Rheumatic fever

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Rheumatic_fever 

 

Rheumatic fever
Other names	Acute rheumatic fever (ARF)
Rheumatic heart disease at autopsy with characteristic findings (thickened mitral valve, thickened chordae tendineae, hypertrophied left ventricular myocardium).
Specialty	Cardiology
Symptoms	Fever, multiple painful joints, involuntary muscle movements, erythema marginatum
Complications	Rheumatic heart disease, heart failure, atrial fibrillation, infection of the valves
Usual onset	2–4 weeks after a streptococcal throat infection, age 5-14 years
Causes	Autoimmune disease triggered by Streptococcus pyogenes
Risk factors	Genetics, malnutrition, poverty
Diagnostic method	Based on symptoms and infection history
Prevention	Antibiotics for strep throat, improved sanitation
Treatment	Prolonged periods of antibiotics, valve replacement surgery, valve repair
Frequency	325,000 children a year
Deaths	319,400 (2015)

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 joints, involuntary muscle movements, and occasionally a characteristic non-itchy rash known as erythema marginatum. The heart is involved in about half of the cases. Damage to the heart valves, known as rheumatic heart disease (RHD), usually occurs after repeated attacks but can sometimes occur after one. The damaged valves may result in heart failure, atrial fibrillation and infection of the valves.

Rheumatic fever may occur following an infection of the throat by the bacterium Streptococcus pyogenes. 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 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 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 antibiotics, such as penicillin, decreases the risk of developing rheumatic fever. In order to avoid antibiotic misuse this often involves testing people with sore throats for the infection; however, testing might not be available in the developing world. Other preventive measures include improved sanitation. 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 or valve repair is required.

Otherwise complications are treated as per normal.

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 and among indigenous peoples in the developed world. 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. The disease is so named because its symptoms are similar to those of some rheumatic disorders.

Signs and symptoms

A culture positive case of streptococcal pharyngitis with typical tonsillar exudate in a 16-year-old.

 

The disease typically develops two to four weeks after a 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. 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 and also increase the risk of atrial fibrillation and infection of the valves.

Pathophysiology

Rheumatic fever is a systemic disease affecting the connective tissue around arterioles, and can occur after an untreated strep throat infection, specifically due to group A streptococcus (GAS), Streptococcus pyogenes. It is believed to be caused by antibody cross-reactivity. This cross-reactivity is a type II hypersensitivity reaction and is termed molecular mimicry. Usually, self reactive B cells remain anergic in the periphery without T cell co-stimulation. During a streptococcal 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. S. pyogenes is a species of aerobic, cocci, gram-positive bacteria that are non-motile, non-spore forming, and forms chains and large colonies.

S. pyogenes has a cell wall composed of branched polymers which sometimes contain M protein, a virulence factor that is highly antigenic. The antibodies which the immune system generates against the M protein may cross-react with heart muscle cell protein myosin, heart muscle glycogen and smooth muscle cells of arteries, inducing cytokine release and tissue destruction. However, the only proven cross-reaction is with perivascular connective tissue. This inflammation occurs through direct attachment of complement and Fc receptor-mediated recruitment of neutrophils and macrophages. Characteristic Aschoff bodies, composed of swollen eosinophilic collagen surrounded by lymphocytes and macrophages can be seen on light microscopy. The larger macrophages may become Anitschkow cells or Aschoff giant cells. Rheumatic valvular lesions may also involve a cell-mediated immunity reaction as these lesions predominantly contain T-helper cells and macrophages.

In rheumatic fever, these lesions can be found in any layer of the heart causing different types of carditis. The inflammation may cause a serofibrinous pericardial exudate described as "bread-and-butter" pericarditis, which usually resolves without sequelae. Involvement of the endocardium typically results in fibrinoid necrosis and wart formation along the lines of closure of the left-sided heart valves. Warty projections arise from the deposition, while subendocardial lesions may induce irregular thickenings called MacCallum plaques.

Rheumatic heart disease

Pathophysiology of rheumatic heart disease

 

Micrograph showing an Aschoff body (right of image), as seen in rheumatic heart disease. H&E stain.

