Rheumatic Fever and Rheumatic Heart Disease DR.ABDUL GHAFFAR MEMON Associate Professor Cardiology LUMHS HYD/JAMSHORO Http://www.Who.Int/cardiovascular_diseases/resources/trs923/en

Learning Objectives: To understand the pathogenesis of acute rheumatic fever and rheumatic heart disease To appreciate the burden of disease To recognize the features of a streptococcal sore throat To know the treatment regimens of a streptococcal sore throat To be aware of secondary prevention measures

Examine the burden of disease within own communities Performance Objectives: Examine the burden of disease within own communities Timely recognition of a streptococcal sore throat with correct treatment Institute secondary prevention programme Join the global community fighting Rheumatic fever and rheumatic heart disease

What is the incidence of acute rheumatic fever and rheumatic heart disease?

Epidemiology 20 % bacterial 80 % viral 15% GABHS 5% other bact. ARF is a disease of child age group 6 – 15 yrs. ARF uncommon < 5 yrs. And recurrence very rare after 34 yrs. Pharyngitis 20 % bacterial 80 % viral 15% GABHS 5% other bact. .3 – 3 % ARF

Incidence of ARF: Population-based Studies Incidence of acute rheumatic fever in the world: a systematic review of population-based studies. Tibazarwa KB, Volmink JA, Mayosi BM. Heart. 2008 Dec;94(12):1534-40. Epub 2008 Jul 31. Review.

What is the prevalence of rheumatic heart disease?

According to the WHO, 15.6 million people worldwide are living with RHD. Of the 500 000 who develop ARF each year, 300 000 go on to develop RHD and 233 000 deaths are attributable each year to ARF/RHD. The are conservative estimates and the true burden of disease is thought to be even greater. This mortality rates are higher than those of rotaviruses, meningitis and hepatitis B and half of those with malaria. Rheumatic fever: neglected again. Watkins DA, Zuhlke LJ, Engel ME, Mayosi BM. Science. 2009 Apr 3;324(5923):37. No abstract available.

Pathobiology environ-ment agent host -GABHS ->100 subtype of M protein Heart-myosin Heart valve- laminin Synovia- vimentin Skin-keratin Brain- lysoganglioside -Extent of immune response to pharyngitis -Genetic susceptibility -Prior history of RF -Over crowding -low socioeconomic status

The pathogenic pathway for rheumatic heart disease starts with the susceptible individual. Twin studies have demonstrated that a genetic component may exist. ( add link)(Repeated streptococcal infections are thought to prime a susceptible individual resulting in a heightened response to an infection with rheumatogenic streptococcus. This results in acute rheumatic fever usually 3 weeks after the initial tonsilllopharyngeal infection. The precise pathogenetic mechanism has not yet been defined, yet strong evidence exists that an autoimmune response mediates the development of RF/RHD in a susceptible host. Genetically determined host factors interacting with the molecular similarity of the streptococcal antigens and host tissues results in the involvement of brain, joints, tissues and heart. The pathogenesis of RF/RHD is a complex maze of events involving major histocompatibility antigens, potential tissue-specific antigens, antibodies and superantigenic activation . However it remains clear that environmental factors such as overcrowding, poor living conditions and poor access to health care is the most significant determinant of disease distribution. Lancet. 2005 Jul 9-15;366(9480):155-68. Acute rheumatic fever. Carapetis JR, McDonald M, Wilson NJ. Carapetis. Lancet 2005;366:155

What is the pathogenesis of acute rheumatic fever?

ACUTE RHEUMATIC FEVER Autoimmune consequence of infection with Group A streptococcal infection Results in a generalised inflammatory response affecting brains, joints, skin, subcutaneous tissues and the heart. RF is a delayed autoimmune response to Group A streptococcal pharyngitis. The clinical manifestation of the response and its severity in an individual is determined by host genetic susceptibility, the virulence of the infecting pathogen and a conducive environment. RF is thought to occur only after GAS infection of the upper respiratory tract although this thinking has been challenged by those working in tropical areas where skin infections are rife. (Low rates of streptococcal pharyngitis and high rates of pyoderma in Australian aboriginal communities where acute rheumatic fever is hyperendemic.McDonald MI, Towers RJ, Andrews RM, Benger N, Currie BJ, Carapetis JR.Clin Infect Dis. 2006 Sep 15;43(6):683-9. Epub 2006 Aug 9. (The challenge of acute rheumatic fever diagnosis in a high-incidence population: a prospective study and proposed guidelines for diagnosis in Australia's Northern Territory. Ralph A, Jacups S, McGough K, McDonald M, Currie BJ. Heart Lung Circ. 2006 Apr;15(2):113-8. Epub 2005 Oct 27.)

