Rheumatic fever
Overview
Rheumatic fever is an inflammatory disease
Disease
A disease is an abnormal condition affecting the body of an organism. It is often construed to be a medical condition associated with specific symptoms and signs. It may be caused by external factors, such as infectious disease, or it may be caused by internal dysfunctions, such as autoimmune...

 that occurs following a Streptococcus pyogenes
Streptococcus pyogenes
Streptococcus pyogenes is a spherical, Gram-positive bacterium that is the cause of group A streptococcal infections. S. pyogenes displays streptococcal group A antigen on its cell wall. S...

infection, such as strep throat
Strep throat
Streptococcal pharyngitis, streptococcal tonsillitis, or streptococcal sore throat is a type of pharyngitis caused by a group A streptococcal infection. It affects the pharynx including the tonsils and possibly the larynx. Common symptoms include fever, sore throat, and enlarged lymph nodes...

 or scarlet fever
Scarlet fever
Scarlet fever is a disease caused by exotoxin released by Streptococcus pyogenes. Once a major cause of death, it is now effectively treated with antibiotics...

. Believed to be caused by antibody
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...

 cross-reactivity
Cross-reactivity
Cross-reactivity is the reaction between an antibody and an antigen that differs from the immunogen. It is sometimes also referred to as crossimmunity or cross-protective immunity...

 that can involve the heart
Heart
The heart is a myogenic muscular organ found in all animals with a circulatory system , that is responsible for pumping blood throughout the blood vessels by repeated, rhythmic contractions...

, joint
Joint
A joint is the location at which two or more bones make contact. They are constructed to allow movement and provide mechanical support, and are classified structurally and functionally.-Classification:...

s, skin
Skin
-Dermis:The dermis is the layer of skin beneath the epidermis that consists of connective tissue and cushions the body from stress and strain. The dermis is tightly connected to the epidermis by a basement membrane. It also harbors many Mechanoreceptors that provide the sense of touch and heat...

, and brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...

, the illness typically develops two to three weeks after a streptococcal infection. Acute rheumatic fever commonly appears in children between the ages of 6 and 15, with only 20% of first-time attacks occurring in adults.
Encyclopedia
Rheumatic fever is an inflammatory disease
Disease
A disease is an abnormal condition affecting the body of an organism. It is often construed to be a medical condition associated with specific symptoms and signs. It may be caused by external factors, such as infectious disease, or it may be caused by internal dysfunctions, such as autoimmune...

 that occurs following a Streptococcus pyogenes
Streptococcus pyogenes
Streptococcus pyogenes is a spherical, Gram-positive bacterium that is the cause of group A streptococcal infections. S. pyogenes displays streptococcal group A antigen on its cell wall. S...

infection, such as strep throat
Strep throat
Streptococcal pharyngitis, streptococcal tonsillitis, or streptococcal sore throat is a type of pharyngitis caused by a group A streptococcal infection. It affects the pharynx including the tonsils and possibly the larynx. Common symptoms include fever, sore throat, and enlarged lymph nodes...

 or scarlet fever
Scarlet fever
Scarlet fever is a disease caused by exotoxin released by Streptococcus pyogenes. Once a major cause of death, it is now effectively treated with antibiotics...

. Believed to be caused by antibody
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...

 cross-reactivity
Cross-reactivity
Cross-reactivity is the reaction between an antibody and an antigen that differs from the immunogen. It is sometimes also referred to as crossimmunity or cross-protective immunity...

 that can involve the heart
Heart
The heart is a myogenic muscular organ found in all animals with a circulatory system , that is responsible for pumping blood throughout the blood vessels by repeated, rhythmic contractions...

, joint
Joint
A joint is the location at which two or more bones make contact. They are constructed to allow movement and provide mechanical support, and are classified structurally and functionally.-Classification:...

s, skin
Skin
-Dermis:The dermis is the layer of skin beneath the epidermis that consists of connective tissue and cushions the body from stress and strain. The dermis is tightly connected to the epidermis by a basement membrane. It also harbors many Mechanoreceptors that provide the sense of touch and heat...

, and brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...

