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风 湿 热Cai Yun
Department of Pediatrics The Third Affiliated Hospital of Sun Yat-sen University E-mail : [email protected]
Rheumatic Fever
Rheumatic fever is an immunological Rheumatic fever is an immunological inflammatory disease inflammatory disease
follows infection with certain strains of group A follows infection with certain strains of group A streptococcistreptococci
easily recur without prophylaxiseasily recur without prophylaxis
carditis
choreamigratory polyarthritis
subcutaneous nodules
permanent valvular disease
erythema marginatum
Epidemiology
incidenceincidence ：： 22/10000022/100000 in Chinain China
seasonseason ：： winter or springwinter or spring
ageage ：： 5 – 15y5 – 15y
Etiology☆ a nonsuppurative complication of group A streptococcal infection of the upper respiratory tract
☆ occurs 1 - 4 weeks after
convalescence of infection
☆ individual propensity
☆ environmental factors
latitude altitude humidity latitude altitude humidity nutrition crowding agenutrition crowding age
Colonies and β-hemolysis
PathogenesisPathogenesis molecular mimicry of bacterial antigens molecular mimicry of bacterial antigens similarity between bacterial and self molecules as similarity between bacterial and self molecules as
recognized by immune cells leading to across-react recognized by immune cells leading to across-react with target organs in the bodywith target organs in the body
circulating immune complexes (CIC)circulating immune complexes (CIC) circulating immune complexes activate the circulating immune complexes activate the
complement system leading to the inflammatory complement system leading to the inflammatory changes changes
Genetic pronenessGenetic proneness HLA-B35HLA-B35 、、 HLA-DR4HLA-DR4
capsulecapsule （（ synovial membranessynovial membranes ））
Cell wall proteinCell wall protein （（ myocardium, endocardiumyocardium, endocardiumm ））
Cell wall Cell wall polysaccharidespolysaccharides （ （ myocardiumyocardium, endocardiumm, endocardium ））
cell membrane proteincell membrane protein （ （ myocardiummyocardium 、、 subthalamisubthalamic nucleusc nucleus 、、 caudate nucleucaudate nucleuss ））
The antigens of Group A streptococci and molecular mimicry
pathologypathology 急性渗出期（acute exudative period）
增生期（proliferative period）
硬化期 (sclerotic period)
1 month 1 month
3~4 months3~4 months
2~3 months2~3 months
connective tissue edemas ,effuse, and degenerate, infiltrated with inflammatory cells.
Aschoff body in myocardium, muscle,
endocardium, subcutaneous tissue
collagen fiber hyperplasia and scar tissue formation
mitral >aortic>tricuspid>pulmonary
acute exudative period
edema and degeneration of collagen and exudation in pericardium
edema and degeneration of collagen and exudation in pericardium
pericardial effusionpericardial effusion fibrinous pericarditisfibrinous pericarditis
proliferative period
Aschoff body in endocardium
中心： fibrinoid necrosis of collagen
外周： lymphocytes, plasma cells and
Aschoff giant cells
Aschoff body in endocardium
中心： fibrinoid necrosis of collagen
外周： lymphocytes, plasma cells and
Aschoff giant cells Aschoff giant cell
large cells with two or more pale nuclei that have prominent nucleoli.
Aschoff giant cell
large cells with two or more pale nuclei that have prominent nucleoli.
sclerotic period
mitral valve shows thickening distorted cusps, adherent commissures with calcification and thrombus deposition, fusion and shortening of chordae tendinae.
mitral valve shows thickening distorted cusps, adherent commissures with calcification and thrombus deposition, fusion and shortening of chordae tendinae.
stenotic mitral valve shows fusion of commissures, thickening and calcification of the cusps.
stenotic mitral valve shows fusion of commissures, thickening and calcification of the cusps.
commissures are fused; cusps are severely thickened. The valve is both incompetent and stenotic.
commissures are fused; cusps are severely thickened. The valve is both incompetent and stenotic.
