View source for Rheumatic fever

{{Short description|Post-streptococcal inflammatory disease}}
{{distinguish|rheumatoid arthritis}}
{{cs1 config|name-list-style=vanc}}
{{Use dmy dates|date=February 2015}}
{{Infobox medical condition (new)
| name            = Rheumatic fever
| synonyms        = Acute rheumatic fever (ARF)
| image           = Rheumatic heart disease, gross pathology 20G0013 lores.jpg
| caption         = Rheumatic heart disease at [[autopsy]] with characteristic findings (thickened [[mitral valve]], thickened [[chordae tendineae]], hypertrophied left ventricular [[myocardium]])
| field           = [[Cardiology]]
| symptoms        = [[Fever]], multiple [[arthralgia|painful joints]], [[chorea|involuntary muscle movements]], [[erythema marginatum]]<ref name=Lancet2012/>
| complications   = [[valvular heart disease#Inflammatory disorders|Rheumatic heart disease]], [[heart failure]], [[atrial fibrillation]], [[infective endocarditis|infection of the valves]]<ref name=Lancet2012/>
| onset           = 2–4 weeks after a [[Streptococcal pharyngitis|streptococcal throat infection]], age 5–14 years<ref name=Lee2012/>
| duration        =
| causes          = [[Autoimmune disease]] triggered by pathogenic strains of ''[[Streptococcus]]''<ref name=Lancet2012/>
| risks           = Genetic factors, [[malnutrition]] and [[poverty]].<ref name=Lancet2012/>
| diagnosis       = Based on symptoms and infection history<ref name=CDC2015Def/>
| differential    =
| prevention      = Prompt [[antibiotic]]s for ''Streptococcus'' infections, improved [[sanitation]]<ref name=Lancet2012/><ref name=Sp2021/>
| treatment       = Prolonged periods of antibiotics, [[valve replacement|valve replacement surgery]], [[heart valve repair|valve repair]]<ref name=Lancet2012/>
| medication      =
| prognosis       =
| frequency       = 325,000 children a year<ref name=Lancet2012/>
| deaths          = 319,400 (2015)<ref name=GBD2015De/>
}}
<!-- Definition and symptoms -->

'''Rheumatic fever''' ('''RF''') is an [[inflammation#Disorders|inflammatory disease]] that can involve the [[heart]], [[joint]]s, [[skin]], and [[brain]].<ref name=Lancet2012/> The disease typically develops two to four weeks after a [[Streptococcal pharyngitis|streptococcal throat infection]].<ref name=Lee2012>{{cite journal|last1=Lee|first1=KY|last2=Rhim|first2=JW|last3=Kang|first3=JH|title=Kawasaki disease: laboratory findings and an immunopathogenesis on the premise of a "protein homeostasis system".|journal=Yonsei Medical Journal|date=March 2012|volume=53|issue=2|pages=262–75|pmid=22318812|doi=10.3349/ymj.2012.53.2.262|pmc=3282974}}</ref> Signs and symptoms include [[fever]], multiple [[arthralgia|painful joints]], [[chorea|involuntary muscle movements]], and occasionally a characteristic non-[[itch]]y rash known as [[erythema marginatum]].<ref name=Lancet2012/> The heart is involved in about half of the cases.<ref name=Lancet2012/> Damage to the heart valves, known as [[valvular heart disease#Inflammatory disorders|rheumatic heart disease]] (RHD), usually occurs after repeated attacks but can sometimes occur after one.<ref name=Lancet2012/> The damaged valves may result in [[heart failure]], [[atrial fibrillation]] and [[infective endocarditis|infection of the valves]].<ref name=Lancet2012/>

<!-- Cause -->
Rheumatic fever may occur following an infection of the throat by the bacterium ''[[Streptococcus pyogenes]]''.<ref name=Lancet2012/> If the infection is left untreated, rheumatic fever occurs in up to three percent of people.<ref>{{cite book|first1=Carol|last1=Turkington|last2=Ashby|first2=Bonnie Lee|title=The Encyclopedia of Infectious Diseases|date=2007|publisher=Facts On File|location=New York|isbn=978-0-8160-7507-2|page=292|edition=3rd|quote = 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 to [[rheumatic heart disease]].}}</ref> The underlying mechanism is believed to involve the production of [[antibody|antibodies]] against a person's own tissues.<ref name=Lancet2012/> Due to their genetics, some people are more likely to get the disease when exposed to the bacteria than others.<ref name=Lancet2012/> Other risk factors include [[malnutrition]] and poverty.<ref name=Lancet2012/> Diagnosis of RF is often based on the presence of signs and symptoms in combination with evidence of a recent streptococcal infection.<ref name=CDC2015Def>{{cite web|title=Rheumatic Fever 1997 Case Definition|url=http://wwwn.cdc.gov/NNDSS/script/casedef.aspx?CondYrID=823&DatePub=1/1/1997%2012:00:00%20AM|website=cdc.gov|access-date=19 February 2015|date=3 February 2015|url-status=live|archive-url=https://web.archive.org/web/20150219064133/http://wwwn.cdc.gov/NNDSS/script/casedef.aspx?CondYrID=823&DatePub=1%2F1%2F1997%2012%3A00%3A00%20AM|archive-date=19 February 2015}}</ref>

<!-- Prevention and treatment -->
Treating people who have strep throat with [[antibiotic]]s, such as [[penicillin]], decreases the risk of developing rheumatic fever.<ref name="Sp2021">{{Cite journal |last1=Spinks |first1=Anneliese |last2=Glasziou |first2=Paul P. |last3=Del Mar |first3=Chris B. |date=2021-12-09 |title=Antibiotics for treatment of sore throat in children and adults |url= |journal=The Cochrane Database of Systematic Reviews |volume=2021 |issue=12 |article-number=CD000023 |doi=10.1002/14651858.CD000023.pub5 |issn=1469-493X |pmc=8655103 |pmid=34881426}}</ref> To avoid [[antibiotic misuse]], this often involves testing people with [[sore throat]]s for the infection; however, testing might not be available in the [[developing world]].<ref name=Lancet2012/> Other [[preventive healthcare|preventive measures]] include improved [[sanitation]].<ref name=Lancet2012/> In those with rheumatic fever and rheumatic heart disease, prolonged periods of antibiotics are sometimes recommended.<ref name=Lancet2012/> Gradual return to normal activities may occur following an attack.<ref name=Lancet2012/> Once RHD develops, treatment is more difficult.<ref name=Lancet2012/> Occasionally [[valve replacement|valve replacement surgery]] or [[heart valve repair|valve repair]] is required.<ref name=Lancet2012/> Otherwise complications are treated as usual.<ref name=Lancet2012/>