, the illness typically develops two to three weeks after a streptococcal infection. Acute rheumatic fever commonly appears in children between the ages of 6 and 15, with only 20% of first-time attacks occurring in adults. The illness is so named because of its similarity in presentation to rheumatism
Rheumatism
Rheumatism or rheumatic disorder is a non-specific term for medical problems affecting the joints and connective tissue. The study of, and therapeutic interventions in, such disorders is called rheumatology.-Terminology:...

.

Diagnosis

Modified Jones criteria were first published in 1944 by T. Duckett Jones, MD. They have been periodically revised by the American Heart Association
American Heart Association
The American Heart Association is a non-profit organization in the United States that fosters appropriate cardiac care in an effort to reduce disability and deaths caused by cardiovascular disease and stroke. It is headquartered in Dallas, Texas...

 in collaboration with other groups. According to revised Jones criteria, the diagnosis of rheumatic fever can be made when two of the major criteria, or one major criterion plus two minor criteria, are present along with evidence of streptococcal infection: elevated or rising antistreptolysin O titre or DNAase. Exceptions are chorea
Chorea (disease)
Choreia is an abnormal involuntary movement disorder, one of a group of neurological disorders called dyskinesias. The term choreia is derived from the Greek word χορεία , see choreia , as the quick movements of the feet or hands are vaguely comparable to dancing or piano playing.The term...

 and indolent carditis, each of which by itself can indicate rheumatic fever.

Major criteria

  • Polyarthritis
    Arthritis
    Arthritis is a form of joint disorder that involves inflammation of one or more joints....

    : A temporary migrating inflammation of the large joints, usually starting in the legs and migrating upwards.
  • Carditis
    Carditis
    Carditis is the inflammation of the heart or its surroundings.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...

    : Inflammation of the heart muscle which can manifest as congestive heart failure
    Congestive heart failure
    Heart failure often called congestive heart failure is generally defined as the inability of the heart to supply sufficient blood flow to meet the needs of the body. Heart failure can cause a number of symptoms including shortness of breath, leg swelling, and exercise intolerance. The condition...

     with shortness of breath, pericarditis
    Pericarditis
    Pericarditis is an inflammation of the pericardium . A characteristic chest pain is often present.The causes of pericarditis are varied, including viral infections of the pericardium, idiopathic causes, uremic pericarditis, bacterial infections of the precardium Pericarditis is an inflammation of...

     with a rub, or a new heart murmur
    Heart murmur
    Murmurs are extra heart sounds that are produced as a result of turbulent blood flow that is sufficient to produce audible noise. Most murmurs can only be heard with the assistance of a stethoscope ....

    .
  • 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.
  • Erythema marginatum
    Erythema marginatum
    Erythema marginatum is described as the presence of pink rings on the trunk and inner surfaces of the limbs which come and go for as long as several months. It is found primarily on extensor surfaces....

    : A long lasting rash
    Rash
    A rash is a change of the 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, cracked or blistered, swell and may be painful. The causes, and...

     that begins on the trunk or arms as macules and spreads outward to form a snake like ring while clearing in the middle. This rash never starts on the face and it is made worse with heat.
  • Sydenham's chorea
    Sydenham's chorea
    Sydenham's chorea or chorea minor is a disease characterized by rapid, uncoordinated jerking movements affecting primarily the face, feet and hands. Sydenham's chorea results from childhood infection with Group A beta-hemolytic Streptococci and is reported to occur in 20-30% of patients with...

     (St. Vitus' dance): A characteristic series of rapid movements without purpose of the face and arms. This can occur very late in the disease for at least three months from onset of infection.

Minor criteria

  • Fever
    Fever
    Fever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...

     of 38.2–38.9 °C (100.8–102 F)
  • Arthralgia
    Arthralgia
    Arthralgia literally means joint pain; it is a symptom of injury, infection, illnesses or an allergic reaction to medication....

    : Joint pain without swelling (Cannot be included if polyarthritis is present as a major symptom)
  • Raised erythrocyte sedimentation rate
    Erythrocyte sedimentation rate
    The erythrocyte sedimentation rate , also called a sedimentation rate or Biernacki Reaction, is the rate at which red blood cells sediment in a period of 1 hour...

     or C reactive protein
  • Leukocytosis
    Leukocytosis
    Leukocytosis is a raised white blood cell count above the normal range in the blood. It is frequently a sign of an inflammatory response, most commonly the result of infection, and is observed in certain parasitic infections...