Clinical Manifestation
Major clinical manifestations: carditis; polyarthritis; chorea; subcutancous nodules; erythema marginatum
Ordinary complaints: fever / arthralgia
Duration of acute rheumatic fever: ≤6 months
rheumatic carditisrheumatic carditisIncidence:Incidence: 40~50%40~50%
One and only permanent damageOne and only permanent damage
EndocarditisEndocarditis Myocarditis Myocarditis PericarditisPericarditis Congestive heart failure during the Congestive heart failure during the
initial episode:initial episode: 5%~10%5%~10%
PancarditisPancarditis
MyocarditisMyocarditis Tachycardia Tachycardia
disproportionate to the feverdisproportionate to the fever Congestive heart failureCongestive heart failure Gallop rhythmGallop rhythm Soft systolic murmur heard Soft systolic murmur heard
at the apexat the apex ECG abnormalitisECG abnormalitis ：： arrhythmias;arrhythmias;
prolongation of the P-R prolongation of the P-R interval;interval;
atrioventricular block (AVB)atrioventricular block (AVB) Cardiomegaly on x-rayCardiomegaly on x-ray
Before treatment
after treatment
Endocarditis
• Mitral regurgitation:
Apical systolic murmur at the apex
• Relative mitral stenosis:
Low-pitched mid-diastolic rumble
• Aortic regurgitation:
Diastolic murmur in the third costa at the left side of the sternum
PericarditisPericarditis
Precordial painPrecordial pain
A friction rubA friction rub
Striking increase in Striking increase in heart size on X-rayheart size on X-ray
Echocardiography: Echocardiography: pericardial effusion pericardial effusion ＞＞ 50ml50ml
CT scanCT scan
Rheumatic arthritisRheumatic arthritis
Incidence: 50%~60% Acute migratory polyarthritis Larger joints of the extremities are affected:
knee 、 ankle 、 elbow 、 wrist Red, hot, swollen, exquisitely tender and painful if
moved as one joint recovered, another joint may be
involved arthritis lasts less than 1 month without deformity
ChoreaChorea Incidence: 3%~10%Female ＞ male; 8~12 yeas oldSudden, aimless, irregular movements of the
extremities and facial muscles that subside during sleep and exaggerated by emotions:
shrug shoulders make eyes bend knees flex wrist
Emotional instability: nervousMuscle weakness and ataxia:
clumsy, stumble, handwriting or speech disorders
normalnormal choreiform movementschoreiform movements
ChoreaChorea
erythema marginatumerythema marginatum
The characteristic rashes consist of an evanescent , pink, erythematous maculae, with a clear center and serpiginous outline. The rash is transient, migratory and nonpruritic , which found primarily on the torso and proximal extremities.
subcutaneous nodulessubcutaneous nodules
Subcutaneous nodules are painless small swellings over bony prominences, primarily over the extensor tendons of the hands, feet, elbows, scalp, scapulae, and vertebrae. Nodules tend to occur in crops and may persist for days to months after the onset of acute rheumatic fever.
Other clinical features
Variable Variable feverfever
TirednessTiredness palenesspaleness PneumoniaPneumonia NosebleedNosebleed
sweatingsweatingAbdominal Abdominal
anginaangina
Laboratory findingsLaboratory findings
Blood routine test: WBC↑,mild anemia
Acute phase reactants ： ESR↑, CRP↑
Isolation of group A streptococci (+)
Serum antibody against the specific strptococci: ASO↑, ASK ↑, AH ↑, anti-DNase B ↑
Immune system: IgG ↑, IgA ↑, C3 ↑
ECG: P-R interval ↑, second degree AVB
Routine roentgenogram
Echocardiography
The Jones Criteria Revised with Addition
of World Health Organization Recommendations
Major Criteria Minor Criteria
Carditis Fever
Polyarthritis, migratory Arthralgia
Erythema marginatum increased acute-phase reactants
Chorea ESR↑, CRP↑
Subcutaneous nodules Prolonged P-R interval
Plus
Evidence of a preceding group A streptococcal infection (culture, rapid
antigen, antibody titers rise/elevation, scarlet fever)
★ two major manifestations + Evidence of S.I (streptococcal infection )
★ one major ＋ two minor manifestations + Evidence of S.I
Fever, body weight ↓, tireness
Tachycardia or arrhythmias