<!-- Epidemiology -->
Rheumatic fever occurs in about 325,000 children each year and about 33.4&nbsp;million people currently have rheumatic heart disease.<ref name=Lancet2012/><ref name=GBD2015Pre>{{cite journal|author=((GBD 2015 Disease and Injury Incidence and Prevalence Collaborators))|title=Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015.|journal=The Lancet|date=8 October 2016|volume=388|issue=10053|pages=1545–1602|pmid=27733282|doi=10.1016/S0140-6736(16)31678-6|pmc=5055577}}</ref> Those who develop RF are most often between the ages of 5 and 14,<ref name=Lancet2012/> with 20% of first-time attacks occurring in adults.<ref name=Robbins>{{Cite book | last1 = Kumar | first1 = Vinay | last2 = Abbas | first2 = Abul K | last3 = Fausto | first3 = Nelson | last4 = Mitchell | first4 = Richard N | year = 2007 | title = Robbins Basic Pathology | edition = 8th | publisher = Saunders Elsevier | pages = 403–6 | isbn = 978-1-4160-2973-1}}</ref> The disease is most common in the [[developing world]] and among [[indigenous people]]s in the [[developed world]].<ref name=Lancet2012>{{cite journal|last1=Marijon|first1=E|last2=Mirabel|first2=M|last3=Celermajer|first3=DS|last4=Jouven|first4=X|s2cid=20197628|title=Rheumatic heart disease.|journal=The Lancet|date=10 March 2012|volume=379|issue=9819|pages=953–64|pmid=22405798|doi=10.1016/S0140-6736(11)61171-9}}</ref> In 2015 it resulted in 319,400 deaths down from 374,000 deaths in 1990.<ref name=GBD2015De>{{cite journal|author=((GBD 2015 Mortality and Causes of Death Collaborators))|title=Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015: a systematic analysis for the Global Burden of Disease Study 2015.|journal=The Lancet|date=8 October 2016|volume=388|issue=10053|pages=1459–1544|pmid=27733281|doi=10.1016/S0140-6736(16)31012-1|pmc=5388903}}</ref><ref name=GDB2013>{{cite journal|author=((GBD 2013 Mortality and Causes of Death Collaborators))|title=Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013.|journal=The Lancet|date=17 December 2014|pmid=25530442|doi=10.1016/S0140-6736(14)61682-2|volume=385|issue=9963|pages=117–171|pmc=4340604}}</ref> Most deaths occur in the developing world where as many as 12.5% of people affected may die each year.<ref name=Lancet2012/> Descriptions of the condition are believed to date back to at least the 5th century BCE in the writings of [[Hippocrates]].<ref>{{cite journal|last1=Quinn|first1=RW|title=Did scarlet fever and rheumatic fever exist in Hippocrates' time?|journal=Reviews of Infectious Diseases|date=1991|volume=13|issue=6|pages=1243–4|pmid=1775859|doi=10.1093/clinids/13.6.1243}}</ref> The disease is so named because its symptoms are similar to those of some [[rheumatic disorders]].<ref>{{DorlandsDict |nine/000956569|rheumatic fever}}</ref>

==Signs and symptoms==
[[File:Pos strep.JPG|thumb|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 [[strep throat|throat infection]].<ref name=Lee2012/> Symptoms include: fever, painful joints with those joints affected changing with time, [[chorea|involuntary muscle movements]], and occasionally a characteristic non-itchy rash known as [[erythema marginatum]].<!-- <ref name=Lancet2012/> --> The heart is involved in about half of the cases.<!-- <ref name=Lancet2012/> --> Damage to the heart valves usually occurs only after several attacks but may occasionally occur after a single case of RF.<!-- <ref name=Lancet2012/> --> The damaged valves may result in [[heart failure]] and also increase the risk of [[atrial fibrillation]] and [[infective endocarditis|infection of the valves]].<ref name=Lancet2012/>

==Pathophysiology==
Rheumatic fever is a [[systemic disease]] affecting the [[connective tissue]] around [[arteriole]]s, and can occur after an untreated [[streptococcal pharyngitis|strep throat]] infection, specifically due to [[streptococcus#Group A|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]].<ref>{{Cite book|chapter-url=https://www.sciencedirect.com/topics/immunology-and-microbiology/type-ii-hypersensitivity|title = Comprehensive Biomaterials II|chapter = 4.2 Biocompatibility and the Relationship to Standards: Meaning and Scope of Biomaterials Testing|year = 2017|pages = 7–29|publisher = Elsevier}}</ref> Usually, self reactive [[B cell]]s remain [[clonal anergy|anergic]] in the periphery without [[T cell]] co-stimulation.  During a streptococcal infection, mature [[antigen-presenting cell]]s such as B cells present the bacterial antigen to [[CD4+ T cells and antitumor immunity|CD4+T cells]] which differentiate into [[T helper cell#Determination of the effector T cell response|helper T<sub>2</sub> cells]]. Helper T<sub>2</sub> cells subsequently activate the B cells to become [[plasma cell]]s and induce the production of antibodies against the cell wall of Streptococcus. However the antibodies may also react against the myocardium and joints,<ref>{{cite book | last1 = Abbas | first1 = Abul K. | last2 = Lichtman | first2 = Andrew H. | last3 = Baker | first3 = David L. | title = Basic immunology: functions and disorders of the immune system | edition = 2 | publisher = Elsevier Saunders | year = 2004 | location = Philadelphia, Pennsylvania | isbn = 978-1-4160-2403-3|display-authors=etal}}</ref> producing the symptoms of rheumatic fever. ''S. pyogenes'' is a species of [[aerobic organism|aerobic]], [[coccus|cocci]], [[gram-positive bacteria]] that are non-motile, non-[[bacterial spore|spore forming]], and forms chains and large [[colony (biology)|colonies]].<ref>{{cite web|url=http://www.phac-aspc.gc.ca/lab-bio/res/psds-ftss/strep-pyogenes-eng.php|title=Streptococcus pyogenes – Pathogen Safety Data Sheets|publisher=[[Public Health Agency of Canada]]|date=18 February 2011|access-date=15 April 2017|url-status=live|archive-url=https://web.archive.org/web/20170117064053/http://www.phac-aspc.gc.ca/lab-bio/res/psds-ftss/strep-pyogenes-eng.php|archive-date=17 January 2017}}</ref>