  • ECG
    Electrocardiogram
    Electrocardiography is a transthoracic interpretation of the electrical activity of the heart over a period of time, as detected by electrodes attached to the outer surface of the skin and recorded by a device external to the body...

     showing features of heart block
    Heart block
    A heart block can be a blockage at any level of the electrical conduction system of the heart .* Blocks that occur within the sinoatrial node are described as SA nodal blocks....

    , such as a prolonged PR interval
    PR interval
    In electrocardiography, the PR interval is measured from the beginning of the P wave to the beginning of the QRS complex. It is usually 120 to 200 ms long. On the usual 25 mm/s ECG tracing, this corresponds to 3 to 5 small boxes. The PR interval reflects the time the electrical impulse takes to...

     (Cannot be included if carditis is present as a major symptom)
  • First Degree AV-Block
  • Previous episode of rheumatic fever or inactive heart disease

Other signs and symptoms

  • Abdominal pain
    Abdominal pain
    Abdominal pain can be one of the symptoms associated with transient disorders or serious disease. Making a definitive diagnosis of the cause of abdominal pain can be difficult, because many diseases can result in this symptom. Abdominal pain is a common problem...

  • Nose bleeds
  • Preceding streptococcal infection: recent scarlet fever, raised antistreptolysin 0 or other streptococcal antibody titre, or positive throat culture.

Pathophysiology

Rheumatic fever is a systemic disease affecting the peri-arteriolar connective tissue and can occur after an untreated Group A Beta hemolytic streptococcal pharyngeal infection. It is believed to be caused by antibody cross-reactivity
Cross-reactivity
Cross-reactivity is the reaction between an antibody and an antigen that differs from the immunogen. It is sometimes also referred to as crossimmunity or cross-protective immunity...

. This cross-reactivity is a Type II hypersensitivity
Type II hypersensitivity
In type II hypersensitivity the antibodies produced by the immune response bind to antigens on the patient's own cell surfaces...

 reaction and is termed molecular mimicry. Usually, self reactive B cells remain anergic in the periphery without T cell co-stimulation. During a Streptococcus infection, mature antigen presenting cells such as B cells present the bacterial antigen to CD4-T cells which differentiate into helper T2 cells. Helper T2 cells subsequently activate the B cells to become plasma cells and induce the production of antibodies against the cell wall of Streptococcus. However the antibodies may also react against the myocardium and joints, producing the symptoms of rheumatic fever.

Group A streptococcus pyogenes
Streptococcus pyogenes
Streptococcus pyogenes is a spherical, Gram-positive bacterium that is the cause of group A streptococcal infections. S. pyogenes displays streptococcal group A antigen on its cell wall. S...

has a cell wall
Cell wall
The cell wall is the tough, usually flexible but sometimes fairly rigid layer that surrounds some types of cells. It is located outside the cell membrane and provides these cells with structural support and protection, and also acts as a filtering mechanism. A major function of the cell wall is to...

 composed of branched polymers which sometimes contain M protein
M protein (Streptococcus)
M protein is a virulence factor that can be produced by certain species of Streptococcus.Viruses, parasites and bacteria are covered in protein and sugar molecules that help them gain entry into a host by counteracting the host's defences. One such molecule is the M protein produced by certain...

 that are highly antigenic. The antibodies which the immune system generates against the M protein may cross react with cardiac myofiber protein myosin
Myosin
Myosins comprise a family of ATP-dependent motor proteins and are best known for their role in muscle contraction and their involvement in a wide range of other eukaryotic motility processes. They are responsible for actin-based motility. The term was originally used to describe a group of similar...

, heart muscle glycogen
Glycogen
Glycogen is a molecule that serves as the secondary long-term energy storage in animal and fungal cells, with the primary energy stores being held in adipose tissue...

 and smooth muscle cells of arteries, inducing cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...

 release and tissue destruction. However, the only proven cross reaction is with perivascular connective tissue
Connective tissue
"Connective tissue" is a fibrous tissue. It is one of the four traditional classes of tissues . Connective Tissue is found throughout the body.In fact the whole framework of the skeleton and the different specialized connective tissues from the crown of the head to the toes determine the form of...