The clinical presentation can be vague and difficult to diagnose. ACUTE RHEUMATIC FEVER The clinical presentation can be vague and difficult to diagnose. Currently the modified Duckett-Jones criteria form the basis of the diagnosis of the condition. Acute rheumatic fever is a systemic inflammatory disease occurring as a sequel to beta haemolytic streptococcal infection. The clinical presentation can be vague, complex and difficult to diagnose. The modified Duckett-Jones criteria to establish the diagnosis arose from research in North America and Europe during the first part of the 20th century and may not apply in other parts of the world. It is thought that 0.3-30% of untreated group A beta haemolytic streptococcal infection progress to develop acute rheumatic fever. Prevention of rheumatic fever and diagnosis and treatment of acute Streptococcal pharyngitis: a scientific statement from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee of the Council on Cardiovascular Disease in the Young, the Interdisciplinary Council on Functional Genomics and Translational Biology, and the Interdisciplinary Council on Quality of Care and Outcomes Research: endorsed by the American Academy of Pediatrics. Gerber MA, Baltimore RS, Eaton CB, Gewitz M, Rowley AH, Shulman ST, Taubert KA. Circulation. 2009 Mar 24;119(11):1541-51. Epub 2009 Feb 26

The Jones criteria were introduced in 1944 as a set of clinical guidelines for the diagnosis of RHF. They have subsequently undergone significant modifications ,the final ones published in 2002. These revised WHO criteria speak to the diagnosis of : a primary episode of RF recurrent attacks of RF in patients without RHD recurrent attacks of RF with RHD rheumatic chorea insidious onset rheumatic carditis chronic RHD It is important to note that in the context of a preceding streptococcal infection, 2 major criteria, or a combination of one major and 2 minor, provide reasonable evidence for a diagnosis of RF. Major criteria: carditis, arthritis, chorea, subcutaneous nodules, erythema marginatum. Minor criteria: Clinical: fever, polyarthralgia Lab: elevated acute phase reactants ESR/CRP This little cartoon character demonstrates the features of acute rheumatic fever. Chorea (St Vitus dance) Flitting polyarthritis- it is important to be aware that monoarthritis is an important presenting complaint in patients from developing countries WEBLINK Erythema marginatum and subcutaneous nodules are the dermatological manifestations of ARF. The only manifestation of ARF with potentially life-threatening and permanent sequelae is the carditis- as evident either as valvulitis( the precursor to rheumatic heart disease) pericarditis and myocarditis.ie a pancarditis. Histologically Aschoff nodules is the hallmark pathognomonic feature and on special investigations the minor criteria such as high ESR or CRP is noted. Evidence of previous infection with GAS either via ASOT/anti-DNAse B titres or with precious evidence of streptococcus being cultured from the throat is an important adjunct to this diagnosis. Currently carditis as diagnosed by echo alone is not included in the major criteria despite repeated calls for its inclusion. It is currently recommended that all patients with the clinical diagnosis of ARF even those without clinical evidence of carditis be referred for an echocardiogram( if available)

RHEUMATIC HEART DISEASE Rheumatic Heart Disease is the permanent heart valve damage resulting from one or more attacks of ARF. It is thought that 40-60% of patients with ARF will go on to developing RHD. Prevention of infective endocarditis: guidelines from the American Heart Association: a guideline from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Wilson W, Taubert KA, Gewitz M, Lockhart PB, Baddour LM, Levison M, Bolger A, Cabell CH, Takahashi M, Baltimore RS, Newburger JW, Strom BL, Tani LY, Gerber M, Bonow RO, Pallasch T, Shulman ST, Rowley AH, Burns JC, Ferrieri P, Gardner T, Goff D, Durack DT; American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee; American Heart Association Council on Cardiovascular Disease in the Young; American Heart Association Council on Clinical Cardiology; American Heart Association Council on Cardiovascular Surgery and Anesthesia; Quality of Care and Outcomes Research Interdisciplinary Working Group. Circulation. 2007 Oct 9;116(15):1736-54. Epub 2007 Apr 19. Erratum in: Circulation. 2007 Oct 9;116(15):e376-7.