''S. pyogenes'' has a [[Bacterial cell structure#Cell wall|cell wall]] composed of branched [[polymers]] which sometimes contain [[M protein (Streptococcus)|M protein]], a [[virulence factor]] that is highly [[antigenic]]. The antibodies which the immune system generates against the M protein may cross-react with [[cardiac muscle cell|heart muscle cell]] protein [[myosin]],<ref>{{cite journal  |vauthors=Faé KC, da Silva DD, Oshiro SE, etal |title=Mimicry in recognition of cardiac myosin peptides by heart-intralesional T cell clones from rheumatic heart disease |journal=J. Immunol. |volume=176 |issue=9 |pages=5662–70 |date=May 2006 |pmid=16622036 |doi= 10.4049/jimmunol.176.9.5662|doi-access=free }}</ref> 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]].{{Citation needed|date=September 2009}} This inflammation occurs through direct attachment of complement and [[Fc receptor]]-mediated recruitment of neutrophils and macrophages.  Characteristic [[Aschoff body|Aschoff bodies]], composed of swollen [[eosinophilic]] [[collagen]] surrounded by lymphocytes and macrophages, can be seen on light microscopy.  The larger macrophages may become [[Anitschkow cell]]s or [[Aschoff cell|Aschoff giant cells]].  Rheumatic valvular lesions may also involve a [[cell-mediated immunity]] reaction as these lesions predominantly contain [[T-helper]] cells and [[macrophages]].<ref name=RobbinsPath>{{cite book |author1=Cotran, Ramzi S. |author2=Kumar, Vinay |author3=Fausto, Nelson |author4=Nelso Fausto |author5=Robbins, Stanley L. |author6=Abbas, Abul K. |title=Robbins and Cotran pathologic basis of disease |publisher=Elsevier Saunders |location=St. Louis, Mo |year=2005 |isbn=978-0-7216-0187-8 |url=http://www.robbinspathology.com/ |archive-url=https://web.archive.org/web/20050910050801/http://www.robbinspathology.com/ |archive-date=10 September 2005}}</ref>

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]].{{citation needed|date=February 2021}}

===Rheumatic heart disease===
[[File:Rheum.heart.disease.jpeg|thumb|Pathophysiology of rheumatic heart disease]]
[[File:Rheumatic heart disease - 3a - very high mag.jpg|thumb|[[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.<ref name=RobbinsPath/> It is caused by an autoimmune reaction to Group A β-hemolytic [[streptococci]] (GAS) that results in valvular damage.<ref>{{cite journal|pmid=14170842|year=1964|last1=Kaplan|first1=MH|last2=Bolande|first2=R|last3=Rakita|first3=L|last4=Blair|first4=J|title=Presence of Bound Immunoglobulins and Complement in the Myocardium in Acute Rheumatic Fever. Association with Cardiac Failure|volume=271|pages=637–45|doi=10.1056/NEJM196409242711301|journal=The New England Journal of Medicine|issue=13}}</ref> Fibrosis and scarring of valve leaflets, [[commissure]]s and [[Cusps of heart valves|cusps]] leads to abnormalities that can result in valve stenosis or regurgitation.<ref name="essential">{{cite book|editor-first=Clive|editor-last=Rosendorff|first1=Edmund A. W|last1=Brice|first2=Patrick J.|last2=Commerford|year=2005|chapter=Rheumatic Fever and Valvular Heart Disease|title=Essential Cardiology: Principles and Practice|location=Totowa, New Jersey|publisher=Humana Press|pages=545–563|isbn=978-1-59259-918-9|doi=10.1007/978-1-59259-918-9_30}}</ref> 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]].<ref>{{cite journal|pmid=18825449|year=2008|last1=Caldas|first1=AM|last2=Terreri|first2=MT|last3=Moises|first3=VA|last4=Silva|first4=CM|last5=Len|first5=CA|last6=Carvalho|first6=AC|last7=Hilário|first7=MO|s2cid=13330575|title=What is the true frequency of carditis in acute rheumatic fever? A prospective clinical and Doppler blind study of 56 children with up to 60 months of follow-up evaluation|volume=29|issue=6|pages=1048–53|doi=10.1007/s00246-008-9242-z|journal=Pediatric Cardiology}}</ref> The majority of morbidity and mortality associated with rheumatic fever is caused by its destructive effects on cardiac valve tissue.<ref name="essential" /> 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 reaction]]s.<ref>{{Cite journal |last1=Guilherme |first1=Luiza |last2=Kalil |first2=Jorge |last3=Cunningham |first3=Madeleine |date=January 2006 |title=Molecular mimicry in the autoimmune pathogenesis of rheumatic heart disease |url=http://www.tandfonline.com/doi/full/10.1080/08916930500484674 |journal=Autoimmunity |language=en |volume=39 |issue=1 |pages=31–39 |doi=10.1080/08916930500484674 |pmid=16455580 |s2cid=16987808 |issn=0891-6934|url-access=subscription }}</ref>

Molecular mimicry occurs when [[epitope]]s are shared between host antigens and ''Streptococcus'' antigens.<ref>{{cite journal|pmid=16455580|year=2006|last1=Guilherme|first1=L|last2=Kalil|first2=J|last3=Cunningham|first3=M|s2cid=16987808|title=Molecular mimicry in the autoimmune pathogenesis of rheumatic heart disease|volume=39|issue=1|pages=31–9|doi=10.1080/08916930500484674|journal=Autoimmunity}}</ref> 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.<ref>{{cite journal|pmid=2786783|year=1989|last1=Kemeny|first1=E|last2=Grieve|first2=T|last3=Marcus|first3=R|last4=Sareli|first4=P|last5=Zabriskie|first5=JB|title=Identification of mononuclear cells and T cell subsets in rheumatic valvulitis|volume=52|issue=2|pages=225–37|journal=Clinical Immunology and Immunopathology|doi=10.1016/0090-1229(89)90174-8}}</ref> 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 cell]]s, 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.<ref name="Roberts">{{cite journal|pmid=11133385|year=2001|last1=Roberts|first1=S|last2=Kosanke|first2=S|last3=Terrence Dunn|first3=S|last4=Jankelow|first4=D|last5=Duran|first5=CM|last6=Cunningham|first6=MW|title=Pathogenic mechanisms in rheumatic carditis: Focus on valvular endothelium|volume=183|issue=3|pages=507–11|doi=10.1086/318076|journal=The Journal of Infectious Diseases|doi-access=free}}</ref> 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.<ref name="Roberts"/>

