Rheumatic Fever

Rheumatic Fever

Prof Ariyanto Harsono MD PhD SpA(K)

1

INTRODUCTIONRheumatic fever is an inflammatory

disease that occurs following a Streptococcus pyogenes infection, such as streptococcal pharyngitis. Believed to be caused byantibody cross-reactivity that can involve the heart, joints, skin, and brain, 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. The illness is so named because of its similarity in presentation to rheumatism.

Prof Ariyanto Harsono MD PhD SpA(K) 2

Believed to be caused by antibody cross-reactivity that can involve the heart, joints, skin, and brain, 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. The illness is so named because of its similarity in presentation to rheumatism.

prof Ariyanto Harsono MD PhD SpA(K) 3

EpidemiologyIn developing countries, the magnitude of ARF is enormous. Recent estimates suggest that 15.6 million people worldwide have rheumatic heart disease and that 470,000 new cases of rheumatic fever (approximately 60% of whom will develop rheumatic heart disease) occur annually, with 230,000 deaths resulting from its complications. Almost all of this toll occurs in the developing world.The incidence rate of rheumatic fever is as high as 50 cases per 100,000 children in many areas. Areas of hyperendemicity (eg, indigenous populations of Australia and New Zealand) see an incidence of 300-500 cases per 100,000 children, while the rates are approximately 50-fold lower in their nonindigenous compatriots. Rheumatic fever in the 21st century appears to be largely a disease of crowding and poverty.


DiagnosisRheumatic heart disease at autopsy with characteristic findings (thickened mitral valve, thickened chorda tendineae, hypertrophied left ventricular myocardium).Modified Jones criteria were first published in 1944 by T. Duckett Jones, MD. They have been periodically revised by the American Heart Association in collaboration with other groups. 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 presentalong with evidence of streptococcal infection: elevated or rising antistreptolysin O titre or DNAase.


Exceptions are chorea and indolent carditis, each of which by itself can indicate rheumatic fever. E & D studies have identified subclinical carditis in patients with acute rheumatic fever, as well as in follow-ups of rheumatic heart disease patients who initially presented as having isolated cases of Sydenham's chorea.


Major criteria

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

2. 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.

3. 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.

4. 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.

5. 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.



Erythema marginatum

Sub cutaneous nodule

Sydenham’s chorea

Minor criteria1. Fever of 38.2–38.9 °C

2. Arthralgia Joint pain without swelling (Cannot be included if polyarthritis is present as a major symptom)

3. Raised erythrocyte sedimentation rate or CRP

4. Leukocytosis

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

6. Previous episode of rheumatic fever or inactive heart disease


Other signs and symptoms

1. Abdominal pain

2. Nose bleeds

3. Preceding streptococcal infection: recent scarlet fever, raised antistreptolysin O or other streptococcal antibody titre, or positive throat culture.



PathophysiologyRheumatic 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, 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, 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. 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 Thelper cells and macrophages.


Micrograph showing an Aschoff body (right of image), as seen in rheumatic heart disease.

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 repair. The cardinal anatomic changes of the valve include leaflet thickening, commissural fusion, and shortening and thickening of the tendinous cords. It is caused by an autoimmune reaction to Group A β-hemolytic streptococci (GAS) that results in valvular damage. Fibrosis and scarring of valve leaflets, commisures and cusps leads to abnormalities that can result in valve stenosis or regurgitation.


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. The majority of morbidity and mortality associated with rheumatic fever is caused by its destructive effects on cardiac valve tissue. 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. 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. 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. 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.


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 human chromosome 6. Certain allele combinations appear to increase RHD autoimmune susceptibility. HLA class II allele DR7 is most often associated with RHD, and its combination with certain DQ alleles is seemingly associated with the development of valvular lesions. 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-a which is also associated with RHD.


High expression levels of TNF-α 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. Aortic valve regurgitation in RHD patients has been associated with different MBL2 alleles that encode for low production of MBL. Other genes are also being investigated to better understand the complexity of autoimmune reactions that occur in RHD.


