Rheumatic fever is an inflammatory disease that occurs following a Group A streptococcal infection, (such as strep throat or scarlet fever). Believed to be caused by antibody cross-reactivity that can involve the heart, joints, skin, and brain, the illness typically develops two to three weeks after a streptococcal infection. Acute rheumatic fever commonly appears in children between the ages of 5 and 15, with only 20% of first-time attacks occurring in adults. The illness is so named because of its similarity in presentation to rheumatism.

Pathophysiology- Rheumatic fever is a systemic disease affecting the peri-arteriolar connective tissue and can occur after an untreated Group A Beta hemolytic streptococcal pharyngeal infection. It is believed to be caused by antibody cross-reactivity. 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 Strep. infection, mature antigen presenting cells such as B cells present the bacterial antigen to CD4-T cells which differentiate into helper T2 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.

Group A streptococcus pyogenes has a cell wall composed of branched polymers which sometimes contain M protein that are highly antigenic. The antibodies which the immune system generates against the M protein may cross react with cardiac myofiber protein myosin,heart muscle glycogen and smooth muscle cells of arteries, inducing cytokine release and tissue destruction. However, the only proven cross reaction is with perivascular connective tissue. This inflammation occurs through direct attachment of complement and Fc receptor-mediated recruitment of neutrophils and macrophages. Characteristic Aschoff bodies, composed of swollen eosinophilic collagen surrounded by lymphocytes and macrophages can be seen on light microscopy. The larger macrophages may become Aschoff giant cells. Acute rheumatic valvular lesions may also involve a cell-mediated immunity

reaction as these lesions predominantly contain T-helper cells and macrophages.

In acute RF, these lesions can be found in any layer of the heart and is hence called pancarditis. The inflammation may cause a serofibrinous pericardial exudates described as “bread-and-butter” pericarditis, which usually resolves without sequelae. Involvement of the endocardium typically results in fibrinoid necrosis and verrucae formation along the lines of closure of the left-sided heart valves. Warty projections arise from the deposition, while subendothelial lesions may induce irregular thickenings called MacCallum plaques.

Chronic rheumatic heart disease is characterized by repeated inflammation with fibrinous resolution. The cardinal anatomic changes of the valve include leaflet thickening, commissural fusion and shortening and thickening of the tendinous cords. Rheumatic heart disease at autopsy with characteristic findings (thickened mitral valve, thickened chordae tendineae, hypertrophied left ventricular myocardium).

Etiology- Acute rheumatic fever (ARF) has been linked definitively with a preceding streptococcal infection,

usually of the upper respiratory tract. Evidence is very strong that the M protein in certain streptococci subtypes is responsible for antigenicity.

Clinical

History- Acute rheumatic fever (ARF) is associated with 2 distinct patterns of presentation.

The first pattern of presentation is sudden onset. It typically begins as polyarthritis 2-6 weeks after streptococcal pharyngitis and is usually characterized by fever and toxicity.

If the initial abnormality is mild carditis, ARF may be insidious or subclinical.

Age at onset influences the order of complications. Younger children tend to develop carditis first, whereas older patients tend to develop arthritis first.

Physical-Modified Jones criteria were first published in 1944 by T. Duckett Jones, MD.They have been periodically revised by the American Heart Association in collaboration with other groups. According to revised Jones criteria, the diagnosis of rheumatic fever can be made when two of the major criteria, or one major

criterion plus two minor criteria, are present along with evidence of streptococcal infection. Exceptions are chorea and indolent carditis, each of which by itself can indicate rheumatic fever.

Major criteria

Migratory polyarthritis: a temporary migrating inflammation of the large joints, usually starting in the legs and migrating upwards.

Carditis: inflammation of the heart muscle which can manifest as congestive heart failure with shortness of breath, pericarditis with a rub, or a new heart murmur.

