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ACUTE RHEUMATIC FEVER
(ARF)
I.U. CERRAHPAŞA MEDICAL FACULTY
DEPARTMENT OF PEDIATRICS
DIVISION OF PEDIATRIC CARDIOLOGY
PROF. DR. AYŞE GÜLER EROĞLU
DEFINITION
* ARF, which consists of delayed nonsupurative
sequelae of upper respiratory tract infection
with group A ß-hemolytic streptococci, is a
diffuse inflammatory disease of the connective
tissue involving the heart, joints, brain, blood
vessels, and subcutaneous tissue.
INCIDENCE
* Worldwide, it is the most common cause of acquired
heart disease in children and young adults.
* Although the incidence of ARF has declined sharply
over the past six decades in the developed countries,
particularly developing countries continue to
experience a high incidence of this disease.
* There is no difference in the incidence of ARF
between males and females (chorea is more common
in females).
EPIDEMIOLOGY
* Crowding in inadequate housing is probably the main risk
factor for acquiring streptococcal infection and resulting
ARF.
* The high incidence of streptococcal respiratory infections
in the winter and spring probably accounts for the
frequency of onset of ARF in these seasons.
* ARF is more common in people with genetic
predisposition.
* Initial attacks of ARF are encountered most commonly in
children between the ages of 5 and 15 years old.
EPIDEMIOLOGY
* An untreated group A streptococcal infections of
the upper respiratory tract may result in ARF.
* A relatively small number of M types are the
most common and dangerous rheumatogenic
pharyngeal strains.
* The necessity for the preceding streptococcal
infection to occur in the upper respiratory tract
rather than skin is well documented.
EPIDEMIOLOGY
Upper respiratory tract infection
Socioeconomic
standarts
Crowding
Winter
5 – 15 years old
School
Group A ß-hemolytic
streptococci
Penicilline (-)
(%2)
ARF
1-5 (3)
weeks
PATHOGENESIS
* ARF results from the interaction of three main factors
– A causative agent (group A ß-hemolytic streptococci)
– An organ site dependence (upper respiratory tract)
– A vulnerable host
* How the organism causes rheumatic fever is still unclear.
*The most popular
autoimmunity.
theory
of
pathogenesis
is
PATHOGENESIS
Grup A Streptococcus
Serotypes; M3, M18
Tissue/Organ
Inflammation
Joints Heart
Brain
Vascular
Connective tissue
Susceptile Host
Positive for
HLA-DR 4,2,1,3,7
Allotype D8 /17
Immune Reaction
Cross-Reactive Antibody
and / or
Cell-Mediated Immunity
ACUTE RHEUMATİC FEVER
Latency period between the occurrence of the streptococcal
pharyngitis and the onset of the clinical manifestations of ARF.
PATHOLOGY
* ARF is characterized pathologically by two main
lesions in the connective tissues occuring particularly
around small blood vessels in heart, brain, joints and
skin.
* The first and the earliest lesion is exudative,
degenerative, and inflammatory. This lesion
contributes to transitory manifestations of ARF and
responds to antiinflammatory agents. This early
phase lasts 2 to 3 weeks and is followed by the
second lesion.
PATHOLOGY
*The second characteristic lesion of ARF is a
proliferative one that may persist for many months and
years. Aschoff’s nodules are characteristic proliferative
lesion of ARF. The proliferative lesion probably does
not respond to the antiinflammatory agents.
* Pericardium-serofibrinous pericarditis
*Myocardium-Aschoff’s
nodules,
interstitial
inflammation
*Endocardium-mitral and aortic valvulitis and rarely
tricuspid or pulmonary valvulitis
* Joints-artritis heals without residual manifestations
* Subcutaneous nodules-heal rapidly without sequelae
J o n e s C r i t e r ia
Major Manifestations
• Polyarthritis
• Carditis
• Sydenham’s chorea
• Erythema marginatum
• Subcutaneous nodules
Minör Manifestations
Clinical
• Fever
• Arthralgia
Laboratory
• Elevated acute phase reactans
Erythrocyte sedimentation
Supporting evidence of antecedent
C-reactive protein
group A Streptococcal infection
• Prolonged P-R interval (> 0.16")
• Elevated ASO
• Positive throat culture or
• Rapid streptococcal antigen test
DIAGNOSIS
If supported by evidence of preceding group A streptococcal
infection, the presence of two major manifestations or of one
major and two minor manifestations indicates a high
probability of ARF.
