CURRENT CONCEPTS AND

MANAGEMENT OF ACUTE
RHEUMATIC FEVER

RAHMAT BUDI KUSWIYANTO

DEPARTMENT OF PEDIATRIC & CHILD HEALTH
FK UNPAD / HASAN SADIKIN HOSPITAL
BANDUNG

LICKS THE BRAIN (JOINT) BITES THE HEART

CHRONIC
LESIONS

Definition

Rheumatic Fever (RF) and Rheumatic Heart Disease

(RHD) are non-suppurative complications of Group A
streptococcal (GAS) pharyngitis due to a delayed
immune response/Immunologically mediated
inflammatory
RHD remains the most serious sequelae of RF and
causes considerable global morbidity and mortality
(Major public health problem)
Preventable and treatable

Group A beta hemolytic Streptococcus = GAS

STRUCTURE

Capsule: hyaluronic acid

Cell Wall: outer, middle and inner layer

Outer layer: proteins M, T and R
M component is the most potent & antigenic

Middle layer:specific carbohydrates eg N acetyl glucoamin and rhamnose

Inner layer:peptidoglycan responsible for cell wall rigidity

Cytoplasm

HISTOPATOLOGIS

Aschoff bodies in myocardium

Pathogenesis pathway for ARF and RHD

Lancet 2005; 366: 15568

Immunologically mediated inflammatory

Abnormal humoral (acute phase) & cellular (chronic phase) immune response occurs
Antigenic mimicry: certain amino acid sequence that is similar btw GAS & human tissue
in individual with genetic predisposition

EPIDEMIOLOGY

Worldwide; rare in developed countries: better living

conditions and control of streptococcal infections. Influx
of immigrants from highly prevalent countries & new
strains of streptococci (new outbreaks)
Still major public health problems among children and
young adults in developing countries
RF is the most frequent cause of heart disease in the 5to 30-year age group
ARF & RHD are important causes of death in young
people
RHD causes 2540% of all cardiovascular disease

INCIDENCE
PHARYNGITIS

GAS
15-20%

RESOLVED

VIRAL
>80%

ARF
0,3-3%

Worldwide: 12 million ARF & RHD (1994); Cause of 3 million CHF & readmission
Annual incidence: 1,0-150/100.000; Prevalence of RHD: 0,2 77,8/1000 children
The overall mean incidence rate of first attack of ARF was 551/100 000 population
(mean 19/100 000; 95% CI 9 to 30/100 000).
Low incidence rate of (10/100 000 per year : America and Western Europe
Higher incidence (>10/100 000): Eastern Europe, Middle East (highest), Asia & Australasia
Mortality rate/100.000: 0,5-8,2; South East Asia 7,6
Heart 2008;94;1534-1540

RISK FACTORS
Family

History of ARF
Genetic predisposition
(HLA-DR1, HLA-DRW6, twin)
Low socioeconomic
Age 6 -15 years (mostly 8 years)
Health System-related factors

Direct and indirect results of environmental and healthsystem determinants on RF & RHD

Clinical Manifestations

MAYOR MANIFESTATION

Clinical Manifestations
CARDITIS
POLYARTHRITIS MIGRAN
SYDENHAMS CHOREA (St. VITUS DANCE)
ERYTEMA MARGINATUM

SUBCUTANEUS NODULE

Rheumatic Carditis

Occur in 40-50% cases

Most serious manifestations
May lead to death in acute phase or at later stage
Common in the first 3 weeks
The single most important prognostic factor in RF;
only valvulitis leads to permanent damage and its
presence determines the prophylactic strategy
Valves affected: Mitral (60%), Aortic (10%); Mitral
and Aortic (30%), Tricuspid and pulmonary valve
rarely affected

Rheumatic Carditis (cont)

Clinical features:
Endokarditis/valvulitis : Presence of apical holosystolic
murmur of MR (with or without apical mid-diastolic
murmur, Carey Coombs), or basal early diastolic murmur.
Children with previous RHD, a definite change in the
character of any of these murmurs or the appearance of a
new significant murmur indicates the presence of carditis
Miokarditis: Unexplained CHF or cardiomegaly
Pericarditis: friction rub, chest pain, effusion, ECG changes
Congestive Heart Failure

