A detailed approach to ACUTE RHEUMATIC FEVER,based on Harrison Principles of internal medicine and Braunwald Textbook of Cardiology.Useful for post graduate seminars.

2.  INTRODUCTION
 EPIDEMIOLOGY
 PATHOGENESIS
 PATHOLOGY
 CLINICAL FEATURES
 LABORATORY FINDINGS
 DIAGNOSIS
 TREATMENT
 PREVENTION
 REFERENCES

3. Acute rheumatic fever (ARF) is a multisystem disease
resulting from an autoimmune reaction to infection
with group A streptococci.
 ARF and RHD are diseases of poverty.
 It is a postsuppurative streptococcal pharyngitis
cascade, leading variably to arthritis , chorea , dermal
manifestations and most importantly, carditis.

4.  The incidence of RF has declined dramatically in
industrialized nations , but remains common in
developing nations.
Accounts for less than 1% of cardiac manifestations in
industrialized countries.
RHD is the most common cause of heart disease in
children in developing countries and is a major cause of
mortality and morbidity in adults as well.
 Estimated in 2005 that approximately 15.6 million people
had RF or RHD.

5.  Age group:5 to 14 years.
 Initial episodes become less common in older
adolescents and young adults and are rare in persons
aged >30 years.
 Recurrent episodes of ARF remain relatively common
in adolescents and young adults.
 No clear gender , race predisposition
 But post-pubertal chorea and the development of
mitral stenosis is more common in females.

6.  Classic triad of agent ,host and environmental all play a
major role.
AGENT FACTORS:
 infection of the upper respiratory tract with group A
beta hemolytic streptococci.
 more than 100 subtypes defined by M protein
surface molecules.
 strains that cause rheumatic fever are -M types
1,3,5,6,18 and 24.

7. Diagrammatic structure of the group A beta
hemolytic streptococcus
Capsule
Cell wall
Protein antigens
Group carbohydrate
Peptidoglycan
Cyto.membrane
Cytoplasm

8. HOST FACTORS:
Susceptibility to ARF is an inherited characteristic.
 HLA class II alleles.
 High levels of circulating mannose-binding lectin
 Polymorphisms of transforming growth factor β1
gene and immunoglobulin genes.
 High-level expression of a particular alloantigen
present on B cells, D8-17, has been found in patients
with a history of ARF in many populations.

9.  Prior history of rheumatic fever is also an important
risk factor.
ENVIRONMENTAL FACTORS:
 overcrowded housing,
 poor personal and community hygiene,
 poor access to medical services.

10. THE IMMUNE RESPONSE:
 An autoimmune reaction results, which leads to
damage to human tissues.
 Cross-reactivity between epitopes on the organism
and the host.
 Epitopes present in the cell wall, cell membrane, and
the A, B, and C repeat regions of the streptococcal M
protein are immunologically similar to molecules in
human:
 myosin, tropomyosin(myocardium),
 keratin (skin)
 actin,

11.  laminin(valves),
 vimentin(synovia),
 N-acetylglucosamine.
 lysogangliosides(subthalamic and caduate nuclei in
the brain).
 This molecular mimicry is the basis for the
autoimmune response that leads to ARF.

12.  Laminin, α-helical coiled protein like myosin and
M protein, found in cardiac endothelium recognized
by anti-myosin, anti-M protein T cells.
 Antibodies to cardiac valve tissue cross-react with
the N-acetylglucosamine of group A streptococcal
carbohydrate.
 These antibodies may be responsible for valvular
damage.

13. Pathogenetic pathway for acute rheumatic fever and rheumatic heart
disease.

14.  Verrucous vegetations on the valve leaflets along the
lines of closure, with extensive inflammation and
edema.

15. EXUDATIVE PHASE:
 first few weeks after the onset of RF
 fibrinoid degeneration of collagen
 inflammation in left ventricular endocardium.
PROLIFERATIVE PHASE:
 from 1 to 6 months after the onset of RF.
 ASCHOFF BODIES ,granulomatous lesions
pathognomonic for rheumatic carditis .
 found in valve tissue as well as endocardium,
myocardium and pericardium.

16. Microscopic appearance of Aschoff body in a patient with acute
rheumatic carditis.

17. Rheumatic arthritis is manifest by
 edema,
lymphocytic and polymorphonuclear infiltration,
 fibrinoid lesions that resolve.
In patients with chorea , inflammatory changes have
been noted in the cerebral cortex ,cerebellum and
basal ganglia.

