2. Objective
At the end of this lecture you need to understand
Definition
Pathogenesis
Clinical presentation
Diagnosis
Treatment and
Prevention of acute rheumatic fever
3. DEFINITION
Acute rheumatic fever (ARF) is a multisystem disease
resulting from an autoimmune reaction to group A
streptococcus infection
The inflammatory process may involve any organ but
common involved organs are joints, heart, skin and
brain
4. EPIDEMIOLOGY
Incidence of ARF and the prevalence of RHD
declined substantially in Europe, North America, and
developed nations
Thisdecline was largely attributable to improved living
conditions
̴95% of ARF cases and RHD deaths now occur in
developing countries, especially in sub-Saharan
Africa, Pacific nations, Australasia, and Asia
470,000 new cases of Acute Rheumatic Fever/year
233,000 deaths due to Rheumatic Fever/year
5.
6. ARF is mainly a disease of children aged 5–14
years, but rare after 30 years
But recurrent episodes of ARF remain relatively
common in adolescents and young adults
No clear gender association for ARF, but RHD and
Sydenham's Chorea are more common in females
There is a temporal relationship between epidemics
of streptococcal pharyngitis and scarlet fever with
the epidemics of acute rheumatic fever
7. Generally occurs 2-3 weeks after Group A
Streptococcal infection (strep throat or scarlet fever)
In developed nations, ARF has become fairly rare due
to use of antibiotics to treat streptococcal infections
Globally, only 3% of those with an untreated
streptococcal infection develop rheumatic fever
̴40% of those with ARF develop mitral stenosis as
adults
Cutaneous streptococcal infections have not been
shown to initiate ARF
Strains of certain M serotypes of streptococci have
higher associations than other genotypes
Types 1, 3, 5, 6, 14, 18, 19, 24, 27, and 29
8. Pathogenetic pathway for ARF & RHD
strong correlation between progression
to RHD & HLA-DR class II alleles &
the inflammatory protein-encoding genes
MBL2 and TNFA
Common antigenic determinants are
shared between components of GAS
(M protein, protoplast membrane,
cell wall group A carbohydrate,
capsular hyaluronate) & specific
mammalian tissues (e.g., heart, brain,
joint)
certain M proteins
(M1, M5, M6, and
M19) share
epitopes with
human
tropomyosin &
myosin
10. Pathogenesis
Exact mechanism of how Group A streptococcal
infection causes ARF is unknown
But, it is believed to be caused by a cross reactivity of
antibodies (molecular mimicry)
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
11. Pathogenesis
Type of response- 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 (valves, myocardium or joints) producing the
symptoms responsible with acute rheumatic fever
Most patient have elevated antibody titers to at least
one streptococcal antibody
Streptolysin O
Hyaluronidase
Streptokinase
12.
13. CLINICAL MANIFESTATIONS
No pathognomonic clinical or laboratory finding for
acute rheumatic fever
Duckett Jones in 1944 proposed guidelines to aid in
diagnosis & to limit overdiagnosis
Jones criteria for the diagnosis of acute rheumatic
fever 2 major criteria or 1 major & 2 minor
criteria along with the absolute requirement
There are 5 major and 4 minor criteria & an absolute
requirement for evidence (microbiologic or serologic)
of recent GABHS infection
16. Tests used to consider other diagnosis
• Repeat blood culture if possible infective
endocarditis
• Joint aspirate to rule out septic arthritis
• Copper, ceruloplasmin, ANA, drug screen
for choreiform movements
• Serology for autoimmune markers for arboviral,
autoimmune, or reactive arthritis
17. DIAGNOSIS
MAJOR
MANIFESTATIONS
MINOR MANIFESTATIONS
SUPPORTING EVIDENCE OF
ANTECEDENT GROUP A
STREPTOCOCCAL INFECTION
Carditis Clinical features:
Arthralgia
Fever
-Elevated or increasing
streptococcal antibody titer (ASO)
History of (<45 days)
-Positive throat culture or rapid
streptococcal antigen test or
streptococcal sore throat or
scarlet fever
Polyarthritis
Laboratory features:
Elevated acute phase
reactants: ESR, C-reactive
protein
Prolonged PR interval
Erythema
marginatum
Subcutaneous
nodules
Chorea
18. Diagnostic Categories Criteria Criteria
Primary episode of ARF 2 major or 1 major and 2
minor manifestations plus evidence
of preceding GABHS
infection
Recurrent rheumatic fever in
a patient without established RHD
2 major or 1 major and 2
minor manifestations plus evidence
of preceding GABHS
infection
Recurrent attack of rheumatic fever in