Rheumatic Carditis (cont)

CXR in a child with acute carditis

After 4 weeks of treatment

Rheumatic Arthritis

The most frequent major manifestation

Occurring in up to 75% of patients in the first attack & early in the course of the
disease

The involvement of joints may present as arthralgia to disabling arthritis

Typically present as migratory polyarthritis

Most often in the larger joints (commonly in the knees and ankles); the wrists,
elbows, shoulders and hips are less frequently involved; and the small joints of the
hands, feet and neck are rarely affected
Inflamed joints are characteristically warm, red and swollen, and an aspirated
sample of synovial fluid may reveal a high average leukocyte count (29000mm-3,
range 200096 000mm-3)
Tenderness may be out of proportion to the objective findings and severe enough
to result in excruciating pain on touch

Subcutaneous rheumatic nodules

The incidence varies; reported in up to 20% of cases

Round, firm, freely movable, painless lesions, size 0.52.0 cm
Easily be missed if not carefully sought on physical exam
They occur in corps over bony prominences or extensor tendons
Common locs: the elbows, wrists, knees, ankles & Achilles tendons
The number varies from one to a few dozen, but usually 3-4
Persist from days to 12 weeks to, rarely > a month
Similar lesions occur in SLE and rheumatoid arthritis.
Associated with the presence of carditis

Subcutaneous rheumatic nodules

Erythema marginatum

Present in 7-15% of patients

Usually occurs early in the course of a rheumatic attack & highly specific to RF

Associated with carditis & tend to occur together with subcutaneous nodules.

May be missed if not specifically sought, particularly in dark-skinned patients

Appear first as a bright pink macule or papule that spreads outward in a circular
or serpiginous pattern
The lesions are multiple, nonpruritic & nonpainful, blanch under pressure, and are
only rarely raised. Individual lesions may come and go in minutes to hours;
appearing like smoke rings beneath the skin
Usually on the trunk or proximal extremities, rarely on the distal extremities, &
never on the face

May persist or recur for months or even years

Not influenced by anti-inflammatory therapy

Erythema marginatum

Sydenhams Chorea

Occurs primarily in children, females and rare after 20 years old

The prevalence 536%

May occur alone, or in association with other manifestations

Usually benign and can last for 1 week - 2 years (median 15 weeks)

Has a longer latency period after GAS infection, as long as 17 months

Characterized by emotional lability, uncoordinated movements & muscular

weakness
The onset may be difficult to determine. First sign: difficulty walking, talking,
writing, then the movements are abrupt and erratic (esp. on the hands, feet and
face are most evident)
tongue bag of worms, speech is jerky and staccato, spoon or dish
configuration , pronator sign, milkmaid grip

Disappear during sleep, decrease with rest & sedation, & can be suppressed by
volition for few movements

MINOR MANIFESTATION

Clinical Manifestations
Fever
Arthralgia
Acute-phase reactant (LED & CRP,
leukocyte)
ECG: prolonged PR interval

Other Clinical Features

Less frequent or less specific to ARF
Epistaxis
Abdominal pain (5%) due to peritonitis
Hematuria (5%)/renal involvement
- When routine biopsy done, in up to 39%
Pneumonitis
Mild pleuritis (5 - 10%)
Encephalitis (extremely rare)

Diagnosis

The Revised Jones Criteria 1992

Highly
probable

2 mayor manifestations
1 mayor + 2 minor manifestations
With proved evidence of GAS
infection (culture or ASTO)

Doubtful

2 mayor manifestations
1 mayor + 2 minor manifestations
Without proved evidence of GAS
infection

20022003 WHO Criteria for The Diagnosis of ARF &

RHD (Based on The Revised Jones Criteria)
DIAGNOSTIC CATEGORIES

CRITERIA

Primary episode of RF

2 Mayor/1 Mayor+2 Minor

manifestations + evidence of a
preceding GAS infection

Recurrent attack of RF in a patient without

established RHD

2 Mayor/1 Mayor+2 Minor

manifestations + evidence of a
preceding GAS infection

Recurrent attack of RF in a patient with

established RHD

2 Minor plus evidence of a

preceding GAS infection

Rheumatic chorea

Other major manifestations or evidence of

GAS infection not required

Insidious onset of rheumatic carditis

Chronic valve lesions of RHD

Do not require any other criteria to be

diagnosed as having RHD

Investigations in Suspected ARF

RECOMMENDED FOR ALL CASES

White blood cell count

Erythrocyte sedimentation rate (repeat weekly once diagnosis confirmed)