ESR↑, CRP↑, neutrocyte↑, antibody titer↑
Dignosis of active rheumatic fever
Differential diagnosisDifferential diagnosis
FeverFever
CarditisCarditis
ArthritisArthritis
Differential diagnosis of carditisDifferential diagnosis of carditis
Infective endocarditis ： anemia, splenomegaly, petechia, embolism
blood culture （ + ） vegetations on endocardium / valves
Viral myocarditis ： arrhythmias ( premature contraction)
evidence of viral infection
Differential diagnosis of arthritisDifferential diagnosis of arthritis
Systemic lupus erythematosus (SLE) : malar rash, proteinuria, hypertension, leukopenia, Coombs(+) hemolytic anemia, antinuclear antibodies(+)
Juvenile rheumatoid arthritis (JRA) ： morning stiffness, iridocyclitis, progression of joint destruction, ANA(+), rheumatoid factor(+)
Bed restBed rest
antibioticsantibiotics
anti-rheumatism therapyanti-rheumatism therapy
heteropathyheteropathy
ManagementManagement
（ 1 ） Bed rest
carditiscarditis cardiamegalycardiamegaly congestive congestive
heart failureheart failure
---- ---- ---- 2 w2 w 2 w2 w
++ ---- ---- 4 w4 w 4 w4 w
++ ++ ---- 6 w6 w 6 w6 w
++ ++ ++ 8 w8 w 3 mon3 mon
（ 2 ） antibiotics
Procaine penicillin G: 4.8 millon U ~ 9.6 millon U / d ， iv drip ×2~3 w PG AST (+) : Erythromycin p.o ×10 d
（ 3 ） anti-rheumatism therapy
Carditis ： Prednisone, 2mg/kg.d ( ≤ 60mg/d ) ×2~4w; reduce dose gradually; full duration = 8~12 w
arthritis ： Aspirin , 80~100mg/kg.d ( ≤ 3g /d ) until remission; gradually reduce to half dose for 4~6w
（ 4 ） heteropathy congestive heart failure ： steroid; oxygen therapy; diuresis;
captopril ； digitalis ( small dose)
chorea ： tranquilizer (chlorpromazine,
barbital )
arthralgia: immobilization of affected joints
prophylaxisprophylaxis
Recurrent rheumatic fever benzathine Penicillin: 1.2million U , Q4W,≥5 years patients with established heart disease may continue for ≥ 10 years, even the whole life.
PG AST (+) : Erythromycin p.o ×6 ~7 d, every month
Bacterial myocarditis Patients with rheumatic heart disease should receive
antibiotic prophylaxis before and after operation to prevent bacterial infection.
EmphasesEmphases
Five major clinical manifestations
Jones criteria
Features of active rheumatic fever
treatment ：
prophylaxis ： long-acting PG
Kawasaki disease
（（ Mucocutaneous lymph node syndromeMucocutaneous lymph node syndrome ））（（ Mucocutaneous lymph node syndromeMucocutaneous lymph node syndrome ））
川 崎 病
Tomisaku Kawasaki described KD in 1967
KD is an acute generalized systemic vasculitis of unknown etiology with fever and rashes.
Coronary artery dilation or aneurysms KD has replaced acute rheumatic fever as
the most common cause of acquired heart disease in children In developed countries
Age ： < 4 years old (80%) < 2 years old (50%)
Sex ： more often in males than in females (1.5:1)
Season ： clusters in winter / spring
Racial background: Asian children, especially those of Japanese descent.
EpidemiologyEpidemiology
Etiology and PathogenesisEtiology and Pathogenesis
etiology of KD remains undiscovered.etiology of KD remains undiscovered. immunopathogenic mechanism for immunopathogenic mechanism for
coronary diseasecoronary disease organism super-antigenorganism super-antigen mimic antigen ( HSP65)mimic antigen ( HSP65) T cell - mediated immune response T cell - mediated immune response cytokine – mediated immune damagecytokine – mediated immune damage
stageⅠ ： 1~10 d ， acute small periarteritis ； cardiac inflammatory changes stageⅡ ： 10~25 d ， coronary arteritis; elastic
laminae and muscular layers split, leading
to thrombus and aneurysms.stage Ⅲ ： 26~31 d ， acute inflammation remission;
fibrous tissue proliferates; intima thickens;
coronary arteries narrow or occlude . stage Ⅳ ：≧ 40 d, cicatrization in myocardium;
occluded arteries reopen.
PathophysiologyPathophysiology—— systemic vasculitis (coronary arteries) systemic vasculitis (coronary arteries)
normal coronary artery stageⅠ
stage Ⅱ
10 days after the onset of symptoms, elastic laminae splits , intima proliferates and thickens in branch of coronary artery.