HISTORY
* History of streptococcal pharyngitis, 1 to 5 weeks
(average, 3 weeks) before the onset of symptoms, is
common. The latent period may be as long as 2 to 6 months
(average, 4 months) in cases of isolated chorea.
* Pallor, malaise, easy fatigability, and other history, such
as epistaxis (5% to 10%) and abdominal pain, may be
present.
* Family history of ARF frequently is positive.
ARTHRITIS
* Arthritis, the most common manifestation of ARF (70% of
cases), usually involves large joints (e.g., knees, ankles,
elbows, wrists). Often more than one joint, is involved, with a
characteristic migratory nature of the arthritis. Swelling, heat,
redness, severe pain, tenderness, and limitation of motion are
common.
* The arthritis responds dramatically to salicylate therapy; if
patients treated with salicylates (with documented therapeutic
levels) do not improve in 48 hours, the diagnosis of ARF
probably is incorrect.
DIFFERENTIAL DIAGNOSIS
•Juvenile rheumatoid arthritis is often misdiagnosed as ARF.
The following findings suggest juvenile rheumatoid arthritis
rather than ARF: involvement of peripheral small joints,
symmetrical involvement of large joints without migratory
arthritis, pallor of the involved joints, a more indolent
course, no evidence of preceding streptococcal infection, and
the absence of prompt response to salicylate therapy within
24 to 48 hours.
DIFFERENTIAL DIAGNOSIS
*
Other collagen vascular diseases (systemic lupus
erythematosus, mixed connective tissue disease); reactive
arthritis, including poststreptococcal arthritis; serum
sickness; and infectious arthritis (such as gonococcal)
occasionally require differentiation.
* Virus-associated acute arthritis (rubella, parvovirus,
hepatitis B virus, herpes viruses, enteroviruses) is much
more common in adults.
* Hematologic disorders, such as sicklemia and leukemia,
should be considered in the differential diagnosis.
* Poststreptococcal reactive artritis
CARDITIS
* Frequency in ARF is 50 %
(in our patients 75,4 %)
* ARF may frequently involve all three layers.
Pancarditis
Endocarditis: Mitral regurgitation, aortic regurgitation, mitral
stenosis (late sequelae)
Myocarditis: Tachycardia (out of proportion to the fever that
persist during sleep), congestive heart failure (CHF)
Pericarditis : Friction rub, pericardial effusion, chest pain, and
ECG changes
MITRAL REGURGITATION (MR)
* MR occurs in about 50-70% of patients with rheumatic
carditis.
* In our patients with ARF is seen in about 78% and occurs in
about 92% of patients with rheumatic carditis
•S1 is normal or diminished.
•S2 may split widely.
•S3 commonly present and loud.
•Regurgitant systolic murmurs at the
apex , grade 2 to 4/6, transmits to
left axilla
•A mid-diastolic apical murmur due
to edematous cusps (Carey-Coombs)
MITRAL REGURGITATION
ECG: Normal in mild cases
Left ventricular hypertrophy (LVH) with or without
left atrial enlargement (LAH)
Atrial fibrillation is rare in children
X-ray: LV and the LA enlarge
Pulmonary vascularity usually is normal
Echo: The two dimentional echo shows dilated LV and LA
Color, Doppler studies can assess the severity of MR
MITRAL REGURGITATION
AORTIC REGURGITATION
* AR occurs in about 20% of patients with rheumatic carditis.