18.  Latent period of ~3 weeks (1–5 weeks) between the
precipitating group A streptococcal infection and the
appearance
of the clinical features of ARF.
Exceptions are chorea and indolent carditis,which may
follow prolonged latent periods lasting up to 6 months.
Clinical manifestations:
 Fever
 Polyarthritis
 Carditis

19.  Sydenham’s chorea
 Erythema marginatum.
 Subcutaneous nodules.
Most common is fever ,polyarthritis followed by
carditis.

20. CARDITIS:
Occurs in 50-60% of patients with ARF.
 The endocardium, pericardium, or myocardium
may be affected.
 Valvular damage is the hallmark of rheumatic
carditis.
 almost always affects the mitral valve causing MR.
 sometimes together with aortic valve.
 isolated aortic valve involvement with AR is rare.
 acute and chronic myocardial dysfunction.
 acute ,although not chronic pericardial disease.

21.  neither pericarditis nor myocarditis can be expected to
occur in the absence of valvulitis.
 Rheumatic tricuspid disease is uncommon ,and
pulmonic valve disease is rare.
 Severe heart failure in acute RF is secondary to altered
myocardial mechanics caused by MR rather than secondary
to myocarditis.
• Severity of left ventricular dysfunction appears to
correlate with the extent of valvulitis rather than with any
myocardial injury.

22. Over ensuing years, usually as a result of recurrent
episodes, leaflet thickening, scarring, calcification,
and valvular stenosis may develop.

23. Pericarditis most commonly causes a friction rub or a
small effusion on echocardiography and may
occasionally cause pleuritic central chest pain.


24. Myocardial inflammation may affect electrical
conduction pathways ,leading to P-R interval
prolongation (first-degree AV block or rarely higher-
level block) which resolves over a few days to weeks.

25.  JOINT INVOLVEMENT:
 Polyarthrits is most common manifestation of RF ,
occuring in 60 to 75% of patients.
To qualify as a major manifestation, joint involvement
must be arthritic, i.e., objective evidence of
inflammation ,with hot, swollen, red and/or tender joints
and involvement of more than one joint (i.e., polyarthritis).
 typically migratory ,moving from one joint to another
over a period of hours.
 almost always affects the large joints— the knees,
ankles, hips, and elbows
 asymmetric.

26.  Arthralgia without objective joint inflammation -
minor criteria.
 Inflammation in individual joints lasts 1 to 2 weeks.
 Polyarthritis as a whole resolves in a month or less.
 Chronic sequelae and disability do not occur ,with
the rare exception of Jaccoud arthropathy.

27. • Arthritic phase frequently overlaps with the onset of
carditis and the two manifestations appear to be
inversely proportional.
 Joint manifestations are highly responsive to
salicylates and other nonsteroidal anti-inflammatory
drugs.

28. CHOREA
 Sydenham’s chorea occurs after a prolonged latent
period of upto 6 months.
 Reported incidence has a wide range between 5 and
35%.
 Found mainly in females.
 Affects particularly the head and upper limb.
 Manifests as involuntary , irregular movements,
fibrillatory muscle movements of tongue.

29.  Characteristic spooning with exterernal rotation of the
hands.
 Abolition with sleep.
 There is a substantial risk of subsequent RHD in these
patients.
 Eventually resolves completely, usually within 6 weeks.
 Other psychological and neurological manifestations of
RF:
 Short term and long term emotional liability.
 Obsessive –compulsive disorder.

30.  Seizures
 Chronic migraine

31. SKIN MANIFESTATIONS:
Occur in <5% of the cases.
Erythema marginatum:
 Classic rash of ARF
 Begins as pink macules that clear centrally, leaving a
serpiginous, spreading edge.
 The rash is evanescent, appearing and disappearing
before the examiner’s eyes.
 It occurs usually on the trunk, sometimes on the
limbs, but almost never on the face.
 Typically occur in conjunction with carditis.

32.  May last for months or years.
 Not specific for RF and occurs with sepsis and drug
reaction.

33. Subcutaneous nodules:
 Painless, small , mobile lumps beneath the skin
overlying bony prominences, of the hands, feet,
elbows, occiput, and occasionally the vertebrae.
 Typically occur in patients with moderate to
severe rheumatic carditis.
 They are a delayed manifestation, appearing
2–3 weeks after the onset of disease, last for just a
few days up to 3 weeks.
 Not diagnostic of RF and can be seen with
other autoimmune disorders.

