Rheumatic Fever (Clinical)

Overview

Definition

Acute rheumatic fever Rheumatic fever Acute rheumatic fever (ARF) is an autoimmune inflammatory process that usually follows Streptococcal pharyngitis. Acute rheumatic fever usually occurs 2-4 weeks after an untreated infection and affects the heart, skin, joints, and nervous system. Rheumatic Fever (ARF) is an autoimmune condition that develops as a complication of streptococcal infection.

Epidemiology^[2,3,7,13]

• More common in children and adolescents (ages 5–15)
• Worldwide prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency: approximately 33.4 million
• Incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency: 19 cases per 100,000 school-age children worldwide
• Incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency: < 2 per 100,000 children in developed countries
• The incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency is higher in socioeconomically deprived areas.

Etiology^[2,7,9,14]

• Recent group A β-hemolytic streptococci (GAS)/ Streptococcus Streptococcus Streptococcus is one of the two medically important genera of gram-positive cocci, the other being Staphylococcus. Streptococci are identified as different species on blood agar on the basis of their hemolytic pattern and sensitivity to optochin and bacitracin. There are many pathogenic species of streptococci, including S. pyogenes, S. agalactiae, S. pneumoniae, and the viridans streptococci. Streptococcus pyogenes infection:
  • Almost exclusively pharyngitis Pharyngitis Pharyngitis is an inflammation of the back of the throat (pharynx). Pharyngitis is usually caused by an upper respiratory tract infection, which is viral in most cases. It typically results in a sore throat and fever. Other symptoms may include a runny nose, cough, headache, and hoarseness. Pharyngitis or tonsillitis Tonsillitis Tonsillitis is inflammation of the pharynx or pharyngeal tonsils, and therefore is also called pharyngitis. An infectious etiology in the setting of tonsillitis is referred to as infectious pharyngitis, which is caused by viruses (most common), bacteria, or fungi. Tonsillitis
  • Associated with strains that are heavily encapsulated Encapsulated Klebsiella and rich in M protein
• Genetic predisposition

Pathophysiology

The pathogenesis is not completely understood.^[2,3,13]

Genetic predisposition is likely, as rheumatic fever Rheumatic fever Acute rheumatic fever (ARF) is an autoimmune inflammatory process that usually follows Streptococcal pharyngitis. Acute rheumatic fever usually occurs 2-4 weeks after an untreated infection and affects the heart, skin, joints, and nervous system. Rheumatic Fever tends to be familial:

• Associated with the class 2 HLA antigens DR2 and DR4
• HLA-B5 HLA-B5 Thromboangiitis Obliterans (Buerger’s Disease)
• Polymorphisms of transforming growth factor beta Transforming growth factor beta Cell-surface proteins that bind transforming growth factor beta and trigger changes influencing the behavior of cells. Two types of transforming growth factor receptors have been recognized. They differ in affinity for different members of the transforming growth factor beta family and in cellular mechanisms of action. Pulmonary Fibrosis (TGF-𝛃) and interleukin-1 Interleukin-1 A soluble factor produced by monocytes; macrophages, and other cells which activates T-lymphocytes and potentiates their response to mitogens or antigens. Interleukin-1 is a general term refers to either of the two distinct proteins, interleukin-1alpha and interleukin-1beta. The biological effects of il-1 include the ability to replace macrophage requirements for t-cell activation. Interleukins (IL-1)

The major implied mechanism is molecular mimicry Molecular Mimicry The structure of one molecule that imitates or simulates the structure of a different molecule. Rheumatic Fever:

• Humoral and cellular response to streptococcal antigens as a result of infection
• Cross-reaction with human proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis that share some structural similarity with bacterial antigens

Acute phase Acute phase Short Bowel Syndrome:

• Immune response caused by molecular mimicry Molecular Mimicry The structure of one molecule that imitates or simulates the structure of a different molecule. Rheumatic Fever between the M protein of GAS and the carbohydrate antigens on human cardiac myosin Myosin A diverse superfamily of proteins that function as translocating proteins. They share the common characteristics of being able to bind actins and hydrolyze mgATP. Myosins generally consist of heavy chains which are involved in locomotion, and light chains which are involved in regulation. Within the structure of myosin heavy chain are three domains: the head, the neck and the tail. The head region of the heavy chain contains the actin binding domain and mgATPase domain which provides energy for locomotion. The neck region is involved in binding the light-chains. The tail region provides the anchoring point that maintains the position of the heavy chain. The superfamily of myosins is organized into structural classes based upon the type and arrangement of the subunits they contain. Skeletal Muscle Contraction and laminin Laminin Large, noncollagenous glycoprotein with antigenic properties. It is localized in the basement membrane lamina lucida and functions to bind epithelial cells to the basement membrane. Evidence suggests that the protein plays a role in tumor invasion. Connective Tissue: Histology
• Binding of cross-reactive antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins: Types and Functions at the valve surface activates CD4 T cells CD4+ T cells A critical subpopulation of T-lymphocytes involved in the induction of most immunological functions. The HIV virus has selective tropism for the T4 cell which expresses the CD4 phenotypic marker, a receptor for HIV. In fact, the key element in the profound immunosuppression seen in HIV infection is the depletion of this subset of T-lymphocytes. T cells: Types and Functions and B lymphocytes B lymphocytes Lymphoid cells concerned with humoral immunity. They are short-lived cells resembling bursa-derived lymphocytes of birds in their production of immunoglobulin upon appropriate stimulation. B cells: Types and Functions:
  • T helper and cytokines Cytokines Non-antibody proteins secreted by inflammatory leukocytes and some non-leukocytic cells, that act as intercellular mediators. They differ from classical hormones in that they are produced by a number of tissue or cell types rather than by specialized glands. They generally act locally in a paracrine or autocrine rather than endocrine manner. Adaptive Immune Response mediate local tissue damage.
  • Aschoff bodies Aschoff Bodies Rheumatic Fever: rheumatic granulomas Granulomas A relatively small nodular inflammatory lesion containing grouped mononuclear phagocytes, caused by infectious and noninfectious agents. Sarcoidosis
  • Pancarditis and pericardial exudates decrease ventricular filling Ventricular filling Cardiac Cycle capacity and can cause heart failure Heart Failure A heterogeneous condition in which the heart is unable to pump out sufficient blood to meet the metabolic need of the body. Heart failure can be caused by structural defects, functional abnormalities (ventricular dysfunction), or a sudden overload beyond its capacity. Chronic heart failure is more common than acute heart failure which results from sudden insult to cardiac function, such as myocardial infarction. Total Anomalous Pulmonary Venous Return (TAPVR).
• Antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins: Types and Functions against GAS carbohydrate antigen Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination cross-react with neuronal cells in the basal ganglia Basal Ganglia Basal ganglia are a group of subcortical nuclear agglomerations involved in movement, and are located deep to the cerebral hemispheres. Basal ganglia include the striatum (caudate nucleus and putamen), globus pallidus, substantia nigra, and subthalamic nucleus. Basal Ganglia: Anatomy → release excess dopamine Dopamine One of the catecholamine neurotransmitters in the brain. It is derived from tyrosine and is the precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. Receptors and Neurotransmitters of the CNS → chorea Chorea Involuntary, forcible, rapid, jerky movements that may be subtle or become confluent, markedly altering normal patterns of movement. Hypotonia and pendular reflexes are often associated. Conditions which feature recurrent or persistent episodes of chorea as a primary manifestation of disease are referred to as choreatic disorders. Chorea is also a frequent manifestation of basal ganglia diseases. Huntington Disease manifestations
• Joint tissue destruction → arthritis Arthritis Acute or chronic inflammation of joints. Osteoarthritis/ arthralgia Arthralgia Pain in the joint. Rheumatic Fever

Chronic phase Chronic phase HIV Infection and AIDS:

• Mostly affects the heart
• Inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body’s defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation leads to neovascularization and healing by fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans.
• Buildup of fibrotic tissue in heart valves
• Stenosis Stenosis Hypoplastic Left Heart Syndrome (HLHS) of heart valves

Clinical Presentation

Clinical diagnostic criteria^[2,14]

• ARF typically presents 2–4 weeks after streptococcal pharyngitis Streptococcal Pharyngitis Rheumatic Fever.
• Clinical manifestations of ARF are known as Jones criteria Jones Criteria Rheumatic Fever.
• Major manifestations:
  • Arthritis Arthritis Acute or chronic inflammation of joints. Osteoarthritis (60%–80%)
  • Carditis Carditis Rheumatic Fever/ valvulitis Valvulitis Rheumatic Fever (50%–80%)
  • Sydenham chorea Sydenham Chorea Rheumatic Fever (10%–30%)
  • Subcutaneous nodules(< 10%) 
  • Erythema marginatum Erythema Marginatum Rheumatic Fever (< 6%)
• Minor manifestations:
  • Arthralgia Arthralgia Pain in the joint. Rheumatic Fever
  • Fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever
  • Elevated acute-phase reactants Acute-Phase Reactants Inflammation:
    • ESR ESR Soft Tissue Abscess
    • CRP
  • Prolonged PR interval PR interval Electrocardiogram (ECG) on electrocardiography Electrocardiography Recording of the moment-to-moment electromotive forces of the heart as projected onto various sites on the body’s surface, delineated as a scalar function of time. The recording is monitored by a tracing on slow moving chart paper or by observing it on a cardioscope, which is a cathode ray tube display. Electrocardiogram (ECG)

