Rheumatic fever (RF) 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.
The pathogenesis and immune mechanisms are not fully understood.
- It is caused by Lancefield group A beta-haemolytic streptococci (GpA BHS) of which those with the M antigen are most likely to cause the disease (M types 3, 5, 18, 19, 24). However, RF and rheumatic heart disease have been discovered in communities where other responsible serotypes have been found.
- 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.
- The decline in RF is not just due to penicillin but also to improved social conditions and a reduction in virulence of the GpA BHS. It remains prevalent in other parts of the world, particularly developing countries.
- The disease affects joints, skin, heart and nervous system.
- Twin studies have shown a 44% monozygotic concordance but only a 12% dizygotic concordance, strongly supporting the idea of a genetic susceptibility to developing rheumatic fever after exposure to the bacterium, rather than a simple throat infection.
- The features of the disease are thought to be the result of a hypersensitivity reaction caused in the main by cross-reacting antibodies. It is thought there is a combined humoral and cell-mediated immune response to the bacterium (pharyngitis or skin streptococcal infection) which may lead to infiltration of the heart valve endothelium by T cells cross-reactive with streptococcal M protein and cardiac myosin.
- Pathological evaluation of the valves of patients dying from acute rheumatic fever (ARF) indicates microscopic disease in each of the four cardiac valves. Clinically, the mitral valve is involved in 90-95% of this group, in whom 20-25% also have aortic valve involvement. Isolated aortic valve, tricuspid valve or pulmonary valve involvement is much less common.
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 obtain reliable epidemiological data.
- The incidence is highest in school-aged children. One study reported a median age of diagnosis of ARF of 10.4 years with an interquartile range between 8.7-14.3 years.
- The incidence of RF in developed countries is low. The incidence of ARF has fallen in high-income countries to less than 1 per 100,000 population.
- Even in developed countries, prevalence is a function of socio-economic 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 those aged 5-14 years. Around 60% of these patients develop rheumatic heart disease. Sub-Saharan Africa has been identified as a high-burden area, although accurate data are hard to collect.
- At least 233,000 deaths are attributable to rheumatic fever or rheumatic heart disease each year.
- Both primary and recurrent episodes of fever are equally common. Recurrence occurs most often in the first five years after the initial episode. The young are most at risk of recurrence. 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.
- Symptoms appear between one and five weeks after a sore throat, with an average of three 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 RF.
- Diagnosis is based on Jones Criteria that were devised in 1944, revised in 1992and updated in 2015. The update included the role of echocardiography to detect subclinical valvular lesions. They can be used to identify patients with a high likelihood of having RF.
A method of identifying patients with a high likelihood of having RF:
- Evidence of recent streptococcal infection (eg, history of scarlet fever, positive throat swab or rising or increased antistreptolysin O titre (ASOT) >200 U/mL or DNase B titre).
- Plus two major criteria; or
- One major and two minor criteria.
Definitions of these criteria are set out below.
- 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 one or two joints are affected at any time with each being only involved for between a few hours and a few days.
- 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 40-60% without chorea and 20-30% with chorea.
- Carditis has characteristic findings on Doppler echocardiography. The mitral valve is the most common to be involved at 65-70%, with the aortic valve second at 25%. Aortic valve disease, unlike most other manifestations of this disease, is more common 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:
- Carey Coombs' murmur is a soft, short diastolic filling murmur due to vegetations on the mitral valve.
- Austin Flint's 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's chorea and 'St Vitus' Dance'):
- Occurs in 10-30% of patients.
- It usually presents in children between 7-12 years, with a female preponderance.
- There are both psychological and physical features. It causes rapid and purposeless movements, particularly of the face and upper extremities.
- Paediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (PANDAS) and Tourette's syndrome are other varieties of movement and neurological disorders described.
- It may stop when the patient sleeps.
- Subcutaneous nodules:
- Occur in 10% of patients.
- They are 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 2 cm in size.
- They are normally in crops of three or four, appearing 2-3 weeks after onset of fever.
- The histology resembles Aschoff bodies found in the heart and they are indicative of severe carditis.
- Erythema marginatum (also known as erythema annulare)
- It occurs in about 5-15% of patients.
- The rash comprises pale-red macules or papules between 1 cm 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.
- This is present in 90% of cases. It is usually over 39°C, stays high for a week and is lower for the following two weeks.