(In our patients isolated AR is seen in about 2% and associated
with MR 85%)
* It can be an isolated finding but is usually associated with MR
AORTIC REGURGITATION
* Early diastolic decrescendo murmur that starts with the aortic componen
of the second heart sound, over the third left intercostal space.
* In the presence of severe AR, the murmur is loud and may be associated
with a diastolic thrill.
* Systolic blood pressure increases (because of volume overload) and
diastolic blood pressure decreases(because of aortic runoff during diastole)
* In such cases, the increased pulse pressure due to the aortic runoff lesion
is reflected by bounding peripheral pulses.
AORTIC REGURGITATION
ECG: Normal in mild cases
In severe cases, LVH usually is present. LAH may
be present.
X-ray: Cardiomegaly involving the LV is present
A dilated ascending aorta and/or a prominent
aortic knob frequently are present.
Pulmonary venous congestion develops if LV
failure supervenes.
Echo: The LV dimention is increased, but the LA remains
normal in size.
Color, Doppler studies can assess the severity of AR
AORTIC REGURGITATION
MYOCARDITIS
Myocarditis is usually accompanied by valvulitis and
leads to:
1) Tachycardia (out of proportion to the fever) that
persists during sleep.
2) Rapid cardiac enlargement.
3) Congestive heart failure
PERICARDITIS
* Pericarditis is encountered in only 5 to 10% of patients with
carditis. In our patients is seen in about 10% and associated
with valvulitis.
* Pericarditis (friction rub, pericardial effusion, chest pain,
and ECG changes) may be present.
* Differential diagnosis; Isolated pericarditis is usually due to
an etiology other than ARF (viral and other pericarditis
collagen vascular diseases).
SYDENHAM'S CHOREA
Frequency 10-15 %
Girls > Boys
Latency period 1-6 months (4 months)
It is a neuropsychiatric disorder consisting of both
neurologic signs (choreic movement and hypotonia) and
psychiatric signs (e.g., emotional lability, hyperactivity,
seperation anxiety, obsessions and compulsions).
SYDENHAM'S CHOREA
* The adventitious movements, weakness, and hypotonia
continue for an average of 7 months (up to 17 months) before
slowly waning in severity.
* Recently, elevated titers of “antineuronal antibodies”
recognizing basal ganglion tissues have been found in over
90% of patients. The levels of the antineuronal antibody titer
are positively related to the severity of choreic movements.
* These findings suggest that chorea may be related to
dysfunction of basal ganglia and cortical neuronal
components.
* Differential diagnosis: congenital choreoathetosis, habitual
spasms, brain tumors, behavior problems
Cardiac involvement of 25 patients with chorea in
the Division of Pediatric Cardiology in Cerrahpaşa
Medical Faculty
17 girls, 8 boys
Carditis clinically (+) 7 (% 28)
Carditis clinically (Ø) 18--In 14 of these patients
(78%),carditis was detected with echocardiography
(silent carditis)
Isolated MR : 9
Isolated AR : 3
MR + AR : 2
ERYTHEMA MARGINATUM
* Frequency in ARF is 5-6 % (in our patients 2.6 %)
* Erythema marginatum is a macular, nonpruritic rash with
a serpiginous erythematous border surronding normallooking skin. They are most commonly located on the
trunk and proximal limbs and do not involve the face.
* Erythema marginatum is not pathognomonic, having been
reported in drug reactions and glomerulonephritis.
SUBCUTANEOUS NODULES
* Recent studies report a frequency of less than 5 %
(in our patients 4,7 %)
* The nodules are located on the extensor surface of the joints,
particularly the elbows, knuckles, knees and ankles.
Occasionally they are found on the scalp and over the spine.
They vary in size from 0.5 to 2 cm and are painless and
freely movable.
