Rheumatic fever (RF) is a systemic inflammatory disease affecting the connective tissue, particularly in the joints, the heart, the skin & subcutaneous tissues, and the brain.
Incidence and prevalence:
The incidence of acute RF has declined markedly in the 20th century in both the United States and Western Europe.
RF is much more prevalent in the developing countries than in the developed countries.
Recent increase in the western countries was, however, observed probably due to the development of new strains of Streptococci.
RF is thought to occur as delayed sequelae to: Group A, ß–hemolytic, streptococcal upper respiratory tract infection.
The streptococcal cell is formed of:
- Capsule (the outermost layer): made of hyaluronic acid, protecting the cell.
- Cell wall (the middle layer): made of carbohydrates, the type of which classifies streptococci into: group A, B, C…etc. Group A causes RF.
- Cell membrane: the innermost layer.
In blood agar medium, the streptococci can be classified into 3 types according to the hemolysis caused by the Streptolysin-S toxin:
- α-hemolytic: causes partial hemolysis in the medium.
- β-hemolytic: causes complete hemolysis in the medium.
- γ-Streptococci: non-hemolytic
β-hemolytic acitivity of Streptococcus.
So RF is caused by: group A (according to the type of carbohydrate in cell wall), β-hemolytic (causes complete hemolysis in blood agar medium), streptococcal infection of the upper respiratory tract.
Rheumatic fever rarely follows Streptococcal skin infection.
Streptococcal carriers are not at risk of developing RF.
RF may be repeated in families probably due to:Similar housing conditions.
- Streptolysin-O: The titer of its antibody; Anti-Streptolysin-O Titer (ASOT) is used as an evidence of recent streptococcal infection. This toxin causes:
- RBC destruction (Hemolysis).
- WBC destruction.
- Cardio toxicity.
- Streptolysin-S: This toxin is used to classify Streptococci as mentioned above.
- Streptokinase: This toxin activates Plasminogen into plasmin (Fibrinolysin); the latter causing lysis of fibrin. That is why streptokinase is used as a thrombolytic therapy in acute myocardial infarction.
- Other Streptococcal toxins include:
- Desoxi-Ribo-Nuclease (DNAse).
- Erythrogenic toxin (the toxin causing Scarlet fever).
Evidence to streptococcal etiology of rheumatic fever:
- Epidemiological studies: showing similar spread regions of both acute RF & streptococcal upper respiratory infection.
- Effectiveness of penicillin in the treatment of both conditions.
- Age of onset: Highest incidence of both conditions at age 5-15 years.
- Positive ASOT in all cases of acute RF.
However; one third of cases of acute RF have no history of sore throat, and negative throat & blood cultures for streptococci.
This might be explained by the fact that acute RF usually develops three weeks after upper respiratory tract infection, which might have passed un-noticed (sub-clinical infection).
Not every patient with group A, β hemolytic streptococcal upper respiratory tract infection will develop acute Rheumatic fever: Only 3 % of these cases will have such a complication.
Hypotheses for the development of acute RF:
- Streptococcal direct heart infection was assumed; but there was no evidence.
- Streptococcal toxins effect on the heart was also assumed; but again no evidence.
- The most accepted hypothesis is that RF is an Immune Response to streptococcal cell wall carbohydrates or cell membrane.
Evidence to immune basis:
- Patients with acute RF were found to be hyper-immune to Streptococcal products.
- With streptococcal infection, the RF attack rate (average of 3%), is proportional to the level of ASOT:
- With strong ASOT: 5 %
- With weak ASOT: < 1 %
- Common antigens and antibodies were isolated between Streptococcal carbohydrates and cardiac glycoproteins.
- Lymphocytes sensitized to cardiac antigens were found in RF patients.
Autoimmune or bacterial allergy:
It is not clear whether RF is an auto-immune disease; with reaction against self antigens: i.e. antibodies to streptococci react directly with cardiac tissue due to presence of common antigens.
Antigenic similarity between streptococcal antigens, mainly M-protein and human tissues, such as heart valves, myosin and tropomyosin, brain proteins, synovial tissue and cartilage has been proposed as the triggering factor leading to autoimmunity in individuals with genetic predisposition.
Streptococcal antibodies cross-react with several human tissues including heart, skin, brain, glomerular basement membrane, striated and smooth muscles.
Another theory is that the antibodies react with bacterial antigens; which causes tissue damage in the heart & other organs.