. This inflammation occurs through direct attachment of complement and Fc receptor
Fc receptor
An Fc receptor is a protein found on the surface of certain cells - including natural killer cells, macrophages, neutrophils, and mast cells - that contribute to the protective functions of the immune system....

-mediated recruitment of neutrophils and macrophages. Characteristic Aschoff bodies
Aschoff body
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...

, composed of swollen eosinophilic collagen surrounded by lymphocytes and macrophages can be seen on light microscopy. The larger macrophages may become Aschoff giant cells. Acute rheumatic valvular lesions may also involve a cell-mediated immunity
Cell-mediated immunity
Cell-mediated immunity is an immune response that does not involve antibodies but rather involves the activation of macrophages, natural killer cells , antigen-specific cytotoxic T-lymphocytes, and the release of various cytokines in response to an antigen...

 reaction as these lesions predominantly contain T-helper cells and macrophages.

In acute rheumatic fever, these lesions can be found in any layer of the heart and is hence called pancarditis. The inflammation may cause a serofibrinous pericardial exudate described as "bread-and-butter" pericarditis
Pericarditis
Pericarditis is an inflammation of the pericardium . A characteristic chest pain is often present.The causes of pericarditis are varied, including viral infections of the pericardium, idiopathic causes, uremic pericarditis, bacterial infections of the precardium Pericarditis is an inflammation of...

, which usually resolves without sequelae. Involvement of the endocardium typically results in fibrinoid necrosis and verrucae formation along the lines of closure of the left-sided heart valves. Warty projections arise from the deposition, while subendothelial lesions may induce irregular thickenings called MacCallum plaques.

Chronic rheumatic heart disease is characterized by repeated inflammation with fibrinous resolution. The cardinal anatomic changes of the valve include leaflet thickening, commissural fusion and shortening and thickening of the tendinous cords.

Prevention

Prevention of recurrence is achieved by eradicating the acute infection and prophylaxis with antibiotics. The American Heart Association
American Heart Association
The American Heart Association is a non-profit organization in the United States that fosters appropriate cardiac care in an effort to reduce disability and deaths caused by cardiovascular disease and stroke. It is headquartered in Dallas, Texas...

 recommends daily or monthly prophylaxis continue long-term, perhaps for life.

Treatment

The management of acute rheumatic fever is geared toward the reduction of inflammation with anti-inflammatory medications such as aspirin
Aspirin
Aspirin , also known as acetylsalicylic acid , is a salicylate drug, often used as an analgesic to relieve minor aches and pains, as an antipyretic to reduce fever, and as an anti-inflammatory medication. It was discovered by Arthur Eichengrun, a chemist with the German company Bayer...

 or corticosteroid
Corticosteroid
Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex. Corticosteroids are involved in a wide range of physiologic systems such as stress response, immune response and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte...

s. Individuals with positive cultures for strep throat should also be treated with antibiotic
Antibiotic
An antibacterial is a compound or substance that kills or slows down the growth of bacteria.The term is often used synonymously with the term antibiotic; today, however, with increased knowledge of the causative agents of various infectious diseases, antibiotic has come to denote a broader range of...

s.
Aspirin is the drug of choice and should be given at high doses of 100 mg/kg/day. One should watch for side effects like gastritis and salicylate poisoning
Aspirin poisoning
Aspirin poisoning or salicylism can be acute or chronic. A single overdose may cause acute poisoning; continuous usage of an elevated dosage over long periods of time may cause chronic poisoning. Acute overdose has a mortality rate of 2%. Chronic overdose is more commonly lethal with a mortality...

. In children and teenagers, the use of aspirin and aspirin-containing products can be associated with Reye's syndrome
Reye's syndrome
Reye's syndrome is a potentially fatal disease that causes numerous detrimental effects to many organs, especially the brain and liver, as well as causing a lower than usual level of blood sugar . The classic features are liver damage, aspirin use and a viral infection...

, 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.
Steroids are reserved for cases where there is evidence of involvement of heart. The use of steroids may prevent further scarring of tissue and may prevent development of sequelae such as mitral stenosis.
Monthly injections of longacting 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 Penidure 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
Penicillin
Penicillin is a group of antibiotics derived from Penicillium fungi. They include penicillin G, procaine penicillin, benzathine penicillin, and penicillin V....