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 [[major histocompatibility complex|MHC]] class II molecules, found on lymphocytes and antigen-presenting cells, specifically the [[HLA-DR|DR]] and [[HLA-DQ|DQ]] alleles on [[chromosome 6 (human)|human chromosome 6]].<ref name="Stanevicha">{{cite journal|pmc=333411|year=2003|last1=Stanevicha|first1=V|last2=Eglite|first2=J|last3=Sochnevs|first3=A|last4=Gardovska|first4=D|last5=Zavadska|first5=D|last6=Shantere|first6=R|title=HLA class II associations with rheumatic heart disease among clinically homogeneous patients in children in Latvia|volume=5|issue=6|pages=R340–R346|doi=10.1186/ar1000| journal=[[Arthritis Research & Therapy]] |pmid=14680508 |doi-access=free }}</ref> 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.<ref name="Stanevicha"/>  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 [[Tumor necrosis factor-alpha|TNF-α]] which is also associated with RHD.<ref name="Stanevicha" /> 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.<ref>{{Cite journal |last1=Middleton |first1=Francis M. |last2=McGregor |first2=Reuben |last3=Webb |first3=Rachel H. |last4=Wilson |first4=Nigel J. |last5=Moreland |first5=Nicole J. |date=2022-12-01 |title=Cytokine imbalance in acute rheumatic fever and rheumatic heart disease: Mechanisms and therapeutic implications |url=https://www.sciencedirect.com/science/article/pii/S1568997222001793 |journal=Autoimmunity Reviews |language=en |volume=21 |issue=12 |article-number=103209 |doi=10.1016/j.autrev.2022.103209 |pmid=36228998 |s2cid=252865544 |issn=1568-9972|url-access=subscription }}</ref> [[Mannose-binding lectin]] (MBL) is an inflammatory protein involved in pathogen recognition.  Different variants of ''[[MBL2]]'' gene regions are associated with RHD.  RHD-induced [[mitral valve stenosis]] has been associated with ''MBL2'' alleles encoding for high production of MBL.<ref>{{cite journal|pmid=18602696|year=2008|last1=Schafranski|first1=MD|last2=Pereira Ferrari|first2=L|last3=Scherner|first3=D|last4=Torres|first4=R|last5=Jensenius|first5=JC|last6=De Messias-Reason|first6=IJ|title=High-producing MBL2 genotypes increase the risk of acute and chronic carditis in patients with history of rheumatic fever|volume=45|issue=14|pages=3827–31|doi=10.1016/j.molimm.2008.05.013|journal=Molecular Immunology}}</ref> Aortic valve regurgitation in RHD patients has been associated with different ''MBL2'' alleles that encode for low production of MBL.<ref>{{cite journal|pmc=2446618|year=2008|last1=Ramasawmy|first1=R|last2=Spina|first2=GS|last3=Fae|first3=KC|last4=Pereira|first4=AC|last5=Nisihara|first5=R|last6=Messias Reason|first6=IJ|last7=Grinberg|first7=M|last8=Tarasoutchi|first8=F|last9=Kalil|first9=J|title=Association of Mannose-Binding Lectin Gene Polymorphism but Not of Mannose-Binding Serine Protease 2 with Chronic Severe Aortic Regurgitation of Rheumatic Etiology|volume=15|issue=6|pages=932–936|doi=10.1128/CVI.00324-07|journal=Clinical and Vaccine Immunology|last10=Guilherme|first10=L.|pmid=18400978}}</ref> 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.<ref>{{Cite journal |last1=Muhamed |first1=Babu |last2=Parks |first2=Tom |last3=Sliwa |first3=Karen |date=March 2020 |title=Genetics of rheumatic fever and rheumatic heart disease |url=https://www.nature.com/articles/s41569-019-0258-2 |journal=Nature Reviews Cardiology |language=en |volume=17 |issue=3 |pages=145–154 |doi=10.1038/s41569-019-0258-2 |pmid=31519994 |hdl=10044/1/99730 |s2cid=202570077 |issn=1759-5010|hdl-access=free |url-access=subscription }}</ref> Other genes are also being investigated to better understand the complexity of autoimmune reactions that occur in RHD.{{citation needed|date=June 2020}}

==Diagnosis==
{{Synovial fluid analysis}}
[[File:Streptococcus_pyogenes_01.jpg|thumb|''[[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 can detect signs of RHD before the development of more obvious symptoms such as tissue scarring and stenosis.<ref>{{Cite journal |last1=Dougherty |first1=Scott |last2=Khorsandi |first2=Maziar |last3=Herbst |first3=Philip |date=2017-01-01 |title=Rheumatic heart disease screening: Current concepts and challenges |journal=Annals of Pediatric Cardiology |language=en |volume=10 |issue=1 |pages=39–49 |doi=10.4103/0974-2069.197051 |issn=0974-2069 |pmc=5241843 |pmid=28163427 |doi-access=free }}</ref> Modified Jones criteria were first published in 1944 by [[T. Duckett Jones]], MD.<ref>{{cite journal | last = Jones | first = T Duckett |title=The diagnosis of rheumatic fever |journal=[[Journal of the American Medical Association|JAMA]] |volume=126 |issue= 8|pages=481–4 |year= 1944 | doi= 10.1001/jama.1944.02850430015005}}</ref> They have been periodically revised by the [[American Heart Association]] in collaboration with other groups.<ref>{{cite journal |last1=Ferrieri |first1=P |title=Proceedings of the Jones Criteria workshop |journal=Circulation |volume=106 |issue=19 |pages=2521–3 |year=2002 |pmid=12417554 |doi=10.1161/01.CIR.0000037745.65929.FA |publisher=Jones Criteria Working Group |last2=Jones Criteria Working |first2=Group |doi-access=free }}</ref><ref name=":1" /> 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]]<ref>{{Cite web|url=https://labtestsonline.org/tests/antistreptolysin-o-aso|title = Antistreptolysin O (ASO)|date = 24 July 2020}}</ref> or [[anti-DNase B]].<ref name =Robbins/><ref>{{Cite web|url=https://labtestsonline.org/tests/anti-dnase-b|title=Anti-DNase B|date=28 June 2021}}</ref> A recurrent episode can be diagnosed when three minor criteria are present.<ref name=":1">{{Cite journal|last1=Gewitz Michael H.|last2=Baltimore Robert S.|last3=Tani Lloyd Y.|last4=Sable Craig A.|last5=Shulman Stanford T.|last6=Carapetis Jonathan|last7=Remenyi Bo|last8=Taubert Kathryn A.|last9=Bolger Ann F.|last10=Beerman Lee|last11=Mayosi Bongani M.|date=2015-05-19|title=Revision of the Jones Criteria for the Diagnosis of Acute Rheumatic Fever in the Era of Doppler Echocardiography|journal=Circulation|volume=131|issue=20|pages=1806–1818|doi=10.1161/CIR.0000000000000205|pmid=25908771|s2cid=46209822|doi-access=free}}</ref> Exceptions are [[chorea (disease)|chorea]] and [[indolent carditis]], each of which by itself can indicate rheumatic fever.<ref>{{cite web | url = http://www.emedicine.com/emerg/topic509.htm | work = eMedicine | title = Rheumatic Fever | first = Steven J | last = Parrillo | publisher = DO, FACOEP, FACEP | access-date = 14 July 2007 | url-status = live | archive-url = https://web.archive.org/web/20070708195326/http://www.emedicine.com/EMERG/topic509.htm | archive-date = 8 July 2007 }}</ref><ref>{{cite journal | title= Guidelines for the diagnosis of rheumatic fever. Jones Criteria, 1992 update | publisher = Special Writing Group of the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on Cardiovascular Disease in the Young of the American Heart Association |journal=JAMA |volume=268 |issue=15 |pages= 2069–73 | year = 1992 |pmid=1404745 |doi = 10.1001/jama.1992.03490150121036}}</ref><ref>{{cite journal|first=Anita|last= Saxena |s2cid= 23052280 | title =Diagnosis of rheumatic fever: Current status of Jones criteria and role of echocardiography|journal = Indian Journal of Pediatrics | volume =67|issue=4|pages=283–6|year=2000|pmid=11129913|doi= 10.1007/BF02758174}}</ref> 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.<ref>{{cite journal|pmc=3724245|year=2013|last1=Kumar|first1=RK|last2=Tandon|first2=R|title=Rheumatic fever & rheumatic heart disease: The last 50 years|volume=137|issue=4|pages=643–658|journal=The Indian Journal of Medical Research|pmid=23703332}}</ref> Signs of a preceding streptococcal infection include: recent [[scarlet fever]], raised antistreptolysin O or other streptococcal antibody titre, or positive throat culture.<ref name="davidson617"/> 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.<ref name=":1" /> 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.<ref name=":1" /> All other populations were categorised as having a moderate or high risk.<ref name=":1" />