Clinical Manifestations

Rheumatic fever manifests as various signs and symptoms that may occur alone or in various combinations. Sore throat: Although estimates vary, only 35%-60% of patients

with rheumatic fever recall having any upper respiratory symptoms in the preceding several weeks. Many symptomatic individuals do not seek medical attention, go undiagnosed, or do not take the prescribed antibiotic for acute rheumatic fever (ARF) prevention. If a course of penicillin or another appropriate antibiotic is taken at this time, the risk of ARF is reduced by approximately 80%.

Polyarthritis: Overall, arthritis occurs in approximately 75% of first attacks of ARF. The likelihood increases with the age of the patient, and arthritis is a major manifestation of ARF in 92% of adults.[11]


Carditis: Of first attacks of ARF, carditis occurs in 30%-60% of cases. It is more common in younger children but does occur in adults.

Severe inflammation can cause congestive heart failure (CHF).

Patients with carditis may present with shortness of breath, dyspnea upon exertion, cough, paroxysmal nocturnal dyspnea, chest pain, and/or orthopnea. Carditis may also be asymptomatic and may be diagnosed solely by auscultation or, perhaps, echocardiography (controversial; see Physical).


Sydenham chorea: This occurs in up to 25% of ARF cases in children but is very rare in adults. It is more common in girls. Sydenham chorea in ARF is likely due to molecular mimicry, with autoantibodies reacting with brain ganglioside. Sydenham chorea may occur with other

symptoms or as an isolated finding. It typically presents 1-6 months after the precipitating streptococcal infection and usually has both neurologic and psychological features.

In the isolated form, laboratory evidence of a preceding streptococcal infection may be lacking.

Like the polyarthritis, Sydenham chorea usually resolves without permanent damage but occasionally lasts 2-3 years and be a major problem for the patient and her family.


Erythema marginatum: In first attacks of ARF in children, erythema marginatum occurs in approximately 10%. Like chorea, it is very rare in adults.

Patients or parents may report a nonpruritic, painless, serpiginous, erythematous eruption on the trunk. It is usually noted only in fair–skinned patients.

The lesions may persist intermittently for weeks to months.


Subcutaneous nodules Subcutaneous nodules are

uncommon and are usually associated with severe carditis. They tend to occur several weeks after illness onset, are usually painless, and usually go unnoticed by the patient.

They are found primarily over the bony surfaces or prominences and in tendon sheaths. The common sites include the elbows, knees, wrists, ankles, over the Achilles tendon, the back of the scalp, and spinous process of the vertebrae.[2]

They usually persist for 1-2 weeks. The main differential diagnosis is the nodules of rheumatoid arthritis.


TreatmentThe 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 salisylate 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 600.000-1.200.000 U 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 aspenicillin, sulfadiazine, or erythromycin 250 mg two times per day) 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.


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 for rheumatic fever is benzathinebenzylpenicillin 600.000-1.200.000 U.


Heart failureInflammation

Patients with significant symptoms may requirecorticosteroids. Salicylates are useful for pain.

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.


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%). 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.


PreventionPrevention of recurrence is achieved by eradicating the acute infection and prophylaxis with antibiotics. The American Heart Association suggests that dental health be maintained, and that people with a history of bacterial endocarditis, a heart transplant, artificial heart valves, or "some types of congenital heart defects" may wish to consider long-term antibiotic prophylaxis.


Reference

Wallace MR. Editor: Bronze MS. Rheumatic Fever.http://emedicine.medscape.com/article/236582-followup#a2649Accessed Nov 19 2014

Khan ZZ, Bronze MS (ed): Group A Streptococcus Infection. http://emedicine.medscape.com/article/228936-overviewAccessed Nov 13 2014.

Rheumatic Fever.http://en.wikipedia.org/wiki/Rheumatic_feverAccessed Nov 13 2014.


http://emedicine.medscape.com/article/236582-followup

http://en.wikipedia.org/wiki/Rheumatic_fever

http://en.wikipedia.org/wiki/Rheumatic_fever

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Rheumatic Fever