Huge coronary artery aneurysm
Clinical manifestationClinical manifestation
Mucocutaneous lymph node abnormalities
Cardiovascular abnormalities
Other nonspecifically manifestations
Main clinical featuresMain clinical features
1. Fever
usually more than 39°C, for at least usually more than 39°C, for at least 5 days5 days
High spiking and remittentHigh spiking and remittent not responds to antibioticsnot responds to antibiotics Generally persists 1-2 weeks Generally persists 1-2 weeks
without treatmentwithout treatment usually resolves in 1-2 days after usually resolves in 1-2 days after
treatment with intravenous gamma treatment with intravenous gamma globulin (IVIG)globulin (IVIG)
2. Bilateral conjunctival injection without exudate
Main clinical featuresMain clinical features
Main clinical featuresMain clinical features
3. inflammation of the lips and oral cavity Injected, dry, fissured- lips injected oral and pharyngeal mucosa Strawberry tongue with prominent papillae and
erythema no oral exudates, ulcerations, or Koplik spots
Main clinical featuresMain clinical features
4. Hands and feet Erythema, or indurative edema of palms and soles Periungual membranous desquamation of fingers
and toes about 2 weeks after onset Transverse grooves across the nails
Main clinical featuresMain clinical features
5. rash of various formsdiffuse, scarlatiniform or
erythema polymorphous rasherythema or desquamation in perineal region
Main clinical featuresMain clinical features
6. non- purulent cervical lymphadenopathy
50-75% of patients With a node size of 1.5 cm or greater in
diameter tenderness, not red
1. carditisTachycardiaGallop rhythm systolic murmursArrhythmia
2. myocardial ischemia angina myocardial infarction
Cardiovascular abnormalities
3. Coronary arterial changes3. Coronary arterial changes — 2~4 weeks after onset / convalescent— 2~4 weeks after onset / convalescent phasephase
coronary arteritis
vessel intima roughened
coronary arteries narrow
coronary arteries dilation(CAD)
coronary artery aneurysm
Aneurysm at left anterior descending ( LAD) coronary artery
Aneurysm at left anterior descending ( LAD) coronary artery
LADLAD
Coronary Artery AneurysmCoronary Artery Aneurysm — 20~30% of untreated children
normal coronary arterynormal coronary artery
High risk factors of CA aneurysmHigh risk factors of CA aneurysm
age: < 6 month or > 3 yearsage: < 6 month or > 3 years male sexmale sex fever for more than 16 days or recurrencefever for more than 16 days or recurrence cardiomegaly or arrhythmiacardiomegaly or arrhythmia lab findings: lab findings:
Hb < 80g/L, WBC > 16~30X10Hb < 80g/L, WBC > 16~30X1099/L, /L,
PLT > 1000X10PLT > 1000X1099/L, ESR > 100mm/h/L, ESR > 100mm/h KD recurrenceKD recurrence
Less-common featuresLess-common features
asepticaseptic
meningitismeningitis abdominal abdominal
painpain otitis mediaotitis media jaundicejaundice diarrheadiarrhea
gallbladder gallbladder
hydropshydrops hepatichepatic
dysfunctiondysfunction arthralgiaarthralgia arthritisarthritis urethritisurethritis
Blood analysis ：
WBC↑; mild anemia;
PLT↑in 2nd~3th week ； ESR↑ ； CRP↑ ； ALT↑; AST↑
Laboratory findingsLaboratory findings
Immune systemImmune system
IgG 、 IgM 、 IgA 、 IgE↑ ； Circulating Immune Complexes ↑ ； C3 normal or ↑
ECG ： ST-T abnormalities of pericarditis
or myocardial infarction
Chest roentgenogram ： nonspecific
perihilar or parenchyma infiltrates ； cardiamegaly.