'''Jones Criteria'''

===Major criteria===

# Joint manifestations are the unique clinical signs that have different implications for different population-risk categories: Only '''[[polyarthritis]]'''<ref name=":0">{{Cite web|url=https://www.who.int/cardiovascular_diseases/publications/trs923/en/|title=WHO {{!}} Rheumatic fever and rheumatic heart disease|website=www.who.int|access-date=2017-02-01|archive-url=https://web.archive.org/web/20170307020841/http://www.who.int/cardiovascular_diseases/publications/trs923/en/|archive-date=7 March 2017}}</ref> (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.<ref name=":1" />
# '''[[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.<ref name=":2">{{Cite journal|last1=Karthikeyan|first1=Ganesan|last2=Guilherme|first2=Luiza|date=July 2018|title=Acute rheumatic fever|journal=The Lancet|volume=392|issue=10142|pages=161–174|doi=10.1016/s0140-6736(18)30999-1|pmid=30025809|s2cid=51702921|issn=0140-6736}}</ref> Carditis is diagnosed clinically (palpitations, shortness of breath, heart failure, or a new [[heart murmur]]) or by echocardiography/Doppler studies revealing mitral or aortic valvulitis. Both clinical and subclinical carditis are now considered a major criterion.<ref name=":1" /><ref name=":2" />
# '''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.{{citation needed|date=February 2021}}
# '''[[Erythema marginatum]]''': A long-lasting reddish [[rash]] that begins on the trunk or arms as [[macule]]s, 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.{{citation needed|date=February 2021}}
# '''[[Sydenham's chorea]]''' (St. Vitus' dance): A characteristic series of involuntary rapid movements of the face and arms. This can occur very late in the disease, for at least three months from the onset of infection.{{citation needed|date=February 2021}}
'''Minor criteria'''

# '''[[Arthralgia]]''': '''Polyarthralgia''' in low-risk populations and '''monoarthralgia''' in others.<ref name=":1" /> However, joint manifestations cannot be considered in both major and minor categories in the same patient.<ref name=":1" />
# '''[[Fever]]''': ≥ 38.5&nbsp;°C (101.3&nbsp;°F) in low-incidence populations and ≥ 38&nbsp;°C (100.4&nbsp;°F) in high-risk populations.<ref name=":1" />
# '''Raised [[erythrocyte sedimentation rate]]''' (≥60&nbsp;mm in the first hour in low-risk populations and ≥30&nbsp;mm/h in others) or '''[[C reactive protein]]''' (>3.0&nbsp;mg/dL).<ref name=":1" />
# [[Electrocardiogram|ECG]] showing a '''prolonged [[PR interval]]'''<ref name=":1" /><ref name="davidson617">Ed Boon, ''Davidson's General Practice of Medicine'', 20th edition. P. 617.</ref><ref>{{cite web | url = http://www.utmb.edu/pedi_ed/CORE/Cardiology/page_40.htm | title = Rheumatic Fever | access-date = 6 August 2011 | last = Aly | first = Ashraf | year = 2008 | work = Core Concepts of Pediatrics | publisher = University of Texas | url-status = live | archive-url = https://web.archive.org/web/20110524035336/http://www.utmb.edu/pedi_ed/CORE/Cardiology/page_40.htm | archive-date = 24 May 2011 }}</ref> after accounting for age variability (Cannot be included if carditis is present as a major symptom)

==Prevention==
Rheumatic fever can be prevented by effectively and promptly treating [[strep throat]] with antibiotics.<ref name=Ger2009>{{cite journal|last1=Gerber|first1=MA|last2=Baltimore|first2=RS|last3=Eaton|first3=CB|last4=Gewitz|first4=M|last5=Rowley|first5=AH|last6=Shulman|first6=ST|last7=Taubert|first7=KA|title=Prevention of rheumatic fever and diagnosis and treatment of acute Streptococcal pharyngitis: a scientific statement from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee of the Council on Cardiovascular Disease in the Young, the Interdisciplinary Council on Functional Genomics and Translational Biology, and the Interdisciplinary Council on Quality of Care and Outcomes Research: endorsed by the American Academy of Pediatrics.|journal=Circulation|date=24 March 2009|volume=119|issue=11|pages=1541–51|pmid=19246689|doi=10.1161/circulationaha.109.191959|doi-access=free}}</ref> Globally, rheumatic fever is seen in populations that are socioeconomically disadvantaged and with limited access to health care.<ref name=Nu2017/> Overcrowding<ref name=Nu2017/><ref name=phillips2017>{{cite journal|vauthors=Phillips DI, Osmond C, Williams ML, Jones A|title=Air pollution in early life and adult mortality from chronic rheumatic heart disease|journal=International Journal of Epidemiology|volume=46|issue=4|year=2017|pages=1107–1114|doi=10.1093/ije/dyw249|doi-access=free|pmid=27773865|pmc=5489081}}</ref> and exposure to [[indoor air pollution|domestic air pollution]]<ref name=phillips2017/> have been cited as associated risk factors.

In those who have previously had rheumatic fever, antibiotics may be used in a preventative manner as [[secondary prophylaxis]].<ref name=Ger2009/>  Antibiotic prophylaxis after an episode of acute rheumatic fever is recommended owing to the high likelihood of recurrence.<ref name=chowdhury2023>{{cite book|vauthors=Chowdhury S, Koziatek CA, Rajnik M|chapter=Acute Rheumatic Fever|title=StatPearls|publisher=StatPearls Publishing|location=Treasure Island, Florida|date=2 August 2023|pmid=37603629|id=National Library of Medicine Bookshelf ID NBK594238}}</ref>  Streptococcal [[pharyngitis]] may occur asymptomatically and rheumatic fever may recur even after a treated infection.<ref name=nishimura2014>{{cite journal|vauthors=Nishimura RA, Otto CM, et al|year=2014|title=2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease|journal=Journal of the American College of Cardiology|volume=63|issue=22|pages=e57–e185 |doi=10.1016/j.jacc.2014.02.536|pmid=24603191|doi-access=free}}</ref>  The [[American 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.<ref name=nishimura2014/> The AHA also supports good dental hygiene in people with RHD, and antibiotics for the prevention of [[infective endocarditis]] during dental procedures are recommended in high-risk patients.<ref name=nishimura2014/>