C-reactive protein

Blood cultures if febrile

Electrocardiogram (repeat as necessary if conduction abnormality more than first degree)

Chest x-ray if clinical or echocardiographic evidence of carditis

Echocardiogram (repeat as necessary in 2-4 weeks if equivocal, or if serious carditis)

Throat swab (preferably before giving antibiotics) - culture for group A streptococcus

Anti-streptococcal serology: both anti-streptolysin O and anti-DNase B titres, (repeat 10-14 days later if
first test not confirmatory)

TESTS FOR ALTERNATIVE DIAGNOSES, DEPENDING ON CLINICAL FEATURES

Repeated blood cultures if possible endocarditis or septic arthritis

Joint aspirate (microscopy and culture) for possible septic arthritis

Joint X-ray

Copper, ceruloplasmin, anti-nuclear antibody, drug screen, and consider CT/MRI head for choreiform
movements
Serology and auto-immune markers for auto-immune or reactive arthritis (including ANA - Anti Nuclear
Antibody).

Diagnosis of Streptococcal Infection

The gold standard for detecting Streptococcus

pyogenes remains a throat swab cultured on blood
agar
If possible, throat swabs should be examined for all
patients with clinically suspected streptococcal
upper respiratory tract infection
Antibody to GAS (Anti-streptolysin O; Anti-Dnase)

Diagnosis of Streptococcal Infection (cont):

Variation in normal antibody titers with age and/or geography

Role of Echocardiography

Provide early evidence of valvular involvement

Confirm suspected valvular regurgitation
Exclude non-rheumatic causes of valvular involvement
Support the diagnosis, but not a criteria for diagnosis

Role of Echocardiography
Prevalence of Rheumatic
Valvular Abnormalities
among Schoolchildren

N Engl J Med 2007;357:470-6.

Diagnosis: Differential Diagnosis of ARF

Juvenile rheumatoid arthritis

Systemic lupus erythematosus

Other connective tissue diseases, including vasculitidies

Bacterial endocarditis

Reactive arthritis

Seronegative spondyloarthropathies

Infections (Hansens Disease, Lyme, Yersinia)

Familial Mediterranean Fever

Antiphospholipid Syndrome

Leukemias

Sickle cell anemia and other hemoglobin disorders

Sarcoidosis

Management

General measures: Bed rest

Antimicrobial therapy: 1). Eradication of the
pharyngeal streptococcal infection, 2). Prevent
recurrent streptococcal infection, RF, and RHD, & 3).
Provide prophylaxis against bacterial endocarditis
Suppression of the inflammatory process
Management of heart failure
Management of chorea

General Measures

Bed rest

Arthritis

Mild Carditis

Moderate
Carditis

Severe
Carditis

1-2 weeks

2-3 weeks

4-6 weeks

2-4 months

(Hospitalization)
Indoor
ambulation

(up to 4 weeks)
1-2 weeks

2-3 weeks

(CHF -)
4-6 weeks

2-3 months

(up to 4 weeks)

Outdoor activity 2 weeks

2-4 weeks

1-3 months

2- 3 months

Full activity

After 3 (6-10)
weeks

After 3-6
months

Variable

After 6-10
weeks

These guidelines should be individualized by clinician(s) according to

patient and family circumstances.

