Rheumatic Fever Tres

RHEUMATIC FEVERSarva Rickhi Anjanie MaharajH ViviOn Bissoon

DefinitionRheumatic fever is a systemic inflammatory disease affecting the peri-arteriolar connective tissues and can occur after an untreated Group A Beta haemolytic streptococcal pharyngeal infection.

ETIOLOGY

Etiology 2/3 with acute rheumatic fever have Hx of an URTI several weeks before. Peak age and seasonal incidence of acute rheumatic fever closely parallel those of GAS infections Patients with rheumatic fever almost always have serologic evidence of a recent GAS infection

Etiology (contd) Outbreaks in GAS pharyngitis in closed communities may be followed by outbreaks of acute rheumatic fever Antimicrobial therapy that eliminates GAS from the pharynx also prevents initial episodes of rheumatic fever Long term continuous prophylaxis that prevents GAS pharyngitis also

Etiology (contd) Not all serotypes of GAS can cause rheumatic fever M type 4 strain, when present in a susceptible population, no recurrences of rheumatic fever occurred. Serotypes most frequently involved with rheumatic fever are M types 1, 3, 5, 6, 18

EPIDEMIOLOGY

Epidemiology Rheumatic heart disease remains the most common form of acquired heart disease in all age groups (50% of all cardiovascular disease and as much as 50% of all cardiac admissions in many developing countries) Differences among different ethnic groups within the same country; some are related to differences in socioeconomic status. A number of studies have suggested that, of the various manifestations of poverty, crowding, which contributes to the spread of GAS infections, is the

Epidemiology (contd) In the US, at the beginning of the 20th century, rheumatic fever was a leading cause of death among children and adolescents (100200/100,000 population) By 1940s, annual incidence decreased to 50/100,000; Decline in incidence accelerated rapidly; by early 1980s, incidence as low as 0.5/100,000

Epidemiology (contd) Explanation for decline in incidence not entirely clear; Decline in incidence during preantibiotic area probably attributed to improvements in living conditions. Further decline in ARF (in 1980s) can be attributed to the greater availability of medical care and widespread use of antibiotics.

Epidemiology (contd) Incidence of initial attacks and recurrences of RF peaks in children 515yrs of age; the age of greatest risk for GAS pharyngitis. Patients with one RF attack tend to have recurrences; C/F mimic initial attack Genetic predisposition to RF Twins Studies: higher concordance rate of RF in monozygotic than dizygotic twin pairs Possible association between presence of specific HLA markers and a specific

PATHOGENESIS

Pathogenesis Pathogenic Link between a GAS infection of URTI and an attack of RF not entirely clear Several theories are proposed but only two are seriously considered: The Cytotoxicity Theory The Immunologic Theory

Pathogenesis (contd) The Cytotoxicity Theory GAS toxin may be involved GAS produces several enzymes that are cytotoxic for mammalian cardiac cells Stretolysin O direct cytotoxic effect on mammalian cells in tissue culture

Major Problem with this theory is its inability to explain the latent period between GAS pharyngitis

Pathogenesis (contd) Immunologic Theory Suggested by similarity of RF to other illnesses produced by immunopathologicprocesses The antigenicity of a large variety of GAS products and constituents, as well as the immunologic cross reactivity between GAS components and mammalian tissues, also lends support to this hypothesis. GAS (M protein, protoplast membrane, cell wall group A carbohydrate, capsular hyaluronate)

Pathogenesis (contd)

Cross reactivity Type II Hypersensitivity reaction mature APC present bacteria to CD4 T cells differentiate into Helper T2 Cells activate self reactive B cells plasma cells production of antibodies against GAS antibodies also react against self tissue (molecular mimicry)

DIAGNOSIS AND CLINICAL MANIFESTATIONS

Diagnosis No clinical or laboratory finding is pathognomonic for RF Jones Criteria Only intended for Dx of initial attacks and NOT for recurrences There are 5 major and 4 minor criteria and an absolute requirement for evidence (microbiologic or serologic) of recent GAS infection

Guidelines for the Diagnosis of Initial Attack of Rheumatic Fever (Jones Criteria, Updated 1992)From Jones criteria, updated 1992. JAMA 1992;268:20692073. Copyright American Medical Association.