Acute RF is characterized by non-suppurative inflammatory lesions of the joints, heart, subcutaneous tissue, and central nervous system.
Pathology in acute RF may be classified into non specific or specific inflammation.
Non specific inflammation occurs in the skin & subcutaneous tissues, the joints, the central nervous system, and the heart.
Specific inflammation: Pan carditis:
- Endocarditis: the commonest.
- Pericarditis: in 10 % of cases.
- Myocarditis: in 5 % of cases.
Rheumatic vegetations on cardiac valves are usually located 2-3 mm. from the edges of the leaflets, at the site of contact between the leaflets during their closure, and may also occur on the chordae tendineae of the mitral valve.
Vegetations are formed of platelets, leucocytes, and fibrin.
The most frequently affected valve is the mitral, followed by aortic, tricuspid, and lastly the pulmonary valve.
Valve affection is thought to correlate with its closing pressure: The mitral closing pressure is the left ventricular (LV) - left atrial (LA) systolic pressure gradient, e.g. 120-10=110 mmHg. The aortic closing pressure is the aortic (AO) – LV diastolic gradient, e.g. 80-5=75 mmHg. The tricuspid closing pressure is the right ventricular (RV) – right atrial (RA) systolic gradient, e.g. 25-10=15 mmHg. The pulmonary closing pressure is the pulmonary artery (PA) – RV diastolic gradient, e.g. 15-5=10 mmHg.
Chronic valvular affection ends in fibrosis & deformity.
Aortic valve showing active valvulitis. The valve is slightly thickened and displays small vegetations. http://www.health.gov.mt/impaedcard/issue/issue11/1231/fig02.jpg
Stenotic mitral valve seen from left atrium. Both commissures are fused; the cusps are severely thickened. The left atrium is huge. The valve is both incompetent and stenotic. http://www.health.gov.mt/impaedcard/issue/issue11/1231/fig08.jpg
Opened stenotic mitral valve showing thickening distorted cusps, adherent commissures with calcification and thrombus deposition, and thickening, fusion and shortening of chordae tendineae.
Stenotic mitral valve seen from left atrium, showing fusion of commissures, thickening and calcification of the cusps. http://www.health.gov.mt/impaedcard/issue/issue11/1231/fig10.jpg
Fibrinous Pericarditis may occur in acute RF, with or without pericardial effusion, but not constrictive pericarditis.
Aschoff nodules or Aschoff bodies in the myocardium are formed of: Giant cells, plasma cells, and lymphocytes, arranged around an amorphous core.
Myocardial Aschoff body.
Age at first attack:RF commonly starts at Age: 5–15 years, with a peak incidence at age 8 years.
It rarely occurs before 5 years or after 30 years of age.
Sex:Acute RF occurs equally in both sexes, but its manifestations may differ:
- Rheumatic Chorea and tight mitral stenosis are more common in females after puberty.
- Aortic stenosis is more common in males.
Onset:Onset is usually two - three weeks after streptococcal upper respiratory tract infection.
In epidemics: The recurrence rate is very high (65 %).
Presentation:Acute RF is extremely variable in its manifestations and remains a clinical syndrome for which no specific diagnostic test exists.
Constitutional symptoms:General constitutional symptoms similar to those of any febrile illness including: Fever, Sweating, Headache, Anorexia, nausea, vomiting, abdominal pain, Weight loss, lassitude, Epistaxis.
Jones has defined major and minor criteria for the diagnosis of acute RF, in the presence of an evidence of recent streptococcal infection.
Jones major criteria:
- Arthritis: in 75 % of first attacks.
- Carditis: in 50 % of first attacks.
- Rheumatic chorea; in15 % of first attacks.
- Erythema marginatum: in 10 % of first attacks.
- Subcutaneous nodules: in 10 % of first attacks.
Jones minor criteria:
- Clinical manifestations:
- Arthralgia, i.e. joint pains, but not other manifestations of joint inflammation.
- Previous History of RF.
- Elevated acute phase reactants: Elevated White blood cell count (WBC count). Elevated Erythrocyte sedimentation rate (ESR). Positive C-Reactive protein (CRP).
- ECG changes: Prolonged PR interval, i.e. first degree atrioventricular block.
There is high probability of acute RF in the presence of:
- 1) Jones criteria: Either two major criteria, or one major plus two minor criteria, together with;
- 2) Evidence of recent streptococcal infection: any of the following:
- Streptococcus organism itself: Positive culture from the throat or the blood.