 

Chronic rheumatic heart disease (RHD) is characterized by repeated inflammation with fibrinous repair. The cardinal anatomic changes of the valve include leaflet thickening, commissural fusion, and shortening and thickening of the tendinous cords. It is caused by an autoimmune reaction to Group A β-hemolytic streptococci (GAS) that results in valvular damage. Fibrosis and scarring of valve leaflets, commissures 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 majority of morbidity and mortality associated with rheumatic fever is caused by its destructive effects on cardiac valve tissue. The pathogenesis of RHD is complex and not fully understood, but it is known to involve molecular mimicry and genetic predisposition that lead to autoimmune reactions.

Molecular mimicry occurs when epitopes 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+ 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 cells, which will begin to produce self-antigen-specific antibodies. This leads to an immune response attack mounted against tissues in the heart that have been misidentified as pathogens. Rheumatic valves display increased expression of VCAM-1, 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. Certain allele combinations appear to increase RHD autoimmune susceptibility. Human leukocyte antigen (HLA) class II allele DR7 (HLA-DR7) is most often associated with RHD, and its combination with certain DQ alleles is seemingly associated with the development of valvular lesions. 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 which is also associated with RHD. High expression levels of TNF-α may exacerbate valvular tissue inflammation, contributing to RHD pathogenesis. 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 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. Other genes are also being investigated to better understand the complexity of autoimmune reactions that occur in RHD.

Diagnosis

Streptococcus pyogenes bacteria (Pappenheim's stain) the trigger for rheumatic fever.

 

Modified Jones criteria were first published in 1944 by T. Duckett Jones, MD. They have been periodically revised by the American Heart Association 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 and indolent carditis, 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, raised antistreptolysin O or other streptococcal antibody titre, or positive throat culture.

Major criteria

• Polyarthritis: A temporary migrating inflammation of the large joints, usually starting in the legs and migrating upwards.
• Carditis: Inflammation of the heart muscle (myocarditis) which can manifest as congestive heart failure with shortness of breath, pericarditis with a rub, or a new heart murmur.
• 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: A long-lasting reddish rash that begins on the trunk or arms as macules, 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 (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

• Fever of 38.2–38.9 °C (100.8–102.0 °F)
• Arthralgia: Joint pain without swelling (Cannot be included if polyarthritis is present as a major symptom)
• Raised erythrocyte sedimentation rate or C reactive protein
• Leukocytosis
• ECG showing features of heart block, such as a prolonged PR interval (Cannot be included if carditis is present as a major symptom)
• Previous episode of rheumatic fever or inactive heart disease

Prevention

Rheumatic fever can be prevented by effectively and promptly treating strep throat 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 suggests that dental health be maintained, and that people with a history of bacterial endocarditis, 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 medications such as aspirin or corticosteroids. Individuals with positive cultures for strep throat should also be treated with antibiotics.

Aspirin is the drug of choice and should be given at high doses.

One should watch for side effects like gastritis and salicylate poisoning. In children and teenagers, the use of aspirin and aspirin-containing products can be associated with Reye's syndrome, 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 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. 

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, sulfadiazine, or erythromycin) to prevent recurrence.

Inflammation

While corticosteroids are often used, evidence to support this is poor. Salicylates 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 which manifests as congestive heart failure. This requires the usual treatment for heart failure: ACE inhibitors, diuretics, beta blockers, and digoxin. Unlike typical heart failure, rheumatic heart failure responds well to corticosteroids.

Epidemiology

Deaths from rheumatic heart disease per million persons in 2012

  0–7

  8–14

  15–20

  21–25

  26–32

  33–38

  39–45

  46–52

  53–63

  64–250

Disability-adjusted life year for rheumatic heart disease per 100,000 inhabitants in 2004.

  no data

  less than 20

  20–40

  40–60

  60–80

  80–100

  100–120

  120–140

  140–160

  160–180

  180–200

  200–330

  more than 330

About 33 million people are affected by rheumatic heart disease with an additional 47 million having asymptomatic 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 infections. While it has been far less common in the United States since the beginning of the 20th century, there have been a few outbreaks since the 1980s. The disease is most common among Indigenous Australians (particularly in central and northern Australia), Māori, and Pacific Islanders, and is also common in Sub-Saharan Africa, Latin America, the Indian Subcontinent, the Middle East, and North Africa.