Subcutaneous nodules: painless, firm collections of collagen fibers over bones or tendons. They commonly appear on the back of the wrist, the outside elbow, and the front of the knees.

Erythema marginatum: a long lasting rash that begins on the trunk or arms as macules and spreads outward to form a snake like ring while clearing in the middle. This rash never starts on the face and it is made worse with heat.

Sydenham's chorea (St. Vitus' dance): a characteristic series of rapid movements without purpose of the face and arms. This can occur very late in the disease.

Minor criteria

Fever Arthralgia: Joint pain without swelling Raised Erythrocyte sedimentation rate or C reactive

protein Leukocytosis ECG showing features of heart block, such as a

prolonged PR interval Supporting evidence of Streptococcal infection:

elevated or rising Antistreptolysin O titre or DNAase. Previous episode of rheumatic fever or inactive heart

disease

Other signs and symptoms-

Abdominal pain Nose bleeds

Differential Diagnoses-

- Aortic Regurgitation -Pediatrics, Scarlet Fever - Atrial Fibrillation -Acute Pericarditis

- Endocarditis - Reactive Arthritis - Huntington Chorea

- Rheumatoid Arthritis - Lyme Disease -Scarlet Fever

- Mitral Regurgitation - Systemic Lupus Erythematosus -Mitral Stenosis

- Myocarditis -Pediatrics, Kawasaki Diseas- Leukemia -Juvenile rheumatoid

arthritis

Diagnosis-

Laboratory Studies

- No specific confirmatory laboratory tests exist for acute rheumatic fever. However, several laboratory findings indicate continuing rheumatic inflammation. Some are part of the Jones minor criteria.

- Streptococcal antibody tests disclose preceding streptococcal infection.

- The CDC has stated that a rapid antigen test in the appropriate clinical setting is sufficient to make the diagnosis of active GABHS infection and begin treatment.

- Isolate group A streptococci via throat culture. A significant percentage will result in a culture positive for group A beta-hemolytic Streptococcus (GABHS). However, a culture positive for GABHS does not definitively prove active infection. Some patients are carriers.

- Acute-phase reactants (eg, erythrocyte sedimentation rate [ESR], C-reactive protein [CRP] in serum and leukocytosis) may show an increase in serum complement, mucoproteins, alpha-2, and gamma globulins. Anemia is usually caused by suppression of erythropoiesis.

- PR-interval prolongation is present in approximately 25% of all cases and is neither specific for nor diagnostic of acute rheumatic fever.

- Although there are a few small studies that show the contrary, troponins have not been shown to be helpful in making the diagnosis because ischemia and necrosis are not the major cardiac problems.

- Synovial fluid analysis may demonstrate an elevated white blood cell count with no crystals or organisms.

- Differences exist among nations in terms of diagnosing and treating GABHS pharyngitis. Most North American, French, and Finnish guidelines consider diagnosis of streptococcal infection essential (with either rapid antigen detection or with formal culture) and advise antibiotic therapy when streptococci is detected. Several European guidelines consider streptococcal infection a self-limited disease and do not recommend antibiotics.

Imaging Studies

- Echocardiography may be helpful in establishing carditis. Some suggest it be performed in all suspected cases.

- Chest radiography should be performed to determine presence of cardiomegaly and congestive heart failure.

Treatment- The goals of treatment for rheumatic fever are to destroy any remaining group A streptococcal

bacteria, relieve symptoms, control inflammation and prevent recurring episodes of rheumatic fever.

Antimicrobials- Because of the direct link between ARF and group A beta-streptococcal infection, the first step in treatment is the eradication of the organism.

-Penicillin G benzathine (Bicillin LA, Bicillin C-R)- Interferes with synthesis of cell wall mucopeptide during active multiplication, resulting in bactericidal activity against susceptible bacteria. Adult- 2.4 million U IM once

-Penicillin G procaine (Crysticillin, Wycillin)- Long-acting parenteral penicillin (IM only) indicated in the treatment of moderately severe infections caused by penicillin G–sensitive microorganisms.Some prefer 10-d therapy.

