RHEUMATIC FEVER

Sarva Rickhi
Anjanie MaharajH
ViviOn Bissoon
Definition
Rheumatic 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 (cont’d)

• 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 (cont’d)
• 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 (cont’d)
• In the US, at the beginning of the
20th century, rheumatic fever was a
leading cause of death among
children and adolescents (100-
200/100,000 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 (cont’d)

• Explanation for decline in incidence

not entirely clear;
• Decline in incidence during pre-
antibiotic 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 (cont’d)

• Incidence of initial attacks and

recurrences of RF peaks in children 5-
15yrs 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 (cont’d)
• 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 (cont’d)
• 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 (cont’d)


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;268:2069–2073. Copyright American Medical Association.

MAJOR MINOR SUPPORTING

MANIFESTATIONS[*] MANIFESTATIONS EVIDENCE OF
ANTECEDENT GROUP A
STREPTOCOCCAL
Carditis Clinical features: Positive
INFECTIONthroat culture or
Arthralgia rapid streptococcal antigen
Fever test
Polyarthritis
Elevated or increasing
streptococcal antibody titer
Erythema marginatum Laboratory features:
Subcutaneous nodules Elevated acute phase
reactants:
Erythrocyte sedimentation
rate,C-reactive protein
Prolonged PR interval

Chorea
Diagnosis (cont’d)
• 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 (cont’d)

• 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.
Sydenham’s 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 milkmaid’s grip
– Spooning and pronation of hands
when patient’s 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 ≥102°F 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 80-
85% 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 Non-

Infectious 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
FEVER
Younger age group Older age group

Less joint pain (relative to other More joint pain (relative to other
clinical findings) clinical findings)

Suggestive features: Suggestive features:

spiking fevers, lymphadenopathy, More dramatic response to salicylate
splenomegaly therapy
Differential Diagnoses
(cont’d)
• 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
(cont’d)
• Chorea
– Huntington chorea, Wilson disease,
systemic lupus erythematosus, and
various encephalitides

 Differential Diagnosis of Acute Rheumatic Fever
ARTHRITIS CARDITIS CHOREA
Rheumatoid arthritis Viral myocarditis Huntington chorea
Reactive arthritis (e.g., Viral pericarditis Wilson disease
Shigella, Salmonella,
Yersinia)
Serum sickness Infective endocarditis Systemic lupus
erythematosus
Sickle cell disease Kawasaki disease Cerebral palsy
Malignancy Congenital heart disease Tics
Systemic lupus Mitral valve prolapse Hyperactivity
erythematosus
Lyme disease (Borrelia Innocent murmurs
burgdorferi)
Gonococcal infection
(Neisseria gonorrhoeae)
TREATMENT
Treatment of Rheumatic
Fever
• General
• Antibiotic therapy
• Anti-inflammatory therapy
– Migratory polyarthritis
– Carditis/CHF
– Sydenham Chorea

Treatment
General


• 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 Therapy
v 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 Therapy
vMigratory 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


 NB: Therapy should only be started after

diagnosis is established as it may obscure the
migrating aspect of the polyarthritis, key to the
diagnosis.
vCarditis without cardiomegaly/CHF
§ Same treatment as migratory
polyarthritis

vCarditis with cardiomegaly/CHF
§ Prednisone
§ Dosage: 2 mg/kg/day in 4 doses for 2-
3 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 Anti-
Inflammatory 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
vSydenham’s 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
2⁰ 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
References
WHO Expert Consultation on Rheumatic
Fever
and Rheumatic Heart Disease, Geneva

2001.


Feigin, Textbook of Pediatric Infectious



Diseases


Nelson’s Textbook of Pediatrics



Abbas and Lechtman. Basic



Immunology:
