[OS 213] LEC 10 Rheumatic Fever and RHD (B)

OS 213: Circulation and Respiration (Cardiovascular Module) LEC 08: RHEUMATIC FEVER and Rheumatic Heart Disease Quiz 1 | Dr. Sanchez-Acosta | July 25, 2012 OUTLINE I. Rheumatic Fever and Rheumatic Heart Disease A. Rheumatic Fever B. Rheumatic Heart Disease C. Epidemiology: RF & RHD D. Risk Factors II. Rheumatic Fever A. Pathogenesis of Rheumatic Fever B. Etiology C. Lab Test for GAS Tonsillopharyngitis D. ARF: Age & Sex Distribution E. Pathology

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F. Diagnosis: Jones Criteria 1992 G. Diagnosis: RF Modified Jones Criteria 1992 H. RF: Other Laboratory Exams I. Management III.Rheumatic Heart Disease A. Description B. Diagnosis C. Medical Management D. Disease Progression and Intervention E. Differentiating RF and RHD F. Management IV. Questions and Answers

RHEUMATIC FEVER AND RHEUMATIC HEART DISEASE Rheumatic Fever Most common cause of acquired heart disease in children, adolescents and young adults worldwide Pathology: diffuse inflammation of connective tissues of heart, joints, brain, blood vessels & subcutaneous tissues Rheumatic process, when it heals, causes fibrosis of heart valves leading to rheumatic heart disease (RHD) as a sequelae and onset depends whether it was detected early or not or treated early or not Relationship with Group A β-hemolytic Streptococcus established

Rheumatic Heart Disease  Chronic valvular heart disease as a sequelae of rheumatic fever (RF)  When recurrent RF causes scarring of the heart, it becomes Rheumatic Heart Disease (RHD) o Must have both the recurrence and the scarring to consider RHD as a sequelae of RF o Exactly when?  It depends on the patient  when in the continuum, did he/she sought intervention? does he/she take medication regularly, etc.

Epidemiology: RF and RHD

 Why?  they can afford a check-up because they have the money

Risk Factors  Risk factors for RF o Poverty o Poor housing, overcrowded housing o Reduced access to health care  Risk factor for RHD o Recurrent episodes of RF RHEUMATIC FEVER Pathogenesis of Rheumatic Fever  Actual mechanism unknown  Postulate: o Autoimmune or hypersensitivity reaction to Group A Strep (GAS) produces pathogenic autoantibodies to cardiac tissues o Anti-streptococcal antibodies made by the infected host cross-react with host connective tissue (ie. cardiac, pulmonary, synovial, peritoneal) antigens and lead to end-organ damage by an immunologic mechanism. o It is believed to be caused by antibody crossreactivity. This cross-reactivity is a Type II hypersensitivity reaction and is termed molecular mimicry. Usually, self-reactive B cells remain anergic in the periphery without T cell co-stimulation. During a Streptococcus infection, mature antigen presenting cells such as macrophages present the bacterial antigen to CD4T cells which differentiate into helper T 2 cells. Helper T2 cells subsequently activate the B cells to become plasma cells and induce the production of antibodies against the cell wall of Streptococcus. However the antibodies may also react against the myocardium and joints producing the symptoms of rheumatic fever.  Myocardial Aschoff’s Body/Nodule – focal inflammatory lesions in the heart; swollen eosinophilic collagen surrounded by lymphocytes and Anitshkow; cells are large, elongated, with large nuclei; some are multinucleate.