RHEUMATIC HEART DISEASE The commonest valves affecting are the mitral and aortic, in that order. However all four valves can be affected. It is important to note that the natural history of valve disease can differ in the developed and developing world with the progression to mitral valve stenosis(for example) having a latency period of several decades as opposed to the early and aggressive presentation of the same lesion in developing countries.

RHEUMATIC HEART DISEASE Sadly, RHD can go undetected with the result that patients present with debilitating heart failure. At this stage surgery is the only possible treatment option. It has been suggested that the medical management of RHD must defer to operative intervention according to echocardiographic and clinical guidelines. The absence of access to cardiac surgery, a reality for many parts of Africa, India and Pacific Islands, implies that patients present in advanced stages of the disease, with cardiac failure and with significant complications. Cardiovasc J Afr. 2007 Sep-Oct;18(5):295-9. Epub 2007 Oct 22. Prevalence and pattern of rheumatic heart disease in the Nigerian savannah: an echocardiographic study.

RHEUMATIC HEART DISEASE Patients living in poor countries have limited or no access to expensive heart surgery. Prosthetic valves themselves are costly and associated with a not insignificant morbidity and mortality. In 2000, the average cost of surgery for RHD in Africa was around US$5000;in low income countries of sub-Saharan Africa with a GDP per capita of less than US$500, such as Ghana, the cost of surgery is therefore prohibitive and would also adversely affect any poverty reduction strategies. Rheumatic and nonrheumatic valvular heart disease: epidemiology, management, and prevention in Africa. Essop MR, Nkomo VT. Circulation. 2005 Dec 6;112(23):3584-91. Review

What are the clinical features of strep sore throat?

Hallmarks of STREP sore throat Tender lymph nodes Close contact with infected person Scarlet fever rash Excoriated nares( crusted lesions) in infants Tonsillar exudates in older children Abdominal pain GOLD STANDARD: POSITIVE THROAT CULTURE Management of group A beta-hemolytic streptococcal pharyngotonsillitis in children. Brook I, Dohar JE. J Fam Pract. 2006 Dec;55(12):S1-11; quiz S12. Review.

Hallmarks of VIRAL sore throat Coryza: runny nose or mouth ulcers Other family with COLD symptoms Evidence of another viral infection Itchy watery eyes Hoarseness and cough: non-specific Fever: not specific Red Throat: not specific

2002-03 WHO criteria for the diagnosis of RF and RHF Diagnostic Categories Criteria Primary episode of rheumatic fever Recurrent attack of RF in a pt. without stablished RHD Recurrent attack of RF in a pt. with stablished RHD Rheumatic chorea OR insidious onset rheumatic carditis. 2 major or 1 major plus 2 minor plus evidence of GAS Infection. Same as above 2minor manifestation plus evidence of GAS infection. No other major manifestations or evidence of GAS infection

Continue…. Diagnostic categories Criteria Chronic valve lesion of RHD (pts presenting for first time with pure MS or mixed mitral valve disease and/or aortic valve disease.) Do not require any other criteria to be diagnose as having RHD

Arthritis Manifest in the 60 – 75% of pt. Painful, migratory, and limited to the major joint of extremities Inflammation in 1 joint lasts for 1-2 week and polyarthritis as whole resolve in 1 month or less. Tenderness out of proportion to other findings. JACCOUD Arthropathy can be occur. Arthritis can overlap carditis but both manifestation inversely related in severity. Very good response to salicylates.

Carditis Manifest as valvulitis – (MR and/or AR) myocarditis or pericarditis or both. 40 – 60% result in RHD Soft blowing pansystolic murmur of MR is hallmark of carditis in RF. HF due to the MR not due to myocardial involvement. Pericarditis cause friction rub and sometime pleuritic chest pain. Myocardial inflammation can cause conduction defect and heart block. There is a linear relationship b/w severity of MR during the first episode of RF and subsequent RHD.

Continue…… In the setting of LV dysfunction or/and pericarditis myocarditis without valvular involvement path- ology is unlikely to rheumatic in origin.

Sydenham's chorea Purposeless, rapid, involuntary, nonrepetitive, jerky dance like movements. Milk maid grip. Lizard tongue. Raising of hand above the head. 5 – 35% pt. of RF Prior to puberty F>>>M, after puberty no male involvement. Risk of developing subsequent RHD is 50%.

Sydenham chorea No residual neurological deficit per se, psychiatric disturbances occur in a small no. of pts. Recurrence are common. PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection) also a manifestation GABHS but not associated with other features of RF.