===Vaccine===
No vaccines are currently available to protect against ''S. pyogenes'' infection, although research is underway to develop one.<ref name="sciencemediacentre.co.nz">{{cite web|title=Collaboration aims for rheumatic fever vaccine|url=http://www.sciencemediacentre.co.nz/2014/09/18/collaboration-aims-for-rheumatic-fever-vaccine/|website=sciencemediacentre.co.nz|access-date=April 16, 2017|date=September 18, 2014|url-status=live|archive-url=https://web.archive.org/web/20170415140325/http://www.sciencemediacentre.co.nz/2014/09/18/collaboration-aims-for-rheumatic-fever-vaccine/|archive-date=15 April 2017}}</ref> 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 number of people that will be needed for appropriate trials for safety and efficacy of the vaccine.<ref>{{cite web|title=Initiative for Vaccine Research (IVR) – Group A Streptococcus|url=https://www.who.int/vaccine_research/diseases/soa_bacterial/en/index3.html|publisher=World Health Organization|access-date=15 June 2012|archive-url=https://web.archive.org/web/20120513105141/http://www.who.int/vaccine_research/diseases/soa_bacterial/en/index3.html|archive-date=13 May 2012}}</ref>

==Treatment==
The management of rheumatic fever is directed toward the reduction of inflammation with [[anti-inflammatory medication]]s such as [[aspirin]] or [[corticosteroid]]s. Individuals with positive cultures for strep throat should also be treated with [[antibiotic]]s.<ref name=":0" />

===Infection===
People with positive cultures for ''Streptococcus pyogenes'' should be treated with penicillin as long as [[allergy]] is not present. The use of antibiotics will not alter cardiac involvement in the development of rheumatic fever.<ref name=":0" /> Some suggest the use of [[benzathine benzylpenicillin]].{{citation needed|date=February 2021}}

Monthly injections of long-acting penicillin must be given for 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.{{citation needed|date=February 2021}}

===Inflammation===
Aspirin at high doses has historically been used to treat rheumatic fever.<ref>{{cite web|title=Aspirin Monograph for Professionals - Drugs.com|url=https://www.drugs.com/monograph/aspirin.html|website=Drugs.com|publisher=American Society of Health-System Pharmacists|access-date=30 March 2017|url-status=live|archive-url=https://web.archive.org/web/20170425142242/https://www.drugs.com/monograph/aspirin.html|archive-date=25 April 2017}}</ref>  However, due to side effects like [[gastritis]] and [[Aspirin poisoning|salicylate poisoning]], necessitating serum monitoring of salicylate levels, and the risk of [[Reye 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.<ref name=chowdhury2023/> While evidence suggests that treatment of rheumatic fever–associated arthritis with [[naproxen]] may be equally effective as with aspirin,<ref name=chowdhury2023/><ref>{{cite journal|vauthors=Hashkes PJ, Tauber T, Somekh E, Brik R, Barash J, Mukamel M, Harel L, Lorder A, Berkovitch M, Uziel Y|title=Naproxen as an alternative to aspirin for the treatment of arthritis of rheumatic fever: a randomized trial|journal=The Journal of Pediatrics|date=2003 |volume=143|issue=3|pages=399–401|doi=10.1067/S0022-3476(03)00388-3|pmid=14517527}}</ref> its role in managing carditis has not been established.<ref>{{cite journal|vauthors=Çetin II, Ekici F, Kocabaş A, Çevik BŞ, Eminoğlu S, Azak E, Kibar AE, Arı ME, Sürücü M, Orgun A|title=The efficacy and safety of naproxen in acute rheumatic fever: The comparative results of 11-year experience with acetylsalicylic acid and naproxen|journal=The Turkish Journal of Pediatrics|volume=58|issue=5|pages=473–479|year=2016|doi=10.24953/turkjped.2016.05.003|doi-access=free|pmid=28621087}}</ref>  Management of carditis in acute rheumatic fever is controversial and based on dated literature.<ref name=chillers2015>{{cite journal|vauthors=Cilliers A, Adler AJ, Saloojee H|title=Anti-inflammatory treatment for carditis in acute rheumatic fever|year=2015|volume=2015|issue=5|id=Art. No. CD003176|doi=10.1002/14651858.CD003176.pub3|pmid=26017576|journal=Cochrane Database of Systematic Reviews|article-number=CD003176 }}</ref>  Corticosteroids may be considered, especially in people with allergies to NSAIDs or severe disease,<ref name=chowdhury2023/> although use of steroids may cause tissue [[atrophy]], which could present challenges during future cardiac surgery for valve repair.<ref name=chillers2015/>

===Heart failure===
Some patients develop significant [[carditis]], which manifests as [[congestive heart failure]]. This requires the usual treatment for heart failure: [[ACE inhibitor]]s, [[diuretic]]s, [[beta blocker]]s, and [[digoxin]].{{citation needed|date=March 2024}} Unlike typical heart failure, rheumatic heart failure responds well to corticosteroids.{{citation needed|date=March 2024}}

==Epidemiology==
[[File:Rheumatic heart disease world map-Deaths per million persons-WHO2012.svg|thumb|upright=1.3|Deaths from rheumatic heart disease per million persons in 2012 {{Div col|small=yes|colwidth=10em}}{{legend|#ffff20|0–7}}{{legend|#ffe820|8–14}}{{legend|#ffd820|15–20}}{{legend|#ffc020|21–25}}{{legend|#ffa020|26–32}}{{legend|#ff9a20|33–38}}{{legend|#f08015|39–45}}{{legend|#e06815|46–52}}{{legend|#d85010|53–63}}{{legend|#d02010|64–250}}{{div col end}}]]
[[File:Rheumatic heart disease world map - DALY - WHO2004.svg|thumb|upright=1.3|[[Disability-adjusted life year]] for rheumatic heart disease per 100,000&nbsp;inhabitants in 2004.<ref>{{cite web | url =https://www.who.int/healthinfo/global_burden_disease/estimates_country/en/ | title = WHO Disease and injury country estimates | year = 2009 | work = World Health Organization | access-date = 11 November 2009 | url-status = live | archive-url = https://web.archive.org/web/20140202213728/http://www.who.int/healthinfo/global_burden_disease/estimates_country/en/ | archive-date = 2 February 2014 }}</ref>{{Div col|small=yes|colwidth=10em}}
{{legend|#b3b3b3|no data}}
{{legend|#ffff65|less than 20}}
{{legend|#fff200|20–40}}
{{legend|#ffdc00|40–60}}
{{legend|#ffc600|60–80}}
{{legend|#ffb000|80–100}}
{{legend|#ff9a00|100–120}}
{{legend|#ff8400|120–140}}
{{legend|#ff6e00|140–160}}
{{legend|#ff5800|160–180}}
{{legend|#ff4200|180–200}}
{{legend|#ff2c00|200–330}}
{{legend|#cb0000|more than 330}}
{{div col end}}]]