- Streptococcus antibodies: Positive ASOT.
- A disease caused by streptococcus: Recent scarlet fever.
There is no definitive diagnostic test for acute rheumatic fever.
Let us now discuss the Jones major criteria in more details.
RF arthritis is characterized by:
It affects mostly large joints; e.g. knees, ankles, elbows & wrists. Small joints are rarely affected, e.g. hand joints & spine.
Very painful; commonly the knees are affected and the child cannot walk due to severe pain.
Fleeting (migratory): one joint is affected; followed by another joint and so on. The evolution, however, tends to overlap so that multiple joints may be affected at the same time.
Responds dramatically to acetyl salicylic acid (ASA).
Leaves no residual deformity: Except for a rare condition called Jaccoud’s arthritis, which is a progressive deformity of the hands and feet in young adults following recurrent rheumatic fever or Systemic Lupus Erythematosus (SLE). In Jaccoud’s arthritis; Subluxation of the proximal phalanges may cause a hook-like deformity of the metacarpal heads. The toes may also be affected.
Jaccoud’s arthritis in x-rays.
Pericarditis:friction rub may occur, with or without pericardial effusion.
Rheumatic myocarditis presents clinically as one or more of the following:
- Tachycardia out of proportion to fever.
- New or changing valvular murmurs: commonly mitral or combined mitral & aortic regurgitation. Mitral mid diastolic rumble may occur (Carey-Coomb’s murmur).
- Third heart sound (S3) gallop.
- Frank left ventricular failure (LVF).
- Cardiomegaly, in x-ray, ECG or Echocardiography.
- Conduction defects.
Mild cases of carditis, however, may be asymptomatic.
Chest radiograph of an 8 year old patient with acute carditis before treatment.
Same patient after 4 weeks.
From the previous discussion, it is clear that RF causes reversible joint inflammation without permanent deformity. On the other hand, RF causes devastating long term cardiac pathology. That is why it is usually said that RF licks the joints but bites the heart.
Subcutaneous nodules in acute RF are characterized by:
- Rounded in shape.
- 0.5-2 cm in diameter.
- Firm in consistency.
- Occur over bony prominences & tendons. The common sites are elbows, knees, wrists, ankles, Achilles tendon, and spinous process of the vertebrae.
- May persist for 1 month.
Subcutaneous nodule on the extensor surface of elbow of a patient with acute RF.
Subcutaneous nodules are Non-specific: They also occur in Rheumatoid Arthritis & SLE.
- Pink circles with pale center.
- Painless, non-itchy.
- Occur over trunk & limbs, never over the face.
- Unusually, they may occur as the isolated manifestation of acute RF.
- Disappear within hours, but may relapse.
Erythema marginatum on the trunk, showing erythematous lesions with pale centers and rounded or serpiginous margins. http://www.health.gov.mt/impaedcard/issue/issue11/1231/fig12a.jpg
Closer view of erythema marginatum in the same patient. http://www.health.gov.mt/impaedcard/issue/issue11/1231/fig12b.jpg
Rheumatic chorea (Sydenham's chorea):
- Purposeless involuntary movements of the hands, feet & face, with muscle weakness.
- Associated with emotional lability.
- They disappear during sleep.
- Never associated with arthritis.
- Rarely occur alone.
- May last for 2 years & may recur.
- After puberty, it occurs only in females.
Manifestations Rheumatic chorea may include:
- Fall of objects from the hands.
- Inability to maintain elevated supinated arms.
- Stretched hands show: wrist flexion with finger extension.
- Rapid tongue withdrawal, when the patient is asked to protrude it.
The hands in patients with rheumatic chorea.
Other clinical manifestations of rheumatic fever:RF may also cause:
- Vasculitis: e.g. mesenteric vasculitis, with acute abdomen.
Chronic rheumatic fever:
The average duration of an acute attack is about 3 months. Chronic rheumatic fever is defined as diseases persisting for more than 6 months. It occurs in less than 5 % of cases.
ECG in acute RF:
- First-degree atrioventricular block is very common.
- On the other hand; second degree and third degree atrioventricular blocks, and serious tachyarrhythmias are very rare.