a patient with established RHD
2 minor manifestations plus evidence of
preceding GABHS infection
Rheumatic chorea
Insidious onset rheumatic carditis
Other major manifestations or
evidence of group A streptococcal
infection not required
CRVHD (patients presenting for
the first time with pure mitral stenosis or
mixed mitral valve disease and/
or aortic valve disease)
Do not require any other criteria to
be diagnosed as having RHD
20. Migratory Polyarthritis
Most common (75%)
Involves larger joints: the knees, ankles, wrists &
elbows
Rheumatic joints: hot, red, swollen & exquisitely
tender (friction of bedclothes is uncomfortable)
The pain can precede & can appear to be
disproportionate to the other findings
21. Migratory Polyarthritis
The joint involvement is characteristically migratory
in nature
Monoarticular arthritis is unusual unless anti
inflammatory therapy is initiated prematurely,
aborting the progression of the migratory
polyarthritis
22. Migratory Polyarthritis
If a child with fever and arthritis is suspected of
having acute rheumatic fever: withhold salicylates &
observe for migratory progression
A dramatic response to even small doses of
salicylates is another characteristic feature of the
arthritis
Rheumatic arthritis is typically non deforming
Arthritis; earliest manifestation of acute rheumatic
fever
Correlate temporally with peak antistreptococcal
antibody titers
An inverse relationship between the severity of
arthritis & the severity of cardiac involvement
23. Carditis
Carditis & chronic rheumatic heart disease: most
serious manifestations of ARF
Account for essentially all of the associated
morbidity and mortality
Occurs in 50% of patients
Rheumatic carditis: pancarditis with active
inflammation of myocardium, pericardium &
endocardium
Acute rheumatic carditis: tachycardia out of
proportion to fever & cardiac murmurs, with or
without evidence of myocardial or pericardial
involvement
24. Carditis
Consists of either isolated mitral valvular disease or
combined aortic & mitral valvular disease
Valvular insufficiency: characteristic of both acute &
convalescent stages of acute rheumatic fever
Mitral regurgitation: a high-pitched apical
holosystolic murmur radiating to the axilla
In patients with significant mitral regurgitation-
associated with an apical mid-diastolic murmur of
relative mitral stenosis
Aortic insufficiency: a high-pitched decrescendo
diastolic murmur at the upper left sternal border
25. Carditis
Valvular stenosis: appears several years or even
decades after the acute illness
However, in developing countries where ARF often
occurs at a earlier age, mitral stenosis & aortic
stenosis may develop in young children
Moderate to severe rheumatic carditis:
cardiomegaly & congestive heart failure with
hepatomegaly, peripheral & pulmonary edema
Myocarditis &/or pericarditis without evidence of
endocarditis: rarely due to rheumatic heart disease
26. During an episode of
ARF, valve changes can
be minor and are still
able to regress
After recurrent
episodes of ARF,
thickening of subvalvar
apparatus, chordal
thickening and
shortening and
progression to
permanent valve damage
is evident
27. Chorea
St. Vitus’dance
Sydenham chorea: 10-15% of patients with acute
rheumatic fever
Often in prepubertal girls (8-12 yrs)
A long latency period (1-6 mo) between
streptococcal pharyngitis & the onset of chorea
Neuropsychiatric disorder
Neurologic signs: choreic movement & hypotonia
Psychiatric signs: emotional lability, hyperactivity,
separation anxiety, obsessions & compulsions
28. Chorea
Begins with emotional lability & personality changes
(poor school performance)
Replace in 1-4 weeks by characteristic spontaneous,
purposeless movement of chorea (lasts 4-8 months)
followed by motor weakness
Exacerbation by stress & disappearing with sleep
are characteristic
Elevated titers of “antineuronal antibodies” against
basal ganglion tissues have been found in over 90%
of patients
29. Chorea
Clinical maneuvers to elicit features of chorea
include
(1) demonstration of milkmaid's grip (irregular
contractions of the muscles of the hands while
squeezing the examiner's fingers)
(2) spooning and pronation of the hands when the
patient's arms are extended
(3) wormian darting movements of the tongue upon
protrusion
(4) examination of handwriting to evaluate fine motor
movements
30. Chorea
Diagnosis: based on clinical findings with supportive
evidence of GABHS antibodies
