Rheumatic Fever

Rheumatic fever used to be a fairly common disease amongst children in developed countries until about the middle of the 20th century. It was a major cause of death in children until 1960 and a common cause of chronic structural heart disease in developed countries. In developing countries it still remains a major cause of death and heart disease.

• It is caused by a beta haemolytic streptococcus Lancefield group A but there are a number of further types of which those with the M antigen are most likely to cause the disease.
• The decline in rheumatic fever is not just due to penicillin but also to improved social conditions and a reduction in virulence of the streptococcus. It remains prevalent in other parts of the world particularly developing countries.¹
• The disease affects joints, skin and heart. The disease is dependent upon the immune response of the individual and only 5 to 6% of people have the genetic configuration.
• The features of the disease are thought to be the result of a hypersensitivity reaction caused by cross-reacting antibodies.
• Cardiac involvement occurs in 30 to 70% of first attacks but subsequent attacks raise that figure to 75 to 90%.

The pathogenesis and immune mechanisms are not fully understood.

• The Lancefield group A beta haemolytic streptococcus is the bacterial agent responsible for acute rheumatic fever.
• It is thought that host susceptibility, virulence of the organism and the environment combine to determine the clinical manifestation and the severity in a particular individual.
• It is thought there is a combined humoral and cell mediated immune response to the bacterium which through molecular mimicry, cross reacts with tissue in heart, joints, skin and central nervous system.
• Certain strains only of the streptococcus have been associated with rheumatic fever. The potential is linked to the M antigen (M types 3, 5, 18, 19, 24). However rheumatic fever and rheumatic heart disease have been discovered in communities where other responsible serotypes have been found.¹

Different methods of collecting data can make comparisons of statistics very difficult. The incidence remains high where there is overcrowding and poor access to healthcare. In these populations with the highest incidence it is often most difficult to get reliable epidemiological data.

• The incidence is highest in school age children, between the ages of 5 and 15 years. The median age is 10 years. 20% of cases occur in adults.
• The incidence of rheumatic fever in developed countries is low. The incidence of acute rheumatic fever has fallen in high income countries to less than 1 per 100,000 population.¹
• Even in developed countries prevalence is a function of socioeconomic status. The incidence is higher particularly when there is overcrowding and in the winter months.
• The incidence in developing countries remains high. The indigenous populations of Australia and New Zealand have some of the highest incidences recorded in recent years with 374 per 100,000 per year in 5 to 14 year olds.¹ Around 60% of these patients develop rheumatic heart disease. Sub-Saharan Africa has the highest estimated regional prevalence of rheumatic heart disease (5.7 per 1000).
• Rheumatic fever still causes 90,000 deaths per year and chronic rheumatic heart disease in up to an estimated 30 million children and adults.
• Both primary and recurrent episodes of fever are equally common. Recurrence occurs most often in the first 5 years after the initial episode. The young are most at risk of recurrence and the risk of carditis and valve damage increases in subsequent attacks.

Overcrowding, poor hygiene and lack of access to medical services are all important. In hot countries, skin infection is a more important source of streptococci than pharyngitis. Young age is a risk factor with most cases occurring between age 5 and 15 years.

• Symptoms appear between 1 and 5 weeks after a sore throat, with an average of 3 weeks.
• In recurrent cases this incubation period is shorter, in keeping with a faster immune response.
• The diagnosis is based on major and minor criteria. In the acute disease the arthritis and toxicity are obvious but it can be more insidious with mild carditis. This probably accounts for only about half of those with typical rheumatic heart disease giving a history of rheumatic fever.
• Diagnosis is based on Jones Criteria that were devised in 1944⁵ but revised in 1992.⁶ They can be used to identify patients with a high likelihood of having Rheumatic fever.

• Major Criteria:
  • Arthritis:
    • The most obvious presenting feature is a flitting or migratory arthritis affecting large joints like the knees, ankles, wrists and elbows.
    • The joints are hot and red with decreased range of movement. Typically, one joint is exquisitely painful and inflamed while another is improving.
    • Usually 1 or 2 joints are affected at any time with each being only involved for between a few hours and a few days.
    Aspirin has been the traditional treatment but nowadays other NSAIDs might be considered in view of Reye's syndrome. If it fails to respond, consider an alternative diagnosis.
  • Carditis (occurs in 40% of patients):
    • There is a pancarditis affecting the pericardium, myocardium and the endocardium.
    • Endocarditis leads to valvular heart disease which, along with myocarditis, is fatal in about 1%.
    • Examination of the pulse will show tachycardia beyond that expected for the temperature.
    • A murmur of aortic regurgitation is common in older children or young adults.
    • Auscultation of the heart may reveal a pericardial rub. It is present in 40 to 60% without chorea and 20 to 30% with chorea.
    • Carditis has characteristic findings on Doppler echocardiography. The mitral valve is the commonest to be involved at 65 to 70% with the aortic valve second at 25%. Aortic valve disease, unlike most other manifestations of this disease, is commoner in males. The tricuspid valve is affected in barely 10% and involvement of the pulmonary valve is very rare.
    • Nearly all acquired mitral valve disease is rheumatic in origin.
    • Certain characteristic murmurs have acquired eponymous names:
      • The Carey Coombs murmur is a soft, short diastolic filling murmur due to vegetations on the mitral valve.
      • The Austin Flint murmur is from aortic regurgitation as the vibration of the anterior leaflet of the mitral valve is buffeted simultaneously by the blood jets from the left atrium and the aorta.
  • Chorea (also known as Sydenham chorea and "St Vitus' Dance"):
    • Occurs in 10 to 30% of patients.
    • It usually presents in children between 7 and 12 years with a female preponderance.
    • There are both psychological and physical features. It causes rapid and purposeless movements of particularly face and upper extremities.
    • Paediatric autoimmune neuropsychiatric disorder associated with Streptococcus (PANDAS) and Tourette syndrome are other varieties of movement and neurological disorders described.
    • It may stop when the patient sleeps.
  • Subcutaneous nodules:
    • Occur in 10% of patients.
    • Infrequent and appear over the extensor surfaces of the elbows, knees, ankles, knuckles, scalp, and spinous processes of the lumbar and thoracic vertebrae.
    • They are firm, painless lumps from a few millimetres to 2cm in size.
    • They are normally in crops of 3 or 4, appearing 2 or 3 weeks after onset of fever.
    • The histology resembles Aschoff bodies found in the heart and they are indicative of severe carditis.
  • Erythema marginatum⁷ is also known as erythema annulare:
    • It occurs in about 5 to 15% of patients.
    • The rash comprises pale red macules or papules between 1 and 3 cm in diameter on the trunk and proximal limbs but never on the face.
    • The rash occurs early in the disease and remains long past the resolution of other symptoms.
    • It is exacerbated by heat and fades when the patient is cool.
• Minor Criteria:
  • Fever:
    • Present in 90% of cases. It is usually over 39°C and stays high for a week and is lower for the next 2 weeks.
    • In pure chorea the patient may be apyrexial.
  • ESR and serum C-reactive protein very raised,
  • Arthralgia (but not if arthritis is one of the major criteria).
  • Prolonged PR interval (but not if carditis is major criterion).
• There are 3 other clinical scenarios that are not part of the Jones criteria but merit attention:
  • Chorea may occur late and be the only feature of the disease.
  • Low grade carditis may present too late for diagnosis of the rheumatic fever.
  • Newly ill patients with a history of rheumatic fever, especially with heart disease, who have supporting evidence of a recent streptococcal infection and who have either a single major or several minor criteria.

The paper looking at the revision of the Jones criteria⁶ also addresses the question of excessive diagnosis.

• Arthritis consider:
  • Rheumatoid arthritis (including Still's disease in children)
  • Henoch-Schonlein purpura
  • Reactive arthritis
  • Erythema nodosum
• Heart disease consider:
  • Cardiomyopathy
  • Kawasaki disease
  • Infective endocarditis
• Rash (erythema marginatum) consider:
  • Drug reactions
  • Lyme disease
• Chorea consider:
  • Drug reactions (especially in young people) to:
    metoclopramide, oral contraceptives, phenytoin, haloperidol or amitriptyline.
  • Huntington's chorea. This does not usually present until at least 30 (peak age 35-45).
  • Chorea gravidarum may occur in pregnancy.
  • Wilson disease

• Throat swabs usually fail to grow streptococci by the time that symptoms of rheumatic fever appear.
• Clinical features begin when antibodies are at a peak. Antistreptococcal antibodies are especially useful in patients with only chorea.
  Sensitivity can be improved by testing for several antibodies.
  • Check antibody titres 2 weeks apart for a rise.
  • The commonest antibodies tested include antistreptolysin O (ASO) and anti-DNase B, antihyaluronidase, antistreptokinase, antistreptococcal esterase, and anti-nicotinamide adenine dinucleotide (anti-NAD).
  • Antibody tests for cellular components of group A streptococci antigens include antistreptococcal polysaccharide, anti-teichoic acid antibody, and anti-M protein antibody.
  • Generally, the antibodies rise during the first month after infection and then plateau for 3 to 6 months before returning to normal levels at 6 to 12 months. ASO titre peaks 2 to 3 weeks after the onset of clinical disease and there is a sensitivity of 80 to 85%.
    Anti-DNase B has a slightly higher sensitivity at 90%.
• ECG may show a prolonged PR interval and possibly other features too. Tachycardia is usual although some children develop bradycardia. ST elevation suggests pericarditis.
• CXR may show features of heart failure.
• Doppler echocardiography is more sensitive than clinical assessment in the detection of carditis in acute rheumatic fever, and can contribute to earlier diagnosis.⁸There are a number of characteristic features.

Rheumatic fever should still be considered as a likely diagnosis even if criteria are not fully satisfied when there is chorea or carditis without apparent cause and recent streptococcal infection or when the patient has had previous rheumatic fever and has symptoms of a recurrence.

The main aims of management are to:

• Eradicate the streptococcal infection if infection is still present (usually a pharyngitis).
• Suppress inflammation arising from the autoimmune response.
• Provide supportive treatment particularly for cardiac complications such as congestive cardiac failure.

• General:
  • This is one of the very few conditions in which bed rest is enforced even if the patient feels well enough to be up and about. Full activity should not be resumed until markers for inflammation and infection (acute-phase reactants) have returned to normal.
• Drugs:
  • Penicillin is given to eradicate any organisms still present. In allergy to penicillin, erythromycin or a cephalosporin are recommended. Penicillin appears to be the drug of choice both in initial infection and to prevent recurrence.^9,10 It may be more effective given by the IM route but the quality of the evidence is poor.^9,1For recurrent pharyngitis a second 10 days of penicillin may be given but carriage is difficult to eradicate with conventional penicillin therapy. Oral clindamycin is recommended.
  • Aspirin usually relieves arthritis within a few days. High doses are required and other NSAID's like naproxen may be safer.¹¹ There is no evidence that NSAIDs, steroids or immunoglobulin reduce the severity of heart disease but trials are rather old and newer methodology would be valuable.¹
  • Heart failure will require diuretics, ACE inhibitors, and digoxin. If this fails consider cardiac surgery even in acute failure. Mitral valve repair or replacement may be life saving.¹
  • Chorea is often self-limiting but is likely to need suppression with diazepam.² Chorea may be treated with haloperidol although this drug can cause extrapyramidal effects.

The most important complications and sequelae derive from :

• Carditis
• Mitral stenosis
• Congestive cardiac failure

About 30 to 50% of first episodes of acute rheumatic fever lead to chronic rheumatic heart disease. With severe carditis or at least one recurrence, this increases to 70%. Patients need long-term follow up of cardiac status and myocarditis leaves the myocardium weak for life. Most recurrences occur within 2 years of the original episode.
Clinical features of rheumatic fever resolve inside 12 weeks in 80% and by 15 weeks in most of the other 20%. Chorea can occasionally continue in remitting fashion for years. Mortality is rare in industrialised countries but is still about 10% in developing countries.²Penicillin is said to have reduced the rate of valvular heart disease from 60 to 70% down to 10
to 40%.²

Secondary prophylaxis requires that every patient should start a long-term programme of regular antibiotics to prevent further group A streptococcal infection.¹ The duration of prophylaxis is the subject of some controversy.

• This should be continued for at least 5 years or until age 21, whichever is longer.
• This should be for 10 years for RF with carditis but no valvular disease (or well into adulthood, whichever is longer).
• However, with substantial valvular disease this should be continued longer. In severe valvular damage, or with valve surgery, prophylaxis should be continued for life¹ (or at least 10 years or until age 40 according to the American Heart Association).²

A vaccine against rheumatic fever is possible in theory but has not yet been developed.¹²
If valves are damaged the need for prophylaxis with antibiotics when infective endocarditis is a risk must be emphasised.

This often dramatic disease has been recognised for centuries. Baillou (1538-1616) realised that the arthritis was different to gout. Sydenham (1624-1668) famously described the chorea. The association of rheumatic fever with sore throat was made in 1880 and the association with scarlet fever in the early 1900s. The arrival of antibiotics in the 1940s heralded the start of treatment and preventive strategies. The incidence in developed countries has declined since. Unfortunately developing countries have not benefited very much from the progress made.