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Rheumatic fever (RF) is an
inflammatory disease Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molecu ...
that can involve the
heart The heart is a muscular organ in most animals. This organ pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste such as carbon dioxide t ...
,
joint A joint or articulation (or articular surface) is the connection made between bones, ossicles, or other hard structures in the body which link an animal's skeletal system into a functional whole.Saladin, Ken. Anatomy & Physiology. 7th ed. McGraw ...
s,
skin Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation. Other cuticle, animal coverings, such as the arthropod exoskeleton, have diffe ...
, and
brain A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a v ...
. The disease typically develops two to four weeks after a streptococcal throat infection. Signs and symptoms include
fever Fever, also referred to as pyrexia, is defined as having a body temperature, temperature above the human body temperature, normal range due to an increase in the body's temperature Human body temperature#Fever, set point. There is not a single ...
, multiple painful joints, involuntary muscle movements, and occasionally a characteristic non-
itch Itch (also known as pruritus) is a sensation that causes the desire or reflex to scratch. Itch has resisted many attempts to be classified as any one type of sensory experience. Itch has many similarities to pain, and while both are unpleasant ...
y rash known as
erythema marginatum Erythema marginatum is a type of erythema (redness of the skin or mucous membranes) involving pink rings on the torso and inner surfaces of the limb (anatomy), limbs which come and go for as long as several months. It is found primarily on extenso ...
. The heart is involved in about half of the cases. Damage to the heart valves, known as
rheumatic heart disease 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 jo ...
(RHD), usually occurs after repeated attacks but can sometimes occur after one. The damaged valves may result in
heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, a ...
, atrial fibrillation and infection of the valves. Rheumatic fever may occur following an infection of the throat by the bacterium ''
Streptococcus pyogenes ''Streptococcus pyogenes'' is a species of Gram-positive, aerotolerant bacteria in the genus ''Streptococcus''. These bacteria are extracellular, and made up of non-motile and non-sporing cocci (round cells) that tend to link in chains. They are ...
''. 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 An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...
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 Malnutrition occurs when an organism gets too few or too many nutrients, resulting in health problems. Specifically, it is "a deficiency, excess, or imbalance of energy, protein and other nutrients" which adversely affects the body's tissues a ...
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
antibiotic An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention of ...
s, such as
penicillin Penicillins (P, PCN or PEN) are a group of β-lactam antibiotics originally obtained from ''Penicillium'' moulds, principally '' P. chrysogenum'' and '' P. rubens''. Most penicillins in clinical use are synthesised by P. chrysogenum using ...
, decreases the risk of developing rheumatic fever. In order to avoid
antibiotic misuse Antibiotic misuse, sometimes called antibiotic abuse or antibiotic overuse, refers to the misuse or overuse of antibiotics, with potentially serious effects on health. It is a contributing factor to the development of antibiotic resistance, includ ...
this often involves testing people with
sore throat Sore throat, also known as throat pain, is pain or irritation of the throat. Usually, causes of sore throat include * viral infections * group A streptococcal infection (GAS) bacterial infection * pharyngitis (inflammation of the throat) * tonsi ...
s for the infection; however, testing might not be available in the
developing world A developing country is a sovereign state with a lesser developed industrial base and a lower Human Development Index (HDI) relative to other countries. However, this definition is not universally agreed upon. There is also no clear agreem ...
. Other preventive measures include improved
sanitation Sanitation refers to public health conditions related to clean drinking water and treatment and disposal of human excreta and sewage. Preventing human contact with feces is part of sanitation, as is hand washing with soap. Sanitation systems ...
. 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 Valve replacement surgery is the replacement of one or more of the heart valves with either an artificial heart valve or a bioprosthesis ( homograft from human tissue or xenograft e.g. from pig). It is an alternative to valve repair. __TOC__ Proc ...
or
valve repair Heart valve repair is a cardiac surgery procedure, carried out to repair one or more faulty heart valves. In some valvular heart diseases repair where possible is preferable to valve replacement. A mechanical heart valve is a replacement valve th ...
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 A developing country is a sovereign state with a lesser developed industrial base and a lower Human Development Index (HDI) relative to other countries. However, this definition is not universally agreed upon. There is also no clear agreem ...
and among
indigenous people Indigenous peoples are culturally distinct ethnic groups whose members are directly descended from the earliest known inhabitants of a particular geographic region and, to some extent, maintain the language and culture of those original people ...
s in the
developed world A developed country (or industrialized country, high-income country, more economically developed country (MEDC), advanced country) is a sovereign state that has a high quality of life, developed economy and advanced technological infrastruct ...
. 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 Hippocrates of Kos (; grc-gre, Ἱπποκράτης ὁ Κῷος, Hippokrátēs ho Kôios; ), also known as Hippocrates II, was a Greek physician of the classical period who is considered one of the most outstanding figures in the history of ...
. The disease is so named because its symptoms are similar to those of some
rheumatic disorders Rheumatism or rheumatic disorders are conditions causing chronic, often intermittent pain affecting the joints or connective tissue. Rheumatism does not designate any specific disorder, but covers at least 200 different conditions, including art ...
.