Table 1. Prevalence of RF and RHD in School Children Country Rate Developing countries 18.6 / 1000 Philippines 1971-1980 0.9 / 1000 1981-1990 0.6 / 1000 2010 0.5 / 1000 Developed countries USA 1971-1980 0.7 / 1000 Australia 1981-1990 12.3 / 1000 (because of aborigines)

Factors in the Development of Rheumatic Fever

 Philippines o In a study at the PGH (1986-1990), the peak incidence of RF and RHD is from 5-15 years old o Deaths from RF and RHD (Achutti & Achutti, 1992)  1% of cardiovascular death  200,000 cases/ year  Worldwide (World Heart Federation) o 15.6 million people affected worldwide o Almost 500,000 new cases each year o Approximately 350,000 deaths each year o Most occur in developing countries (for developed countries, this is already part of the grand rounds)

o Skin infection only leads to AGN but never RF  Persistence of virulent strain GAS organism  Antibody response  Age: usually at ages 5-15 because of exposure to school grounds  Genetic or familial tendency: specific B cell alloantigen (D817) & HLA identified (not yet proven)  Socio-economic status o Poverty, overcrowded housing, reduced access to health care  still the most common risk factor

JEREEL, SITTI, DAYAN

 Site of GAS infection o Throat → rheumatic fever (RF), sometimes acute glomerulonephritis (AGN) o If the patient complains to you of tonsillitis, ask yourself whether it is a viral infection or not o Check for presence of exudates

 No exudate does not mean no risk for RF  Exudate will usually appear after several days so reexamine the patient  If still no exudate, usually viral infection. If with exudate, consider risk for RF.  Features suggestive of viral etiology: conjunctivitis, coryza (inflammation of mucus membranes lining the nasal cavity), cough, diarrhea

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OS 213: Circulation and Respiration (Cardiovascular Module) LEC 08: RHEUMATIC FEVER and Rheumatic Heart Disease Quiz 1 | Dr. Sanchez-Acosta | July 25, 2012

o In the Philippines (and probably in other developing countries as well) we are capable of treating it; it is just that the patients do not have the money to seek consult Rheumatic Fever: Attack Rate  Strep, tonsillitis treated penicillin = 0.3%  Strep, tonsillitis, untreated = 3%  Known rheumatic patients with strep infection = 60%

Etiology  Relationship with Group A β-hemolytic Streptococcus established  Inflammation of pharynx and tonsils – patchy discrete exudates  Good thing it’s still sensitive to penicillin  Cell wall (virulence factors) o M-protein o Induces antibodies o Serotypes 5, 6 & 19 cross react with myosin  Enzymes o Streptolysin o Deoxyribonuclease o Fibrinolysin o Diphosphopyridine nucleotidase o Hyaluronidase

o Valuable for confirmation of previous streptococcal infections in patients suspected of having acute RF (ARF) or post-streptococcal glomerulonephritis (PSGN) o Helpful in prospective epidemiological studies for distinguishing patients with acute infection from patients who are carriers o A positive anti-streptococcal antibody titers does not necessarily mean that RF is present, Jones criteria must still be followed o cut-off: > 220 units  In summary, the Diagnosis of GAS Tonsillopharyngitis o Clinical & Epidemiological Findings o Laboratory test/s – throat culture and/or Rapid Antigen ARF: Age and Distribution  Most common in ages 5-15 years old  Rare in children less than 5 years old  In the Philippines, with regard to peak incidence, there are less than 5 cases who are aged 2-3 years old Pathology Exudative degenerative inflammatory lesions o Transient manifestations o Responds to anti-inflammatory agents  Proliferative lesions o Aschoff’s nodules 

 Areas of inflammation of the connective tissue of the heart, or focal interstitial inflammation  Fully developed: granulomatous structures consisting of fibrinoid change, lymphocytic infiltration, occasional plasma cells and characteristically abnormal macrophages (may fuse to form multinucleated giant cells) surrounding necrotic cells  Diagnostic for RF  Done on biopsy but today in RP, not done anymore.