Eradication of The Pharyngeal Streptococcal Infection

Benzathine benzylpenicillin
600.000 U IM: weight < 30 kg
1,2 juta U IM: weight > 30 kg
As a first dose of 2nd-prophylaxis

Allergy to Benzathine benzylpenicillin

Erythromisine 40-50 mg/Kg/day in 24 doses for 10 days

Suppression of The Inflammatory Process

Clinical Manifestation

Therapy

ATHRALGIA

ANALGESIC (PARACETAMOL)

ARTHRITIS

SALICYLATES 90-100
mg/Kg/day for 2 weeks
25 mg/Kg/day for 4-6 weeks
Prednisone 2 mg/Kg/day for
2 weeks tapp off 2 weeks
salisilate 75 mg/Kg/day
for 2-6 weeks

CARDITIS

Suppression of The Inflammatory Process

Arthritis

Mild carditis

Moderate
carditis

Severe
carditis

Prednisone

2-4 weeks

2-6 weeks

Salicylates

1-2 weeks

2-4 weeks

6-8 weeks

2-4 months

Prednisone:12mg/kg-day, to a maximum of 80mg/day given in divided

doses). After 23 weeks of therapy the dosage may be decreased by 20
25% each week. While reducing the steroid dosage, a period of overlap
with aspirin is recommended to prevent rebound of disease activity
Salicylates: 90-100 mg/kg/day/divided into 4-5 doses for 2 weeks
6070mg/kg-day for 36 weeks

Management of Chorea
Reducing activity & emotional disturbance
The signs and symptoms of chorea generally do not respond
well to anti-inflammatory agents
In severe case:
Neuroleptics, benzodiazepines and antiepileptics are
indicated, in combination with supportive measures such as rest
in a quiet room
Carbamazepine 710 mg/kg/day po tid
Phenobarbital 35 mg/kg/day po bid
Haloperidol 0.010.03 mg/kg/day po bid
Valproic acid 1520 mg/kg/day po tid

Potential Preventive Measures for Rheumatic Fever and

Rheumatic Heart Disease

The most important way to prevent

rheumatic fever is by proper and
prompt treatment of GAS pharyngitis

Primordial Prevention

Primordial prevention of the disease

Immunization

(?)
Socio economic
Nutrition
Public education (school going age, parents, teachers,
all personnel involve with children, etc)

Control spread of disease to others

Reduce

risk of cross-transmission of organisms

Infection control policies
Handwashing
Overcrowding
Availability to prompt medical care

Primary VS Secondary Prevention

The primary prevention of rheumatic fever (RF) is

defined as the adequate antibiotic therapy of
group A streptococcal upper respiratory tract
infections (URTI) to prevent an initial attack of acute
RF
Secondary prevention of RF is defined as the
continuous administration of specific antibiotics to
patients with a previous attack of RF, or a welldocumented RHD to prevent colonization or URTI
with GAS and the development of recurrent attacks
of RF

Primary vs Secondary Prevention

The most important way to prevent
rheumatic fever is by proper and prompt
treatment of GAS pharyngitis

GAS PHARYNGITIS

PRIMARY
XXX

ARF
SECONDARY
XXX

RHD

Rationale decision making

The WHO Acute Respiratory
Infection:
In the absence of laboratory
diagnosis for children under
15 years of age, Acute GAS
pharyngitis should be
suspected & presumptively
treated when pharyngeal
exudate plus enlarged &
tender cervical lymph nodes
are found

The most important way to prevent

rheumatic fever is by proper and prompt
treatment of GAS pharyngitis

GAS pharyngitis th options

Reasons to treat GAS pharyngitis with AB:
To prevent RF
To prevent peritonsilar abcess
To reduce symptoms---there is a modest (-1 day)
reduction in symptoms with early treatment
To prevent transmission-this is important in pediatric
due to extensive exposure but not in adults

Modified CENTOR score (JAMA 2007)

Criteria

Points

Temperature >38C

Absence of cough

Swollen & tender cervical node

Tonsillar swelling /exudate

Ages: 3-14 years

15-44 years

>44 year

-1

TOTAL
0-1

No further test or AB th/

2-3

Culture all

>4

Treat empirically

Sign & Symptom of GAS Infection

SIGNS/SYMPTOMS

INFANT

CHILDREN

ADOLESCENT/ADULT

ANTERIOR CERVICAL
LYMPHADENITIS (PAIN)

++++

++++

++++

CONTACT

++++

++++

++++

SCARLATINIFORM RASHES

++++

++++

NOSE EXCORIATION

++++

++++

++++

TONSIL
EXUDATE/PHARYNX

++++

++++

THROAT CULTURE (+)