, sulfadiazine
Sulfadiazine
Sulfadiazine is a sulfonamide antibiotic.-Uses:It eliminates bacteria that cause infections by stopping the production of folic acid inside the bacterial cell, and is commonly used to treat urinary tract infections ....

, or erythromycin
Erythromycin
Erythromycin is a macrolide antibiotic that has an antimicrobial spectrum similar to or slightly wider than that of penicillin, and is often used for people who have an allergy to penicillins. For respiratory tract infections, it has better coverage of atypical organisms, including mycoplasma and...

) to prevent recurrence.

Infection

Patients with positive cultures for Streptococcus pyogenes should be treated with penicillin as long as allergy
Allergy
An Allergy is a hypersensitivity disorder of the immune system. Allergic reactions occur when a person's immune system reacts to normally harmless substances in the environment. A substance that causes a reaction is called an allergen. These reactions are acquired, predictable, and rapid...

 is not present. This treatment will not alter the course of the acute disease.

The most appropriate treatment stated in the Oxford Handbook of Clinical Medicine
Oxford Handbook of Clinical Medicine
The Oxford Handbook of Clinical Medicine is a pocket textbook aimed at medical students and junior doctors, and covers all aspects of clinical medicine. It is published by Oxford University Press, and is available in print format and online.-Description:...

for rheumatic fever is benzathine benzylpenicillin
Benzathine benzylpenicillin
Benzathine benzylpenicillin is a form of penicillin also known as benzathine penicillin. It is slowly absorbed into the circulation, after intramuscular injection, and hydrolysed to benzylpenicillin in vivo...

.

Inflammation

Patients with significant symptoms may require corticosteroids. Salicylates are useful for pain.

Heart failure

Some patients develop significant carditis
Carditis
Carditis is the inflammation of the heart or its surroundings.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...

 which manifests as congestive heart failure
Congestive heart failure
Heart failure often called congestive heart failure is generally defined as the inability of the heart to supply sufficient blood flow to meet the needs of the body. Heart failure can cause a number of symptoms including shortness of breath, leg swelling, and exercise intolerance. The condition...

. This requires the usual treatment for heart failure: ACE Inhibitor
ACE inhibitor
ACE inhibitors or angiotensin-converting enzyme inhibitors are a group of drugs used primarily for the treatment of hypertension and congestive heart failure...

s, diuretic
Diuretic
A diuretic provides a means of forced diuresis which elevates the rate of urination. There are several categories of diuretics. All diuretics increase the excretion of water from bodies, although each class does so in a distinct way.- Medical uses :...

s, beta blocker
Beta blocker
Beta blockers or beta-adrenergic blocking agents, beta-adrenergic antagonists, beta-adrenoreceptor antagonists or beta antagonists, are a class of drugs used for various indications. They are particularly for the management of cardiac arrhythmias, cardioprotection after myocardial infarction ,...

s and digoxin
Digoxin
Digoxin INN , also known as digitalis, is a purified cardiac glycoside and extracted from the foxglove plant, Digitalis lanata. Its corresponding aglycone is digoxigenin, and its acetyl derivative is acetyldigoxin...

. Unlike normal heart failure, rheumatic heart failure responds well to corticosteroids.

Epidemiology

Rheumatic fever is common worldwide and responsible for many cases of damaged heart valve
Heart valve
A heart valve normally allows blood flow in only one direction through the heart. The four valves commonly represented in a mammalian heart determine the pathway of blood flow through the heart...

s. In Western countries, it became fairly rare since the 1960s, probably due to widespread use of antibiotics to treat streptococcus
Streptococcus
Streptococcus is a genus of spherical Gram-positive bacteria belonging to the phylum Firmicutes and the lactic acid bacteria group. Cellular division occurs along a single axis in these bacteria, and thus they grow in chains or pairs, hence the name — from Greek στρεπτος streptos, meaning...

 infections. While it has been far less common in the United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...

since the beginning of the 20th century, there have been a few outbreaks since the 1980s. Although the disease seldom occurs, it is serious and has a case-fatality rate of 2–5%.

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 suffered 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. Heart complications may be long-term and severe, particularly if valves are involved.

Survivors of rheumatic fever often have to take penicillin to prevent streptococcal infection which could possibly lead to another case of rheumatic fever that could prove fatal.

External links

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