Signs and symptoms

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 Erythema marginatum is a type of erythema (redness of the skin or mucous membranes) involving pink rings on the torso and inner surfaces of the limb (anatomy), limbs which come and go for as long as several months. It is found primarily on extenso ...
. 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 Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, a ...
and also increase the risk of atrial fibrillation and infection of the valves.


Pathophysiology

Rheumatic fever is a
systemic disease A systemic disease is one that affects a number of organs and tissues, or affects the body as a whole. Examples * Mastocytosis, including mast cell activation syndrome and eosinophilic esophagitis * Chronic fatigue syndrome * Systemic vasculi ...
affecting the
connective tissue Connective tissue is one of the four primary types of animal tissue, along with epithelial tissue, muscle tissue, and nervous tissue. It develops from the mesenchyme derived from the mesoderm the middle embryonic germ layer. Connective tiss ...
around
arteriole An arteriole is a small-diameter blood vessel in the microcirculation that extends and branches out from an artery and leads to capillaries. Arterioles have muscular walls (usually only one to two layers of smooth muscle cells) and are the primar ...
s, and can occur after an untreated
strep throat Streptococcal pharyngitis, also known as streptococcal sore throat (strep throat), is pharyngitis (an infection of the pharynx, the back of the throat) caused by ''Streptococcus pyogenes'' a gram-positive, group A streptococcus. Common symptom ...
infection, specifically due to
group A streptococcus Lancefield grouping is a system of classification that classifies catalase-negative Gram-positive cocci based on the carbohydrate composition of bacterial antigens found on their cell walls. The system, created by Rebecca Lancefield, was historic ...
(GAS), ''
Streptococcus pyogenes ''Streptococcus pyogenes'' is a species of Gram-positive, aerotolerant bacteria in the genus ''Streptococcus''. These bacteria are extracellular, and made up of non-motile and non-sporing cocci (round cells) that tend to link in chains. They are ...
''. The similarity between antigens of ''
Streptococcus pyogenes ''Streptococcus pyogenes'' is a species of Gram-positive, aerotolerant bacteria in the genus ''Streptococcus''. These bacteria are extracellular, and made up of non-motile and non-sporing cocci (round cells) that tend to link in chains. They are ...
'' and multiple cardiac proteins can cause a life-threatening type II hypersensitivity reaction. Usually, self reactive
B cell B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or ...
s remain
anergic In immunology, anergy is a lack of reaction by the body's defense mechanisms to foreign substances, and consists of a direct induction of peripheral lymphocyte tolerance. An individual in a state of anergy often indicates that the immune system ...
in the periphery without
T cell A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...
co-stimulation. During a streptococcal infection, mature
antigen-presenting cell An antigen-presenting cell (APC) or accessory cell is a cell that displays antigen bound by major histocompatibility complex (MHC) proteins on its surface; this process is known as antigen presentation. T cells may recognize these complexes using ...
s 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 cell Plasma cells, also called plasma B cells or effector B cells, are white blood cells that originate in the lymphoid organs as B lymphocytes and secrete large quantities of proteins called antibodies in response to being presented specific substan ...
s 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 Aerobic means "requiring air," in which "air" usually means oxygen. Aerobic may also refer to * Aerobic exercise, prolonged exercise of moderate intensity * Aerobics, a form of aerobic exercise * Aerobic respiration, the aerobic process of cellu ...
,
cocci A coccus (plural cocci) is any bacterium or archaeon that has a spherical, ovoid, or generally round shape. Bacteria are categorized based on their shapes into three classes: cocci (spherical-shaped), bacillus (rod-shaped) and spiral ( of whi ...
,
gram-positive bacteria In bacteriology, gram-positive bacteria are bacteria that give a positive result in the Gram stain test, which is traditionally used to quickly classify bacteria into two broad categories according to their type of cell wall. Gram-positive bact ...
that are non-motile, non- spore forming, and forms chains and large
colonies In modern parlance, a colony is a territory subject to a form of foreign rule. Though dominated by the foreign colonizers, colonies remain separate from the administration of the original country of the colonizers, the '' metropolitan state'' ...
. ''S. pyogenes'' has a
cell wall A cell wall is a structural layer surrounding some types of cells, just outside the cell membrane. It can be tough, flexible, and sometimes rigid. It provides the cell with both structural support and protection, and also acts as a filtering mech ...
composed of branched
polymers A polymer (; Greek '' poly-'', "many" + ''-mer'', "part") is a substance or material consisting of very large molecules called macromolecules, composed of many repeating subunits. Due to their broad spectrum of properties, both synthetic an ...
which sometimes contain M protein, a
virulence factor Virulence factors (preferably known as pathogenicity factors or effectors in plant science) are cellular structures, molecules and regulatory systems that enable microbial pathogens (bacteria, viruses, fungi, and protozoa) to achieve the following ...
that is highly
antigenic In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response. ...
. The antibodies which the immune system generates against the M protein may cross-react with heart muscle cell protein
myosin Myosins () are a superfamily of motor proteins best known for their roles in muscle contraction and in a wide range of other motility processes in eukaryotes. They are ATP-dependent and responsible for actin-based motility. The first myosin ...
, heart muscle
glycogen Glycogen is a multibranched polysaccharide of glucose that serves as a form of energy storage in animals, fungi, and bacteria. The polysaccharide structure represents the main storage form of glucose in the body. Glycogen functions as one o ...
and smooth muscle cells of arteries, inducing
cytokine Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
release and tissue destruction. However, the only proven cross-reaction is with perivascular
connective tissue Connective tissue is one of the four primary types of animal tissue, along with epithelial tissue, muscle tissue, and nervous tissue. It develops from the mesenchyme derived from the mesoderm the middle embryonic germ layer. Connective tiss ...
. This inflammation occurs through direct attachment of complement and Fc receptor-mediated recruitment of neutrophils and macrophages. Characteristic
Aschoff bodies In medicine, Aschoff bodies are nodules found in the hearts of individuals with rheumatic fever. They result from inflammation in the heart muscle and are characteristic of rheumatic heart disease. These nodules were discovered independently by L ...
, composed of swollen
eosinophilic Eosinophilic (Greek suffix -phil-, meaning ''loves eosin'') is the staining of tissues, cells, or organelles after they have been washed with eosin, a dye. Eosin is an acidic dye for staining cell cytoplasm, collagen, and muscle fibers. ''Eosi ...
collagen Collagen () is the main structural protein in the extracellular matrix found in the body's various connective tissues. As the main component of connective tissue, it is the most abundant protein in mammals, making up from 25% to 35% of the whole ...
surrounded by lymphocytes and macrophages can be seen on light microscopy. The larger macrophages may become
Anitschkow cell In pathology, Anitschkow (or Anichkov) cells are often cells associated with rheumatic heart disease. Anitschkow cells are enlarged macrophages found within granulomas (called Aschoff bodies) associated with the disease. The cells are also calle ...
s or Aschoff giant cells. Rheumatic valvular lesions may also involve a
cell-mediated immunity Cell-mediated immunity or cellular immunity is an immune response that does not involve antibodies. Rather, cell-mediated immunity is the activation of phagocytes, antigen-specific cytotoxic T-lymphocytes, and the release of various cytokines in ...
reaction as these lesions predominantly contain
T-helper The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considere ...
cells and
macrophages Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer ce ...
. In rheumatic fever, these lesions can be found in any layer of the heart causing different types of
carditis Carditis (pl. carditides) is the inflammation of the heart. It is usually studied and treated by specifying it as: * Pericarditis is the inflammation of the pericardium * Myocarditis is the inflammation of the heart muscle * Endocarditis is the in ...
. The inflammation may cause a serofibrinous pericardial exudate described as "bread-and-butter"
pericarditis Pericarditis is inflammation of the pericardium, the fibrous sac surrounding the heart. Symptoms typically include sudden onset of sharp chest pain, which may also be felt in the shoulders, neck, or back. The pain is typically less severe when sit ...
, which usually resolves without sequelae. Involvement of the endocardium typically results in
fibrinoid necrosis Fibrinoid necrosis is a specific pattern of irreversible, uncontrolled cell death that occurs when antigen-antibody complexes are deposited in the walls of blood vessels along with fibrin. It is common in the immune-mediated vasculitides which ar ...
and
wart Warts are typically small, rough, hard growths that are similar in color to the rest of the skin. They typically do not result in other symptoms, except when on the bottom of the feet, where they may be painful. While they usually occur on the ...
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 William George MacCallum (18 April 1874 – 3 February 1944) was a Canadian-American physician and pathologist. He was of Scottish descent and was born in Dunnville village in Canada, where his father was a physician. He was educated at the Univ ...
.