34. SUBCUTANEOUS NODULE

35. OTHER FEATURES:
 Fever occurs in most cases of ARF.
 Although high-grade fever (≥39°C) is the rule,
lower grade temperature elevations are not
uncommon.

36. Polyarthritis

Infectious
Staphylococcus,
gonococcus
Endocarditis,
Lyme disease,
Mycobacterial,fungal,Viral
 Reactive
Poststreptococcal,
Enteric infection
Reiter syndrome,
Inflammatory bowel

37. Connective tissue disease
Rheumatoid arthritis
Systemic lupus
Systemic vasculitis
 Miscellaneous :
Gout, Leukemia, lymphoma , Sarcoidosis, Cancer ,
Familial Mediterranean fever , Henoch-Schönlein
purpura , Mucocutaneous disorders , “Growth pains” in
children, Serum sickness .

38. Carditis
 Murmur
Physiological murmur
Mitral valve prolapse
Bicuspid aortic valve
Anemia
Straight back syndrome
 Congenital heart disease
Ventricular septal defect
Subvalvular aortic stenosis
Primum atrial septal defect
 Viral myocarditis
 Endocarditis
 Pericarditis

39. Chorea
 Familial chorea—Huntington
 Hormone-induced
Oral contraceptives, pregnancy
 Drug-induced
Anticonvulsants , antidepressant,
metoclopramide.
 Connective tissue
Systemic lupus, Periarteritis
 Lyme disease , Wilson disease , Atypical
seizures , Hyperthyroidism,
Hypoparathyroidism , Tourette syndrome,
PANDAs.

40. Elevated ESR and CRP.
 Mild elevation of the peripheral leucocyte count.
 Evidence of a Preceding Group A Streptococcal
Infection:
 Positive throat swab culture
 Rapid streptococcal antigen test-generally
specific but sensitivity is low
 Rising streptococcal antibody titres which
includes:
a. antistreptolysin O.
b. anti-deoxyribonuclease B.

41. c. antihyaluronidase
d. streptozyme.
Antibody titre testing is more specific although they
are affected by non-GABHS infections.
Time course of antibody level increase:
 within 1 month of onset of streptococcal
pharyngitis.
 plateaus for 3 t0 6 months, followed by a
decline.
 levels elevated from the patient’s baseline
typically last 1 year or less.

42.  Electrocardiographic findings:
 Sinus arrythmia
 Tachycardia
 Conduction disturbances-first degree AV
block.
 Prolongation of QT interval.
 Rare episodes of torsades de pointes and
sudden death.

43.  Echocardiography:
 Miral insufficiency is the most common finding
associated subsequently with restricted leaflet motion
 Occasionally aortic insufficiency has been diagnosed
in a minority of patients.
Echocardiography is useful :
 For confirming the findings on auscultation.
 Excluding non-rheumatic causes(physiological
murmurs or congenital heart disease).
 Sequential follow up of valvular insufficiency,

44. chamber size ,pulmonary hypertension, valve
thickening and left ventricular systolic function.

45.  Associated post-streptococcal syndromes:
 Post streptococcal reactive arthritis:
(1) small-joint involvement that is often symmetric.
(2) a short latent period following streptococcal
infection (usually <1 week).
(3) occasional causation by non-group A β-hemolytic
streptococcal infection.
(4) slower responsiveness to salicylates.
(5) the absence of other features of ARF, particularly
carditis.

46.  Pediatric Autoimmune Neuropsychiatric Disorders
Associated with Streptococcal infection (PANDAS) :
Consists of a range of tic disorders and obsessive-
compulsive symptoms associated with group A
streptococcal infections.
 People with PANDAS are said not to be at risk of
carditis, unlike patients with Sydenham’s chorea.
 The diagnoses of PANDAS and PSRA should rarely be
made in populations with a high incidence of ARF

47.  Based on the WHO modification of the 1992 Revised
Jones criteria.
Major manifestations:
 Carditis
 Polyarthritis
 Chorea
 Erythema marginatum
 Subcutaneous nodules