About 33 million people are affected by rheumatic heart disease with an additional 47 million having [[asymptomatic]] damage to their heart valves.<ref name=Nu2017>{{cite journal|last1=Nulu|first1=S|last2=Bukhman|first2=G|last3=Kwan|first3=GF|title=Rheumatic Heart Disease: The Unfinished Global Agenda.|journal=Cardiology Clinics|date=February 2017|volume=35|issue=1|pages=165–180|pmid=27886787|doi=10.1016/j.ccl.2016.08.006}}</ref> As of 2010 globally it resulted in 345,000 deaths, down from 463,000 in 1990.<ref name=Loz2012>{{cite journal |vauthors = Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, Abraham J, Adair T, Aggarwal R, Ahn SY, Alvarado M, Anderson HR, Anderson LM, Andrews KG, Atkinson C, Baddour LM, Barker-Collo S, Bartels DH, Bell ML, Benjamin EJ, Bennett D, Bhalla K, Bikbov B, Bin Abdulhak A, Birbeck G, Blyth F, Bolliger I, Boufous S, Bucello C, Burch M, Burney P, Carapetis J, Chen H, Chou D, Chugh SS, Coffeng LE, Colan SD, Colquhoun S, Colson KE, Condon J, Connor MD, Cooper LT, Corriere M, Cortinovis M, de Vaccaro KC, Couser W, Cowie BC, Criqui MH, Cross M, Dabhadkar KC, Dahodwala N, De Leo D, Degenhardt L, Delossantos A, Denenberg J, Des Jarlais DC, Dharmaratne SD, Dorsey ER, Driscoll T, Duber H, Ebel B, Erwin PJ, Espindola P, Ezzati M, Feigin V, Flaxman AD, Forouzanfar MH, Fowkes FG, Franklin R, Fransen M, Freeman MK, Gabriel SE, Gakidou E, Gaspari F, Gillum RF, Gonzalez-Medina D, Halasa YA, Haring D, Harrison JE, Havmoeller R, Hay RJ, Hoen B, Hotez PJ, Hoy D, Jacobsen KH, James SL, Jasrasaria R, Jayaraman S, Johns N, Karthikeyan G, Kassebaum N, Keren A, Khoo JP, Knowlton LM, Kobusingye O, Koranteng A, Krishnamurthi R, Lipnick M, Lipshultz SE, Ohno SL, Mabweijano J, MacIntyre MF, Mallinger L, March L, Marks GB, Marks R, Matsumori A, Matzopoulos R, Mayosi BM, McAnulty JH, McDermott MM, McGrath J, Mensah GA, Merriman TR, Michaud C, Miller M, Miller TR, Mock C, Mocumbi AO, Mokdad AA, Moran A, Mulholland K, Nair MN, Naldi L, Narayan KM, Nasseri K, Norman P, O'Donnell M, Omer SB, Ortblad K, Osborne R, Ozgediz D, Pahari B, Pandian JD, Rivero AP, Padilla RP, Perez-Ruiz F, Perico N, Phillips D, Pierce K, Pope CA, Porrini E, Pourmalek F, Raju M, Ranganathan D, Rehm JT, Rein DB, Remuzzi G, Rivara FP, Roberts T, De León FR, Rosenfeld LC, Rushton L, Sacco RL, Salomon JA, Sampson U, Sanman E, Schwebel DC, Segui-Gomez M, Shepard DS, Singh D, Singleton J, Sliwa K, Smith E, Steer A, Taylor JA, Thomas B, Tleyjeh IM, Towbin JA, Truelsen T, Undurraga EA, Venketasubramanian N, Vijayakumar L, Vos T, Wagner GR, Wang M, Wang W, Watt K, Weinstock MA, Weintraub R, Wilkinson JD, Woolf AD, Wulf S, Yeh PH, Yip P, Zabetian A, Zheng ZJ, Lopez AD, Murray CJ, AlMazroa MA, Memish ZA|s2cid=1541253 |display-authors=6 |title=Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010 |journal=Lancet |volume=380 |issue=9859 |pages=2095–128 |year=2012 |pmid=23245604 |doi=10.1016/S0140-6736(12)61728-0 |pmc=10790329 |hdl=10536/DRO/DU:30050819 |url=https://zenodo.org/record/2557786 |hdl-access=free }}</ref>

In Western countries, rheumatic fever has become fairly rare since the 1960s, probably due to the 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.<ref>{{Cite web | url = https://www.medlineplus.gov/ency/article/003940.htm | publisher = NLM/NIH | website = Medline Plus Medical Encyclopedia | title = Rheumatic fever | url-status = live | archive-url = https://web.archive.org/web/20160407011041/https://www.nlm.nih.gov/medlineplus/ency/article/003940.htm | archive-date = 7 April 2016 }}</ref> The disease is most common among [[Indigenous Australians]] (particularly in central and northern Australia), [[Māori people|Māori]], and [[Pacific Islander]]s, and is also common in [[Sub-Saharan Africa]], [[Latin America]], the [[Indian subcontinent]], and [[North Africa]].<ref>{{cite web|url=https://www.menzies.edu.au/page/Research/Global_and_Tropical_Health/Rheumatic_Heart_Disease/|title=Rheumatic heart disease|publisher=[[Menzies Institute for Medical Research]]|access-date=1 September 2018}}</ref>

Rheumatic fever primarily affects children between the ages of 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|date=February 2021}}

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%).<ref>{{cite book | last =Porth | first = Carol |title=Essentials of pathophysiology: concepts of altered health states | publisher =Lippincott Williams & Wilkins |location=Hagerstown, MD |year=2007 | isbn= 978-0-7817-7087-3}}</ref> The rate of development is far lower in individuals who have received antibiotic treatment. People who have had a case of rheumatic fever have a tendency to develop flare-ups with repeated strep infections.{{citation needed|date=February 2021}}