In patients with a long latent period: antibody levels
may have declined to normal
SUBCLINICAL CARDITIS-30%
Although the acute illness is distressing, chorea
rarely, if ever, leads to permanent neurologic
sequelae
31. Erythema Marginatum
<3% of patients with acute rheumatic fever
A rare but characteristic rash of acute rheumatic
fever
It consists of erythematous,
serpiginous, macular lesions with
pale centers that are not pruritic
It occurs primarily on the trunk
& extremities, not on the face &
it can be accentuated by warming
the skin
32. Subcutaneous Nodules
Rare, ≤1% of patients with acute rheumatic fever
Consist of firm nodules approximately 1 cm in
diameter along the extensor surfaces of tendons
near bony prominences
A correlation between the presence of these
nodules & significant RHD
33. MINOR MANIFESTATIONS
Clinical:
1. Arthralgia (in the absence of polyarthritis as a
major criterion)
2. Fever (typically temperature ≥ 39ᵒC & occurring
early in the course of illness)
Laboratory :
1.Elevated acute-phase reactants (C-reactive protein,
ESR, polymorphonuclear leukocytosis)
2. Prolonged PR interval on ECG
34. ESSENTIAL CRITERIA
An absolute requirement for the diagnosis of
acute rheumatic fever is supporting evidence of a
recent GABHS infection
35. Recent Group A Streptococcus infection
Hallmarks of GAS sore throat:
High grade fever, tender anterior cervical lymph
nodes
Close contact with infected person
Strawberry tongue, petechiae on palate
Excoriated nares( crusted lesions) in infants
Tonsillar exudates in older children
Abdominal pain
36. Streptococcal throat infection
Redness & swelling
of throat & tonsils;
Beefy, swollen, red
uvula; Soft palate
petechiae
(“doughnut
lesions”)
Tonsillopharyngeal
erythema &
exudates
Sore throat: fever,
white draining
patches on the
throat & swollen or
tender lymph glands
in the neck
37. Recent Group A Streptococcus infection
ARF typically develops 2-4 wks after an acute episode
of GABHS pharyngitis at a time when clinical findings
of pharyngitis are no longer present & only 10-20% of
the throat culture or rapid streptococcal antigen test
results are positive
Therefore, evidence of an antecedent GABHS
infection is usually based on elevated or increasing
serum antistreptococcal antibody titers (ASO)
38. Recent Group A Streptococcus infection
1. ASO titre:
well standardized
elevated in 80% of patients with ARF
ASO titre of 333 Todd unit in children & 250 Todd
unit in adults are considered elevated
2. Antideoxyribonuclease B titre:
≥240 Todd unit in children & ≥120 Todd unit in adults
39. Recent Group A Streptococcus infection
3. Slide agglutination test (Streptozyme):
Detect antibodies against 5 different GABHS
antigens
Rapid, relatively simple to perform & widely available
Less standardized & less reproducible than other
tests and should not be used as a diagnostic test for
evidence of an antecedent GAS infection
GOLD STANDARD: POSITIVE THROAT CULTURE
40. Recent Group A Streptococcus infection
Single antibody measured: 80-85% of patients have
an elevated titer
If 3 different antibodies (antistreptolysin O, anti-
DNase B, antihyaluronidase) measured: 95-100% have
an elevation
Therefore in suspected ARF clinically: perform
multiple antibody tests
Diagnosis of ARF should not be made in patients with
elevated or increasing streptococcal antibody titers
who do not fulfill the Jones criteria
True for younger, school-aged children having GABHS
pyoderma or GABHS pharyngitis
44. TREATMENT
Bed rest
1.Antibiotic Therapy:
10 days of orally administered penicillin or
erythromycin or a single intramuscular injection of
benzathine penicillin to eradicate GABHS from the
upper respiratory tract
Afterwards, the patient should be started on long-
term antibiotic prophylaxis
45. TREATMENT
2. Anti-inflammatory Therapy:
If arthralgia or atypical arthritis is the only clinical
manifestation of presumed acute rheumatic fever
Acetaminophen can be used
Patients with typical migratory polyarthritis & with
carditis and without cardiomegaly or congestive heart
failure:
treat with oral salicylates, 100 mg/kg/day in 4 divided doses
PO for 3-5 days, followed by 75 mg/kg/day in 4 divided
doses PO for 4-8 wk
46. TREATMENT
Patients with carditis & cardiomegaly or congestive
heart failure:
treatment with corticosteroids
Prednisone 2 mg/kg/day in 4 divided doses for 2-6 wk
followed by a tapering of the dose that reduces the dose by
5 mg/24 hr every 2-3 days.