MAJOR MANIFESTATIONS[*] Carditis Polyarthritis

MINOR MANIFESTATIONS Clinical features: Arthralgia Fever

SUPPORTING EVIDENCE OF ANTECEDENT GROUP A STREPTOCOCCAL Positive throat culture or INFECTION rapid streptococcal antigen test Elevated or increasing streptococcal antibody titer

Erythema marginatum Subcutaneous nodules

Laboratory features: Elevated acute phase reactants: Erythrocyte sedimentation rate,C-reactive protein Prolonged PR interval

Chorea

Diagnosis (contd) Diagnosis of RF can be established by the Jones criteria when a patient fulfills 2 Major Criteria (and meets the absolute requirement) OR 1 Major Criteria and 2 Minor Criteria (and meets the absolute requirement)

Even with strict application of Jones Criteria, overdiagnosis as well as underdiagnosis may occur

Diagnosis (contd) Three Circumstances in which diagnosis of RF can be made without strict adherence to Jones Criteria: Chorea may be sole manifestation

Indolent Carditis May be sole manifestation

Recurrences of ARF Although most patients with recurrences fulfill JC, some may not

CLINICAL MANIFESTATIONS

Carditis Most serious manifestation of RF and accounts for essentially all of the associated morbidity and mortality. Occurs in about 50-60% of all cases of RF. Characterized by pancarditis, with active inflammation of the myocardium, pericardium and endocardium Varies in severity from fulminant, potentially fatal exudative pancarditis to mild, transient cardiac involvement

Carditis Endocarditis (valvulitis), which manifests by 1 or more cardiac murmurs is a universal finding Presence of pericarditis or myocarditis variable Without evidence of endocarditis: rarely due to rheumatic heart disease.

Most involved mitral VD or combined mitral and aortic VD; isolated aortic

Carditis Acute rheumatic carditis usually presents as tachycardia and cardiac murmurs Moderate to severe rheumatic carditis can result in cardiomegaly, CHF with hepatomegaly and peripheral and pulmonary oedema. ECHO findings - pericardial effusion, decreased ventricular contractility, and aortic and/or mitral regurgitation. Echocardiographic demonstration of valvular regurgitation without accompanying auscultatory evidence

Carditis Recurrent attacks of acute rheumatic fever in patients who had carditis with the initial attack are associated with high rates of carditis Major consequence of ARC is chronic, progressive valvular diseases

Migratory Polyarthritis Occurs in 75% of patients with ARF Typically involves larger joints; particularly the knees, ankles, wrists and elbows Uncommonly - Spine involvement, small joints of hands and feet or hips In most cases, not deforming

Migratory Polyarthritis Rheumatic joints are generally hot, red, swollen and delicately tender (friction of bed with clothes uncomfortable) Joint involvement is characteristically migratory in nature May persist for several weeks in untreated patients Monoarticular arthritis in unusual; unless anti inflammatory therapy

Migratory Polyarthritis If suspected, it is useful to withhold salicylates and observe for migratory progression Dramatic response to small doses of salicylates is another characteristic feature of arthritis Absence of such a response suggest an alternative diagnosis

Synovial Fluid in ARF (usually): 10,000-100,000 WBC/mm3 (mostly neutrophils) Protein approx 4g/dL Normal glucose

Migratory Polyarthritis Frequently, arthritis is the earliest manifestation of ARF May correlate temporally with AntiStreptococcal Antibody Titers Inverse relationship between severity of arthritis and severity of cardiac involvement.

Sydenhams Chorea Occurs in about 10-15% of patients with RF Usually presents as an isolated, subtle, neurologic behaviour disorder. Emotional lability incoordination, poor school performance, uncontrollable movements, facial grimacing exacerbated by stress and disappearing on sleep (characteristic)

Can be bilateral (mostly) or unilateral

Chorea Clinical manoeuvers to elicit features of chorea include: Demonstration of milkmaids grip Spooning and pronation of hands when patients arms are extended Wormian darting movements of tongue upon protrusion Examination of handwriting to examine fine motor movements

Chorea Diagnosis based on clinical findings with supportive evidence of GAS Antibodies However, due to long latent period, antibody levels may have declined to normal Rarely, if ever, leads to permanent neurologic sequelae.