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 to [[valvular 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.<ref>{{Cite journal|last1=Marijon|first1=Eloi|last2=Ou|first2=Phalla|last3=Celermajer|first3=David S.|last4=Ferreira|first4=Beatriz|last5=Mocumbi|first5=Ana Olga|last6=Jani|first6=Dinesh|last7=Paquet|first7=Christophe|last8=Jacob|first8=Sophie|last9=Sidi|first9=Daniel|s2cid=28936439|date=2007-08-02|title=Prevalence of rheumatic heart disease detected by echocardiographic screening|journal=The New England Journal of Medicine|volume=357|issue=5|pages=470–476|doi=10.1056/NEJMoa065085|issn=1533-4406|pmid=17671255|doi-access=free}}</ref><ref>{{Cite journal|last1=Rothenbühler|first1=Martina|last2=O'Sullivan|first2=Crochan J.|last3=Stortecky|first3=Stefan|last4=Stefanini|first4=Giulio G.|last5=Spitzer|first5=Ernest|last6=Estill|first6=Janne|last7=Shrestha|first7=Nikesh R.|last8=Keiser|first8=Olivia|last9=Jüni|first9=Peter|date=2014-12-01|title=Active surveillance for rheumatic heart disease in endemic regions: a systematic review and meta-analysis of prevalence among children and adolescents|journal=The Lancet Global Health|volume=2|issue=12|pages=e717–726|doi=10.1016/S2214-109X(14)70310-9|issn=2214-109X|pmid=25433627|url=https://boris.unibe.ch/61447/1/Rothenb%C3%BChler%20LancetGlobHealth%202014.pdf|doi-access=free}}</ref><ref>{{Cite journal|last1=Shrestha NR|last2=Karki P|last3=Mahto R|date=2016-03-02|title=Prevalence of subclinical rheumatic heart disease in eastern nepal: A school-based cross-sectional study|journal=JAMA Cardiology|doi=10.1001/jamacardio.2015.0292|pmid=27437661|issn=2380-6583|display-authors=etal|volume=1|issue=1|pages=89–96|doi-access=free}}</ref><ref>{{Cite journal|last1=Beaton|first1=Andrea|last2=Okello|first2=Emmy|last3=Lwabi|first3=Peter|last4=Mondo|first4=Charles|last5=McCarter|first5=Robert|last6=Sable|first6=Craig|date=2012-06-26|title=Echocardiography screening for rheumatic heart disease in Ugandan schoolchildren|journal=Circulation|volume=125|issue=25|pages=3127–3132|doi=10.1161/CIRCULATIONAHA.112.092312|issn=1524-4539|pmid=22626741|doi-access=free}}</ref> To assist in the identification of RHD in low resource settings and where prevalence of GAS infections is high, the [[World Heart Federation]] has developed criteria for RHD diagnosis using echocardiography, supported by clinical history if available.<ref>{{cite journal|vauthors=Reményi B, Wilson N, Steer A, Ferreira B, Kado J, Kumar K, Lawrenson J, Maguire G, Marijon E, Mirabel M, Mocumbi AO, Mota C, Paar J, Saxena A, Scheel J, Stirling J, Viali S, Balekundri VI, Wheaton G, Zühlke L, Carapetis J|title=World Heart Federation criteria for echocardiographic diagnosis of rheumatic heart disease—an evidence-based guideline|journal=Nature Reviews Cardiology|volume=9|pages=297–309|year=2012|doi=10.1038/nrcardio.2012.7|pmid=22371105|pmc=5523449|issue=5}}</ref>  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.<ref name=Nu2017/>  However, spontaneous regression is more likely in borderline RHD than in definite cases, and its natural history may vary between populations.<ref name=Nu2017/>  

Echocardiographic [[screening (medicine)|screening]] 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.<ref>{{cite journal |last1=Karki |first1=Prahlad |last2=Uranw |first2=Surendra |last3=Bastola |first3=Santosh |last4=Mahato |first4=Rajan |last5=Shrestha |first5=Nikesh Raj |last6=Sherpa |first6=Kunjang |last7=Dhungana |first7=Sahadeb |last8=Odutayo |first8=Ayodele |last9=Gurung |first9=Keshar |last10=Pandey |first10=Naveen |last11=Agrawal |first11=Krishna |last12=Shah |first12=Prashant |last13=Rothenbühler |first13=Martina |last14=Jüni |first14=Peter |last15=Pilgrim |first15=Thomas |display-authors=6 |title=Effectiveness of Systematic Echocardiographic Screening for Rheumatic Heart Disease in Nepalese Schoolchildren: A Cluster Randomized Clinical Trial |journal=JAMA Cardiology |year=2021 |volume=6 |issue=4 |pages=420–426 |doi=10.1001/jamacardio.2020.7050 |issn=2380-6583  |pmid=33471029|pmc=7818193 |doi-access=free }}</ref><ref name=beaton2022>{{cite journal|vauthors=Beaton A, Okello E, Rwebembera J, Grobler A, Engelman D, Alepere J, Canales L, Carapetis J, DeWyer A, Lwabi P, Mirabel M, Mocumbi AO, Murali M, Nakitto M, Ndagire E, Nunes MC, Omara IO, Sarnacki R, Scheel A, Wilson N, Zimmerman M, Zühlke L, Karhikeyan G, Sable GA, Steer AC|display-authors=6|title=Secondary Antibiotic Prophylaxis for Latent Rheumatic Heart Disease|journal=New England Journal of Medicine|year=2022|doi=10.1056/NEJMoa2102074|volume=386|issue=3|pages=230–240|pmid=34767321}}</ref>  The efficacy of treating latent [[Rheumatic heart disease|RHD]] in populations with high prevalence is balanced by the potential development of [[antibiotic resistance]], which might be offset through use of [[narrow-spectrum antibiotic]]s like benzathine benzapenicillin.<ref name=beaton2022/>  Public health research is ongoing to determine if screening is beneficial and cost effective.

==See also==
* [[Rapid strep test]]
* [[Chronic post–RF arthropathy]] – joint changes that may arise following multiple episodes of rheumatic fever, also called Jaccoud's arthropathy<ref>{{cite journal|vauthors=Grahame M, Mitchell AB, Scott JT|title=Chronic post-rheumatic fever (Jaccoud's) arthropathy|year=1970|volume=29|issue=6|pages=622–625|doi=10.1136/ard.29.6.622|doi-access=free|pmid=5496065|pmc=1010593|journal=Annals of the Rheumatic Diseases}}</ref>
{{clear}}

==References==
{{Reflist}}

==External links==
* {{cite web|title=Jones major criteria|url=http://www.lifehugger.com/moc/289/rheumatic-fever-diagnosis-jones-major-criteria|archive-url=https://web.archive.org/web/20170804170416/http://www.lifehugger.com/moc/289/rheumatic-fever-diagnosis-jones-major-criteria|archive-date=4 August 2017}}

{{Medical condition classification and resources
| DiseasesDB     = 11487
| ICD10          = {{ICD10|I|00||i|00}}-{{ICD10|I|02||i|00}}
| ICD9           = {{ICD9|390}}–{{ICD9|392}}
| ICDO           =
| OMIM           =
| MedlinePlus    = 003940
| eMedicineSubj  = med
| eMedicineTopic = 3435
| eMedicine_mult = {{eMedicine2|med|2922}} {{eMedicine2|emerg|509}} {{eMedicine2|ped|2006}}
| MeshID         = D012213
}}
{{Gram-positive bacterial diseases}}
{{Circulatory system pathology}}
{{Hypersensitivity and autoimmune diseases}}
{{Authority control}}

{{DEFAULTSORT:Rheumatic Fever}}
[[Category:Chronic rheumatic heart diseases]]
[[Category:Inflammations]]
[[Category:Pediatrics]]
[[Category:Rheumatology]]
[[Category:Wikipedia medicine articles ready to translate]]
[[Category:Wikipedia emergency medicine articles ready to translate]]