Figure 1. Streptococcal Tonsillopharyngitis. Note the presence of patchy discrete exudates (“nana”) and the beefy-red color of the pharynx and tonsils which are characteristic of bacterial (versus viral) tonsillopharyngitis. Clinical & Epidemiological Finding & Diagnosis of GAS Tonsillopharyngitis 1.History of exposure 2.Patient aged 5–15 years 3.Sudden onset sore throat 4.Fever & Headache 5.Inflammation of pharynx and tonsils patchy discrete exudates 6.Presentation in winter or early spring 7.Tender, enlarged anterior cervical nodes 8.Nausea, vomiting, and abdominal pain Laboratory Test for GAS Tonsillopharyngitis  Throat swab and culture (gold standard) o Standard for documentation of GAS in upper respiratory tract & for confirmation of clinical diagnosis of acute strep pharyngitis o If done correctly – sensitivity of 90-95% o Disadvantage – there is delay (after about 48 hours) in obtaining the result  Rapid Antigen Detection Tests (RADT) – but this is very expensive so not done anymore  Anti-streptococcal Antibody Titers (done in PGH) o Can reflect past but not present immunologic events o No value in the diagnosis of acute pharyngitis

JEREEL, SITTI, DAYAN

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Persists for many years

Diagnosis: Jones Criteria 1992  Establish initial attack of acute rheumatic fever  Not intended o To establish diagnosis of inactive or chronic RHD o To measure rheumatic activity o To predict course or severity of disease  Previous RF or RHD not included as manifestation  Major Manifestations o Carditis – most common among hospitalized patients o Polyarthritis – most common manifestation overall (migratory) o Chorea o Erythema marginatum (least common) o Subcutaneous nodule  Minor Manifestations o Fever (high-grade, should last for at least 5 days) o Arthralgia o Increased acute phase reactants: elevated erythrocyte sedimentation rate (ESR) and Creactive protein (CRP) o Prolonged PR interval via ECG test will cause 1 st degree AV block How to Use Jones Criteria  There is a high probability of RF when the patient has o 2 major manifestations, or o 1 major and 2 minor manifestations plus supporting evidence of preceding GAS infection (always!)

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OS 213: Circulation and Respiration (Cardiovascular Module) LEC 08: RHEUMATIC FEVER and Rheumatic Heart Disease Quiz 1 | Dr. Sanchez-Acosta | July 25, 2012

o GAS infection: through (1) antibody sensing and (2) streptococcal culture – gold standard o Note: manifestations should be two unrelated symptoms such as if you use polyarthritis as major criterion, you cannot combine it with arthralgia as minor and carditis with prolonged PR interval o Exception to the rule: Chorea! WHY? Must have vasculitis to affect the brain which would take months to come up. By the natural history of diseases, everything else might have disappeared at the time of consultation. Major Manifestation 1: Rheumatoid Carditis  worst sequela and the only symptom that is not selflimiting  Valvulitis – means ‘leaky valves’ o Most common manifestation and the most severe o Almost always present o Primary valvular involvement o Pancarditis – involves all layers of the heart (like Kawasaki disease) o Mnemonic: MATP (Mitral, Aortic, Tricuspid and Pulmonic) in order of being affected the most  Cardiomegaly o not present in mild carditis  Resting tachycardia – know if the resting tachycardia is due to fever or carditis o Usually associated with fever o General rule in children: an increase of one degree Celsius in temperature corresponds to an increase of heart rate by 10 beats per minute  Pericardial friction rub o Once pericardial effusion is present, no more sound o Usually seen in post-op patients or usually very early in a disease  Congestive heart failure o gallop rhythm (S3) o muffled heart sounds o arrhythmia o Edema in both L and R o For R: pulmonary edema

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Rapid healing without sequelae o in contrast with Juvenile Rheumatoid Arthritis which is prolonged and can cause deformities  Usually resolves in 38oC  Arthralgia

o Diagnostic:

 ECG – PR interval is prolonged suggesting 1o AV block  Increased acute phase reactants: ESR & CRP are increased  Complete Blood Count (CBC) and Chest X-Ray (CXR) not specific to RF

