CXR

MORNING REPORTDECEMBER 19TH 2008

BY: SIMA PATEL

ACUTE RHEUMATIC FEVER

DEFINITION

Rheumatic fever is an inflammatory process which can involve the joints, heart, skin and brain

It is caused by antibody cross reactivity and occurs 2-3 weeks after a Group A Streptococcal infection.

HISTORY

16th century: Baillou distinguishes acute arthritis from gout

17th century: Thomas Sydenham described chorea but did not associate it with other entities of Acute Rheumatic Heart Disease

1812: William Charles Wills made association of Rheumatism and carditis and described subcutaneous nodules

HISTORY

Jean-Baptiste Bouillard (1836) and Walter B Cheadle (1889) published many studies of rheumatic arthritis and carditis

1880: J.K. Fowler made association between sore throat and rheumatic fever

Early 1900’s: Bela Schick identified Acute Rheumatic Fever as a sequelae of scarlet fever

1904: Ludwig Aschoff: described specific rheumatic lesions in the myocardium

1930’s-1950’s: multiple studies identified Group A Streptococcus as the causative agent and development of antibiotic agents for primary and secondary prevention of rheumatic fever

EPIDEMIOLOGY

470,000 new cases of Acute Rheumatic Fever/year

233,000 deaths due to Rheumatic Fever/yearMajority of deaths occur in developing countriesIncidence in the US: 2-14 cases/100,000Historically, there is a temporal relationship

between epidemics of streptococcal pharyngitis and scarlet fever with the epidemics of acute rheumatic fever

No clear gender predilection overall, but mitral stenosis and syndenham’s chorea occur more in females than males.

BACKGROUND

Primarily affects children between ages 5-12Generally occurs 2-3 weeks after Group A

Streptococcal infection (strep throat or scarlet fever)

In the US, Rheumatic fever has become fairly rare due to use of antibiotics to treat streptococcal infections

Globally, 3% of those with an untreated streptococcal infection develop rheumatic fever

40% of those with Acute Rheumatic Fever develop mitral stenosis as adults

BACKGROUND

Cutaneous streptococcal infections have not been shown to initiate Acute Rheumatic Fever.

Strains of certain M serotypes/genotypes of streptococci have higher associations than other genotypes

Epidemics of Acute Rheumatic Fever in Trinidad and Chile showed that streptococci causing Acute Rheumatic Fever belonged to different serotypes than those that cause Acute Glomerulonephritis.

PATHOPHYSIOLOGY

Exact mechanism of how Group A streptococcal infection causes Acute Rheumatic Fever is unknown however it is believed to be caused by a cross reactivity of antibodies

Suggested Theories Toxic effects of streptococcal products (streptolysin S

or O) which then cause direct tissue injury Serum Sickness-like reaction mediated by antigen-

antibody complexes Autoimmune phenomenon

PATHOPHYSIOLOGY

More support for an autoimmune phenomenon (Type II hypersensitivity reaction)

During strep infection, antigen presenting cells present bacterial antigen to helper T cells. These helper T cells then activate B cells to induce production of antibodies against the Streptococcal cell wall. These antibodies can also interact with other cells in the body (for example, myocardium or joints, etc) producing the symptoms responsible with acute rheumatic fever

PATHOGENESIS

Most patient have elevated antibody titers to at least one streptococcal antibody Streptolysin O Hyaluronidase Streptokinase

PATHOPHYSIOLOGY (CARDIAC)

In early stages of disease there is fragmentation of collagen fibers, and a predominantly lymphocytic infiltration of tissues with fibrinoid deposition

Then, there is appearance of myocardial Aschoff Nodules (Bodies). These are areas with perivascular inflammation with an area of central necrosis surrounded by mononuclear and giant multinuclear cells. (“owl-eyed nucleus” or a “caterpillar” appearance)

Cardiac findings: pericarditis, myocarditis, endocarditis (usually involving the left side of the heart)

May have a thickened area in the left atrium (above the base of the posterior leaflet of the MV) called MacCullum’s Patch.

As time progresses these areas develop scarring leading to mitral valve deformities resulting in valvular stenosis or insufficiency.

PATHOPHYSIOLOGY (CARDIAC)

Aschoff nodule with owl-eyed shape in the cross section and catapillar-shaped

in the longitudinal section

PATHOPHYSIOLOGY (CARDIAC)

Thickened fused chordae of the mitral valve

PATHOPHYSIOLOGY (JOINTS)

Initially have fibrinous exudates over the synovial membrane with serous effusions.

Histology shows cellular infiltration and fibrinoid degeneration.

Usually show a central area of fibrinous necrosis surrounded by fibroblasts and histiocytes.

Just as in the heart, there is also perivascular changes with infiltration of lymphocytes and PMNs

CLINICAL MANIFESTATIONS

Latent period: time between preceding streptococcal pharyngitis and Acute Rheumatic fever is about 19 days (range 1-5 weeks)

If initial complaint is polyarthritis, disease generally has more abrupt onset compared to if initial presentation is with myocarditis.

