| Rheumatic fever | |
|---|---|
| Other names | Acute rheumatic fever (ARF) |
 | |
| Rheumatic heart disease atautopsy with characteristic findings (thickenedmitral valve, thickenedchordae tendineae, hypertrophied left ventricularmyocardium) | |
| Specialty | Cardiology |
| Symptoms | Fever, multiplepainful joints,involuntary muscle movements,erythema marginatum[1] |
| Complications | Rheumatic heart disease,heart failure,atrial fibrillation,infection of the valves[1] |
| Usual onset | 2–4 weeks after astreptococcal throat infection, age 5–14 years[2] |
| Causes | Autoimmune disease triggered by pathogenic strains ofStreptococcus[1] |
| Risk factors | Genetic factors,malnutrition andpoverty.[1] |
| Diagnostic method | Based on symptoms and infection history[3] |
| Prevention | Promptantibiotics forStreptococcus infections, improvedsanitation[1][4] |
| Treatment | Prolonged periods of antibiotics,valve replacement surgery,valve repair[1] |
| Frequency | 325,000 children a year[1] |
| Deaths | 319,400 (2015)[5] |
Rheumatic fever (RF) is aninflammatory disease that can involve theheart,joints,skin, andbrain.[1] The disease typically develops two to four weeks after astreptococcal throat infection.[2] Signs and symptoms includefever, multiplepainful joints,involuntary muscle movements, and occasionally a characteristic non-itchy rash known aserythema marginatum.[1] The heart is involved in about half of the cases.[1] Damage to the heart valves, known asrheumatic heart disease (RHD), usually occurs after repeated attacks but can sometimes occur after one.[1] The damaged valves may result inheart failure,atrial fibrillation andinfection of the valves.[1]
Rheumatic fever may occur following an infection of the throat by the bacteriumStreptococcus pyogenes.[1] If the infection is left untreated, rheumatic fever occurs in up to three percent of people.[6] The underlying mechanism is believed to involve the production ofantibodies against a person's own tissues.[1] Due to their genetics, some people are more likely to get the disease when exposed to the bacteria than others.[1] Other risk factors includemalnutrition and poverty.[1] Diagnosis of RF is often based on the presence of signs and symptoms in combination with evidence of a recent streptococcal infection.[3]
Treating people who have strep throat withantibiotics, such aspenicillin, decreases the risk of developing rheumatic fever.[4] In order to avoidantibiotic misuse this often involves testing people withsore throats for the infection; however, testing might not be available in thedeveloping world.[1] Otherpreventive measures include improvedsanitation.[1] In those with rheumatic fever and rheumatic heart disease, prolonged periods of antibiotics are sometimes recommended.[1] Gradual return to normal activities may occur following an attack.[1] Once RHD develops, treatment is more difficult.[1] Occasionallyvalve replacement surgery orvalve repair is required.[1] Otherwise complications are treated as usual.[1]
Rheumatic fever occurs in about 325,000 children each year and about 33.4 million people currently have rheumatic heart disease.[1][7] Those who develop RF are most often between the ages of 5 and 14,[1] with 20% of first-time attacks occurring in adults.[8] The disease is most common in thedeveloping world and amongindigenous peoples in thedeveloped world.[1] In 2015 it resulted in 319,400 deaths down from 374,000 deaths in 1990.[5][9] 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 ofHippocrates.[10] The disease is so named because its symptoms are similar to those of somerheumatic disorders.[11]
The disease typically develops two to four weeks after athroat infection.[2] Symptoms include: fever, painful joints with those joints affected changing with time,involuntary muscle movements, and occasionally a characteristic non-itchy rash known aserythema marginatum. The heart is involved in about half of the cases. Damage to the heart valves usually occurs only after several attacks but may occasionally occur after a single case of RF. The damaged valves may result inheart failure and also increase the risk ofatrial fibrillation andinfection of the valves.[1]
Rheumatic fever is asystemic disease affecting theconnective tissue aroundarterioles, and can occur after an untreatedstrep throat infection, specifically due togroup A streptococcus (GAS),Streptococcus pyogenes. The similarity between antigens ofStreptococcus pyogenes and multiple cardiac proteins can cause a life-threateningtype II hypersensitivity reaction.[12] Usually, self reactiveB cells remainanergic in the periphery withoutT cell co-stimulation. During a streptococcal infection, matureantigen-presenting cells such as B cells present the bacterial antigen toCD4+T cells which differentiate intohelper T2 cells. Helper T2 cells subsequently activate the B cells to becomeplasma cells and induce the production of antibodies against the cell wall of Streptococcus. However the antibodies may also react against the myocardium and joints,[13] producing the symptoms of rheumatic fever.S. pyogenes is a species ofaerobic,cocci,gram-positive bacteria that are non-motile, non-spore forming, and forms chains and largecolonies.[14]
