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 fever may occur following an infection of the throat by the bacterium Streptococcus pyogenes. If the infection is untreated rheumatic fever can occur 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, which may 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 per normal. 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. 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. 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. 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 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.