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RF: Other Laboratory Exams  CBC o Anemia (hemolysis and dilutional anemia due to heart failure) o Leukocytosis (inflammation, infection)  ECG o Sinus tachycardia o 1o AV block—prolonged PR interval o No chamber enlargement (as opposed to RHD) o Rarely 2o AV block, low voltages, ST-T wave changes  CXR o Normal (but may depend on severity of valvular lesion) o Cardiomegaly o Pulmonary congestion and edema Management  Prophylaxis  Anti-inflammatory agents

Durati on Once

Oral

10 d

Oral

10 d

20-40 mg/kg/d

Oral

10 d

2-4 x /day (max: 1g/d)

Oral

10 d

40 mg/kg/d 2-4 x daily (max: 1g/d)

Oral

10 d

600,000 U for patients ≤ 27 kg 1,200,000 U for patients ≤ 27 kg Children: 250 mg 2-3x/day Adolescents/adults: 500 mg 2-3x/day

500 mg on first day Oral 5d 250 mg/d for the next 4 d Bonow et al., ACC/AHA TASK FORCE REPORT JACC Vol. 32, No. 5, Nov 1998: 1486-1588ACC/AHA Guidelines for the Management of Patients WithValvular Heart Disease

 Secondary Prophylaxis : prevents recurrences of RF o Penicillin (PCN) VK 250 mg twice daily o Benzathine PCN 1.2 M units every 21 days best choice because long acting, cost effective and due to good compliance; administered via the intramuscular route or depot because this makes the levels in the blood constant  for Filipinos: every 21 days because penicillin levels go down after 21 days  Short acting benzyl penicillin  Oral penicillin - 2x a day for 10 days (important to stress compliance with the number of days the antibiotic is administered to ensure that the microorganism will be completely eradicated)  Azithromycin - given only for 5 days

o Duration of recurrence)

 Primary prophylaxis : prevents 1st episode of RF

2o prophylaxis (or prevention of

 Arthritis - minimum of 5 years or until age 21 whichever is longer assuming no recurrence of the disease between 5-21 years. If there is recurrence, add more 5 years from last onset.  Carditis - at least 10 years assuming recurrence free & no residual heart disease or 21 whichever is longer  if RHD, long-term prophylaxis because of scarring  if both are present, choose the long-term so treat carditis!

Table 4. Secondary Prevention of Rheumatic Fever Agent Benzathine Penicillin G

Prophylaxis

JEREEL, SITTI, DAYAN

Mod e IM

Azithromycin

 Notes minor manifestations o Clinical vs Diagnostic

 Jones Criteria 1992, Supporting Evidence Antecedent Group A Streptococcal Infection o Positive throat culture or rapid antigen test o Elevated or rising Streptococcal antibody titer

For people allergic to Penicillin: Erythromycin

Dose

Penicillin V

Dose 1,200,000 U every 21 days for Filipinos (very important!!!!!!) (every 3 wk for high risk patients such as those with residual carditis) 250 mg 2x/day

UPCM 2016 B: XVI, Walang Kapantay!

Mode IM

Oral

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Sulfadiazine

OS 213: Circulation and Respiration (Cardiovascular Module) LEC 08: RHEUMATIC FEVER and Rheumatic Heart Disease Quiz 1 | Dr. Sanchez-Acosta | July 25, 2012 0.5 g once daily for patients ≤ 27 kg 1.0 g once daily for patients ≥ 27 kg

Oral

For people allergic to penicillin and sulfadiazine: Erythromycin 250 mg twice daily Oral *High-risk patients include those with residual rheumatic carditis as well as patients from economically disadvantaged populations.