First degree heart block: The PR interval in ECG is measured from the beginning of the P-wave to the beginning of the QRS complex. Normally it is 0.12 – 0.20 second (3 – 5 small squares of the ECG paper (1 small square = 1mm = 0.04 second). If it is increased > 0.20 second, it is said to be prolonged and first degree heart block is said to be present. This condition represents prolongation of the normal physiologic delay of the cardiac impulse in the AV node, but all the impulses are ultimately conducted.
Chest x-ray:Frequently shows cardiomegaly in the acute phase, particularly in presence of myocarditis, which may resolve later on, as shown above.
Echocardiography:Echocardiography both in the acute phase & in chronic rheumatic heart disease will show cardiac affection; e.g. pericarditis, pericardial effusion, valve lesions, vegetations…etc
Two-dimensional color flow Doppler image of the left ventricular inflow of a patient with mitral regurgitation in the four-chamber view (top panel) and two-dimensional parasternal long-axis view (lower panel), showing lack of apposition of the leaflets of the mitral valve during systole (arrow).
Two-dimensional parasternal long-axis view of a patient with mitral stenosis, showing thickened valve cusps (arrow), with poor leaflet separation in diastole. Left atrium is enlarged, with a thrombus in the posterior aspect of it. Aortic valve is also stenotic.
Pressure gradient half-time and mitral area is calculated from the diastolic mitral orifice Doppler velocities signals (lower panel). LV = left ventricle; LA = left atrium; RV = right ventricle; RA = right atrium.
Prevention of rheumatic fever:
- Primary prevention: preventing first attack in those who never had RF:
- Improving housing conditions.
- Prompt treatment of Streptococcal infection.
- Secondary prevention: preventing the recurrence of RF in those who already had the disease: this is achieved by antibiotic prophylaxis as follows:
- Benzathine penicillin 1.2 MU / 3weeks, IM injection.
- Penicillin-V: 250 mg BID, PO, if injections are refused by the patient.
- Erythromycin : 250 mg BID, PO, in those sensitive to penicillin.
Duration of prophylaxis:It is not definitely known for how long should we continue antibiotic prophylaxis in secondary prevention, opinions differ;
- Up to age: 18, 25, or 35 years ?
- If no carditis; 5 years from the last attack of RF may be enough.
- In presence of rheumatic heart disease; some advise life-long prophylaxis.
Treatment of acute RF:
Treatment of acute RF should include:
- Eradication of streptococcal infection.
- Control of symptoms and manifestations of the acute attack.
- Prevention of complications.
The main drugs used in acute RF are:
- Acetyl salicylic acid (ASA = aspirin).
For eradication of streptococcal infection:
- Benzathine penicillin: 1.2 MU single dose given IM.
- Or Procaine penicillin 400,000 U. daily IM. for 7-10 days.
In the presence of penicillin allergy:
- Oral Cephalosporins can be used, but be cautious of the 20% cross-reactivity of the Cephalosporins with penicillin.
- Oral erythromycin may be used; 500 mg / 12h.
Value of anti-microbial therapy:By promptly treating streptococcal pharyngitis in susceptible hosts, repetitive exposure to pathologically reactive antigens can be avoided.
However, management of the current infection probably will not affect the course of the current attack.
Antimicrobial therapy does not alter the course, frequency, or severity of cardiac involvement.
Aspirin is used for symptomatic control of fever & the pain of arthritis.
Dose; 90-120 mg/kg/day; (max: 8 gm/day): until clinical improvement,
Then: 2/3 of the above dose until normal ESR, CRP & WBC. (Total duration is usually: 6- 8 weeks). Aspirin is then tapered gradually.
Dramatic response to aspirin is characteristic to acute RF, with rapid improvement of arthritis.
Gastrointestinal side effects may be troublesome and may require dose reduction.
Indications of Prednisolone in acute RF:
- Cases resistant to Aspirin.
- Presence of carditis.
Dose: 2 mg/kg/day, up to a maximum of 60 mg/day, for 3-4 weeks.
Then taper gradually: 25% of the dose each week, and start aspirin at 75mg/kg/day, for 2-6 months.
Other drugs used in acute RF:
- Chorea may be controlled by; Diazepam, Haloperidol.
- Congestive heart failure may be controlled by: Digoxin, Diuretics, Vasodilators.
Other care of the patients with acute RF:
Surgery or balloon dilatation for the management of valve lesions may be required in the acute phase, e.g.
- Valve lesions not responding to medical treatment.
- Patients requiring high doses of Prednisolone for long periods.