Rheumatic Fever is an inflammatory disease that occurs following a Streptococcus pyogenes

infection, such as streptococcal pharyngitis or scarlet fever. Believed to be caused by antibody

cross-reactivity that can involve the heart, joints, skin, and brain,[1] the illness typically develops two
to three weeks after a streptococcal infection. Acute rheumatic fever commonly appears in children
between the ages of 6 and 15, with only 20% of first-time attacks occurring in adults.[1] The illness is
so named because of its similarity in presentation to rheumatism.[2]

Rheumatic heart disease at autopsy with characteristic findings (thickened mitral valve, thickened chordae
tendineae, hypertrophied left ventricular myocardium).

Modified Jones criteria were first published in 1944 by T. Duckett Jones, MD.[3] They have been
periodically revised by the American Heart Association in collaboration with other groups.[4]
According to revised Jones criteria, the diagnosis of rheumatic fever can be made when two of the
major criteria, or one major criterion plus two minor criteria, are present along with evidence of
streptococcal infection: elevated or rising antistreptolysin O titre or DNAase.[1] Exceptions are
chorea and indolent carditis, each of which by itself can indicate rheumatic fever.[5][6][7]

Major criteria
Polyarthritis: A temporary migrating inflammation of the large joints, usually starting in the
legs and migrating upwards.

Carditis: Inflammation of the heart muscle (myocarditis) which can manifest as congestive
heart failure with shortness of breath, pericarditis with a rub, or a new heart murmur.

Subcutaneous nodules: Painless, firm collections of collagen fibers over bones or tendons.
They commonly appear on the back of the wrist, the outside elbow, and the front of the knees.

Erythema marginatum: A long-lasting reddish rash that begins on the trunk or arms as
macules, which spread outward and clear in the middle to form rings, which continue to spread
and coalesce with other rings, ultimately taking on a snake-like appearance. This rash typically
spares the face and is made worse with heat.
Sydenham's chorea (St. Vitus' dance): A characteristic series of rapid movements without purpose of
the face and arms. This can occur very late in the disease for at least three months from onset of
infection.

Minor criteria
Fever of 38.238.9 C (101102 F)

Arthralgia: Joint pain without swelling (Cannot be included if polyarthritis is present as a

major symptom)

Raised erythrocyte sedimentation rate or C reactive protein

Leukocytosis

ECG showing features of heart block, such as a prolonged PR interval[8] [9] (Cannot be
included if carditis is present as a major symptom)

Previous episode of rheumatic fever or inactive heart disease

Other signs and symptoms
Abdominal pain

Nose bleeds

Preceding streptococcal infection: recent scarlet fever, raised antistreptolysin O or other

streptococcal antibody titre, or positive throat culture.[9]

Pathophysiology of rheumatic heart disease

Micrograph showing an Aschoff body (right of image), as seen in rheumatic heart disease. H&E stain.
Rheumatic fever is a systemic disease affecting the peri-arteriolar connective tissue and can occur
after an untreated Group A Beta hemolytic streptococcal pharyngeal infection. It is believed to be
caused by antibody cross-reactivity. This cross-reactivity is a Type II hypersensitivity reaction and is
termed molecular mimicry. Usually, self reactive B cells remain anergic in the periphery without T cell
co-stimulation. During a Streptococcus infection, mature antigen presenting cells such as B cells
present the bacterial antigen to CD4-T cells which differentiate into helper T2 cells. Helper T2 cells
subsequently activate the B cells to become plasma cells and induce the production of antibodies
against the cell wall of Streptococcus. However the antibodies may also react against the
myocardium and joints,[10] producing the symptoms of rheumatic fever.
Group A streptococcus pyogenes has a cell wall composed of branched polymers which sometimes
contain M protein that are highly antigenic. The antibodies which the immune system generates
against the M protein may cross react with cardiac myofiber protein myosin,[11] heart muscle
glycogen and smooth muscle cells of arteries, inducing cytokine release and tissue destruction.
However, the only proven cross reaction is with perivascular connective tissue.[citation needed] This
inflammation occurs through direct attachment of complement and Fc receptor-mediated recruitment
of neutrophils and macrophages. Characteristic Aschoff bodies, composed of swollen eosinophilic
collagen surrounded by lymphocytes and macrophages can be seen on light microscopy. The larger
macrophages may become Anitschkow cells or Aschoff giant cells. Acute rheumatic valvular lesions
may also involve a cell-mediated immunity reaction as these lesions predominantly contain T-helper
cells and macrophages.[12]
In acute rheumatic fever, these lesions can be found in any layer of the heart and is hence called
pancarditis. The inflammation may cause a serofibrinous pericardial exudate described as "bread-
and-butter" pericarditis, which usually resolves without sequelae. Involvement of the endocardium
typically results in fibrinoid necrosis and verrucae formation along the lines of closure of the left-
sided heart valves. Warty projections arise from the deposition, while subendocardial lesions may
induce irregular thickenings called MacCallum plaques.