Rheumatic heart disease

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 ''Streptococcus'' is a genus of gram-positive ' (plural ) or spherical bacteria that belongs to the family Streptococcaceae, within the order Lactobacillales (lactic acid bacteria), in the phylum Bacillota. Cell division in streptococci occurs ...
(GAS) that results in valvular damage. Fibrosis and scarring of valve leaflets,
commissure A commissure () is the location at which two objects abut or are joined. The term is used especially in the fields of anatomy and biology. * The most common usage of the term refers to the brain's commissures, of which there are five. Such a commi ...
s 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 endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel ...
. 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 Molecular mimicry is defined as the theoretical possibility that sequence similarities between foreign and self-peptides are sufficient to result in the cross-activation of autoreactive T or B cells by pathogen-derived peptides. Despite the preva ...
via group A streptococci carbohydrates and
genetic predisposition A genetic predisposition is a genetic characteristic which influences the possible phenotypic development of an individual organism within a species or population under the influence of environmental conditions. In medicine, genetic susceptibilit ...
involving HLA Class II genes that trigger
autoimmune reaction An autoimmune disease is a condition arising from an abnormal immune response to a functioning body part. At least 80 types of autoimmune diseases have been identified, with some evidence suggesting that there may be more than 100 types. Nearly a ...
s. Molecular mimicry occurs when
epitope An epitope, also known as antigenic determinant, is the part of an antigen that is recognized by the immune system, specifically by antibodies, B cells, or T cells. The epitope is the specific piece of the antigen to which an antibody binds. The p ...
s 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 In molecular biology, CD4 (cluster of differentiation 4) is a glycoprotein that serves as a co-receptor for the T-cell receptor (TCR). CD4 is found on the surface of immune cells such as T helper cells, monocytes, macrophages, and dendritic ...
+ 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 cell B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or ...
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 Vascular cell adhesion protein 1 also known as vascular cell adhesion molecule 1 (VCAM-1) or cluster of differentiation 106 (CD106) is a protein that in humans is encoded by the ''VCAM1'' gene. VCAM-1 functions as a cell adhesion molecule. Stru ...
, 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 Chromosome 6 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 6 spans more than 170 million base pairs (the building material of DNA) and represents between 5.5 and 6% of the total D ...
. Certain allele combinations appear to increase RHD autoimmune susceptibility.
Human leukocyte antigen The human leukocyte antigen (HLA) system or complex is a complex of genes on chromosome 6 in humans which encode cell-surface proteins responsible for the regulation of the immune system. The HLA system is also known as the human version of th ...
(HLA) class II allele DR7 (
HLA-DR7 HLA-DR7 (DR7) is a HLA- DR serotype that recognizes the DRB1*0701 to *0705 gene products. Serology The serological reaction of DR7 is excellent for *0701. The serology of *0703 to *0705 to *0709, and *0711 to *0714 serotypes is unknown. DRB1*0 ...
) 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 Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolog ...
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 Mitral stenosis is a valvular heart disease characterized by the narrowing of the opening of the mitral valve of the heart. It is almost always caused by rheumatic valvular heart disease. Normally, the mitral valve is about 5 cm2 during d ...
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