* Subcutaneous are not pathognomic of ARF, since they
occur in juvenile rheumatoid arthritis and systemic lupus
Major manifestations in 400 patients with ARF in the Division of
Pediatric Cardiology in Cerrahpaşa Medical Faculty
Major belirti
1965-74
N
%
Carditis (isolated)
Arthritis (isolated)
Corea (isolated)
105 56,1 68 32 173 43,3
29 15,5 44 21 73 18,5
13
7
17 8 30
7,5
Carditis+Arthritis
Carditis+Chorea
Carditis+Nodules
Carditis+Eritema
22
4
4
2
Carditis+Arthritis+Nodules
Carditis+Eritema+Nodules
Carditis+Arthritis+Chorea
Carditis+Arthritis+Eritema
Carditis+Chorea+Nodules
2
1
1
1
1
1988-98 Toplam
N % N
%
11,8 76 36 98
2,1 2 0,9 6
2,1 1 0,5 5
1,1
2
1,1
0,5
0,5
0,5
0,5
Carditis+Arthritis+Nodules+Eritema
5 major manifestations
0
3 1,4
2 0,9
2 0,9
1 0,5
0
24,5
1,5
1,3
0,5
5
1
3
3
1
1,3
0,3
0,8
0,8
0,3
1
0,3
%
69,1
29,6
3,5
0,3
MINOR MANIFESTATIONS
Clinical findings
* Arthralgia refers to joint pain without the objective changes of
arthritis. It must not be considered a minor manifestation when
arthritis is present.
•Fever (usually with a temperature of at least 102°F [38.8°C]) is
present early in the course of untreated rheumatic fever. The classical
form is very rare nowadays.
Laboratory findings
*Elevated acute-phase reactants (elevated C-reactive protein levels
and elevated erythrocyte sedimentation rate) are objective evidence
of an inflammatory process.
* A prolonged PR interval on the ECG is neither specific for ARFnor
an indication of active carditis.
Supporting evidence of antecedent
group A streptococcal infection
* Elevated ASO
* Positive throat culture or
* Rapid streptococcal antigen test
Antistreptolysin O (ASO) titer is well standardized and
therefore is the most widely used test. It is elevated in 80%
of patients with acute rheumatic fever and in 20% of
normal individuals. Only 67% of patients with isolated
chorea have an elevated ASO titer.
A single low ASO titer does not exclude acute rheumatic
fever.
Department of Pediatrics in Cerrahpaşa Medical Faculty
ASO levels in ARF and other arthritisi
N
X
FMF(1976-78)
<200 >200
%
%
26 1007 15,4 84,6
>400 >800 >1200
%
%
%
61,5 41,0 34,6
Henoch-Schönlein
(1977-86)
76
904
75,0
48,7
52,9
35,7
22,9
22,7 77,3
57,0
43,0 27,3
74,1
42,0
JRA (1967-79) 70
653
14,4 85,5
34,3 65,7
Non ARF arthritis
172 777
ARF (1965-74)
162
963
7,4
92,6
29,0
25,1
The antideoxyribonuclease B test is favored over other
tests. Titers of 240 Todd units or greater in children and
120 Todd units or greater in adults are considered
elevated.
The Streptozyme test (Wampole Laboratories) is a
relatively simple slide agglutination test, but it is less
standardized and less reproducible than the other
antibody tests. It should not be used as a definitive test
for evidence of antecedent group A streptococcal
infection.
DIAGNOSIS
A diagnosis of acute rheumatic fever is highly probable
when either two major manifestations or one major and two
minor
manifestations,
plus
evidence
streptococcal infection, are present.
of
antecedent
DIAGNOSIS
* Two major manifestations are always stronger than
one major plus two minor manifestations.
* Arthralgia cannot be used as a minor manifestation in
the presence of arthritis.
* The absence of evidence of an antecedent group A
streptococcal infection is a warning that ARF is
unlikely (except when chorea is present).
The patients who show no evidence of cardiac
involvement on initial examination should be monitored
closely for evidence of carditis over the following 2 to 3
weeks.