48.  Minor manifestations:
 Clinical: fever, polyarthralgia
 Laboratory: elevated erythrocyte sedimentation
rate or leukocyte count
 Electrocardiogram: prolonged P-R interval
Supporting evidence of a preceding streptococcal
infection within the last 45 days
 Elevated or rising anti-streptolysin O or other
streptococcal antibody, or
 A positive throat culture, or
 Rapid antigen test for group A streptococcus, or
 Recent scarlet fever

49. Primary episode of rheumatic fever:
 Two major or one major and two minor
manifestations plus evidence of preceding group A
streptococcal infection.
Recurrent attack of rheumatic fever in a patient
without established rheumatic heart disease:
 Two major or one major and two minor
manifestations plus evidence of preceding group A
streptococcal infection

50. Recurrent attack of rheumatic fever in a patient
with established rheumatic heart disease.
 Two minor manifestations plus evidence of
preceding group A streptococcal infection.
Rheumatic chorea and Insidious onset rheumatic
carditis:
 Other major manifestations or evidence of
group
A streptococcal infection not required.

51. Chronic valve lesions of rheumatic heart disease
(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 rheumatic heart disease.

52. ANTIBIOTICS:
 All patients with ARF should receive antibiotics
sufficient to treat the precipitating group A
streptococcal infection.
 Penicillin is the drug of choice
 can be given orally , 500 mg twice daily for 10 days or
 as a single dose of 1.2 million units IM benzathine
penicillin G.
 Erythromycin, 250 mg bid, may be used for patients
with penicillin allergy.
 Followed by long term secondary prophylaxis.

53.  SALICYLATES AND NSAIDS
Used for the treatment of arthritis, arthralgia, and
fever, once the diagnosis is confirmed.
 Aspirin is the drug of choice.
 Initial dose of 80–100 mg/kg per day in children (4–8
g/d in adults) in 4–5 divided doses for the first few
days up to 2 weeks.
 When the acute symptoms are substantially resolved,
the dose can be reduced to 60–70 mg/kg per day for
a further 2–4 weeks.

54.  GLUCOCORTICOIDS:
 Can be used in cases of severe carditis (causing heart
failure)
may reduce the acute inflammation and result in more
rapid resolution of failure.
 Prednisolone:1–2 mg/kg per day (maximum, 80 mg)
Intravenous methylprednisolone may be used in very
severe carditis.
 Often required for a few days or up to a maximum of
3 weeks.

55.  MANAGEMENT OF HEART FAILURE
 BED REST:
Recommended only for arthritis and arthralgia
and for patients with heart failure.
 MANAGEMENT OF CHOREA
 Milder cases can usually be managed by providing a
calm environment.
 In severe chorea, carbamazepine or sodium valproate
are preferred to haloperidol.

56.  Response may not be seen for 1–2 weeks.
 Medication should be continued for 1–2 weeks after
symptoms subside.
INTRAVENOUS IMMUNOGLOBULIN(IVIG):
 Studies have suggested that IVIg may lead to more
rapid resolution of chorea.
 But has shown no benefit on the short- or long-term
outcome of carditis in ARF without chorea.
 IVIg is not recommended except in cases of severe
chorea refractory to other treatments.

57.  PRIMARY PREVENTION:
I. Elimination of the major risk factors for
streptococcal infection, particularly overcrowded
housing and inadequate hygiene infrastructure.
II. Primary prophylaxis:
 Timely and complete treatment of group A
streptococcal sore throat with antibiotics.
 If commenced within 9 days of sore throat onset,
a course of 10 days of penicillin V (500 mg bid PO in
adults) or

58.  A single IM injection of 1.2 million units of
benzathine penicillin G should be administered.
SECONDARY PREVENTION:
 The mainstay of controlling ARF and RHD.
 Patients with ARF should receive long term
penicillin prophylaxis to prevent recurrences.
 The best antibiotic for secondary prophylaxis is
benzathine penicillin G:
1.2 million units, or 600,000 units if <30 kg delivered
every 4 weeks or more frequently to persons
considered to be at particularly high risk.

59.  Oral penicillin V (250 mg) can be given twice-daily
instead.
 less effective than benzathine penicillin G.
Penicillin allergic patients can receive erythromycin
(250 mg) twice daily.

61. Harrison’s Principles of Internal Medicine,17th
edt.
 Braunwald’s diseases of the heart,8th
edt.
 Oxford text book of medicine -4th
edt.
 Nelson’s text book of Pediatrics.
 Robbins and Cotran ,Pathological Basis of Diseases,8th
edt.
 Cecil text book of Medicine,22nd
edt.