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 The American Heart Association (AHA) is a nonprofit organization in the United States that funds cardiovascular medical research, educates consumers on healthy living and fosters appropriate cardiac care in an effort to reduce disability and death ...
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 Anti-streptolysin O (ASO or ASLO) is the antibody made against streptolysin O, an immunogenic, oxygen-labile streptococcal hemolytic exotoxin produced by most strains of group A and many strains of groups C and G ''Streptococcus'' bacteria. The "O ...
or
anti-DNase B Anti-Deoxyribonuclease B (anti-DNase B) titres are a quantitative measure of the presence of serologic antibodies obtained from patients suspected of having a recent group A (Beta-hemolytic) streptococcus bacteria infection, from ''Streptococcus p ...
. A recurrent episode is also diagnosed when three minor criteria are present. Exceptions are
chorea Chorea (or choreia, occasionally) is an abnormal involuntary movement disorder, one of a group of neurological disorders called dyskinesias. The term ''chorea'' is derived from the grc, χορεία ("dance"; see choreia), as the quick movement ...
and
indolent carditis Indolent may refer to: *Laziness *A music label owned by Bertelsmann Music Group *indolent condition, a slowly progressive medical condition associated with little or no pain *The lowest of three grades of non-Hodgkin's lymphoma (NHL) *Indolent ul ...
, 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 Scarlet fever, also known as Scarlatina, is an infectious disease caused by ''Streptococcus pyogenes'' a Group A streptococcus (GAS). The infection is a type of Group A streptococcal infection (Group A strep). It most commonly affects childr ...
, 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 (pl. carditides) is the inflammation of the heart. It is usually studied and treated by specifying it as: * Pericarditis is the inflammation of the pericardium * Myocarditis is the inflammation of the heart muscle * Endocarditis is the in ...
'': 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. Carditis is diagnosed clinically (palpitations, shortness of breath, heart failure, or a new
heart murmur Heart murmurs are unique heart sounds produced when blood flows across a heart valve or blood vessel. This occurs when turbulent blood flow creates a sound loud enough to hear with a stethoscope. Turbulent blood flow is not smooth. The sound di ...
) or by echocardiography/Doppler studies revealing mitral or aortic valvulitis. Both of clinical and subclinical carditis are now considered a major criterion. # ''Subcutaneous nodules'': Painless, firm collections of collagen fibers over bones or
tendons A tendon or sinew is a tough, high-tensile-strength band of dense fibrous connective tissue that connects muscle to bone. It is able to transmit the mechanical forces of muscle contraction to the skeletal system without sacrificing its ability ...
. They commonly appear on the back of the wrist, the outside elbow, and the front of the knees. # ''Erythema marginatum'': A long-lasting reddish
rash A rash is a change of the human skin which affects its color, appearance, or texture. A rash may be localized in one part of the body, or affect all the skin. Rashes may cause the skin to change color, itch, become warm, bumpy, chapped, dry, cr ...
that begins on the trunk or arms as
macule A skin condition, also known as cutaneous condition, is any medical condition that affects the integumentary system—the organ system that encloses the body and includes skin, nails, and related muscle and glands. The major function of this sy ...
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. # ''
Sydenham's chorea Sydenham's chorea, also known as rheumatic chorea, is a disorder characterized by rapid, uncoordinated jerking movements primarily affecting the face, hands and feet. Sydenham's chorea is an autoimmune disease that results from childhood infecti ...
(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 onset of infection. Minor criteria # ''
Arthralgia Arthralgia (from Greek ''arthro-'', joint + ''-algos'', pain) literally means ''joint pain''. Specifically, arthralgia is a symptom of injury, infection, illness (in particular arthritis), or an allergic reaction to medication. According to MeSH, ...
'': ''Polyarthralgia'' in low-risk populations and ''monoarthralgia'' in others. However, joint manifestations cannot be considered in both major and minor categories in the same patient. # ''
Fever Fever, also referred to as pyrexia, is defined as having a body temperature, temperature above the human body temperature, normal range due to an increase in the body's temperature Human body temperature#Fever, set point. There is not a single ...
'': ≥ 38.5 °C (101.3 °F) in low-incidence populations and ≥ 38 °C (100.4 °F) in high-risk populations. # ''Raised
erythrocyte sedimentation rate The erythrocyte sedimentation rate (ESR or sed rate) is the rate at which red blood cells in anticoagulated whole blood descend in a standardized tube over a period of one hour. It is a common hematology test, and is a non-specific measure of ...
'' (≥60 mm in the first hour in lox-risk populations and ≥30 mm/h in others) or ''C reactive protein'' (>3.0 mg/dL). #
ECG Electrocardiography is the process of producing an electrocardiogram (ECG or EKG), a recording of the heart's electrical activity. It is an electrogram of the heart which is a graph of voltage versus time of the electrical activity of the hear ...
showing a ''prolonged
PR interval In electrocardiography, the PR interval is the period, measured in milliseconds, that extends from the beginning of the P wave (the onset of atrial depolarization) until the beginning of the QRS complex (the onset of ventricular depolarization) ...
''Ed Boon, Davidson's General Practice of Medicine, 20th edition. P. 617. 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 Streptococcal pharyngitis, also known as streptococcal sore throat (strep throat), is pharyngitis (an infection of the pharynx, the back of the throat) caused by ''Streptococcus pyogenes'' a gram-positive, group A streptococcus. Common symptom ...
with antibiotics. In those who have previously had rheumatic fever, antibiotics in a preventative manner are occasionally recommended. As of 2017 the evidence to support long term antibiotics in those with underlying disease is poor. The
American Heart Association The American Heart Association (AHA) is a nonprofit organization in the United States that funds cardiovascular medical research, educates consumers on healthy living and fosters appropriate cardiac care in an effort to reduce disability and death ...
suggests that dental health be maintained, and that people with a history of
bacterial endocarditis Infective endocarditis is an infection of the inner surface of the heart, usually the valves. Signs and symptoms may include fever, small areas of bleeding into the skin, heart murmur, feeling tired, and low red blood cell count. Complications ...
, a heart transplant, artificial heart valves, or "some types of congenital heart defects" may wish to consider long-term antibiotic prophylaxis.