- In pure chorea the patient may be apyrexial.
- ESR and serum CRP are very raised.
- Arthralgia (but not if arthritis is one of the major criteria).
- Prolonged PR interval (but not if carditis is the major criterion).
Other clinical scenarios
There are three 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 RF.
- Newly ill patients with a history of RF, 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 Criteria also addresses the question of excessive diagnosis.
- Arthritis - consider:
- Heart disease - consider:
- Rash (erythema marginatum) - consider:
- Chorea - consider:
- Throat swabs are usually performed but may fail to grow streptococci by the time symptoms of RF 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 two weeks apart for a rise.
- The most common antibodies tested include ASO and anti-DNase B, antihyaluronidase, antistreptokinase, antistreptococcal esterase and anti-nicotinamide adenine dinucleotide (anti-NAD).
- Generally, the antibodies rise during the first month after infection and then plateau for 3-6 before returning to normal levels at 6-12 months. ASOT peaks 2-3 weeks after the onset of clinical disease and there is a sensitivity of 80-85%. 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 RF and can contribute to earlier diagnosis. The use of handheld echocardiography is being explored in low resource settings.
RF 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 RF 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.
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.
- Penicillin is given to eradicate any organisms still present. In allergy to penicillin, erythromycin or a cephalosporin is recommended. Penicillin appears to be the drug of choice both in initial infection and to prevent recurrence. The World Health Organization (WHO) recommends that this should be given intramuscularly unless there are issues of compliance, in which case oral treatment may be given. Other authorities recommend oral therapy first-line with a single injection of benzylpenicillin reserved for patients unlikely to complete the course.
- For 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 NSAIDs like naproxen may be safer. 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[2, 19].
- Heart failure will require diuretics, angiotensin-converting enzyme (ACE) inhibitors and digoxin. If this fails, consider cardiac surgery - even in acute failure. Mitral valve repair or replacement may be life-saving.
- Chorea is often self-limiting but is likely to need suppression with diazepam. Chorea may be treated with haloperidol, although this drug can cause extrapyramidal effects.
The most important complications and sequelae derive from:
- Mitral stenosis.
- Congestive cardiac failure.
Rheumatic heart disease occurs in 30-45% of patients with acute RF. Severe chronic valvular disease is associated with severe carditis and recurrent RF. Patients need long-term follow-up of cardiac status and myocarditis leaves the myocardium weak for life. Most recurrences occur within five years of the original episode.
Clinical features of RF resolve inside 12 weeks in 80%.
Chorea can occasionally continue in remitting fashion for years. Mortality is rare in industrialised countries but is about 1.5% per year globally. Penicillin is said to have significantly reduced the rate of valvular heart disease.
Secondary prophylaxis requires that every patient should start a long-term programme of regular antibiotics to prevent further GpA BHS infection. The duration of prophylaxis is the subject of some controversy:
- This should be continued for at least five years or until age 21 years, whichever is longer.
- This should be for ten 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 life (or at least ten years or until age 40 years, according to the American Heart Association)[2, 17].
A vaccine against RF is possible in theory but has not yet been developed. Prophylactic antibiotics before dental or surgical treatment (to prevent infective endocarditis) are no longer recommended for patients with acquired valve disease.
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 RF 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 preventative strategies. The incidence in developed countries has declined since. Unfortunately, developing countries have not benefited very much from the progress made.
Further reading and references
Saxena A, Kumar RK, Gera RP, et al; Consensus guidelines on pediatric acute rheumatic fever and rheumatic heart disease. Indian Pediatr. 2008 Jul45(7):565-73.
Ralph AP, Fittock M, Schultz R, et al; Improvement in rheumatic fever and rheumatic heart disease management and prevention using a health centre-based continuous quality improvement approach. BMC Health Serv Res. 2013 Dec 1813(1):525. doi: 10.1186/1472-6963-13-525.
Cunningham MW; Streptococcus and rheumatic fever. Curr Opin Rheumatol. 2012 Jul24(4):408-16. doi: 10.1097/BOR.0b013e32835461d3.
Cilliers AM; Rheumatic fever and its management. BMJ. 2006 Dec 2333(7579):1153-6.
Webb RH, Grant C, Harnden A; Acute rheumatic fever. BMJ. 2015 Jul 14351:h3443. doi: 10.1136/bmj.h3443.