Major symptoms^{[1,2,9,11,13]}

• ARF arthritis Arthritis Acute or chronic inflammation of joints. Osteoarthritis:
  • Migratory polyarthritis Migratory Polyarthritis Rheumatic Fever 
  • Affects the larger joints
  • Commonly seen in knees, ankles, elbows, and wrists
• Rheumatic heart disease Rheumatic Heart Disease Cardiac manifestation of systemic rheumatological conditions, such as rheumatic fever. Rheumatic heart disease can involve any part the heart, most often the heart valves and the endocardium. Rheumatic Fever:
  • Typically pancarditis: endocarditis Endocarditis Endocarditis is an inflammatory disease involving the inner lining (endometrium) of the heart, most commonly affecting the cardiac valves. Both infectious and noninfectious etiologies lead to vegetations on the valve leaflets. Patients may present with nonspecific symptoms such as fever and fatigue. Endocarditis, myocarditis Myocarditis Myocarditis is an inflammatory disease of the myocardium, which may occur alone or in association with a systemic process. There are numerous etiologies of myocarditis, but all lead to inflammation and myocyte injury, most often leading to signs and symptoms of heart failure. Myocarditis, and pericarditis Pericarditis Pericarditis is an inflammation of the pericardium, often with fluid accumulation. It can be caused by infection (often viral), myocardial infarction, drugs, malignancies, metabolic disorders, autoimmune disorders, or trauma. Acute, subacute, and chronic forms exist. Pericarditis 
  • Endocarditis Endocarditis Endocarditis is an inflammatory disease involving the inner lining (endometrium) of the heart, most commonly affecting the cardiac valves. Both infectious and noninfectious etiologies lead to vegetations on the valve leaflets. Patients may present with nonspecific symptoms such as fever and fatigue. Endocarditis is usually the most prominent manifestation.
  • Most commonly affects mitral valve Mitral valve The valve between the left atrium and left ventricle of the heart. Heart: Anatomy (65% of cases):
    • Mitral regurgitation Regurgitation Gastroesophageal Reflux Disease (GERD) or prolapse is an early sign.
    • Carey Coombs murmur (a short mid-diastolic apical murmur due to increased flow Flow Blood flows through the heart, arteries, capillaries, and veins in a closed, continuous circuit. Flow is the movement of volume per unit of time. Flow is affected by the pressure gradient and the resistance fluid encounters between 2 points. Vascular resistance is the opposition to flow, which is caused primarily by blood friction against vessel walls. Vascular Resistance, Flow, and Mean Arterial Pressure through the mitral valve Mitral valve The valve between the left atrium and left ventricle of the heart. Heart: Anatomy) is indicative of moderate-severe mitral regurgitation Regurgitation Gastroesophageal Reflux Disease (GERD).
    • Mitral stenosis Stenosis Hypoplastic Left Heart Syndrome (HLHS) is a late sign (chronic).
  • Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship may have shortness of breath Shortness of breath Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea, dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea on exertion, chest pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways, or orthopnea Orthopnea Pulmonary Edema, depending on severity.
  • Endocarditis Endocarditis Endocarditis is an inflammatory disease involving the inner lining (endometrium) of the heart, most commonly affecting the cardiac valves. Both infectious and noninfectious etiologies lead to vegetations on the valve leaflets. Patients may present with nonspecific symptoms such as fever and fatigue. Endocarditis and myocarditis Myocarditis Myocarditis is an inflammatory disease of the myocardium, which may occur alone or in association with a systemic process. There are numerous etiologies of myocarditis, but all lead to inflammation and myocyte injury, most often leading to signs and symptoms of heart failure. Myocarditis can lead to dilated cardiomyopathy Dilated Cardiomyopathy Dilated cardiomyopathy (DCM) is the most common type of non-ischemic cardiomyopathy and a common cause of heart failure (HF). The cause may be idiopathic, familial, or secondary to a variety of underlying conditions. The disease is characterized by the enlargement of 1 or both ventricles and reduced systolic function. Dilated Cardiomyopathy (10% of cases).
• Sydenham chorea Sydenham Chorea Rheumatic Fever:
  • Purposeless, involuntary, nonstereotypical movements  
  • Affects the trunk and extremities 
  • Often presents with associated muscle weakness and emotional lability
• Subcutaneous nodules:
  • Firm, painless protuberances found on extensor surfaces 
  • Affect the knees, elbows, and wrists
• Erythema Erythema Redness of the skin produced by congestion of the capillaries. This condition may result from a variety of disease processes. Chalazion marginatum:
  • Unique, evanescent, pink  rash Rash Rocky Mountain Spotted Fever
  • Pale center and rounded or serpiginous margins 
  • Typically on trunk and proximal extremities (spares the face)

Mnemonic

To recall the main clinical manifestations in acute rheumatic fever Rheumatic fever Acute rheumatic fever (ARF) is an autoimmune inflammatory process that usually follows Streptococcal pharyngitis. Acute rheumatic fever usually occurs 2-4 weeks after an untreated infection and affects the heart, skin, joints, and nervous system. Rheumatic Fever, remember the Jones criteria Jones Criteria Rheumatic Fever (written as J❤NES):

• Joints ( migratory polyarthritis Migratory Polyarthritis Rheumatic Fever)
• ❤ ( carditis Carditis Rheumatic Fever)
• Nodules (subcutaneous)
• Erythema marginatum
• Sydenham chorea Chorea Involuntary, forcible, rapid, jerky movements that may be subtle or become confluent, markedly altering normal patterns of movement. Hypotonia and pendular reflexes are often associated. Conditions which feature recurrent or persistent episodes of chorea as a primary manifestation of disease are referred to as choreatic disorders. Chorea is also a frequent manifestation of basal ganglia diseases. Huntington Disease

Diagnosis

Diagnostic criteria^[1,12,14]