Table 5. Duration of Secondary Prophylaxis Group ARF (no carditis) Mild-moderate carditis (or healed carditis)

Duration of Secondary Prophylaxis Minimum of 5 years after last ARF, or Until age 21 years whichever is longer Minimum of 10 years after last ARF, or Until age 25 years (whichever is longer) Continue for life

Severe RHD; after surgery a 2007 World Health Federation b We start counting the duration of prophylaxis WHEN rheumatic fever is cured c For carditis, you start counting 10 years from the time the heart was cleared from carditis d In the Philippines, the cut off age is 21 years

Anti-inflammatory Agents  For 6-8 weeks o prednisone – 2 mg/kg/day o aspirin – 100 mg/kg/day  plus complete bed rest for at least 3 months for severe carditis (may even stop schooling)

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RHEUMATIC HEART DISEASE Description Heart disease as a sequelae of chronic RF and its recurrences Heart valves are scarred due to healing process following ARF RHD is more likely to develop following ARF if o The initial episode of ARF was severe o The heart was affected with ARF o ARF occurred at a young age o There has been recurrent ARF 50% of people with RHD do not remember having ARF because some symptoms are self-limiting Valve Regurgitation suggests that heart valves o Are thickened and stick against the walls of the heart o Leakage (the blood flows backwards over the valve) Valve Stenosis suggests that heart valves o Become stiff o Do not allow blood to flow through easily (restricted forward flow)

Diagnosis Clinical history and physical examination Blood examinations (CBC, ESR, Anti-Strep Antibody Titers, CRP, blood culture study) & urinalysis  ECG and CXR  Echocardiography: TTE (transthoracic), TEE (transesophageal)  

Mitral Regurgitation 

a pansystolic murmur heard loudest at the apex and radiating laterally to the axilla; soft S1

JEREEL, SITTI, DAYAN

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Why does it radiate to the axilla?  the left atrium is the most posterior chamber of the heart  Most common o ECG - normal; LAE, LVH o CXR - normal; LAE, LVH; pulmonary congestion o Echo - thickened valve; dilated MV annulus; ECGNormal; LAE, LVH Mitral Stenosis  low-pitched, diastolic rumble heard best at the apex with the bell of the stethoscope and with the person lying in the left lateral position.  Once the mitral valve is damaged, when the patient is cured it can return to its normal state  When the aortic valve is damaged, it cannot return to its original state, it’s forever damaged o In 10-30% of cases o Produces a thrill upon PE; though not all do  ECG - Normal; LAE, RVH  CXR - LAE, RVH; Pulmonary congestion; Dilated MPA  Echo - Thickened fixed leaflets; Small MVA (fishmouth commisure)  History of CHF, RVF

Aortic Regurgitation  a diastolic blowing decrescendo murmur best heard at the left sternal border with the person sitting up and leaning forward in full expiration  ECG - LVH; Strain pattern  CXR - LVH; Dilated aorta  Echocardiogram - thickened leaflets with prolapsed  Heave indicative of volume overload  Fibrosis and contracture of the aortic valve  Regurgitation across incompetent valve, increase in LV volume, aortic run-off  LV dilation decreased myocardial contractility  Rarely isolated (bicuspid aortic valve if isolated); usually with MR  Prominent carotid pulse  Corrigan’s pulse  Natural History: CHF, chest pain (in AR vs MR), infective endocarditis o Ischemic AR less coronary perfusion during diastole Others     

Aortic stenosis: not common; if there is, then it’s most probably congenital Tricuspid regurgitation Tricuspid stenosis: rare (least common) Pulmonary regurgitation: related to pulmonary hypertension Pulmonary stenosis: very rare

Summary of ECG and CXR 

ECG Normal if lesions are mild MR: LAE, LVH MS: LAE, RVH AR: LVH TR: RAE, RVH  Chest X-Ray o Pulmonary venous congestion; chronic & severe lesions o o o o o

dilated

MPA

if

Medical Management  Anti-CHF

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OS 213: Circulation and Respiration (Cardiovascular Module) LEC 08: RHEUMATIC FEVER and Rheumatic Heart Disease Quiz 1 | Dr. Sanchez-Acosta | July 25, 2012