Engel ME, Stander R, Vogel J, et al; Genetic susceptibility to acute rheumatic fever: a systematic review and meta-analysis of twin studies. PLoS One. 20116(9):e25326. doi: 10.1371/journal.pone.0025326. Epub 2011 Sep 30.
Kumar RK, Tandon R; Rheumatic fever & rheumatic heart disease: the last 50 years. Indian J Med Res. 2013 Apr137(4):643-58.
Sudeep D et al; The Descriptive Epidemiology of Acute Rheumatic Fever and Rheumatic Heart Disease in Low and Middle-Income Countries, American Journal of Epidemiology and Infectious Disease, 2013, Vol. 1, No. 4, 34-40.
Zuhlke LJ, Steer AC; Estimates of the global burden of rheumatic heart disease. Glob Heart. 2013 Sep8(3):189-95. doi: 10.1016/j.gheart.2013.08.008. Epub 2013 Sep 26.
Carapetis JR.; Rheumatic heart disease in developing countries. N Engl J Med. 2007357:439–441
Carvalho SM, Dalben I, Corrente JE, et al; Rheumatic fever presentation and outcome: a case-series report. Rev Bras Reumatol. 2012 Mar-Apr52(2):241-6.
No authors listed; Guidelines for the diagnosis of rheumatic fever. Jones Criteria, 1992 update. Special Writing Group of the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on Cardiovascular Disease in the Young of the American Heart Association. JAMA. 1992 Oct 21268(15):2069-73.
Steer AC, Vidmar S, Ritika R, et al; Normal ranges of streptococcal antibody titers are similar whether streptococci are endemic to the setting or not. Clin Vaccine Immunol. 2009 Feb16(2):172-5. doi: 10.1128/CVI.00291-08. Epub 2008 Dec 3.
Ploutz M, Lu JC, Scheel J, et al; Handheld echocardiographic screening for rheumatic heart disease by non-experts. Heart. 2016 Jan102(1):35-9. doi: 10.1136/heartjnl-2015-308236. Epub 2015 Oct 5.
Antibiotic use for the Prevention and Treatment of Rheumatic Fever and Rheumatic Heart Disease in Children; World Health Organization (WHO) 2008
Seckeler MD, Hoke TR; The worldwide epidemiology of acute rheumatic fever and rheumatic heart disease. Clin Epidemiol. 2011 Feb 223:67-84. doi: 10.2147/CLEP.S12977.
Hashkes PJ, Tauber T, Somekh E, et al; Naproxen as an alternative to aspirin for the treatment of arthritis of rheumatic fever: a randomized trial. J Pediatr. 2003 Sep143(3):399-401.
Cilliers A, Adler AJ, Saloojee H; Anti-inflammatory treatment for carditis in acute rheumatic fever. Cochrane Database Syst Rev. 2015 May 28(5):CD003176. doi: 10.1002/14651858.CD003176.pub3.
Guilherme L, Cury P, Demarchi LM, et al; Rheumatic heart disease: proinflammatory cytokines play a role in the progression and maintenance of valvular lesions. Am J Pathol. 2004 Nov165(5):1583-91.
Meira ZM, Goulart EM, Colosimo EA, et al; Long term follow up of rheumatic fever and predictors of severe rheumatic valvar disease in Brazilian children and adolescents. Heart. 2005 Aug91(8):1019-22.
Gerber MA, Baltimore RS, Eaton CB, et al; Prevention of rheumatic fever and diagnosis and treatment of acute Streptococcal pharyngitis: a scientific statement from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee of the Council on Cardiovascular Disease in the Young, the Interdisciplinary Council on Functional Genomics and Translational Biology, and the Interdisciplinary Council on Quality of Care and Outcomes Research: endorsed by the American Academy of Pediatrics. Circulation. 2009 Mar 24119(11):1541-51. doi: 10.1161/CIRCULATIONAHA.109.191959. Epub 2009 Feb 26.
Good MF, Batzloff MR, Pandey M; Strategies in the development of vaccines to prevent infections with group A streptococcus. Hum Vaccin Immunother. 2013 Jun 289(11).
Kadri SM; Diagnosis of Rheumatic Fever, Indian Journal for the Practising Doctor, 2005