Erythema marginatum 5 – 13% of RF Begin 1-3 cm, pink to red, nonpruritic, macule or papule. Trunk and proximal limb but never on face. Central clearing in serpegious fashion Exacerbate by heat. Also can seen in sepsis, drug reaction, glomerulonephritis, JRA, Lyme disease. Occur in conjunction with milder form of carditis. May lasts for months or years.

Closer view of erythema marginatum in the same patient

Subcutaneous nodules 0 – 8% of pt. of RF External surface of elbow, knee, ankles, knuckles, scalp and spinal process. Firm, nontender, free from attachment of underlying skin. Strongly support the severity of carditis Resolve within weeks to 1 or 2 months. Not diagnostic for rheumatic fever can seen with other autoimmune disorder.

Recommended test in case of possible acute rheumatic fever.. CBC ESR CRP BLOOD CULTURE ECG X-RAY CHEST PA VIEW 2D-ECHO THROAT SWAB CULTURE FOR GAS (gold standard) ASO TITRE (rising) much specific for RF

What are the treatment regimens of streptococcal sore throat?

Treatment of ARF First line of symptomatic therapy is antiinflammatory agent ranging from salicylates to steroid. Naproxen can be alternative for Aspirin. Bed rest in carditis pts. Effective antibiotic treatment acutely (starting less than 10 days.)almost completely eliminates risk of the dis.

Treatment Drug Name :Aspirin -- Begin administration immediately after diagnosis of RF. Initiation of therapy may mask manifestations of disease. Adult Dose: 4-8 g/d PO divided q4-6h; maintain aspirin levels in 20-25 mg/dL range until all symptoms have resolved and APRs have returned to normal

Treatment Drug Name: Prednisone -- Used in carditis and CHF. High-dose prednisone is administered for 2-3 wk, then tapered over 3 wk. IV corticosteroids are reserved for fulminant cases. Adult Dose :40-60 mg PO qd for 2-3 wk initially, then discontinue by gradual taper over 3 wk

Treatment Pediatric Dose :0.05-2 mg/kg PO qd for 2-3 wk initially, then discontinue by gradual taper over 3 wk Contraindications Documented hypersensitivity; viral infection; peptic ulcer disease; hepatic dysfunction; connective tissue infections; fungal or tubercular skin infections; GI disease

Treatment of GABHS Infection Benzathine 1.2 million U. One time Acutely penicillin G IM one Penicillin V 500 mg oral BD 10 days Amoxicillin 500 mg oral TDS 10 days Erythromycin 250 mg oral BD 10 days

Antibiotics The roles for antibiotics are to (1)initially treat GAS pharyngitis, (2) prevent recurrent streptococcal pharyngitis, RF, and RHD, and (3) provide prophylaxis against bacterial endocarditis.

Treatment Drug Name: Penicillin V -- DOC for treatment of GAS pharyngitis. Do not use tetracycline and sulfonamides to treat GAS pharyngitis. For recurrent GAS pharyngitis, a second 10-d course of same antibiotic may be repeated.

Treatment Drug Name: Benzathine /procaine penicillin -- Adult Dose: Eradication: 1.2 million U of benzathine penicillin G or a combination of 900,000 U of benzathine penicillin G with 300,000 U of procaine penicillin G IM as a single dose

Treatment Erythromycin -- Used for patients who are allergic to penicillin. Other options include clarithromycin, azithromycin, or a narrow-spectrum cephalosporin (ie, cephalexin). As many as 15% of penicillin-allergic patients also are allergic to cephalosporins.

Treatment Drug Name: Clarithromycin -- Alternate antibiotic for treating GAS pharyngitis in patients allergic to penicillin. Adult Dose: 250-500 mg PO bid for 10d Pediatric Dose: 7.5 mg/kg PO bid for 10 d

Treatment Drug Name: Azithromycin -- Alternate antibiotic for treating GAS pharyngitis in patients allergic to penicillin. Adult Dose :12 mg/kg (not to exceed 500 mg) PO qd for 5 d Pediatric Dose :Administer as in adults

Treatment Cephalexin -- Alternate antibiotic for treating GAS pharyngitis in patients allergic to penicillin. Adult Dose: 250-500 mg PO qid for 10d Pediatric Dose: 25-50 mg/kg/d PO divided qid for 10 d

Primordial prevention 1. Improvements in socioeconomic status. 2. Prevention of overcrowding. 3. Prevention of under nutrition and malnutrition.