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o ionotropes (dopamine); diuretics and ACE inhibitors; β-blockers only if with arrythmia 2o prophylaxis Benzathine penicillin- 21 days Infective Endocarditis prophylaxis o antibiotics Anticoagulant (coumadin) so that there will be no thrombus Arrhythmia management Surgical o MR - Valvuloplasty, annular placation, valve replacement o MS – Commisurotomy o AR - Valvuloplasty or valve replacement Remember: o If porcine valves used, need to be replaced later in life due to calcifications o If pediatrics patient, primary drug to give are diuretics because it will relieve pulmonary causes of RHD (remember, children rely more on breathing for survival) o MI in children mainly due to pulmonary congestion Disease Progression and Intervention Primary Prophylaxis

END OF TRANSCRIPTION

Ate Dayan:  Sitti: Hello everyone. Watch out for RF. Baka nagkaron kayo ng symptoms nung bata pero di nyo lang matandaan. Hala… Joke lang, don’t be paranoid. Guys watch Bourne Legacy, hindi ko alam kung maganda, promote lang dahil shinoot sa Manila. RSO and MSSR are selling tickets for the benefit of a very unfortunate elementary school and Unang Yakap Program  Jereel: Babawi ako sa greeting dahil nakalimutan ko sa first trans namin. hahaha. Anyway, hi 2016! helLU4 na! Sana okay pa tayong lahat. Hi Block A friends kung mababasa ninyo ‘to. And syempre, hello Block B! Ang toxic ng cardio pero sana kayanin natin!  MSSR-IPPNW go! Kung interested kayo, pwede pa mag-apply. Wag kayong matakot, sobrang mababait kami. heehee. Nood nga pala kayo ng block screening ng Bourne Legacy by MSSR and RSO! woohoo! Hello sa Mangotukola! I miss y’all and our toxic days NOT. haha. Hello to my new seatmate Tato. Hello bestie Allie!  Hello nga pala kay Niko! Nami-miss na kita. Wala na kong kinikiliti. Wag masyadong malandi ah. Ikaw na bahalang maghanap ng MTTh sched niya. hahaha.  Hoy Clintaba! Wag kang mag-IPad forever. Umayos ka! hihi. Hoy Jim! Naiintindihan ko na hindi tayo mag-seatmate dahil busy ka. Sinusuportahan kita dyan pero hinay-hinay lang ha! ;) Heya virGinnie! AlexeisCelina(block A ), coffee shop review na! Oi Jer, kumusta ang mebendazole mo? haha. Good luck sa atin sa cardio. Kayanin natin ang lahat ng transes! 

Jones Criteria, 20 Prophylaxis Tertiary Prophylaxis

Medication of Penicillin only

Figure 4. Summary of the Lecture (Important!)

Differentiating RF and RHD Table 5. Differences Between RF and RHD

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Management Education (most important) o you really have to make them understand their situations especially the parents and unruly adolescents Adherence to secondary prophylaxis Regular clinical assessment and follow-up echocardiography Management of cardiac failure Management of atrial fibrillation Dental care and Infective endocarditis prophylaxis Family planning referral (for women) Vaccination Appropriate surgical intervention

QUESTIONS AND ANSWERS  Indications for tonsillectomy o repeated acute tonsillitis with treatment for a year o obstructive apnea  We still don’t know yet if there is a genetic factor but there is a familial predisposition

JEREEL, SITTI, DAYAN

RF

RHD

History (not always useful)

symptoms occur early, usually in younger population

can be initially asymptomatic but is actually chronic: usual in adults but not always

CXR

Valvular lesions

Valvular lesions; with pulmonary artery hypertention (dilated vessels)

PE

No chronic heart disease

Precordial bulge

ECG

No tachycardia, chamber enlargement

Prognosis

Px, heart structures return to normal

Valvular disease which is lifetime

UPCM 2016 B: XVI, Walang Kapantay!

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