Erythema Marginatum Rare - < 3% of patients with ARF Characteristic rash Erythematous, serpiginous, macular lesions with pale centers that are not pruritic Primarily on the trunk and extremities (not on face) Can be accentuated by warming the skin

Subcutaneous Nodules Rare (< 1% of patients of ARF) Consists of firm nodules Approximately 1cm in diameter Along the extensor surfaces of tendons near bony prominences

Correlation between the presence of nodules and significant rheumatic heart disease

Minor Manifestations Clinical Arthralgia In the absence of polyarthritis as a major criterion

Fever typically temperature 102F and occurring early in the course of illness

Laboratory Elevated Acute Phase Reactants Eg. CRP, ESR

Prolonged PR Interval on ECG (1st heart block) Does not consititute evidence of carditis or predict long term cardiac sequelae.

RECENT Group A Strep Infection Its evidence is an absolute requirement RF typically develops 2-4wk after an acute episode of GAS pharyngitis Clinical findings no longer present 10-20% of throat culture or rapid streptococcal Ag test are +ve 1/3 of patients have no Hx of prior pharyngitis

Evidence of antecedent GAS infection usually based on elevated or increasing serum antistreptococcal antibody titers. A slide agglutination test (Streptozyme) has been introduced Detects antibodies against 5 different GAS antigens Rapid, simple to perform, widely available Less standardized and less reproducible

When ARF is suspected clinically, multiple antibody tests are performed If only single antibody is measured (usually antistreptolysin O) only 8085% or patients with ARF have an elevated titer If 3 different antibodies (antistreptolysin O, anti-DNase B, antihyaluronidase) 95-100% with ARF have elevated titers.

Clinical findings of RF generally coincide with peak antistreptococcal antibody responses (except patients with chorea) Diagnosis of ARF should not be made in patients with elevated streptococcal antibody titers who do not fulfill Jones Criteria

DIFFERENTIAL DIAGNOSES

Differential Diagnoses Includes Infectious and NonInfectious Illnesses Children who present with arthritis; consider a collagen vascular disease. SLE vs ARF presence of ANA in SLE Rheumatoid Arthritis vs Acute Rheumatic Fever

Other causes of arthritis, such as gonococcal arthritis, malignancies, serum sickness, Lyme disease, sickle cell disease, and reactive arthritis related to gastrointestinal infections (e.g., Shigella, Salmonella, Yersinia) should also be considered.

RHEUMATOID ARTHRITIS ACUTE RHEUMATIC FEVERYounger age group Less joint pain (relative to other clinical findings) Older age group More joint pain (relative to other clinical findings)

Suggestive features: spiking fevers, lymphadenopathy, splenomegaly

Suggestive features: More dramatic response to salicylate therapy

Differential Diagnoses (contd) Carditis Viral myocardits, viral pericarditis, Kawasaki disease, infective endocarditis

Infective endocarditis may present with both joint and cardiac manifestations Distinguished from ARF by blood cultures and presence of associated findings (e.g. haematuria, splenomegaly, splinter haemorrhages.)

Absence of auscultatory evidence of a significant murmur excludes the diagnosis of acute rheumatic

Differential Diagnoses (contd) Chorea Huntington chorea, Wilson disease, systemic lupus erythematosus, and various encephalitides

Differential Diagnosis of Acute Rheumatic FeverARTHRITISRheumatoid arthritis Reactive arthritis (e.g., Shigella, Salmonella, Yersinia) Serum sickness Sickle cell disease Malignancy Systemic lupus erythematosus Lyme disease (Borrelia burgdorferi) Gonococcal infection (Neisseria gonorrhoeae)

CARDITISViral myocarditis Viral pericarditis

CHOREAHuntington chorea Wilson disease

Infective endocarditis

Systemic lupus erythematosus Kawasaki disease Cerebral palsy Congenital heart disease Tics Mitral valve prolapse Hyperactivity Innocent murmurs

TREATMENT

Treatment of Rheumatic Fever General Antibiotic therapy Anti-inflammatory therapy Migratory polyarthritis Carditis/CHF Sydenham Chorea

TreatmentGeneral All patients should be on bed rest and monitored closely for carditis

Patients with chorea should be placed in a safe environment

These restrictions can be relaxed as soon as acute inflammation has subsided and there is no carditis

Carditis patients should be on bed rest for 4

Antibiotic Therapyv Eradication of pharyngeal streptococcal infection. v Initiated once diagnosis has been made, regardless of throat cultures.

Penicillin/Erythromycin Oral 10 days

OR

Benzathine Penicillin Single IM injection

NOTE: Antibiotic therapy does NOT alter the course, frequency and severity of cardiac involvement.

