rheumatic fever rheumatic fever rheumatic fever (rf) is an inflammatory disease that can involve the heart, joints, skin, and brain. the disease typically develops two to four weeks after a streptococcal throat infection. signs and symptoms include fever, multiple painful joints, involuntary muscle movements, and occasionally a characteristic non-itchy rash known as erythema marginatum. the heart is involved in about half of the cases. damage to the heart valves, known as rheumatic heart disease (rhd), usually occurs after repeated attacks but can sometimes occur after one. the damaged valves may result in heart failure, atrial fibrillation and infection of the valves. rheumatic feverother namesacute rheumatic fever (arf)rheumatic heart disease at autopsy with characteristic findings (thickened mitral valve, thickened chordae tendineae, hypertrophied left ventricular myocardium).specialtycardiologysymptomsfever, multiple painful joints, involuntary muscle movements, erythema marginatumcomplicationsrheumatic heart disease, heart failure, atrial fibrillation, infection of the valvesusual onset2–4 weeks after a streptococcal throat infection, age 5-14 yearscausesautoimmune disease triggered by streptococcus pyogenesrisk factorsgenetics, malnutrition, povertydiagnostic methodbased on symptoms and infection historypreventionantibiotics for strep throat, improved sanitationtreatmentprolonged periods of antibiotics, valve replacement surgery, valve repairfrequency325,000 children a yeardeaths319,400 (2015) rheumatic fever may occur following an infection of the throat by the bacterium streptococcus pyogenes. if the infection is left untreated, rheumatic fever occurs in up to three percent of people. the underlying mechanism is believed to involve the production of antibodies against a person's own tissues. due to their genetics, some people are more likely to get the disease when exposed to the bacteria than others. other risk factors include malnutrition and poverty. diagnosis of rf is often based on the presence of signs and symptoms in combination with evidence of a recent streptococcal infection. treating people who have strep throat with antibiotics, such as penicillin, decreases the risk of developing rheumatic fever. in order to avoid antibiotic misuse this often involves testing people with sore throats for the infection; however, testing might not be available in the developing world. other preventive measures include improved sanitation. in those with rheumatic fever and rheumatic heart disease, 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 valve repair is required. otherwise complications are treated as usual. rheumatic fever occurs in about 325,000 children each year and about 33.4 million people currently have rheumatic heart disease. those who develop rf are most often between the ages of 5 and 14, with 20% of first-time attacks occurring in adults. the disease is most common in the developing world and among indigenous peoples in the developed world. in 2015 it resulted in 319,400 deaths down from 374,000 deaths in 1990. most deaths occur in the developing world where as many as 12.5% of people affected may die each year. descriptions of the condition are believed to date back to at least the 5th century bce in the writings of hippocrates. the disease is so named because its symptoms are similar to those of some rheumatic disorders. 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. symptoms include: fever, painful joints with those joints affected changing with time, involuntary muscle movements, and occasionally a characteristic non-itchy rash known as erythema marginatum. the heart is involved in about half of the cases. damage to the heart valves usually occurs only after multiple attacks but may occasionally occur after a single case of rf. the damaged valves may result in heart failure and also increase the risk of atrial fibrillation and infection of the valves. pathophysiology rheumatic fever is a systemic disease affecting the connective tissue around arterioles, and can occur after an untreated strep throat infection, specifically due to group a streptococcus (gas), streptococcus pyogenes. the similarity between antigens of streptococcus pyogenes and multiple cardiac proteins can cause a life-threatening type ii hypersensitivity reaction. usually, self reactive b cells remain anergic in the periphery without t cell co-stimulation. during a streptococcal 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. s. pyogenes is a species of aerobic, cocci, gram-positive bacteria that are non-motile, non-spore forming, and forms chains and large colonies. s. pyogenes has a cell wall composed of branched polymers which sometimes contain m protein, a virulence factor that is highly antigenic. the antibodies which the immune system generates against the m protein may cross-react with heart muscle cell 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. rheumatic valvular lesions may also involve a cell-mediated immunity reaction as these lesions predominantly contain t-helper cells and macrophages. in rheumatic fever, these lesions can be found in any layer of the heart causing different types of carditis. 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 wart 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. 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, commissures 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 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 complicated pathogenesis of rhd is not fully understood, though it has been observed to use molecular mimicry via group a streptococci carbohydrates and genetic predisposition involving hla class ii genes that trigger autoimmune reactions. molecular mimicry occurs when epitopes are shared between host antigens and streptococcus 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 bacterial 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 streptococcal 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 chromosome 6. 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. 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. high expression levels of tnf-α may exacerbate valvular tissue inflammation, because as this cytokine circulates in the bloodstream, it triggers the activation of multiple pathways that stimulate further pro-inflammatory cytokine secretion. 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. in addition, the allele ighv4-61, located on chromosome 14, which helps code for the immunoglobulin heavy chain (igh) is linked to greater susceptibility to rhd because it may affect protein structure of the igh. other genes are also being investigated to better understand the complexity of autoimmune reactions that occur in rhd. diagnosis streptococcus pyogenes bacteria (pappenheim's stain), the trigger for rheumatic fever the original method of diagnosing rheumatic heart disease was through heart auscultation, specifically listening for the sound of blood regurgitation from possibly dysfunctional valves. however, studies have shown that echocardiography is much more efficient in detecting rhd due to its high sensitivity. an echocardiogram has the ability to detect signs of rhd before the development of more obvious symptoms such as tissue scarring and stenosis. 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 present along with evidence of streptococcal infection: elevated or rising antistreptolysin o titre or anti-dnase b. a recurrent episode is also diagnosed when three minor criteria are present. exceptions are chorea and indolent carditis, each of which by itself can indicate rheumatic fever. 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 rheumatic fever, as well as in follow-ups of rheumatic heart disease patients who initially presented as having isolated cases of sydenham's chorea. signs of a preceding streptococcal infection include: recent scarlet fever, raised antistreptolysin o or other streptococcal antibody titre, or positive throat culture. the last revision of 2015 suggested variable diagnostic criteria in low-risk and high-risk populations to avoid overdiagnosis in the first category and underdiagnosis in the last one. low-risk populations were defined as those with acute rheumatic fever annual incidence ≤2 per 100 000 school-aged children or all-age rheumatic heart disease prevalence of ≤1 per 1000. all other populations were categorised as having a moderate or high risk. major criteria joint manifestations are the unique clinical signs that have different implications for different population-risk categories : only polyarthritis (a temporary migrating inflammation of the large joints, usually starting in the legs and migrating upwards) is considered as a major criterion in low-risk populations, whereas monoarthritis, polyarthritis and polyarthralgia (joint pain without swelling) are all included as major criteria in high-risk populations. carditis: carditis can involve the pericardium (pericarditis which resolves without sequelae), some regions of the myocardium (which might not provoke systolic dysfunction), and more consistently the endocardium in the form of valvulitis.