrated that pain can be significantly reduced when 1% lidocaine (lignocaine) was used to reconstitute benzathine penicillin for injection. This did not affect serum penicillin levels .

89. Secondary Prevention Penicillin Dose & Frequency Bez . Penicillin plus Lignocaine A recent New Zealand study 170 with rheumatic fever patients receiving monthly IM benzathine penicillin for prophylaxis has demonstrated a reduction in the subjective experience of pain when two analgesic interventions were offered : Intramuscular delivery of benzathine penicillin with either 0.25ml of 2 % lignocaine alone or 0.25ml of 2% lignocaine with a vibrating device with cold pack (Buzzy ®). Lignocaine and Buzzy® together resulted in a greater reduction in pain than lignocaine alone, but only in children aged 13 years or younger. In this age group, the fear of injection was also reduced

90. Secondary Prevention Oral Agents Oral penicillin V (250 mg) can be given twice-daily instead but is somewhat less effective than benzathine penicillin G. Penicillin allergic patients can receive erythromycin (250 mg) twice daily.

91. Secondary Prevention *Administration every 3 wk is recommended in certain high-risk situations. †Macrolide antibiotics should not be used in persons taking other medications that inhibit cytochrome P450 3A , such as azole antifungal agents, HIV protease inhibitors, and some selective serotonin reuptake inhibitors .

92. Secondary Prevention Special Scenarios Pregnancy & Breast feeding Penicillins and erythromycin are considered safe for use in pregnancy (Grade C ) Low dose lignocaine is safe in pregnancy Penicillins are excreted into breast milk in low concentrations and are considered safe for use in breast feeding. Erythromycin is also excreted into breast milk and has been considered as compatible in breast f eeding Lignocaine can be administered to breast feeding women

93. Secondary Prevention Special Scenarios Anti-Coagulated Patients Intramuscular bleeding from benzathine penicillin injections, used in conjunction with anticoagulation therapy is rare. Thus , benzathine penicillin injections should be continued for those who are anti-coagulated, unless there is evidence of uncontrolled bleeding or the INR is outside the defined therapeutic window (Grade D). Benzathine penicillin should not be administered if the INR is greater than 4.5. The INR level should be monitored monthly as a minimum for adults, more frequently in children. Patients discharged from hospital on oral penicillin following valve surgery should recommence benzathine penicillin as soon as is practical

94. Secondary Prevention Duration The duration of secondary prophylaxis is determined by many factors, in particular The duration since the last episode of ARF (recurrences become less likely with increasing time), Age (recurrences are less likely with increasing age), and The severity of RHD (if severe, it may be prudent to avoid even a very small risk of recurrence because of the potentially serious consequences)

95. Secondary Prevention Duration AHA 2009 Category of Patient Duration of Prophylaxis Rheumatic fever without carditis For 5 years after the last attack or 21 years of age (whichever is longer) Rheumatic fever with carditis but no residual valvular disease For 10 years after the last attack, or 21 years of age (whichever is longer) Rheumatic fever with persistent valvular disease, evident clinically or on echocardiography For 10 years after the last attack, or 40 years of age (whichever is longer). Sometimes lifelong prophylaxis.

96. Secondary Prevention Duration

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