Acute Rheumatic Fever

Traudel Saurenmann, MD University Childrens Hospital Zrich, Switzerland

What is Acute Rheumatic Fever?

Immunologic response to Group A hemolytic streptococci (GAS) Cross reaction of antibodies with proteins in tissue of heart, joint, skin, brain (molecular mimikri) inflammation

Rheumatic Fever: Diagnosis

Evidence of preceeding Group A Strep. Infection

Positive Throat swab or rapid streptococcal antigen test Elevated or rising Streptococcal antibody titre

Modified Jones Criteria -1992

or

for diagnosis of an initial attack of rheumatic fever 2 major criteria 1 major plus 2 minor criteria indicate high probability of rheumatic fever

Modified Jones Criteria -1992

FOR DIAGNOSIS OF AN INITIAL ATTACK OF RHEUMATIC FEVER

MAJOR CRITERIA Carditis Polyarthritis Chorea Subcutaneous nodules Erythema Marginatum

MINOR CRITERIA Fever Arthralgia

(NOT combined with arthritis!)

Elevated ESR/CRP Prolonged PR interval

(NOT combined with carditis!)

2 major or 1 major plus two minor criteria indicate high probability of rheumatic fever

Rheumatic Fever: Epidemiology

Epidemiology follows that of GAS upper respiratory tract infections Widely variable incidence of ARF around the world: annual incidence 100-200 times greater in developing countries (=100-200/ 100,000 children 5-18yrs) Up to 3% with untreated GAS pharyngitis ARF 92% of cases occur <18 years of age - Peak age incidence 5 - 15 years of age. - Rare under 3yrs or older than 30 yrs Same sex frequency (Chorea more common in 2:1)

Rheumatic Fever: Epidemiology

Decline in overall incidence of ARF in developed countries between 1950 and 1970s
BUT Persistent prevalence among lower socioeconomic groups

Rheumatic Fever: Epidemiology

Crude Death Rates from Rheumatic Fever: U.S. 1910 - 1977
8 7

Death Rate Per 100,000 population

5
Classification of Strep

4
Sulphonamides

3
Penicillin

1910

1920

1930

1940
Year

1950

1960

1970

1977

From: Gordis L The Virtual Disappearance of Rheumatic fever in the United States: lessons in the rise and fall of disease Circulation 72 (6): 1155-1162

Rheumatic Fever: Epidemiology

Massell BF et al. Penicillin and the marked decrease in morbidity and mortality from rheumatic fever in the United States. NEJM 318(5): 280-286

Rheumatic Fever: Pathogenesis

Pathogenic Environment
- Overpopulation - Access to health care

Organism

RF
Individual Predisposition
Adapted from: Denny FW. A 45-year perspective on the streptococcus and rheumatic fever: the Edward H. Kass Lecture in infectious disease history . Clinical and Infectious Diseases 1994 (19); 1110-22

Pathogenesis - Organism
Virulence factors and ARF:

Concept of Rheumatogenic in addition to Nephritogenic serotypes

Glomerulonephritis

- Post pharyngeal: 1- 4, 12, 15 - Post pyoderma: 49, 52, 55, 59, 60, 61 ARF - Serotypes: M- 1, 3, 5, 14, 18, 19, 24
Mucoid colonies during epidemics

Group A Streptococcus

Group Carbohydrate Group Carbohydrate Antigen (C substance) Antigen (C substance) R and T Proteins R and T Proteins

MM Protein Protein Over serologic types Over 8080 serologic types

Pathogenesis - Organism

Molecular mimicry
Streptococcal component
M-like protein in Cell wall (some strains) Glycoprotein of cell membrane Cell membrane of all Group A strains Type 1 streptococcal cells Group A polysaccharide Streptococcal hyaluronic acid Type 1 M protein Antigen of cell membrane

Human component
Myocardium Glycoprotein of glomerular basement membrane Myocardial sarcolemma Myocardial intercalated discs Glycoproteins of heart valves Mammalian hyaluronic acid and protein polysaccharide Several HLA antigens Neuronal cytoplasm of caudate and subthalamic nuclei

Adapted from DiSciascio et al. Rheumatic fever in children. Am Heart J: 99(5); 635-658. Adapted from Dale JB Infectious Disease Clinics of North America 13(1): 227-43