• Evidence of preceding GAS infection
• Initial episode:
  • 2 major manifestations
  • 1 major + 2 minor manifestations
• Recurrent episode:
  • 2 major manifestations
  • 1 major + 2 minor manifestations
  • 3 minor manifestations
• Exceptions to the above criteria:
  • Chorea Chorea Involuntary, forcible, rapid, jerky movements that may be subtle or become confluent, markedly altering normal patterns of movement. Hypotonia and pendular reflexes are often associated. Conditions which feature recurrent or persistent episodes of chorea as a primary manifestation of disease are referred to as choreatic disorders. Chorea is also a frequent manifestation of basal ganglia diseases. Huntington Disease as the only manifestation
  • Indolent carditis Carditis Rheumatic Fever as the only manifestation becoming evident months after acute infection

Laboratory studies

• Evidence of streptococcal infection (helpful, but not required)^{[9, 10]}:
  • Throat Throat The pharynx is a component of the digestive system that lies posterior to the nasal cavity, oral cavity, and larynx. The pharynx can be divided into the oropharynx, nasopharynx, and laryngopharynx. Pharyngeal muscles play an integral role in vital processes such as breathing, swallowing, and speaking. Pharynx: Anatomy culture: negative in 75% of cases by the time ARF develops 
  • Streptococcal antigen Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination test: commonly negative by the time of ARF presentation
  • Antibody titers (most helpful for ARF diagnosis):
    • Antistreptolysin Antistreptolysin Antibodies specific to streptolysins which indicate streptococcal infections. Postinfectious Glomerulonephritis O (ASO)
    • Antideoxyribonuclease B (ADB)
    • Antistreptokinase
    • Antihyaluronidase
• Other findings:^[4,14]
  • Leukocytosis Leukocytosis A transient increase in the number of leukocytes in a body fluid. West Nile Virus
  • Anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types
  • ↑ CRP
  • ↑ ESR ESR Soft Tissue Abscess

Imaging^{[1,2,8,12–14]}

• Echocardiography Echocardiography Ultrasonic recording of the size, motion, and composition of the heart and surrounding tissues. The standard approach is transthoracic. Tricuspid Valve Atresia (TVA) with Doppler Doppler Ultrasonography applying the doppler effect, with frequency-shifted ultrasound reflections produced by moving targets (usually red blood cells) in the bloodstream along the ultrasound axis in direct proportion to the velocity of movement of the targets, to determine both direction and velocity of blood flow. Ultrasound (Sonography):
  • Required in all cases of confirmed and suspected RF RF Rheumatoid Arthritis
  • Carditis Carditis Rheumatic Fever
  • Valvular vegetations
  • Mitral and/or aortic regurgitation Regurgitation Gastroesophageal Reflux Disease (GERD) ( acute phase Acute phase Short Bowel Syndrome)
  • Mitral stenosis Stenosis Hypoplastic Left Heart Syndrome (HLHS) ( chronic phase Chronic phase HIV Infection and AIDS)
• Chest X-ray X-ray Penetrating electromagnetic radiation emitted when the inner orbital electrons of an atom are excited and release radiant energy. X-ray wavelengths range from 1 pm to 10 nm. Hard x-rays are the higher energy, shorter wavelength x-rays. Soft x-rays or grenz rays are less energetic and longer in wavelength. The short wavelength end of the x-ray spectrum overlaps the gamma rays wavelength range. The distinction between gamma rays and x-rays is based on their radiation source. Pulmonary Function Tests:
  • Cardiomegaly Cardiomegaly Enlargement of the heart, usually indicated by a cardiothoracic ratio above 0. 50. Heart enlargement may involve the right, the left, or both heart ventricles or heart atria. Cardiomegaly is a nonspecific symptom seen in patients with chronic systolic heart failure (heart failure) or several forms of cardiomyopathies. Ebstein’s Anomaly
  • Pulmonary edema Pulmonary edema Pulmonary edema is a condition caused by excess fluid within the lung parenchyma and alveoli as a consequence of a disease process. Based on etiology, pulmonary edema is classified as cardiogenic or noncardiogenic. Patients may present with progressive dyspnea, orthopnea, cough, or respiratory failure. Pulmonary Edema in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship in whom heart failure Heart Failure A heterogeneous condition in which the heart is unable to pump out sufficient blood to meet the metabolic need of the body. Heart failure can be caused by structural defects, functional abnormalities (ventricular dysfunction), or a sudden overload beyond its capacity. Chronic heart failure is more common than acute heart failure which results from sudden insult to cardiac function, such as myocardial infarction. Total Anomalous Pulmonary Venous Return (TAPVR) has developed

Management

The following is based on recommendations by US medical societies. Management can be location-specific like the UK recommendations (paywall).