S. pyogenes has acell wall composed of branchedpolymers which sometimes containM protein, avirulence factor that is highlyantigenic. The antibodies which the immune system generates against the M protein may cross-react withheart muscle cell proteinmyosin,[15] heart muscleglycogen and smooth muscle cells of arteries, inducingcytokine release and tissue destruction. However, the only proven cross-reaction is with perivascularconnective tissue.[citation needed] This inflammation occurs through direct attachment of complement andFc receptor-mediated recruitment of neutrophils and macrophages. CharacteristicAschoff bodies, composed of swolleneosinophiliccollagen surrounded by lymphocytes and macrophages can be seen on light microscopy. The larger macrophages may becomeAnitschkow cells orAschoff giant cells. Rheumatic valvular lesions may also involve acell-mediated immunity reaction as these lesions predominantly containT-helper cells andmacrophages.[16]
In rheumatic fever, these lesions can be found in any layer of the heart causing different types ofcarditis. 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 infibrinoid necrosis andwart 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 calledMacCallum plaques.[citation needed]
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.[16] It is caused by an autoimmune reaction to Group A β-hemolyticstreptococci (GAS) that results in valvular damage.[17] Fibrosis and scarring of valve leaflets,commissures andcusps leads to abnormalities that can result in valve stenosis or regurgitation.[18] 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 valvularendothelium.[19] The majority of morbidity and mortality associated with rheumatic fever is caused by its destructive effects on cardiac valve tissue.[18] The complicated pathogenesis of RHD is not fully understood, though it has been observed to usemolecular mimicry via group A streptococci carbohydrates andgenetic predisposition involving HLA Class II genes that triggerautoimmune reactions.[20]
Molecular mimicry occurs whenepitopes are shared between host antigens andStreptococcus antigens.[21] 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.[22] 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 activateB 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 ofVCAM-1, a protein that mediates the adhesion of lymphocytes.[23] 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.[23]
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 ofMHC class II molecules, found on lymphocytes and antigen-presenting cells, specifically theDR andDQ alleles onhuman chromosome 6.[24] 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.[24] 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 cytokineTNF-α which is also associated with RHD.[24] 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.[25]Mannose-binding lectin (MBL) is an inflammatory protein involved in pathogen recognition. Different variants ofMBL2 gene regions are associated with RHD. RHD-inducedmitral valve stenosis has been associated withMBL2 alleles encoding for high production of MBL.[26] Aortic valve regurgitation in RHD patients has been associated with differentMBL2 alleles that encode for low production of MBL.[27] 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.[28] Other genes are also being investigated to better understand the complexity of autoimmune reactions that occur in RHD.[citation needed]
| Type | WBC (per mm3) | % neutrophils | Viscosity | Appearance |
|---|---|---|---|---|
| Normal | <200 | 0 | High | Transparent |
| Osteoarthritis | <5000 | <25 | High | Clear yellow |
| Trauma | <10,000 | <50 | Variable | Bloody |
| Inflammatory | 2,000–50,000 | 50–80 | Low | Cloudy yellow |
| Septic arthritis | >50,000 | >75 | Low | Cloudy yellow |
| Gonorrhea | ~10,000 | 60 | Low | Cloudy yellow |
| Tuberculosis | ~20,000 | 70 | Low | Cloudy yellow |
| Inflammatory:Arthritis,gout,rheumatoid arthritis,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 thatechocardiography 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.[31] Modified Jones criteria were first published in 1944 byT. Duckett Jones, MD.[32] They have been periodically revised by theAmerican Heart Association in collaboration with other groups.[33][34] 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 risingantistreptolysin O titre[35] oranti-DNase B.[8][36] A recurrent episode can be diagnosed when three minor criteria are present.[34] Exceptions arechorea andindolent carditis, each of which by itself can indicate rheumatic fever.[37][38][39] An April 2013 review article in theIndian 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.[40] Signs of a preceding streptococcal infection include: recentscarlet fever, raised antistreptolysin O or other streptococcal antibody titre, or positive throat culture.[41] 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.[34] 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.[34] All other populations were categorised as having a moderate or high risk.[34]
Minor criteria
Rheumatic fever can be prevented by effectively and promptly treatingstrep throat with antibiotics.[45] Globally, rheumatic fever is seen in populations that are socioeconomically disadvantaged and with limited access to health care.[46] Overcrowding[46][47] and exposure todomestic air pollution[47] have been cited as associated risk factors.
