Rheumatic fever

Rheumatic fever
Streptococcus pyogenes bacteria (Pappenheim's stain) the trigger for rheumatic fever.
Classification and external resources
Specialty	Cardiology
ICD-10	I00-I02
ICD-9-CM	390–392
DiseasesDB	11487
MedlinePlus	003940
eMedicine	med/3435 med/2922 emerg/509 ped/2006
Patient UK	Rheumatic fever
MeSH	D012213

Rheumatic fever, also known as acute rheumatic fever (ARF), is an inflammatory disease that can involve the heart, joints, skin, and brain.^[1] The disease typically develops two to four weeks after a throat infection.^[2] Signs and symptoms include fever, multiple painful joints, involuntary muscle movements, and a characteristic but uncommon non itchy rash known as erythema marginatum. The heart is involved in about half of cases. Permanent damage to the heart valves, known as rheumatic heart disease (RHD), usually only occurs after multiple attacks but may occasionally occur after a single case of ARF. The damaged valves may result in heart failure. The abnormal valves also increase the risk of the person developing atrial fibrillation and infection of the valves.^[1]

Acute rheumatic fever may occur following an infection of the throat by the bacteria Streptococcus pyogenes.^[1] If it is untreated ARF occurs in up to three percent of people.^[3] The underlying mechanism is believed to involve the production of antibodies against a person's own tissues. Some people due to their genetics are more likely to get the disease when exposed to the bacteria than others. Other risk factors include malnutrition and poverty.^[1] Diagnosis of ARF is often based on the presence of signs and symptoms in combination with evidence of a recent streptococcal infection.^[4]

Treating people who have strep throat with antibiotics, such as penicillin, decreases their risk of getting ARF.^[5] This often involves testing people with sore throats for the infection, which may not be available in the developing world. Other preventative measures include improved sanitation. In those with ARF and RHD prolonged periods of antibiotics are sometimes recommended. Gradual return to normal activities may occur following an attack. Once RHD develops, treatment is more difficult. Occasionally valve replacement surgery or repair is required. Otherwise complications are treated as per normal.^[1]

Acute rheumatic fever occurs in about 325,000 children each year and about 18 million people currently have rheumatic heart disease. Those who get ARF are most often between the ages of 5 and 14,^[1] with 20% of first-time attacks occurring in adults.^[6] The disease is most common in the developing world and among indigenous peoples in the developed world.^[1] In 2013 it resulted in 275,000 deaths down from 374,000 deaths in 1990.^[7] Most deaths occur in the developing world where as many as 12.5% of people affected may die each year.^[1] Descriptions of the condition are believed to date back to at least the 5th century BCE in the writings of Hippocrates.^[8] The disease is so named because its symptoms are similar to those of some rheumatic disorders.^[9]

Signs and symptoms

A culture positive case of streptococcal pharyngitis with typical tonsillar exudate in a 16-year-old.

The disease typically develops two to four weeks after a throat infection.^[2] Symptoms include: fever, multiple painful joints with the joints affected changing with time, involuntary muscle movements, and a characteristic but uncommon non itchy rash known as erythema marginatum. The heart is involved in about half of cases. Permanent damage to the heart valves usually only occurs after multiple attacks but may occasionally occur after a single case of ARF. The damaged valves may result in heart failure. The abnormal valves also increase the risk of the person developing atrial fibrillation and infection of the valves.^[1]

Other

• Abdominal pain
• Nose bleeds

Pathophysiology

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. 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

Pathophysiology of rheumatic heart disease

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

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.^[12] It is caused by an autoimmune reaction to Group A β-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-α which is also associated with RHD.^[19] 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.^[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.

Diagnosis

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.^[22] They have been periodically revised by the American Heart Association in collaboration with other groups.^[23] 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.^[6] Exceptions are chorea and indolent carditis, each of which by itself can indicate rheumatic fever.^[24][25][26] An April 2013 review article in the Indian Journal of Medical Research stated that echocardiographic and Doppler (E & D) studies, despite some reservations about their utility, have identified a massive burden of rheumatic heart disease, which suggests the inadequacy of the 1992 Jones' criteria. 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.^[27] Signs of a preceding streptococcal infection include: recent scarlet fever, raised antistreptolysin O or other streptococcal antibody titre, or positive throat culture.^[28]

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 38.2–38.9 °C (100.8–102.0 °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^[28][29] (Cannot be included if carditis is present as a major symptom)
• Previous episode of rheumatic fever or inactive heart disease

Prevention

Prevention 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.^[30]

Treatment

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.^[31]

Infection

People 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

While corticosteroids are often used, evidence to support this is poor.^[1] 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.^[32]

  no data

  less than 20

  20–40

  40–60

  60–80

  80–100

  100–120

  120–140

  140–160

  160–180

  180–200

  200–330

  more than 330

Rheumatic fever is common worldwide and responsible for many cases of damaged heart valves. As of 2010 globally it resulted in 345,000 deaths, down from 463,000 in 1990.^[33]

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 2–5%.^[34]

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%).^[35] 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.

References

External links

• Rheumatic fever information from Seattle Children's Hospital Heart Center
• Jones major criteria, Mnemonic
• Rheumatic Heart Disease Network