At the beginning of the tapering of the prednisone dose,
aspirin should be started at 75 mg/kg/day in 4 divided
doses to complete 12 wk of therapy
47. TREATMENT
3. Supportive therapies for patients with moderate to
severe carditis include
digoxin, fluid & salt restriction, diuretics & oxygen
NB: The cardiac toxicity of digoxin is enhanced
with myocarditis
48. TREATMENT
Sydenham Chorea
Anti-inflammatory agents are usually not indicated
Occurs after the resolution of the acute phase of the disease
Sedatives: phenobarbital (16-32 mg every 6-8 hr PO)
is the drug of choice
If phenobarbital is ineffective, then haloperidol
(0.01-0.03 mg/kg/24 hr divided bid PO) or
chlorpromazine (0.5 mg/kg every 4-6 hr PO) should
be initiated
Long-term antibiotic prophylaxis is recommended
49. PREVENTION
PREVENTION
PRIMARY- 10 days
course of penicillin
therapy; complete
treatment of group A
streptococcal sore throat
with antibiotics
SECONDARY- directed at
preventing acute GABHS
pharyngitis in patients at
substantial risk of
recurrent ARF
50. SECONDARY PREVENTION
Who should receive prophylaxis?
Patients with documented history of rheumatic fever,
including those with isolated chorea & those without
evidence of rheumatic heart disease must receive
prophylaxis
51. SECONDARY PREVENTION
For how long?
CATEGORY DURATION
Rheumatic fever without carditis At least for 5 yr or until age 21
year, whichever is longer
Rheumatic fever with carditis but
without residual heart disease (no
valvular disease)
At least for 10 yr or well into
adulthood, whichever is
longer
Rheumatic fever with carditis &
residual heart disease (persistent
valvular disease)
At least 10 yr since last
episode & at least until age
40 yr; sometime lifelong
52. SECONDARY PREVENTION
What drugs?
DRUG DOSE ROUTE
Penicillin G benzathine
600,000 U for children, ≤27 kg
1.2 million U for children >27 kg,
every 3-4 wks
IM
OR
Penicillin V 250 mg, twice a day Oral
OR
Sulfadiazine or
sulfisoxazole
0.5 g, once a day for patients
≤60 lb; 1.0 g, once a day for
patients >60 lb
Oral
For people who are allergic to penicillin and sulfonamide drugs
Macrolide or azalide Variable Oral
It is caused by antibody cross reactivity and occurs 2-3 weeks after a Group A Streptococcal infection.
Key pathologic features is Rheumatic Granuloma.
According to the WHO, 15.6 million people worldwide are living with RHD. Of the 500 000 who develop ARF each year, 300 000 go on to develop RHD and 233 000 deaths are attributable each year to ARF/RHD. The are conservative estimates and the true burden of disease is thought to be even greater. This mortality rates are higher than those of rotaviruses, meningitis and hepatitis B and half of those with malaria.
Rheumatic fever: neglected again.
Watkins DA, Zuhlke LJ, Engel ME, Mayosi BM.
Science. 2009 Apr 3;324(5923):37. No abstract available.
This long axis parasternal images demonstrates the progression of valvular disease in the period between ARF and RHD. It is important to remember that timeous diagnosis, treatment and secondary prevention may in cases prevent this progression.
The efficacy of echocardiographic criterions for the diagnosis of carditis in acute rheumatic fever.
Vijayalakshmi IB, Vishnuprabhu RO, Chitra N, Rajasri R, Anuradha TV.
Cardiol Young. 2008 Dec;18(6):586-92. Epub 2008 Oct 10