Treatment

Goals^[9,14]:

• Eradication of streptococci and bacterial antigens from the pharyngeal region
• Supportive/symptomatic treatment for arthritis Arthritis Acute or chronic inflammation of joints. Osteoarthritis, carditis Carditis Rheumatic Fever, and chorea Chorea Involuntary, forcible, rapid, jerky movements that may be subtle or become confluent, markedly altering normal patterns of movement. Hypotonia and pendular reflexes are often associated. Conditions which feature recurrent or persistent episodes of chorea as a primary manifestation of disease are referred to as choreatic disorders. Chorea is also a frequent manifestation of basal ganglia diseases. Huntington Disease
• Prevention of cardiac complications

Eradication of streptococcal infection^[8–10,14]:

• Penicillin Penicillin Rheumatic Fever is the drug of choice.
  • Penicillin Penicillin Rheumatic Fever V:
    • Children: 250 mg 2 or 3 times daily for 10 days
    • Adolescents and adults: 250 mg 4 times daily OR 500 mg 2 times daily for 10 days
  • Penicillin Penicillin Rheumatic Fever G benzathine:
    • Individuals < 27 kg: 600,000 units IM x 1 dose
    • Individuals > 27 kg: 1,200,000 units IM x 1 dose
• Amoxicillin Amoxicillin A broad-spectrum semisynthetic antibiotic similar to ampicillin except that its resistance to gastric acid permits higher serum levels with oral administration. Penicillins is used if penicillin Penicillin Rheumatic Fever is not available.
  • Children 3–18 years: (immediate release) 50 mg/kg daily OR 25 mg/kg twice daily for 10 days
  • Adults: 500 mg 2 times daily OR 1 g daily for 10 days
• For those with a penicillin Penicillin Rheumatic Fever allergy Allergy An abnormal adaptive immune response that may or may not involve antigen-specific IgE Type I Hypersensitivity Reaction:
  • Cephalexin
    • Children: 20 mg/kg 2 times daily for 10 days (max: 500 mg/dose)
    • Adults: 500 mg 2 times daily for 10 days
  • Cefadroxil
    • Children: 30 mg/kg daily OR 15 mg/kg 2 times daily for 10 days (max: 1 g/dose)
    • Adults: 1 g daily for 10 days
  • Clindamycin Clindamycin An antibacterial agent that is a semisynthetic analog of lincomycin. Lincosamides
    • Children: 7 mg/kg 3 times daily for 10 days
    • Adults: 300 mg 3 times daily for 10 days
  • Azithromycin Azithromycin A semi-synthetic macrolide antibiotic structurally related to erythromycin. It has been used in the treatment of Mycobacterium avium intracellulare infections, toxoplasmosis, and cryptosporidiosis. Macrolides and Ketolides
    • Children: 12 mg/kg (max: 500 mg) for 1 dose, then 6 mg/kg daily for 4 days (max: 250 mg)
    • Adults: 12 mg/kg/d (max: 500 mg/dose) for 5 days
  • Clarithromycin Clarithromycin A semisynthetic macrolide antibiotic derived from erythromycin that is active against a variety of microorganisms. It can inhibit protein synthesis in bacteria by reversibly binding to the 50s ribosomal subunits. This inhibits the translocation of aminoacyl transfer-RNA and prevents peptide chain elongation. Macrolides and Ketolides
    • Children: 7.5 mg/kg 2 times daily for 10 days (max: 250 mg/dose)
    • Adults: 250 mg 2 times daily for 10 days

Arthritis Arthritis Acute or chronic inflammation of joints. Osteoarthritis:^[2]

• Aspirin Aspirin The prototypical analgesic used in the treatment of mild to moderate pain. It has anti-inflammatory and antipyretic properties and acts as an inhibitor of cyclooxygenase which results in the inhibition of the biosynthesis of prostaglandins. Aspirin also inhibits platelet aggregation and is used in the prevention of arterial and venous thrombosis. Nonsteroidal Antiinflammatory Drugs (NSAIDs)
• Nonsteroidal anti-inflammatory drugs ( NSAIDs NSAIDS Primary vs Secondary Headaches): ibuprofen Ibuprofen A nonsteroidal anti-inflammatory agent with analgesic properties used in the treatment of rheumatism and arthritis. Nonsteroidal Antiinflammatory Drugs (NSAIDs), naproxen Naproxen An anti-inflammatory agent with analgesic and antipyretic properties. Both the acid and its sodium salt are used in the treatment of rheumatoid arthritis and other rheumatic or musculoskeletal disorders, dysmenorrhea, and acute gout. Nonsteroidal Antiinflammatory Drugs (NSAIDs)

Severe carditis Carditis Rheumatic Fever^[2,13]:

• Corticosteroids Corticosteroids Chorioretinitis
• Bed rest
• Heart failure Heart Failure A heterogeneous condition in which the heart is unable to pump out sufficient blood to meet the metabolic need of the body. Heart failure can be caused by structural defects, functional abnormalities (ventricular dysfunction), or a sudden overload beyond its capacity. Chronic heart failure is more common than acute heart failure which results from sudden insult to cardiac function, such as myocardial infarction. Total Anomalous Pulmonary Venous Return (TAPVR) medications:
  • Diuretics Diuretics Agents that promote the excretion of urine through their effects on kidney function. Heart Failure and Angina Medication 
  • Vasodilators Vasodilators Drugs used to cause dilation of the blood vessels. Thromboangiitis Obliterans (Buerger’s Disease) such as nitroglycerin Nitroglycerin A volatile vasodilator which relieves angina pectoris by stimulating guanylate cyclase and lowering cytosolic calcium. It is also sometimes used for tocolysis and explosives. Nitrates can reduce strain on the heart.
  • Digoxin Digoxin A cardiotonic glycoside obtained mainly from digitalis lanata; it consists of three sugars and the aglycone digoxigenin. Digoxin has positive inotropic and negative chronotropic activity. It is used to control ventricular rate in atrial fibrillation and in the management of congestive heart failure with atrial fibrillation. Its use in congestive heart failure and sinus rhythm is less certain. The margin between toxic and therapeutic doses is small. Cardiac Glycosides
• Monitoring and treating for arrhythmias caused by myocarditis Myocarditis Myocarditis is an inflammatory disease of the myocardium, which may occur alone or in association with a systemic process. There are numerous etiologies of myocarditis, but all lead to inflammation and myocyte injury, most often leading to signs and symptoms of heart failure. Myocarditis
  • Third-degree AV block Third-degree AV block Atrioventricular block (AV block) is often transient.
  • Persistent third-degree AV block Third-degree AV block Atrioventricular block (AV block) requires pacemaker Pacemaker A device designed to stimulate, by electric impulses, contraction of the heart muscles. It may be temporary (external) or permanent (internal or internal-external). Bradyarrhythmias placement.
• Surgery is not performed in the acute phase Acute phase Short Bowel Syndrome except for emergent indications:
  • Valve leaflet rupture
  • Chordae tendineae Chordae tendineae The tendinous cords that connect each cusp of the two atrioventricular heart valves to appropriate papillary muscles in the heart ventricles, preventing the valves from reversing themselves when the ventricles contract. Heart: Anatomy rupture
• Surgical repair may be required in the chronic phase Chronic phase HIV Infection and AIDS for mitral stenosis Stenosis Hypoplastic Left Heart Syndrome (HLHS).

Sydenham chorea Sydenham Chorea Rheumatic Fever: usually self-limited and does not require specific treatment^[2,11]

• Psychologic and social support
• Minimize stress
• Symptomatic measures if interfering with daily activity:
  • Dopamine Dopamine One of the catecholamine neurotransmitters in the brain. It is derived from tyrosine and is the precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. Receptors and Neurotransmitters of the CNS 2 receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors blocking agents
    • Fluphenazine Fluphenazine A phenothiazine used in the treatment of psychoses. Its properties and uses are generally similar to those of chlorpromazine. First-Generation Antipsychotics
    • Haloperidol Haloperidol A phenyl-piperidinyl-butyrophenone that is used primarily to treat schizophrenia and other psychoses. It is also used in schizoaffective disorder, delusional disorders, ballism, and tourette syndrome (a drug of choice) and occasionally as adjunctive therapy in intellectual disability and the chorea of huntington disease. It is a potent antiemetic and is used in the treatment of intractable hiccups. First-Generation Antipsychotics
    • Pimozidine
  • Clonidine Clonidine An imidazoline sympatholytic agent that stimulates alpha-2 adrenergic receptors and central imidazoline receptors. It is commonly used in the management of hypertension. Sympathomimetic Drugs
  • Levitiracetam
  • Carbamazepine Carbamazepine A dibenzazepine that acts as a sodium channel blocker. It is used as an anticonvulsant for the treatment of grand mal and psychomotor or focal seizures. It may also be used in the management of bipolar disorder, and has analgesic properties. First-Generation Anticonvulsant Drugs
  • Valproic acid Valproic acid A fatty acid with anticonvulsant and anti-manic properties that is used in the treatment of epilepsy and bipolar disorder. The mechanisms of its therapeutic actions are not well understood. It may act by increasing gamma-aminobutyric acid levels in the brain or by altering the properties of voltage-gated sodium channels. First-Generation Anticonvulsant Drugs
• Severe chorea Chorea Involuntary, forcible, rapid, jerky movements that may be subtle or become confluent, markedly altering normal patterns of movement. Hypotonia and pendular reflexes are often associated. Conditions which feature recurrent or persistent episodes of chorea as a primary manifestation of disease are referred to as choreatic disorders. Chorea is also a frequent manifestation of basal ganglia diseases. Huntington Disease which fails other therapies:
  • Prednisone Prednisone A synthetic anti-inflammatory glucocorticoid derived from cortisone. It is biologically inert and converted to prednisolone in the liver. Immunosuppressants 1–2 mg/kg daily for 2 weeks, then taper over 3 weeks
  • IVIG IVIG Dermatomyositis
  • Plasmapheresis Plasmapheresis Procedure whereby plasma is separated and extracted from anticoagulated whole blood and the red cells retransfused to the donor. Plasmapheresis is also employed for therapeutic use. Stevens-Johnson Syndrome

Prevention^[2,8,14]

• Primary: prompt antibiotic treatment of streptococcal pharyngitis Pharyngitis Pharyngitis is an inflammation of the back of the throat (pharynx). Pharyngitis is usually caused by an upper respiratory tract infection, which is viral in most cases. It typically results in a sore throat and fever. Other symptoms may include a runny nose, cough, headache, and hoarseness. Pharyngitis
• Secondary:
  • Intramuscular penicillin G benzathine is widely used to prevent recurrence.
    • Dosing:
      • Children: 600,000 units
      • Adults 1.2 million units
    • Administered every 21–28 days
  • In patients with a penicillin allergy, oral macrolides are an alternative.
  • Initiated after treatment for original infection ends
  • Duration of prophylaxis Prophylaxis Cephalosporins depends on original presentation and severity.

Prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas^[3]

• Carditis Carditis Rheumatic Fever will resolve without sequelae in 65%–75% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship.
• 90% of acute episodes last < 3 months.
• Risk of recurrence is greatest within the first year.

Differential Diagnosis

• Bacterial sepsis Sepsis Systemic inflammatory response syndrome with a proven or suspected infectious etiology. When sepsis is associated with organ dysfunction distant from the site of infection, it is called severe sepsis. When sepsis is accompanied by hypotension despite adequate fluid infusion, it is called septic shock. Sepsis and Septic Shock: a life-threatening syndrome that occurs when a bacterial pathogen and its products move from the infection source into the bloodstream. Pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia is the most common known precipitating event. Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship commonly present with fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, tachycardia Tachycardia Abnormally rapid heartbeat, usually with a heart rate above 100 beats per minute for adults. Tachycardia accompanied by disturbance in the cardiac depolarization (cardiac arrhythmia) is called tachyarrhythmia. Sepsis in Children, tachypnea Tachypnea Increased respiratory rate. Pulmonary Examination, hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension, and/or altered mentation. Management is based on the cause and includes treatment with antibiotics.
• Kawasaki disease Kawasaki disease An acute, febrile, mucocutaneous condition accompanied by swelling of cervical lymph nodes in infants and young children. The principal symptoms are fever, congestion of the ocular conjunctivae, reddening of the lips and oral cavity, protuberance of tongue papillae, and edema or erythema of the extremities. Kawasaki Disease: a febrile vasculitic syndrome of early childhood characterized by vasculitis Vasculitis Inflammation of any one of the blood vessels, including the arteries; veins; and rest of the vasculature system in the body. Systemic Lupus Erythematosus of medium-sized arteries Medium-Sized Arteries Kawasaki Disease. Kawasaki disease Kawasaki disease An acute, febrile, mucocutaneous condition accompanied by swelling of cervical lymph nodes in infants and young children. The principal symptoms are fever, congestion of the ocular conjunctivae, reddening of the lips and oral cavity, protuberance of tongue papillae, and edema or erythema of the extremities. Kawasaki Disease is also known as infantile polyarteritis nodosa Polyarteritis nodosa A form of necrotizing non-granulomatous inflammation occurring primarily in medium-sized arteries, often with microaneurysms. It is characterized by muscle, joint, and abdominal pain resulting from arterial infarction and scarring in affected organs. Polyarteritis nodosa with lung involvement is called churg-strauss syndrome. Vasculitides and mucocutaneous lymph Lymph The interstitial fluid that is in the lymphatic system. Secondary Lymphatic Organs node syndrome. Multiple systems are involved, but the most serious is involvement of the coronary arteries Arteries Arteries are tubular collections of cells that transport oxygenated blood and nutrients from the heart to the tissues of the body. The blood passes through the arteries in order of decreasing luminal diameter, starting in the largest artery (the aorta) and ending in the small arterioles. Arteries are classified into 3 types: large elastic arteries, medium muscular arteries, and small arteries and arterioles. Arteries: Histology. Management involves intravenous immunoglobulin and high-dose aspirin Aspirin The prototypical analgesic used in the treatment of mild to moderate pain. It has anti-inflammatory and antipyretic properties and acts as an inhibitor of cyclooxygenase which results in the inhibition of the biosynthesis of prostaglandins. Aspirin also inhibits platelet aggregation and is used in the prevention of arterial and venous thrombosis. Nonsteroidal Antiinflammatory Drugs (NSAIDs). 
• Septic arthritis Arthritis Acute or chronic inflammation of joints. Osteoarthritis: refers to the invasion of the joint space by microorganisms such as bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology, viruses Viruses Minute infectious agents whose genomes are composed of DNA or RNA, but not both. They are characterized by a lack of independent metabolism and the inability to replicate outside living host cells. Virology, and fungi Fungi A kingdom of eukaryotic, heterotrophic organisms that live parasitically as saprobes, including mushrooms; yeasts; smuts, molds, etc. They reproduce either sexually or asexually, and have life cycles that range from simple to complex. Filamentous fungi, commonly known as molds, refer to those that grow as multicellular colonies. Mycology. Septic arthritis Arthritis Acute or chronic inflammation of joints. Osteoarthritis can be caused by a variety of organisms, with the most common being Staphylococcus aureus Staphylococcus aureus Potentially pathogenic bacteria found in nasal membranes, skin, hair follicles, and perineum of warm-blooded animals. They may cause a wide range of infections and intoxications. Brain Abscess. Orthopedic procedures are a common cause of S. aureus S. aureus Potentially pathogenic bacteria found in nasal membranes, skin, hair follicles, and perineum of warm-blooded animals. They may cause a wide range of infections and intoxications. Staphylococcus infection. Cultures from joint aspiration are diagnostic, with antibiotic therapy tailored to the specific organism found. Antibiotic treatment is aimed at the causative agent. 