Pathogenesis - Environment
Reduction in incidence prior to widespread availability of antimicrobials Well established differing rates in different regions of world and even within different socioeconomic classes of the same population Specific issues of 1) Crowding 2) Sanitation

Pathogenesis - Host
Constant incidence of rheumatic fever (1-3% of GAS infection cases) suggests limited number of people uniquely susceptible to ARF Concordance for disease occurrence and manifestations between
Monozygotic twins > Dizygotic twins Non-twin sibs > Chance

>

Pathogenesis - Host
Host immune response is crucial

Rare before 4yrs:

need for relatively mature immune response need for several infections to sensitize individuals Higher titres of ASOT in patients with ARF ARF patients sera contain cross-reacting antibodies lymphocytic infiltrate in cardiac tissue

Humoral:

Cellular:

Pathogenesis - Final Common Pathway

Pathogenic Organism
Increased virulence Ability to adhere to host Ability to evade phagocytosis Antigenicity

Environment
Transmission optimized Poor access to eradication therapies

RF
Individual Predisposition
Genetically determined cross reactivity Genetically determined host response

Adapted from: Denny FW. A 45-year perspective on the streptococcus and rheumatic fever: the Edward H. Kass Lecture in infectious disease history. Clinical and Infectious Diseases 1994 (19); 1110-22

The clinical picture of ARF

History of preceding pharyngeal infection not reliable! Latent period 1-3 (5) weeks from infection to ARF Onset most commonly with high fever and arthritis Cardiac manifestations may be present at onset or appear within days Sometimes insidious onset with several weeks of low grade fever, fatigue, loss of appetite, arthralgias but cardiac failure at first examination Chorea often develops without apparent prior other manifestation of ARF

Cardiac manifestations

Only manifestation of ARF that results in sequelae!!

Jones criteria: carditis = newly developed cardiac murmur and/or cardiac failure M proteins of rheumatogenic strains share epitope with human cardiac tissue ( myosin,
sarcolemmal membrane proteins)

Can affect endocard, myocard and pericard

Carditis clinical signs

40-60% of patients with ARF have clinical carditis

Further 20% will have subtle mitral valve abnormalities without a murmur (ECHO findings in the absence of a murmur DO NOT establish carditis according to Jones criteria)

Sinus tachycardia Murmur of Mitral regurgitation Gallop rhythm or arrythmias Friction rub of pericarditis Cardiomegaly and signs of cardiac failure

Pancarditis common

Course of carditis
Great range of possible outcomes! Can be rapidly progressive to heart failure and death Can be slowly evolving Can be self limited with sequelae Can heal completely

CNS manifestations

Sydenham Chorea seen in <10% of ARF patients (up to 50% in studies 1920-1950!) Purposeless, involuntary, rapid movements More common in girls (2:1) Uncommon after puberty, rare >20y Onset 1-8 months after inciting infection May have associated

Mechanisms?

Dysarthria Hypotonia and muscle weakness hemiballismus gait disturbances

Genetic predisposition Anti-neuronal antibodies

Chorea Course

Self-limited, no sequelae Average duration 3-6 months Symptoms may wax and wane, aggravate by stress and disappear with sleep Recurrences occur Carditis may be present or develops subsequently if no prophylaxis is given

Joint manifestations

Most common symptom of ARF! Migratory polyarthritis seen in 75% of ARF patients Predominantly large joints (knees, ankles, elbows, wrists) Exquisitely painful, often disproportionate to objective findings Involvement for a few days only in quick succession => Overlap Total duration of untreated arthritis rarely >4 weeks Very sensitive to aspirin, though other agents may be just as effective (eg. Naproxen, Tolmentin) Non deforming. Persistence rare (RF licks the joints but bites the heart)

Erythema marginatum

Appearance often delayed About 10% of cases Begins as small pink macula and extends outwards with sharp ring or wave-like margins and healing center Trunc or inner aspects of upper arms and thighs, accentuated by heat (Fever, warm bath) May occur intermittently for many months Not specific for ARF:

Drug reactions Glomerulonephritis idiopathic

Subcutaneous nodules

5-20% of patients with ARF Never present at onset, appear after several weeks only Very characteristic symptom Hard, painless, non pruritic, freely movable, over extensor surfaces of the joints and on the scalp Most common in children with severe prolonged carditis

subcutaneous nodules

Minor Criteria

Fever: almost always present at onset, no characteristic pattern, reflects severity of inflammation Arthralgia: very common, only counts as minor sign in absence of overt arthritis ESR/CRP: almost always abnormal except in children with chorea only Prolonged P-R interval: 1 heart block in 2540%. May be present in GAS without ARF!