Arthritis occurs in 75% of initial attacks, carditis in 40-50% and chorea in 15% with subcutaneous nodules and erythema marginatum in <10%

CLINICAL MANIFESTATIONS (CARDITIS)

Usually manifests within the first 3 weeks of Acute Rheumatic Fever

Signs: new heart murmur, cardiomegaly, CHF, perciardial friction rub, effusions

Chronic inflammatory changes may lead to development of rheumatic heart disease.

Characteristic murmur or Rheumatic heart disease: mitral regurgitation Low-pitched mid diastolic flow murmur at the apex (Carey

Coombs murmur Aortic regurgitation

Can also get AV conduction delays

CLINICAL MANIFESTATIONS (JOINTS)

Arthralgias and arthritis (may be migratory)Warm, swollen, tender jointsUsually involves the knees, ankles, elbows

and wristsLasts 2-3 weeks

CLINICAL MANIFESTATIONS

Subcutaneous Nodules: usually associated with severe carditis and occur several weeks after onset. Firm, painless nodules (up to 2cm) found over bony

surfaces and tendons Occur near elbows, knees, wrists, achilles tendon,

vertebral joints Usually persist for 1-2 weeks

SUBCUTANEOUS NODULES

CLINICAL MANIFESTATIONS

Erythema Marginatum: nonpruritic, painless erythematous rash on trunk and/or proximal extremities Macular lesions with raised margins and central clearing May last from weeks to months

Sydenham’s Chorea: neurologic disorder with muscular weakness, emotional lability and involuntary, uncoordinated, purposeless movements Disappear during sleep Mainly occur in hands, feet and face Sensation intact Lasts 2-4 months

ERYTHEMA MARGINATUM

DIFFERENTIAL DIAGNOSIS

Poststreptococcal reactive arthritis: is non-migratory

Rheumatoid ArthritisSLEInfective endocarditisSickle Cell diseaseDrug reactionsTBLyme DiseaseSerum Sickness

DIAGNOSIS

JONES CRITERIA Developed by Dr. T Duckett Jones in 1944 Need 2 major criteria or 1 major and 2 minor criteria

in the presence of a prior strep infection to make the diagnosis

Evidence of prior strep infection with positive throat culture or antigen test, elevated streptococcal antibody titer, or history of rheumatic fever/heart disease

MAJOR CRITERIA

Migratory Polyarthritis: migrating arthritis with inflammation involving the large joints (knees, ankles, elbows, wrists) and typically affects the leg joints first

Carditis: can manifest with new murmur, pericarditis, congestive heart failure

Subcutaneous Nodules: a form of aschoff bodies. Are painless nodules on the back of the wrists, elbows, knees

Erythema Marginatum: rash beginning on the arms or trunk and spreads outward. Lesion with ring with central clearing. Worsens with heat. Does not involve the face

Sydenham’s Chorea (St. Vitus’ Dance): purposeless movements of the face and arms. Late finding

MINOR CRITERIA

FeverArthralgia: joint pain without inflammationElevated CRP, ESR or leukocytosisEKG changes: primarily prolonged PR intervalEvidence of Group A Streptococcal infection

via elevated antistreptolysin O titer or DNAase

Prior history of rheumatic fever or heart disease

TREATMENT

Anti-inflammatory AgentsAntibioticsProphylaxis

ANTI-INFLAMMATORY AGENTS

Aspirin 4-8grams/day for adultsContinue anti-inflammatory therapy until ESR

or CRP are normalMay need steroids if there is cardiac

involvement to help prevent sequelae such as mitral stenosis

Corticosteroids, if indicated, are given at prednisone 2mg/kg/day for 2 weeks and then tapered

ANTIBIOTICS

Penicillin for at least 10 daysPenicillin 500mg BID-TIDCan use erythromycin for PCN allergic

patients (given at 40mg/kg/day given in 2-4 doses/day)

PROPHYLAXIS

Prophylaxis needed to prevent recurrence of Acute Rheumatic Fever

Start prophylaxis after acute episode resolvesCan use:

Penicillin V 250mg BID or, Sulfadiazine 1000mg daily, or Penicillin G 1.2 million units IM q4weeks For PCN allergic patients: erythromycin 250mg PO BID

Recurrence of disease generally occurs in the first couple years

PROPHYLAXIS

WHO GUIDELINES At least 5 years of prophylaxis or if child until age 18

if not cardiac involvement 10 years prophylaxis or if child until age 25 if has mild

mitral regurgitation Lifelong prophylaxis if has severe valve disease

PROGNOSIS/PREVENTION

Generally resolve over 12 weeks in 80% of patients

Prognosis depends on severity of cardiac involvement during acute attack

Primary Prevention: treatment of streptococcal infection (limitation is that 30% of streptococcal infections are subclinical)

Secondary Prevention: prevention of recurrent attacks of Rheumatic Fever with prophylactic antibiotics.

REFERENCES

Shulman, Stanford. Rheumatic Fever in America and Britain: A biological, epidemiological, and medical history. New England Journal of Medicine May 4, 2000; Volume 342: 1373-1374.

Mandell G, Bennett J, and Raphael Dolin. Principles and Practice of Infectious Disease, 6th Edition. Churchill Livingstone. Philadelphia, PA 2005.

Cohen J and William Powderly. Infectious Diseases, 2nd Edition. Harcourt Publishers. 2004.

www.uptodate.com