• Systemic lupus erythematosus Systemic lupus erythematosus Systemic lupus erythematosus (SLE) is a chronic autoimmune, inflammatory condition that causes immune-complex deposition in organs, resulting in systemic manifestations. Women, particularly those of African American descent, are more commonly affected. Systemic Lupus Erythematosus ( SLE SLE Systemic lupus erythematosus (SLE) is a chronic autoimmune, inflammatory condition that causes immune-complex deposition in organs, resulting in systemic manifestations. Women, particularly those of African American descent, are more commonly affected. Systemic Lupus Erythematosus): an autoimmune disorder Autoimmune Disorder Septic Arthritis characterized by the production of antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins: Types and Functions against nuclear and cytoplasmic antigens, multisystem inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body’s defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation, and protean clinical manifestations. Symptoms include malar rash Malar Rash Systemic Lupus Erythematosus, joint pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways, fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, proteinuria Proteinuria The presence of proteins in the urine, an indicator of kidney diseases. Nephrotic Syndrome in Children, hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension, anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types, lymphopenia, seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures, and/or psychosis. Management includes topical steroids Steroids A group of polycyclic compounds closely related biochemically to terpenes. They include cholesterol, numerous hormones, precursors of certain vitamins, bile acids, alcohols (sterols), and certain natural drugs and poisons. Steroids have a common nucleus, a fused, reduced 17-carbon atom ring system, cyclopentanoperhydrophenanthrene. Most steroids also have two methyl groups and an aliphatic side-chain attached to the nucleus. Benign Liver Tumors, IV steroids Steroids A group of polycyclic compounds closely related biochemically to terpenes. They include cholesterol, numerous hormones, precursors of certain vitamins, bile acids, alcohols (sterols), and certain natural drugs and poisons. Steroids have a common nucleus, a fused, reduced 17-carbon atom ring system, cyclopentanoperhydrophenanthrene. Most steroids also have two methyl groups and an aliphatic side-chain attached to the nucleus. Benign Liver Tumors, or methotrexate Methotrexate An antineoplastic antimetabolite with immunosuppressant properties. It is an inhibitor of tetrahydrofolate dehydrogenase and prevents the formation of tetrahydrofolate, necessary for synthesis of thymidylate, an essential component of DNA. Antimetabolite Chemotherapy. 
• Infective endocarditis Infective endocarditis Infective endocarditis (IE) is caused by infection or inflammation of the inner lining of the heart (endocardium), most commonly affecting the heart valves. Endocarditis: a condition characterized by inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body’s defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation of the inner lining of the heart and valves caused by infection. Diagnosis is made with echocardiography Echocardiography Ultrasonic recording of the size, motion, and composition of the heart and surrounding tissues. The standard approach is transthoracic. Tricuspid Valve Atresia (TVA), and management is based on treatment of the causative agent. 
• Lyme disease Lyme disease Lyme disease is a tick-borne infection caused by the gram-negative spirochete Borrelia burgdorferi. Lyme disease is transmitted by the black-legged Ixodes tick (known as a deer tick), which is only found in specific geographic regions. Patient presentation can vary depending on the stage of the disease and may include a characteristic erythema migrans rash. Lyme Disease: a zoonotic infection Zoonotic infection Diseases of non-human animals that may be transmitted to humans or may be transmitted from humans to non-human animals. Brucella/Brucellosis caused by Borrelia burgdorferi Borrelia burgdorferi A specific species of bacteria, part of the borrelia burgdorferi group, whose common name is lyme disease spirochete. Borrelia, which presents initially with a localized rash Rash Rocky Mountain Spotted Fever and ultimately causes systemic infection involving the joints, skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions, and nervous system Nervous system The nervous system is a small and complex system that consists of an intricate network of neural cells (or neurons) and even more glial cells (for support and insulation). It is divided according to its anatomical components as well as its functional characteristics. The brain and spinal cord are referred to as the central nervous system, and the branches of nerves from these structures are referred to as the peripheral nervous system. Nervous System: Anatomy, Structure, and Classification. Neurologic, cardiac, ocular, and joint manifestations are also common in later stages. Diagnosis relies on clinical findings and a tick exposure and is supported by serologic testing. Antibiotics are used for treatment. 
• Rheumatoid arthritis Arthritis Acute or chronic inflammation of joints. Osteoarthritis: a chronic inflammatory autoimmune disorder Autoimmune Disorder Septic Arthritis characterized by pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways, swelling Swelling Inflammation, and destruction of synovial joints. The main symptoms on presentation are morning stiffness and swelling Swelling Inflammation of small joints of the hand Hand The hand constitutes the distal part of the upper limb and provides the fine, precise movements needed in activities of daily living. It consists of 5 metacarpal bones and 14 phalanges, as well as numerous muscles innervated by the median and ulnar nerves. Hand: Anatomy. Diagnosis is based on a strong clinical suspicion and confirmed by the presence of serologic markers and acute-phase reactants Acute-Phase Reactants Inflammation. Treatment involves NSAIDs NSAIDS Primary vs Secondary Headaches and immunosuppressive medications.