Administer by deep IM injection only into the upper outer quadrant of the buttock. In infants and small children, the midlateral aspect of the thigh may be the best site for administration. Adult- 2.4 million U IM once.

- Penicillin VK (Beepen-VK, Betapen-VK, Robicillin VK, Veetids), Amoxicillin- Inhibits the biosynthesis of the cell-wall mucopeptide and is effective during the stage of active multiplication. Inadequate concentrations may

produce only bacteriostatic effects. Penicillin VK is the oral alternative for the treatment of rheumatic fever.

Some authors suggest that once-daily amoxicillin is as effective and can be recommended as an alternative because compliance is likely to be better. Adult- 500 mg PO q6h for 10 d

- Erythromycin (EES, E-Mycin, Ery-Tab, Erythrocin)- DOC(drug of choice) for patients allergic to penicillin; inhibits RNA-dependent protein synthesis, possibly by stimulating the dissociation of peptidyl tRNA from ribosomes, which inhibits bacterial growth.

In children, age, weight, and severity of infection determine the proper dosage. When bid dosing is desired, one-half the daily dose may be administered q12h. For more severe infections, the dose may be doubled. Adult- 1 g/d PO divided bid for 10 d

-Azithromycin (Zithromax)- Acts by binding to 50S ribosomal subunit of susceptible microorganisms and blocks dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest.

Treats mild-to-moderate microbial infections. Adult- 500 mg on day 1 followed by 250 mg/d for 4 additional days.

Glucocorticoids- These agents possess anti-inflammatory (ie, glucocorticoid) and salt-retaining (ie, mineralocorticoid) properties. Glucocorticoids cause profound and varied metabolic effects. In addition, these agents modify the body's immune response to diverse stimuli.

Prednisone (Deltasone, Sterapred)- Patients with carditis require prednisone instead of aspirin. The goal is to decrease myocardial inflammation. Some authors suggest that carditis without associated cardiomegaly or congestive heart failure be treated with aspirin instead of glucocorticoids.

Glucocorticoids are useful in treatment of inflammatory and autoimmune disorders. Adult- 60-80 mg/d PO

Neuroleptic agents- These agents may help to control the chorea associated with ARF.

Haloperidol (Haldol)- A dopamine receptor blocker useful in the treatment of irregular spasmodic movements of

limbs or facial muscles. Adult- 0.5-2 mg PO bid/tid

Inotropic agents- Some believe that digoxin may be helpful in congestive heart failure.

Digoxin (Lanoxin)- Cardiac glycoside with direct inotropic effects and indirect effects on the cardiovascular system.

Effects on the myocardium involve a direct action on cardiac muscle that increases myocardial systolic contractions and indirect actions that result in increased carotid sinus nerve activity and enhanced sympathetic withdrawal for any given increase in mean arterial pressure. Adult- 0.125-0.375 mg PO qd

Anti-inflammatory agents- Reduce the inflammation associated with the disease process. Joints and heart are the targets of inflammation, but carditis is treated with glucocorticoids as noted above.

Aspirin - Treats mild to moderate pain. Inhibits prostaglandin synthesis, which prevents formation of platelet-aggregating thromboxane A2. Adult- 6-8 g/d PO for 2 mo or until ESR has returned to normal

Naproxen (Anaprox, Naprelan, Naprosyn)- For relief of mild to moderate pain; inhibits inflammatory reactions and pain by decreasing activity of cyclooxygenase, which is responsible for prostaglandin synthesis.

NSAIDs decrease intraglomerular pressure and decrease proteinuria. Adult- 250-500 mg PO bid; may increase to 1.5 g/d for limited periods.

Complications-

- Carditis- Mitral stenosis- Mitral regurgitation- Aortic stenosis- Congestive heart failure (CHF)