DIFFERENTIAL DIAGNOSIS
* The heart murmurs of ARF must be differentiated
from functional murmurs, mitral valve prolapse,
myocarditis, pericarditis and congenital heart
diseases.
* The possibility of the early suppression of full
clinical manifestations should be sought during
the history taking. Subtherapeutic doses of aspirin
may suppress full manifestations.
CLINICAL COURSE
* In 1884 Laseque noted, ‘ARF is a disease that licks the
joints but bites the heart’
* Only carditis can cause permanent cardiac damage
(Rheumatic heart disease). Signs of mild carditis disappear
rapidly in weeks, but those of severe carditis may last for 2
to 6 months.
* Arthritis subsides within a few days to several weeks,
even without treatment, and does not cause permanent
damage.
* Chorea gradually subsides in 6 to 7 months or longer and
usually does not cause permanent neurologic sequelae.
PROGNOSİS
Onat T, Ahunbay G: Long-term prognosis of rheumatic mitral regurgitation:
Presentation of yearly prognostic regressions in relation to affecting factors.
The Turkish Journal of Pediatrics 31: 185-199, 1989
Onat T, Ahunbay G: Long-term prognosis of rheumatic mitral regurgitation:
Presentation of yearly prognostic regressions in relation to affecting factors.
The Turkish Journal of Pediatrics 31: 185-199, 1989
Onat T, Ahunbay G: Long-term prognosis of acute rheumatic carditis with
combined aortic and mitral regurgitation
The Turkish Journal of Pediatrics 31: 185-199, 1989
TREATMENT
* Streptococcal eradication and prophylaxis
* Treatment of clinical manifestations
Streptococcal Eradication
Benzathine penicillin G
Penicillin-V
Erithromycin
600.000 Ü Im <27 kg
Single dose
1.200.000 Ü Im >27 kg
Single dose
3x250 mg oral children
10 days
3x500 mg oral adolescents, adults 10 days
20-40 mg/kg/day 2-4 doses oral 10 days
Prophylaxis: carditis along the life, arthritis until 21 years
old or 5 years after last attack-which is longer
Benzathine penicillin G
600.000 Ü Im <27 kg Every 3 weeks
1.200.000 Ü Im >27 kg Every 3 weeks
Penicillin-V
2x500 mg or 2x1000 mg
Sulfadiazine
1.0 gr
Erithromycin
2x250 mg
oral
oral
oral
Treatment of Clinical Manifestations
Antiinfinflammatory agents should be delayed until a proper clinical an
laboratory diagnosis has been established.Neither salicylates n
corticosteroids guarantee termination of the disease and its cardiac damage
Carditis
Oral prednisolon 2 mg/kg/day (mak.60 mg) 2-3 wk.
After improvement, the therapy is with drawn
gradually over 4 to 6 weeks
Arthritis Alone
Salicylate 90-100 mg/kg/day (4 dose) 2- 3 wk. After
improvement, therapy is with drawn gradually over 3
weeks
The serum salicylate level should be about 25 mg/dL
and should not exceed 30 mg/dL
General Guidelines for Bed Rest and Indoor Ambulation
Arthritis
Alone
Mild
Carditis *
Moderate
Carditis **
Bed rest
1-2 wk
3-4 wk
4-6 wk
Indoor
ambulation
1-2 wk
3-4 wk
4-6 wk
* Questionable cardiomegaly.
** Definite but mild cardiomegaly.
*** Marked cardiomegaly (>0,56) or heart failure.
Severe
Carditis ***
As long as
CHF is present
2-3 mo
Management of Sydenham's chorea
Haloperidol 3 x 0.5 mg (3 x 2.0 mg)
Phenobarbital 15-30 mg (every 6-8 h.)
Valproate 15-20 mg/kg/day
Anti-inflammatory agents are not needed in patients with isolated chorea.
Without the prophylaxis, about 25% of patients with isolated chorea
(without carditis) develop rheumatic valvular heart disease in 20-year
follow-up.