Other symptoms

Nose bleeds: common but not characteristic Abdominal pain: up to 5% of ARF, often early in disease course, may mimic acute appendicitis and lead to surgery!

Rheumatic Fever: Diagnosis

Throat Culture

ASOT (anti-Streptolysin O titer)

Positive in 30% (10% if previous antimicrobial therapy) at time of development of symptoms Serotyping - rheumatogenic and nephritogenic strains Reduction in surveillance programs

Elevated in 80% of patients following GAS infection NOT specific for GAS, as Streptolysin-O also produced by
Bacillus species Clostridial species and Listeria Monocytogenes

Titers of 200-400 are common in healthy school-aged children

Rheumatic Fever: Diagnosis

Rapid Hemagglutination test

Detects antibodies to a mixture of Streptococcal antigens

(Streptozyme)

Simpler, quicker but more expensive Concerns about reproducibility

Anti-DNase B

More specific than ASO When used in combination with ASO, increases sensitivity to 90%

ESR/CRP

Non specific Give good guide to degree of persistent inflammatory disease Usually normal in isolated chorea

Rheumatic Fever: Treatment

Goals of the therapy in ARF: Anti-microbial therapy for GAS
All patients should be treated as if they have GAS infection at the time of diagnosis of ARF (irrespective of culture)

Treatment of symptoms of disease

Prevention of non-suppurative complications

Prevention of recurrence after recovery

Rheumatic Fever: Treatment

50-100mg/kg/d

NO / MILD CARDITIS

50% Dose

ASA
2.0 mg/kg/d

Taper

Or voltaren 2-3 mg/kg

MOD/SEVERE

penicillin
on Diagnosis

IM or PO

CARDITIS

50% Dose

Prednisone
2-3 w 2-3 w

Taper

voltaren
2-3 w

CHOREA

Haloperidol/Phenobarbitone

Prophylaxis
Adapted from AHA guidelines 1995

The clinical course of ARF

Untreated attack: average duration 3 months, rarely >6 months Arthritis: 1-2 weeks, rarely >4 weeks Carditis: 85% within 2 weeks of onset, active disease may persist 3-6 months Chronic carditis more common after recurrent attacks Risk for cardiac damage in subsequent attacks highest for patients with prior episode of carditis Antibiotic prophylaxis very effective in preventing further damage

Clinical Course: Cardiac manifestations

From: Zabriskie JB Rheumatic fever the interplay between host, genetics, and microbe. Circulation: 71 (6); 1077 - 1086

Rheumatic Fever: Prophylaxis

Continuous sub-clinical GAS pharyngitis can trigger recurrent ARF (recurrence risk up to 60% !) Recurrence risk particularly high in the first 5 years, in young children and in those with rheumatic heart disease Additional organ involvement may occur in subsequent attacks Suggested regimes: Penicillin V 250 mg po BID Sulfadiazine 0.5-1.0g Daily Erythromycin 250mg BID Benzathine Penicillin G 1.2 MU Q3-4 weekly

Rheumatic Fever: Prophylaxis

Post ARF with persistent rheumatic heart disease (RHD):
10years and at least until age 40 (consider lifelong)

Prophylaxis Duration
(AHA, 1995)

Post ARF with carditis but NO residual RHD:

10 years or well into adulthood (whichever is longer)

Post ARF without carditis;

5 years or until age 21 (whichever is longer)

Summary Acute Rheumatic Fever

In up to 3% of GAS throat infections Antibodies against GAS bind to cellular proteins of heart, skin, joints and brain (molecular mimicry) and produce inflammation Modified Jones criteria licks the joints but bites the heart: main cause of acquired heart disease Subsequent attacks tend to be heavier and may involve additional organs