Treatment

The management of rheumatic fever is directed toward the reduction of inflammation with
anti-inflammatory medication Anti-inflammatory is the property of a substance or treatment that reduces inflammation or swelling. Anti-inflammatory drugs, also called anti-inflammatories, make up about half of analgesics. These drugs remedy pain by reducing inflammation as op ...
s such as
aspirin Aspirin, also known as acetylsalicylic acid (ASA), is a nonsteroidal anti-inflammatory drug (NSAID) used to reduce pain, fever, and/or inflammation, and as an antithrombotic. Specific inflammatory conditions which aspirin is used to treat inc ...
or
corticosteroid Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are involv ...
s. Individuals with positive cultures for strep throat should also be treated with
antibiotic An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention of ...
s. Aspirin is the drug of choice and should be given at high doses. One should watch for side effects like
gastritis Gastritis is inflammation of the lining of the stomach. It may occur as a short episode or may be of a long duration. There may be no symptoms but, when symptoms are present, the most common is upper abdominal pain (see dyspepsia). Other possi ...
and
salicylate poisoning Salicylate poisoning, also known as aspirin poisoning, is the acute or chronic poisoning with a salicylate such as aspirin. The classic symptoms are ringing in the ears, nausea, abdominal pain, and a fast breathing rate. Early on, these may be s ...
. In children and teenagers, the use of aspirin and aspirin-containing products can be associated with
Reye's syndrome Reye syndrome is a rapidly worsening brain disease. Symptoms of Reye syndrome may include vomiting, personality changes, confusion, seizures, and loss of consciousness. While liver toxicity typically occurs in the syndrome, jaundice usually d ...
, a serious and potentially deadly condition. The risks, benefits, and alternative treatments must always be considered when administering aspirin and aspirin-containing products in children and teenagers. Ibuprofen for pain and discomfort and corticosteroids for moderate to severe inflammatory reactions manifested by rheumatic fever should be considered in children and teenagers.


