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Rheumatic Fever
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.
Pathogenesis [1]
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 [2] .
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 [3] .
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 [4] .
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 [1] .
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 [5] .
Epidemiology
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 [6] .
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 [2] .
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. SubSaharan Africa has been identified as a high-burden area, although accurate data are hard to
collect [7] .
At least 233,000 deaths are attributable to rheumatic fever or rheumatic heart disease each year [8] .
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At least 233,000 deaths are attributable to rheumatic fever or rheumatic heart disease each year [8] .
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 [9] .
Risk factors
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 [6] .
Presentation [3]
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 1992 [10, 11] and updated in
2015. The update included the role of echocardiography to detect subclinical valvular lesions [3] . They
can be used to identify patients with a high likelihood of having RF.
Jones Criteria
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.
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 one or two 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 non-steroidal anti-inflammatory drugs
(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 40-60% 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.
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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) [12]
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.
Minor criteria
Fever:
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 [10] .
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Differential diagnosis [13]
Arthritis - consider:
Rheumatoid arthritis (including Still's disease in children).
Henoch-Schönlein 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 disease. This does not usually present until at least the age of 30 years (peak
age 35-45).
Chorea gravidarum may occur in pregnancy.
Wilson's disease.
Investigations [5, 13]
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 [14] .
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 [15] .
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.
Management [5, 13]
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.
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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 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 [16] .
Other authorities recommend oral therapy first-line with a single injection of benzylpenicillin reserved
for patients unlikely to complete the course [17] .
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 [18] . 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 lifesaving [2] .
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.
Complications
The most important complications and sequelae derive from:
Carditis.
Mitral stenosis.
Congestive cardiac failure.
Prognosis
Rheumatic heart disease occurs in 30-45% of patients with acute RF [20] . Severe chronic valvular disease is
associated with severe carditis and recurrent RF [21] . 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 [9] .
Clinical features of RF resolve inside 12 weeks in 80% [13] .
Chorea can occasionally continue in remitting fashion for years. Mortality is rare in industrialised countries but is
about 1.5% per year globally [5] . Penicillin is said to have significantly reduced the rate of valvular heart
disease [22] .
Prevention
Secondary prophylaxis requires that every patient should start a long-term programme of regular antibiotics to
prevent further GpA BHS infection [2] . 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 [23] . Prophylactic antibiotics before
dental or surgical treatment (to prevent infective endocarditis) are no longer recommended for patients with
acquired valve disease.
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Historical perspective [24]
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 & references
Saxena A, Kumar RK, Gera RP, et al; Consensus guidelines on pediatric acute rheumatic fever and rheumatic heart
disease. Indian Pediatr. 2008 Jul;45(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
18;13(1):525. doi: 10.1186/1472-6963-13-525.
1. Cunningham MW; Streptococcus and rheumatic fever. Curr Opin Rheumatol. 2012 Jul;24(4):408-16. doi:
10.1097/BOR.0b013e32835461d3.
2. Cilliers AM; Rheumatic fever and its management. BMJ. 2006 Dec 2;333(7579):1153-6.
3. Webb RH, Grant C, Harnden A; Acute rheumatic fever. BMJ. 2015 Jul 14;351:h3443. doi: 10.1136/bmj.h3443.
4. 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. 2011;6(9):e25326. doi: 10.1371/journal.pone.0025326. Epub 2011 Sep 30.
5. Kumar RK, Tandon R; Rheumatic fever & rheumatic heart disease: the last 50 years. Indian J Med Res. 2013
Apr;137(4):643-58.
6. 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.
7. Zuhlke LJ, Steer AC; Estimates of the global burden of rheumatic heart disease. Glob Heart. 2013 Sep;8(3):189-95. doi:
10.1016/j.gheart.2013.08.008. Epub 2013 Sep 26.
8. Carapetis JR.; Rheumatic heart disease in developing countries. N Engl J Med. 2007;357:439–441
9. Carvalho SM, Dalben I, Corrente JE, et al; Rheumatic fever presentation and outcome: a case-series report. Rev Bras
Reumatol. 2012 Mar-Apr;52(2):241-6.
10. 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 21;268(15):2069-73.
11. Jones criteria for diagnosis of acute rheumatic fever; Cardiophile MD, March 2010
12. Erythema marginatum; Medical Pictures
13. The Australian guideline for prevention, diagnosis and management of acute rheumatic fever and rheumatic heart disease
(2nd edition); RHD Australia, 2012
14. 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 Feb;16(2):172-5. doi: 10.1128/CVI.00291-08. Epub 2008 Dec 3.
15. Ploutz M, Lu JC, Scheel J, et al; Handheld echocardiographic screening for rheumatic heart disease by non-experts. Heart.
2016 Jan;102(1):35-9. doi: 10.1136/heartjnl-2015-308236. Epub 2015 Oct 5.
16. Antibiotic use for the Prevention and Treatment of Rheumatic Fever and Rheumatic Heart Disease in Children; World
Health Organization (WHO) 2008
17. Seckeler MD, Hoke TR; The worldwide epidemiology of acute rheumatic fever and rheumatic heart disease. Clin
Epidemiol. 2011 Feb 22;3:67-84. doi: 10.2147/CLEP.S12977.
18. 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 Sep;143(3):399-401.
19. 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.
20. 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 Nov;165(5):1583-91.
21. 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 Aug;91(8):1019-22.
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 24;119(11):1541-51. doi:
10.1161/CIRCULATIONAHA.109.191959. Epub 2009 Feb 26.
23. Good MF, Batzloff MR, Pandey M; Strategies in the development of vaccines to prevent infections with group A
streptococcus. Hum Vaccin Immunother. 2013 Jun 28;9(11).
24. Kadri SM; Diagnosis of Rheumatic Fever, Indian Journal for the Practising Doctor, 2005
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For details see our conditions.
Original Author:
Dr Richard Draper
Current Version:
Dr Oliver Starr
Peer Reviewer:
Dr Laurence Knott
Document ID:
2731 (v24)
Last Checked:
24/02/2017
Next Review:
23/02/2022
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