Rheumatic heart disease

Chronic rheumatic heart disease (RHD) is characterized by repeated inflammation with fibrinous
resolution. The cardinal anatomic changes of the valve include leaflet thickening, commissural
fusion, and shortening and thickening of the tendinous cords.[12] It is caused by an autoimmune
reaction to Group A -hemolytic streptococci (GAS) that results in valvular damage.[13] Fibrosis and
scarring of valve leaflets, commissures and cusps leads to abnormalities that can result in valve
stenosis or regurgitation.[14] The inflammation caused by rheumatic fever, usually during childhood,
is referred to as rheumatic valvulitis. About half of patients with acute rheumatic fever develop
inflammation involving valvular endothelium.[15] The majority of morbidity and mortality associated
with rheumatic fever is caused by its destructive effects on cardiac valve tissue.[14] The
pathogenesis of RHD is complex and not fully understood, but it is known to involve molecular
mimicry and genetic predisposition that lead to autoimmune reactions.
Molecular mimicry occurs when epitopes are shared between host antigens and GAS antigens.[16]
This causes an autoimmune reaction against native tissues in the heart that are incorrectly
recognized as "foreign" due to the cross-reactivity of antibodies generated as a result of epitope
sharing. The valvular endothelium is a prominent site of lymphocyte-induced damage. CD4+ T cells
are the major effectors of heart tissue autoimmune reactions in RHD.[17] Normally, T cell activation
is triggered by the presentation of GAS antigens. In RHD, molecular mimicry results in incorrect T
cell activation, and these T lymphocytes can go on to activate B cells, which will begin to produce
self-antigen-specific antibodies. This leads to an immune response attack mounted against tissues
in the heart that have been misidentified as pathogens. Rheumatic valves display increased
expression of VCAM-1, a protein that mediates the adhesion of lymphocytes.[18] Self-antigen-
specific antibodies generated via molecular mimicry between human proteins and GAS antigens up-
regulate VCAM-1 after binding to the valvular endothelium. This leads to the inflammation and valve
scarring observed in rheumatic valvulitis, mainly due to CD4+ T cell infiltration.[18]
While the mechanisms of genetic predisposition remain unclear, a few genetic factors have been
found to increase susceptibility to autoimmune reactions in RHD. The dominant contributors are a
component of MHC class II molecules, found on lymphocytes and antigen-presenting cells,
specifically the DR and DQ alleles on human chromosome 6.[19] Certain allele combinations appear
to increase RHD autoimmune susceptibility. Human leukocyte antigen (HLA) class II allele DR7
(HLA-DR7) is most often associated with RHD, and its combination with certain DQ alleles is
seemingly associated with the development of valvular lesions.[19] The mechanism by which MHC
class II molecules increase a host's susceptibility to autoimmune reactions in RHD is unknown, but it
is likely related to the role HLA molecules play in presenting antigens to T cell receptors, thus
triggering an immune response. Also found on human chromosome 6 is the cytokine TNF- which is
also associated with RHD.[19] High expression levels of TNF- may exacerbate valvular tissue
inflammation, contributing to RHD pathogenesis. Mannose-binding lectin (MBL) is an inflammatory
protein involved in pathogen recognition. Different variants of MBL2 gene regions are associated in
RHD. RHD-induced mitral valve stenosis has been associated with MBL2 alleles encoding for high
production of MBL.[20] Aortic valve regurgitation in RHD patients has been associated with different
MBL2 alleles that encode for low production of MBL.[21] Other genes are also being investigated to
better understand the complexity of autoimmune reactions that occur in RHD.