Vaccine

No vaccines are currently available to protect against ''S. pyogenes'' infection, although research is underway to develop one. Difficulties in developing a vaccine include the wide variety of strains of ''S. pyogenes'' present in the environment and the large amount of time and people that will be needed for appropriate trials for safety and efficacy of the vaccine.


Infection

People with positive cultures for ''Streptococcus pyogenes'' should be treated with penicillin as long as
allergy Allergies, also known as allergic diseases, refer a number of conditions caused by the hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic derma ...
is not present. The use of antibiotics will not alter cardiac involvement in the development of rheumatic fever. Some suggest the use of
benzathine benzylpenicillin Benzathine benzylpenicillin, also known as benzathine penicillin G, is an antibiotic medication useful for the treatment of a number of bacterial infections. Specifically it is used to treat strep throat, diphtheria, syphilis, and yaws. It is a ...
. 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 as
penicillin Penicillins (P, PCN or PEN) are a group of β-lactam antibiotics originally obtained from ''Penicillium'' moulds, principally '' P. chrysogenum'' and '' P. rubens''. Most penicillins in clinical use are synthesised by P. chrysogenum using ...
,
sulfadiazine Sulfadiazine is an antibiotic. Used together with pyrimethamine, a dihydrofolate reductase inhibitor, it is the treatment of choice for toxoplasmosis, which is caused by a protozoan parasite. It is a second-line treatment for otitis media, p ...
, or
erythromycin Erythromycin is an antibiotic used for the treatment of a number of bacterial infections. This includes respiratory tract infections, skin infections, chlamydia infections, pelvic inflammatory disease, and syphilis. It may also be used duri ...
) to prevent recurrence.


Inflammation

While
corticosteroids Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are involve ...
are often used, evidence to support this is poor.
Salicylates Salicylic acid is an organic compound with the formula HOC6H4CO2H. A colorless, bitter-tasting solid, it is a precursor to and a metabolite of aspirin (acetylsalicylic acid). It is a plant hormone, and has been listed by the EPA Toxic Substance ...
are useful for pain. Steroids are reserved for cases where there is evidence of an involvement of the heart. The use of steroids may prevent further scarring of tissue and may prevent the development of sequelae such as mitral stenosis.


Heart failure

Some patients develop significant
carditis Carditis (pl. carditides) is the inflammation of the heart. It is usually studied and treated by specifying it as: * Pericarditis is the inflammation of the pericardium * Myocarditis is the inflammation of the heart muscle * Endocarditis is the in ...
which manifests as
congestive heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, a ...
. This requires the usual treatment for heart failure:
ACE inhibitor Angiotensin-converting-enzyme inhibitors (ACE inhibitors) are a class of medication used primarily for the treatment of hypertension, high blood pressure and heart failure. They work by causing relaxation of blood vessels as well as a decrease i ...
s,
diuretic A diuretic () is any substance that promotes diuresis, the increased production of urine. This includes forced diuresis. A diuretic tablet is sometimes colloquially called a water tablet. There are several categories of diuretics. All diuretics in ...
s,
beta blocker Beta blockers, also spelled β-blockers, are a class of medications that are predominantly used to manage cardiac arrhythmia, abnormal heart rhythms, and to protect the heart from a second myocardial infarction, heart attack after a first heart ...
s, and
digoxin Digoxin (better known as Digitalis), sold under the brand name Lanoxin among others, is a medication used to treat various heart conditions. Most frequently it is used for atrial fibrillation, atrial flutter, and heart failure. Digoxin is on ...
. Unlike typical heart failure, rheumatic heart failure responds well to corticosteroids.