EchocardiographyEchocardiography
coronary arteritis
intima roughened coronary arteries
narrow or dilation coronary artery
aneurysm pericardial effusion mitral , aortic, or
tricuspid disturbed
flow
coronary arteritis
intima roughened coronary arteries
narrow or dilation coronary artery
aneurysm pericardial effusion mitral , aortic, or
tricuspid disturbed
flow
1. coronary artery aneurysm
2. right coronary artery trunk
3. aorta
diameter of normal CA ( main stem)
0 ～ 3 y <2.5 mm 3 ～ 9 y <3 mm 9 ～ 14 y <3.5 mm
diameter of normal CA ( main stem)
0 ～ 3 y <2.5 mm 3 ～ 9 y <3 mm 9 ～ 14 y <3.5 mm
grades of CAD ( diameter of CA) mild 3mm ~ 4mm
moderate 4mm ~ 7mm
severe ≥8mm （ CA aneurysm ）
Coronary angiographyCoronary angiography
— — myocardial ischemia / multiple coronary myocardial ischemia / multiple coronary aneurysms aneurysms
normalnormal aneurysmaneurysm
LAD dilation and narrowLAD dilation and narrow
Diagnostic guidelinesDiagnostic guidelines ((for typical cases)for typical cases)
fever lasting more than 5 daysfever lasting more than 5 days + 4 of the following 5 criteria + 4 of the following 5 criteria (other (other
illnesses must be excluded):illnesses must be excluded):
1. polymorphous rash
2. bilateral conjunctival injection without exudate
3. diffuse injection of oral mucosa, erythema or fissuring of
the lips, strawberry tongue
4. nonpurulent cervical lymph node enlargement (one lymph node >1.5 cm)
5. extremity changes: erythema of palms / soles,
indurative edema of hands / feet, Membranous desquamation of the fingertips
Diagnostic guidelinesDiagnostic guidelines ( (for atypical cases)for atypical cases)
fever lasting more than 5 daysfever lasting more than 5 days
≤≤3 of the 5 criteria3 of the 5 criteria
coronary arteries dilation or aneurysm detected by
echocardiography
Differential diagnosisDifferential diagnosis
Scarlet fever Red rash blanches with pressure, which is diffuse
but spares the palms, soles, and face. The face appears flushed. The skin rash fades in a week and is followed by extensive desquamation. Patient has good response to PG.
Differential diagnosisDifferential diagnosis
Exudative and Erythema Multiforme polymorphous Erythema, herpes and extensive
desquamation; oral ulcers; conjunctival exudate; no indurative edema of palms or soles
Differential diagnosisDifferential diagnosis
septicemia blood curture (+), good response to antibiotics detected focus
systemic onset of juvenile rheumatoid arthritis NO conjunctival injection NO injection of oral mucosa or fissuring of the lips NO Indurative edema of hands and feet , or desquamation NO coronary artery damage
• relieve vasculitis
• inhibit PLT aggregation
• relieve vasculitis
• inhibit PLT aggregation
Treatment & MedicationTreatment & Medication
（ 1 ） aspirin
administered for anti-inflammatory and
antithrombotic effects acute phase : 80-100 mg/kg/d PO in tid/qid 72h after defervescence: reduce dose
gradually 2 weeks after defervescence: 3-5 mg/kg/d
p.o×6~8 weeks until ESR , PLT and coronary arteries return to normal （ Ø<3mm ）
reduce the prevalence of coronary abnormalities and lead to rapid defervescence
2 g/kg IV infusion over 8-12 h within 10d after onset
Patient with incomplete response can receive a second course of IVIG.
defer using live viral vaccines until about 11 months after IVIG administration
(2) intravenous gammaglobulin ( IVIG)
indications of administration
pancarditis
no available IVIG
no response to IVIG prednisone / methylprednisolone
combination with aspirin + persantine
(3) corticosteriods
persantine 3~5mg/kg/dmaintenance treatment in patient with huge or
multiple coronary aneurysms
aspirin 3~5mg/kg/d + warfarin
(4) inhibit PLT aggregation
(5) Other therapy
Liquid therapy thrombolytic medicationscoronary artery bypass graft
PrognosisPrognosis
principal cause of death: myocardial infarction fatality rate ： 0.5-1% recurrence rate: 1-2% incidence of CA aneurysms: 20~30% in untreated patient 15% in IVIG treated patient
outpatient follow-upoutpatient follow-up
systemic examination
no CA abnormality:
the first 1,3,6,12 month
CA abnormality:
the first 1,3,6 month, then
every 6-12 month until CA return to normal
EmphasesEmphases
acute generalized systemic
vasculitis coronary artery abnormalities diagnostic guidelines treatment ： goals / medication out patient follow-up
M(y) Heart
M : mucocutaneous H : hand / feet E (eye) ： conjunctiva A : adenopathy
(lymphadenopathy) R : rash T （ tempreture ）： fever