In those who have previously had rheumatic fever, antibiotics may be used in a preventative manner assecondary prophylaxis.[45] Antibiotic prophylaxis after an episode of acute rheumatic fever is recommended owing to the high likelihood of recurrence.[48] Streptococcal pharyngitis may occur asymptomatically and rheumatic fever may recur even after a treated infection.[49] TheAmerican Heart Association recommends, based on low quality evidence but with high predicted efficacy, that people with mitral stenosis due to rheumatic heart disease receive prophylactic antibiotics for 10 years or until age 40, whichever would be longer.[49] The AHA also supports good dental hygiene in people with RHD, and antibiotics for the prevention ofinfective endocarditis during dental procedures are recommended in high-risk patients.[49]
No vaccines are currently available to protect againstS. pyogenes infection, although research is underway to develop one.[50] Difficulties in developing a vaccine include the wide variety of strains ofS. pyogenes present in the environment and the large amount of time and number of people that will be needed for appropriate trials for safety and efficacy of the vaccine.[51]
The management of rheumatic fever is directed toward the reduction of inflammation withanti-inflammatory medications such asaspirin orcorticosteroids. Individuals with positive cultures for strep throat should also be treated withantibiotics.[42]
People with positive cultures forStreptococcus pyogenes should be treated with penicillin as long asallergy is not present. The use of antibiotics will not alter cardiac involvement in the development of rheumatic fever.[42] Some suggest the use ofbenzathine benzylpenicillin.[citation needed]
Monthly injections of long-acting 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 aspenicillin,sulfadiazine, orerythromycin) to prevent recurrence.[citation needed]
Aspirin at high doses has historically been used for treatment of rheumatic fever.[52] However, due to side effects likegastritis andsalicylate poisoning, necessitating serum monitoring of salicylate levels, and the risk ofReye syndrome, a serious and potentially deadly condition that may arise in children treated with aspirin or aspirin-containing products, alternatives to aspirin have been sought, especially in children.[48] While evidence suggests that treatment of rheumatic fever–associated arthritis withnaproxen may be equally effective as with aspirin,[48][53] its role in managing carditis has not been established.[54] Management of carditis in acute rheumatic fever is controversial and based on dated literature.[55] Corticosteroids may be considered, especially in people with allergies to NSAIDs or severe disease,[48] although use of steroids may cause tissue atrophy, which could present challenges during future cardiac surgery for valve repair.[55]
Some patients develop significantcarditis which manifests ascongestive heart failure. This requires the usual treatment for heart failure:ACE inhibitors,diuretics,beta blockers, anddigoxin.[citation needed] Unlike typical heart failure, rheumatic heart failure responds well to corticosteroids.[citation needed]
About 33 million people are affected by rheumatic heart disease with an additional 47 million havingasymptomatic damage to their heart valves.[46] As of 2010 globally it resulted in 345,000 deaths, down from 463,000 in 1990.[57]
In Western countries, rheumatic fever has become fairly rare since the 1960s, probably due to the widespread use of antibiotics to treatstreptococcus infections. While it has been far less common in theUnited States since the beginning of the 20th century, there have been a few outbreaks since the 1980s.[58] The disease is most common amongIndigenous Australians (particularly in central and northern Australia),Māori, andPacific Islanders, and is also common inSub-Saharan Africa,Latin America, theIndian subcontinent, andNorth Africa.[59]
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.[citation needed]
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%).[60] The rate of development is far lower in individuals who have received antibiotic treatment. Persons who have had a case of rheumatic fever have a tendency to develop flare-ups with repeated strep infections.[citation needed]
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. Recurrent bouts of rheumatic fever can lead tovalvular heart disease. Heart complications may be long-term and severe, particularly if valves are involved. In countries in Southeast-Asia, sub-Saharan Africa, and Oceania, the percentage of people with rheumatic heart disease detected by listening to the heart was 2.9 per 1000 children and by echocardiography it was 12.9 per 1000 children.[61][62][63][64] To assist in the identification of RHD in low resource settings and where prevalence of GAS infections is high, theWorld Heart Federation has developed criteria for RHD diagnosis using echocardiography, supported by clinical history if available.[65] The WHF additionally defines criteria for use in people younger than age 20 to diagnose "borderline" RHD, as identification of cases of RHD among children is a priority to prevent complications and progression.[46] However, spontaneous regression is more likely in borderline RHD than in definite cases, and its natural history may vary between populations.[46]
Echocardiographicscreening among children and timely initiation of secondary antibiotic prophylaxis in children with evidence of early stages of rheumatic heart disease may be effective to reduce the burden of rheumatic heart disease in endemic regions.[66][67] The efficacy of treating latent RHD in populations with high prevalence is balanced by the potential development ofantibiotic resistance, which might be offset through use ofnarrow-spectrum antibiotics like benzathine benzapenicillin.[67] Public health research is ongoing to determine if screening is beneficial and cost effective.
The risk of severe complications is the primary concern with strep throat, and the reason why it is so important to be properly diagnosed and treated. One of the most serious complications is rheumatic fever, a disease that affects up to 3 percent of those with untreated strep infection. Rheumatic fever can lead torheumatic heart disease.
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