Anti-Inflammatory TherapyvMigratory Polyarthritis Oral salicylates (aspirin) Dosage: 100 mg/kg/day in 4 doses PO for 3-5 days 75 mg/kg/day in 4 doses PO for 4 weeks

Therapy should only be started after diagnosis is established as it may obscure the migrating aspect of the polyarthritis, key to the diagnosis.

NB:

vCarditis without cardiomegaly/CHF Same treatment as migratory polyarthritis

vCarditis with cardiomegaly/CHF Prednisone Dosage: 2 mg/kg/day in 4 doses for 23 weeks Tapering: reduce dose by 5 mg/day every 2-3 days Aspirin: 75 mg/kg/day in 4 doses for 6 weeks

vCarditis with cardiomegaly/CHF

Supportive therapy Digoxin Fluid and salt restriction Diuretics eg. ACE inhibitors Oxygen

Termination of AntiInflammatory Therapy May result in a rebound of clinical manifestations and laboratory abnormalities Usually resolve spontaneously If severe symptoms- hospitalisation and reinstitution of salicylates or steroids as necessary

vSydenhams Chorea Considered to be a benign self limiting disease Usually requires no therapy

Phenobarbitol may be helpful 16-32 mg every 6-8 hrs

Haloperidol 0.01-0.03mg/kg/24hrs

Chlorpromazine 0.5 mg/kg/24hrs

COMPLICATIONS

Complications Infective Endocarditis

Valvular heart disease Aortic stenosis Aortic regurgitation Mitral regurgitation Mitral stenosis

Complications Infective Endocarditis Patients with cardiac valvular disease 2 to RHF Develops during episodes of transient bacteremia Prophylaxis Required for any invasive procedure Good dental hygiene is strongly recommended

Prophylaxis Regimes Standard Amoxicillin: 2g PO 1 hr before procedure

Non-penicillin allergic patients unable to take oral medication Ampicillin: 2g IM/IV 30min before procedure

Penicillin allergic patients 1 hr before procedure Clindamycin 600 mg PO Azithromycin/Clarithromycin 500mg PO

Penicillin allergic patients unable to take oral medication 30 min before procedure Clindamycin 600 mg IV Cefazolin 1g IV/IM

PROGNOSIS

Prognosis Depends on Clinical manifestations at initial episode Severity of initial episode Presence of recurrences

Risk of recurrence is highest immediately after initial episode & decreases with time

70% of patients with carditis recover without residual heart disease

Patients without carditis rarely have recurrences with carditis

Patients with carditis tend to recur with carditis, increasing the risk of permanent heart damage each time

Factors influencing recurrence of RF Age Prescence of Rheumatic Heart Disease Time elapsed from last attack Number of previous attacks Degree of crowding in the family A family history of RF/RHD Socioeconomic & educational status Risk of streptococcal infection in the area Willingness of patient to receive

Acute Rheumatic Fever leaves the patient susceptible to recurrent attacks after reinfection of the pharynx with Group A Streptococci

Therefore long term prophylaxis is necessary, even in patients with chorea as the only manifestation 20% of pure chorea patients developed rheumatic heart disease within 20 years.

PREVENTION

Primary Prevention Definition Adequate antibiotic therapy of group A streptococcal upper respiratory tract infections to prevent an initial attack of acute Rheumatic Fever

Administered only when there is GAS URTI Therapy is intermittent Patient factors to be considered in diagnosis in patients < 15 yrs History of fever Tonsillar swelling or exudate Tender anterior cervical lymphadenopathy Absence of cough

Antibiotic therapy started within 9 days of onset of symptoms eradicates Group A Streptococci and prevents Rheumatic Fever

Group A Streptococci remains sensitive to penicillin therefore it is the drug of choice

Penicillin V or Penicillin G for 10 full days OR Single dose of IM benzathine benzylpenicillin

Secondary Prevention Definition The continuous administration of specific antibiotics to patients with a previous attack of Rheumatic Fever, or a well documented Rheumatic Heart Disease

Purpose- to prevent colonisation or infection of upper respiratory tract by Group A Streptococci and the development of recurrent attacks of Rheumatic Fever

Mandatory for all patients who have had an attack of Rheumatic Fever, regardless of any residual valvular heart disease

ReferencesWHO Expert Consultation on Rheumatic Fever and Rheumatic Heart Disease, Geneva 2001.

Feigin, Textbook of Pediatric Infectious Diseases Nelsons Textbook of Pediatrics Abbas and Lechtman.Basic Immunology: