Acute Rheumatic fever. Rheumocarditis

01Definition and overview

Acute rheumatic fever is a multisystem inflammatory disease that follows infection of the throat with group A streptococcus (Streptococcus pyogenes). It is not an infection of the heart or a toxic effect: it is an autoimmune reaction, triggered in a susceptible host, against the heart, the joints, the brain and the skin.

Only the heart is left damaged. Rheumatic carditis inflames all three layers of the heart, a pancarditis, but its importance lies in the valvulitis. The chronic valve disease that remains after one severe attack or several milder ones is rheumatic heart disease, the cause of most mitral stenosis in the world.

The disease is described as a first episode or a recurrence, and by the population the patient comes from: the 2015 Jones criteria are stricter for patients from low-risk populations, such as most of Europe, than for those from moderate- or high-risk ones.

02Etiology and pathophysiology

The trigger

Rheumatic fever follows pharyngitis with group A streptococcus, usually by 2 to 4 weeks. Streptococcal skin infection may contribute in some high-risk populations. Only a small minority of untreated streptococcal sore throats lead to rheumatic fever, from about 0.3 per cent in the community to 3 per cent in epidemics, so the host matters as much as the organism:

• an inherited susceptibility, suggested by clustering in families and by twin studies;
• poverty and overcrowding, which spread streptococcal infections and bring repeated exposure;
• limited access to medical care, so sore throats go untreated.

Molecular mimicry

1. 1

   The immune response

   The throat infection raises antibodies and T cells against the M protein of the streptococcal wall and against its group A carbohydrate.
2. 2

   Cross-reaction

   These antigens resemble human proteins: cardiac myosin and tropomyosin, laminin and other proteins of the valve endothelium and matrix, keratin in the skin, and proteins of neurons in the basal ganglia. Antibodies against the shared shapes bind the host tissues.
3. 3

   Valvulitis

   Antibodies bind the endothelium of the valves, which then lets in T cells. The inflamed valve swells, and small, wart-like vegetations form along its closure line. In the myocardium, granulomatous nodules called Aschoff bodies form, the characteristic lesion of rheumatic carditis.
4. 4

   Scarring

   As the inflammation heals, the valve fibroses: the commissures fuse, the leaflets thicken and the chordae shorten and fuse. Each recurrence adds to the damage, and over years the valve becomes stenotic or regurgitant, or both.

The heart in the acute attack

• Endocarditis (valvulitis) affects the mitral valve most often, then the aortic, and rarely the tricuspid. In the acute attack it causes regurgitation, through dilatation of the annulus, elongation of the chordae and prolapse of the leaflet tips. Stenosis takes years to form.
• Myocarditis is seen as tachycardia and conduction delay; heart failure in the acute attack comes mainly from the leaking valves.
• Pericarditis causes chest pain, a rub and an effusion, but rarely tamponade, and never constriction.

Antibodies against neurons of the basal ganglia cause the chorea, which explains why it can occur on its own, months after the infection.

03Clinical features

The illness starts with fever and malaise about three weeks (1 to 5 weeks) after the sore throat, which many patients have forgotten. The major manifestations, with their usual frequency:

• Carditis, in 50 to 70 per cent when echocardiography is used: a new apical pansystolic murmur of mitral regurgitation, sometimes with a soft mid-diastolic murmur at the apex from the inflamed mitral valve (the Carey Coombs murmur), the early diastolic murmur of aortic regurgitation, a pericardial rub, tachycardia out of proportion to the fever, or heart failure. Carditis may be found only on echocardiography.
• Arthritis, in 35 to 66 per cent: a migratory polyarthritis of the large joints (knees, ankles, elbows, wrists), each joint hot, swollen and very painful for a few days, then the next. It responds dramatically to aspirin or an NSAID and never leaves permanent damage. In high-risk populations it can affect a single joint.
• Sydenham chorea, in 10 to 30 per cent, more often in girls and adolescents: involuntary, jerky, purposeless movements of the face and limbs that disappear in sleep, with clumsiness, emotional lability and a grip that squeezes and relaxes ("milkmaid's grip"). It appears late, often 1 to 6 months after the infection or longer, and lasts weeks to months.
• Subcutaneous nodules, in up to 10 per cent: firm, painless nodules from a few millimetres to 2 cm across over bony prominences and extensor tendons (elbows, knees, knuckles, spine and occiput), which come with severe carditis.
• Erythema marginatum, in under 6 per cent: pink, non-itchy rings with pale centres and spreading edges on the trunk and upper limbs, sparing the face, coming and going over hours.

Fever, joint pains without arthritis, raised inflammatory markers and a prolonged PR interval are the minor manifestations.

04Diagnosis and management

Tests

• Antistreptococcal antibodies: the antistreptolysin O titre (peaking 3 to 6 weeks after the infection) and the anti-DNase B titre (peaking later, at 6 to 8 weeks). A raised or rising titre is the usual evidence of the preceding infection; the throat swab is often negative by the time the fever starts.
• A throat culture or a rapid antigen test for group A streptococcus.
• ESR and CRP, which are usually high, except in isolated chorea.
• Echocardiography with Doppler, in every case, repeated during the illness. It shows the regurgitation and the changes of the valves (a dilated annulus, elongated or ruptured chordae, prolapse and thickening of the leaflet tips), pericardial effusion and ventricular function.
• ECG: a prolonged PR interval is common, but it is nonspecific and does not predict valve disease.
• A chest X-ray for heart size and heart failure, and blood cultures when endocarditis is a possibility.

The Jones criteria, 2015

A low-risk population is one with an incidence of 2 or fewer cases per 100,000 school-aged children a year, or a prevalence of rheumatic heart disease of 1 per 1000 or less. With evidence of a recent group A streptococcal infection:

• a first episode needs two major manifestations, or one major and two minor;
• a recurrence, in a patient known to have had rheumatic fever or rheumatic heart disease, needs two major, one major and two minor, or three minor once other causes are excluded.

Two presentations need no evidence of a recent infection, because it may be gone by the time they appear: chorea alone, once other causes are excluded, and carditis that develops slowly and is found late.

The same joint signs cannot count twice, as major and minor. The differential diagnosis includes septic arthritis, juvenile idiopathic arthritis, reactive arthritis (including post-streptococcal reactive arthritis), Lyme disease, lupus, leukaemia, sickle cell crisis, viral myocarditis and infective endocarditis.

Treating the attack

Secondary prophylaxis

Patients who have had rheumatic fever are at high risk of a recurrence with every new streptococcal infection, and recurrences cause most rheumatic heart disease. Continuous penicillin prevents them:

• benzathine benzylpenicillin 1.2 million units by deep intramuscular injection every 4 weeks, every 3 weeks in some high-risk settings or after a recurrence despite good adherence; 600,000 units for children under 27 kg;
• oral penicillin V twice daily is an alternative, though less effective, because daily doses are easily missed;
• a macrolide such as erythromycin for patients allergic to penicillin.

The duration, by American guidance:

The patient also needs regular dental care and follow-up echocardiography. Endocarditis prophylaxis is not given for rheumatic heart disease alone, and the penicillin taken for rheumatic fever does not prevent endocarditis.

Primary prevention

Treating a streptococcal sore throat with penicillin V or amoxicillin for 10 days, started within 9 days of its onset, prevents rheumatic fever. Where the disease is common, echocardiographic screening of schoolchildren finds latent rheumatic heart disease, and a large trial showed that penicillin injections greatly reduced its progression over two years. Vaccines against group A streptococcus are in development.

05Epidemiology

About 55 million people lived with rheumatic heart disease in 2021, and it caused about 360,000 deaths that year. The burden lies in sub-Saharan Africa, South Asia, the Pacific islands, and in Indigenous Australians and Māori and Pacific peoples in New Zealand, who have some of the highest rates in the world. First attacks peak between 5 and 15 years of age and are rare under 3 and over 30; recurrences continue into adult life. Rheumatic heart disease is more common in women.

In Western Europe rheumatic fever has become rare, with improved housing, less crowding and antibiotics for sore throats. The rheumatic heart disease seen there is mostly in older people who had rheumatic fever as children and in migrants from countries where it is common.

06Prognosis

The acute attack usually lasts up to three months. The arthritis heals without damage, the chorea settles within months though it can return (for example in pregnancy), and the carditis heals, but may scar the valves. About half of patients with carditis develop chronic rheumatic heart disease, mitral regurgitation early and mitral stenosis after 10 to 20 years or more, often with aortic disease. Recurrences are most likely in the first five years after an attack and tend to repeat the pattern of the first: a patient who had carditis is likely to have it again.

Adherence to secondary prophylaxis decides the outcome. With it, mild valve lesions often regress, and some more severe ones improve; without it, recurrences pile up damage. Established rheumatic heart disease brings heart failure, atrial fibrillation, stroke, endocarditis and pulmonary hypertension, and it is a major cause of death in pregnancy where it is common.