Primary prevention

Effective eradication of GABHS from the pharynx define the role of primary prevention. Antibiotic Administration Dose Benzathine benzyl penicillin Single IM injection 1.2 MU > 30kg 600 000 U < 30 kg Phenoxymethyl penicillin (Pen VK) PO for 10 days 250-500mg qds for 10 days 125mg qds X 10 if <30 kg Erythromycin ethylsuccinate Use same dose as above. Oral penicillin is less efficacious than Penicillin IMI Anaphylaxis is extremely unusual

Secondary Prevention Stops sore throat, prevents recurrences of ARF and aids in regression of RHD Antibiotic Administration Dose Benzathine benzyl penicillin Single IM injection monthly 1.2 MU > 30kg 600 000 U < 30 kg Phenoxymethyl penicillin (Pen VK) BD PO daily 250-500mg bd Erythromycin ethylsuccinate BD po daily Use same dose as above. There is evidence to suggest that oral penicillin results in poorer rates of adherence and serum penicillin concentration may also be less predictable compared to intramuscular penicillin. The rate of anaphylactic reactions is about 0.2% with fatalities being extremely rare. Oral penicillin has been shown to be less effective than Penicillin IMI Anaphylaxis is extremely unusual

During an episode of ARF, valve changes can be minor and are still able to regress. After recurrent episodes of ARF, thickening of subvalvar apparatus, chordal thickening and shortening and progression to permanent valve damage is evident. This long axis parasternal images demonstrates the progression of valvular disease in the period between ARF and RHD. It is important to remember that timeous diagnosis, treatment and secondary prevention may in cases prevent this progression. The efficacy of echocardiographic criterions for the diagnosis of carditis in acute rheumatic fever. Vijayalakshmi IB, Vishnuprabhu RO, Chitra N, Rajasri R, Anuradha TV. Cardiol Young. 2008 Dec;18(6):586-92. Epub 2008 Oct 10

Secondary prevention: Duration CATEGORY DURATION OF PROPHYLAXIS All persons with ARF with no or mild carditis MINIMUM 10 years after most recent episode or age 21 All persons with ARF and moderate carditis MINIMUM 10 years after most recent episode or age 35 All persons with ARF and severe carditis MINIMUM 10 years after most recent episode or age 35 and then specialist review for need to continue. Post surgical cases definitely lifelong. Awareness ♦ Surveillance ♦ Advocacy ♦ Prevention

Secondary prevention: specifics PENCILLIN Secondary prophylaxis also reduces the severity of RHD. It is associated with regression of heart disease in approximately 50-70% of those with good adherence over a decade and reduces mortality. Route: BPG is most effective when given as a deep intramuscular injection. Rheumatic fever diagnosis, management, and secondary prevention: a New Zealand guideline. Atatoa-Carr P, Lennon D, Wilson N; New Zealand Rheumatic Fever Guidelines Writing Group. N Z Med J. 2008 Apr 4;121(1271):59-69. Review.

Secondary prevention: Adherence How can we reduce the pain associated with IM Penicillin? Use a 23-gauge needle- deeper is better Local pressure to area for 10 secs Warm syringe to room temperature First allow alcohol to dry or use ethylchloride spray .

Secondary prevention: Adherence Deliver injection very slowly(over 2-3mins) Distraction techniques Good rapport with the case, is a significant aid to injection comfort, compliance and understanding. Use 0.5-1ml of 1% lignocaine. Reduces pain significantly and excellent for younger patients.

Ensuring that patients understand their disease, are informed regarding their future and receive secondary prophylaxis EDUCATION Health education is critical at all levels Lack of parental awareness of the causes and consequences of ARF/RHD is a key contributor to poor adherence amongst children on long-term prophylaxis.

A.S.A.P. Programme for the Control of RHD in Africa: Focus areas for action Awareness raising: public, healthcare workers Surveillance: incidence, prevalence, temporal trends Advocacy: appropriate funding of the treatment and prevention programmes Prevention: application of existing knowledge in primary & secondary prevention Robertson KA et al SAMJ 2006:96:241-5 The PASCAR-driven( Pan-African Society of Cardiology) ASAP programme was launched in 2005 at a meeting in the Drakensberg and the Drakensberg declaration was published in 2006. This meeting brought together interested cardiologists and physicians from all over Africa dealing with rheumatic heart disease on a daily basis in an attempt to develop a method to eradicate rheumatic fever and rheumatic heart disease using a multi-pronged approach.

Summary Rheumatic heart disease is the only truly preventable chronic heart condition Primary prevention: Penicillin for suspected strep sore throat Secondary prevention Penicillin prophylaxis