++++

++++

++++

FEVER

++

++

++

ACUTE ONSET

++

++

ABDOMINAL PAIN

++

++

CORYZA

++

PHARYNX
ERYTHEMATOUS

++

++

++

HOARSENESS

COUGH

Primary vs Secondary Prevention

PRIMARY

SECONDARY

BENZATHINE BENZYHL PENICILLIN G

BENZATHINE BENZYHL PENICILLIN G

600.000 U IM wt < 30 kg
1,2 juta U IM wt > 30 kg

(every 3-4 weeks)

600.000 U IM wt < 30 kg
1,2 juta U IM wt 30 kg

PHENOXYMETHYL PENICILLIN (PENICILIN V)

PENICILLIN V 2 x 250 mg

3-4x 250 mg for 10 days

ERYTRHOMYCIN

ERITHROMYCIN 250 mg twice daily

20-40 mg/kg/day /2-4 doses/10 days

Azithromycine :12.5 mg/kg/day once daily

500 mg on first day, 250 mg per day for the next 4 days
Clindamycin 20 mg/kg per day divided in 3 doses
(maximum 1.8 g/d) Oral 10 days
Clarithromycin 15 mg/kg per day divided BID (maximum
250 mg BID) Oral 10 days
First Generation Cephalosporine
(cephalexin, cephadroxil) 15-20 mg/kg/dose bid

SULFONAMID po
Wt <30 kg 0.5 gr once daily
Wt 30 1 gr once daily

Suggested Duration of Secondary Prophylaxis

Category of patient

Duration of prophylaxis

Patient without proven carditis

For 5 years after the last attack,

or until 18-21 years of age
(whichever is longer)
For 10 years after the last attack,
or until 21-25 years of age
(whichever is longer)
10 years or until 40 years of age
(whichever is longer), sometimes
lifelong prophylaxis
Lifelong

Patient with carditis

(mild MR or healed carditis)
More severe valvular disease

After valve surgery

Pathogenesis pathway for ARF and RHD

CHRONIC LESIONS
MITRAL REGURGITATION/STENOSIS
AORTIC REGURGITATION/STENOSIS

Lancet 2005; 366: 15568

INDICATION FOR SURGERY

54

CHF >NYHA II
Progressive LV dilatation
Pulmonary Hypertension
Atrial Fibrillation
Thromboembolism
Endocarditis
Diastolic dysfunction with LVEDD >45mm & EF <60%

Katup Starr-Edward

A. Hancock porcine valve

B. Carpentier-Edward pericardial valve

CLINICAL CHARACTERISTIC AND

OUTCOMES OF MITRAL VALVE
SURGERY IN CHILDREN WITH
RHEUMATIC HEART DISEASE

Kuswiyanto RB Et Al. Sari Pediatri 2009

Clinical characteristic
Median of age at surgery (year)

14 2.7

Female

14 (50%)

Preoperative NYHA class 3 / 4

22 (79%)

Rhythm

27 (96%)

Sinus
AF

Endocarditis

1 (4%)
4 (14%)

Result; pre-op assessment

N=28

stenotic/mixed
severe reg
moderate reg
mild regurgitation

mitral

aortic

tricuspid

pulmonary

Result; type of surgery

57%
N=28

29%
21%

14%

MV repaired

MV replacement

double
replacement

tricuspid
anuloplasty

Result; immediate post-op

N=28
21%
14%

7%
4%
0%

paravalvular leak

Mild MR

Moderate/severe MR

mild stenosis

mixed MRMS

Result; echocardiography
Pre-op

1 week
Post-op

LVEF (%)

61.5 10.4

60.3 9.9

< 0.530

LVEDD (mm)

50.8 7.3

47.9 7.4

< 0.064

LVFS (%)

32.7 5.0

34.2 5.6

< 0.177

Long term management post-op

Restenosis detection or neo regurgitation
LV & valves function monitoring
Long life secondary prophylaxis
Long life anticoagulant

Long term outcome

63

Valves Thrombosis (0,01-0,5%/year)

Damage of the valve structures
Thromboembolic (2-5% / year)
Endocarditis (0,2-1,2% /year )
Bleeding (1-4% /year)
Paravalvular leak (0,1-1,5% /year)