Epidemiology

About 33 million people are affected by rheumatic heart disease with an additional 47 million having
asymptomatic In medicine, any disease is classified asymptomatic if a patient tests as carrier for a disease or infection but experiences no symptoms. Whenever a medical condition fails to show noticeable symptoms after a diagnosis it might be considered asy ...
damage to their heart valves. As of 2010 globally it resulted in 345,000 deaths, down from 463,000 in 1990. In Western countries, rheumatic fever has become fairly rare since the 1960s, probably due to the widespread use of antibiotics to treat
streptococcus ''Streptococcus'' is a genus of gram-positive ' (plural ) or spherical bacteria that belongs to the family Streptococcaceae, within the order Lactobacillales (lactic acid bacteria), in the phylum Bacillota. Cell division in streptococci occurs ...
infections. While it has been far less common in the
United States The United States of America (U.S.A. or USA), commonly known as the United States (U.S. or US) or America, is a country primarily located in North America. It consists of 50 states, a federal district, five major unincorporated territorie ...
since the beginning of the 20th century, there have been a few outbreaks since the 1980s. The disease is most common among
Indigenous Australians Indigenous Australians or Australian First Nations are people with familial heritage from, and membership in, the ethnic groups that lived in Australia before British colonisation. They consist of two distinct groups: the Aboriginal peoples ...
(particularly in central and northern Australia),
Māori Māori or Maori can refer to: Relating to the Māori people * Māori people of New Zealand, or members of that group * Māori language, the language of the Māori people of New Zealand * Māori culture * Cook Islanders, the Māori people of the C ...
, and
Pacific Islander Pacific Islanders, Pasifika, Pasefika, or rarely Pacificers are the peoples of the list of islands in the Pacific Ocean, Pacific Islands. As an ethnic group, ethnic/race (human categorization), racial term, it is used to describe the original p ...
s, and is also common in
Sub-Saharan Africa Sub-Saharan Africa is, geographically, the area and regions of the continent of Africa that lies south of the Sahara. These include West Africa, East Africa, Central Africa, and Southern Africa. Geopolitically, in addition to the List of sov ...
,
Latin America Latin America or * french: Amérique Latine, link=no * ht, Amerik Latin, link=no * pt, América Latina, link=no, name=a, sometimes referred to as LatAm is a large cultural region in the Americas where Romance languages — languages derived f ...
, the
Indian Subcontinent The Indian subcontinent is a list of the physiographic regions of the world, physiographical region in United Nations geoscheme for Asia#Southern Asia, Southern Asia. It is situated on the Indian Plate, projecting southwards into the Indian O ...
, and
North Africa North Africa, or Northern Africa is a region encompassing the northern portion of the African continent. There is no singularly accepted scope for the region, and it is sometimes defined as stretching from the Atlantic shores of Mauritania in ...
. Rheumatic fever primarily affects children between ages 5 and 17 years and occurs approximately 20 days after strep throat. In up to a third of cases, the underlying strep infection may not have caused any symptoms. The rate of development of rheumatic fever in individuals with untreated strep infection is estimated to be 3%. The incidence of recurrence with a subsequent untreated infection is substantially greater (about 50%). 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. 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 Valvular heart disease is any cardiovascular disease process involving one or more of the four valves of the heart (the aortic and mitral valves on the left side of heart and the pulmonic and tricuspid valves on the right side of heart). These ...
. 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. Echocardiographic 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.


See also

*
Rapid strep test The rapid strep test (RST) is a rapid antigen detection test (RADT) that is widely used in clinics to assist in the diagnosis of bacterial pharyngitis caused by group A streptococci (GAS), sometimes termed strep throat. There are currently sever ...


References


External links

* {{DEFAULTSORT:Rheumatic Fever Chronic rheumatic heart diseases Inflammations Pediatrics Rheumatology Wikipedia medicine articles ready to translate Wikipedia emergency medicine articles ready to translate