Prevention
Prevention of recurrence is achieved by eradicating the acute infection and prophylaxis with
antibiotics. The American Heart Association recommends that daily or monthly prophylaxis continue
long-term, perhaps for life.[22]

Treatment
This section needs additional citations for verification. Please help improve this article by adding
citations to reliable sources. Unsourced material may be challenged and removed. (February 2012)
The management of acute rheumatic fever is geared toward the reduction of inflammation with anti-
inflammatory medications such as aspirin or corticosteroids. Individuals with positive cultures for
strep throat should also be treated with antibiotics. Aspirin is the drug of choice and should be given
at high doses of 100 mg/kg/day. One should watch for side effects like gastritis and salicylate
poisoning. In children and teenagers, the use of aspirin and aspirin-containing products can be
associated with Reye's syndrome, a serious and potentially deadly condition. The risks, benefits and
alternative treatments must always be considered when administering aspirin and aspirin-containing
products in children and teenagers. Ibuprofen for pain and discomfort and corticosteroids for
moderate to severe inflammatory reactions manifested by rheumatic fever should be considered in
children and teenagers. Steroids are reserved for cases where there is evidence of involvement of
heart. The use of steroids may prevent further scarring of tissue and may prevent development of
sequelae such as mitral stenosis. Monthly injections of longacting penicillin must be given for a
period of five years in patients having one attack of rheumatic fever. If there is evidence of carditis,
the length of therapy may be up to 40 years. Another important cornerstone in treating rheumatic
fever includes the continual use of low-dose antibiotics (such as penicillin, sulfadiazine, or
erythromycin) to prevent recurrence.

Vaccine
No vaccines are currently available to protect against S. pyogenes infection, although there has
been research into the development of one. Difficulties in developing a vaccine include the wide
variety of strains of S. pyogenes present in the environment and the large amount of time and
people that will be needed for appropriate trials for safety and efficacy of the vaccine.[23]
Infection
Patients with positive cultures for Streptococcus pyogenes should be treated with penicillin as long
as allergy is not present. This treatment will not alter the course of the acute disease.
The most appropriate treatment stated in the Oxford Handbook of Clinical Medicine for rheumatic
fever is benzathine benzylpenicillin.

Inflammation
Patients with significant symptoms may require corticosteroids. Salicylates are useful for pain.

Heart failure
Some patients develop significant carditis which manifests as congestive heart failure. This requires
the usual treatment for heart failure: ACE Inhibitors, diuretics, beta blockers, and digoxin. Unlike
normal heart failure, rheumatic heart failure responds well to corticosteroids.

Epidemiology

Disability-adjusted life year for rheumatic heart disease per 100,000 inhabitants in 2004.[24]

no data

less than 20

2040

4060

6080
 80100

100120

120140

140160

160180

180200

200330

more than 330

Rheumatic fever is common worldwide and responsible for many cases of damaged heart valves. In
Western countries, it became fairly rare since the 1960s, probably due to widespread use of
antibiotics to treat streptococcus infections. While it has been far less common in the United States
since the beginning of the 20th century, there have been a few outbreaks since the 1980s. Although
the disease seldom occurs, it is serious and has a case-fatality rate of 25%.[25]
Rheumatic fever primarily affects children between ages 5 and 17 years and occurs approximately
20 days after strep throat. In up to a third of cases, the underlying strep infection may not have
caused any symptoms.
The rate of development of rheumatic fever in individuals with untreated strep infection is estimated
to be 3%. The incidence of recurrence with a subsequent untreated infection is substantially greater
(about 50%).[26] The rate of development is far lower in individuals who have received antibiotic
treatment. Persons who have suffered a case of rheumatic fever have a tendency to develop flare-
ups with repeated strep infections.
The recurrence of rheumatic fever is relatively common in the absence of maintenance of low dose
antibiotics, especially during the first three to five years after the first episode. Heart complications
may be long-term and severe, particularly if valves are involved.
Survivors of rheumatic fever often have to take penicillin to prevent streptococcal infection which
could possibly lead to another case of rheumatic fever that could prove fatal.

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