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. Recurrent bouts of rheumatic fever can lead to valvular heart disease. Heart complications may be long-term and severe, particularly if valves are involved. In countries in Southeast-Asia, sub-saharan Africa, and Oceania, the percentage of people with rheumatic heart disease detected by listening to the heart was 2.9 per 1000 children and by echocardiography it was 12.9 per 1000 children.

Scarlet fever

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Scarlet_fever 

Scarlet fever
Other names	Scarlatina, scarletina
Strawberry tongue seen in scarlet fever
Specialty	Infectious disease
Symptoms	Sore throat, fever, headaches, swollen lymph nodes, characteristic rash
Complications	Glomerulonephritis, rheumatic heart disease, arthritis
Usual onset	5–15 years old
Causes	Strep throat, streptococcal skin infections
Diagnostic method	Throat culture
Prevention	Handwashing, not sharing personal items, staying away from sick people
Treatment	Antibiotics
Prognosis	Typically good

Scarlet fever is a disease resulting from a group A streptococcus (group A strep) infection, also known as Streptococcus pyogenes. The signs and symptoms include a sore throat, fever, headaches, swollen lymph nodes, and a characteristic rash. The rash is red and feels like sandpaper and the tongue may be red and bumpy. It most commonly affects children between five and 15 years of age.

Scarlet fever affects a small number of people who have strep throat or streptococcal skin infections. The bacteria are usually spread by people coughing or sneezing. It can also be spread when a person touches an object that has the bacteria on it and then touches their mouth or nose. The characteristic rash is due to the erythrogenic toxin, a substance produced by some types of the bacterium. The diagnosis is typically confirmed by culturing the throat.

There is no vaccine. Prevention is by frequent handwashing, not sharing personal items, and staying away from other people when sick. The disease is treatable with antibiotics, which prevent most complications. Outcomes with scarlet fever are typically good if treated. Long-term complications as a result of scarlet fever include kidney disease, rheumatic heart disease, and arthritis. In the early 20th century, before antibiotics were available, it was a leading cause of death in children.

Signs and symptoms

Characteristic strawberry tongue of scarlet fever

 

The rash of scarlet fever

 

Red cheeks and pale area around the mouth in scarlet fever

 

Characteristic red cheeks and rash of scarlet fever

 

Rash which has a characteristic appearance, spreading pattern, and desquamating process "Strawberry tongue"

• The tongue initially has a white coating on it, while the papillae of the tongue are swollen and reddened. The protrusion of the red papillae through the white coating gives the tongue a "white strawberry" appearance.
• A few days later (following the desquamating process, or the shedding of the tissue which created the white coating), the whiteness disappears, and the red and enlarged papillae give the tongue the "red strawberry" appearance. The symptomatic appearance of the tongue is part of the rash that is characteristic of scarlet fever.
• Pastia's lines
• Lines of petechiae, which appear as pink/red areas located in arm pits and elbow pits
• Vomiting and abdominal pain

Strep throat

Typical symptoms of streptococcal pharyngitis (also known as strep throat):

• Sore throat, painful swallowing
• Fever - typically over 39 °C (102.2 °F)
• Fatigue
• Enlarged and reddened tonsils with yellow or white exudates present (this is typically an exudative pharyngitis)
• Enlarged and tender lymph nodes usually located on the front of the neck

The following symptoms will usually be absent: cough, hoarseness, runny nose, diarrhea, and conjunctivitis. Such symptoms indicate what is more likely a viral infection.

Rash

The rash begins 1–2 days following the onset of symptoms caused by the strep pharyngitis (sore throat, fever, fatigue). This characteristic rash has been denoted as "scarlatiniform," and it appears as a diffuse redness of the skin with small papules, or bumps, which resemble goose bumps. These bumps are what give the characteristic sandpaper texture to the rash. The reddened skin will blanch when pressure is applied to it. The skin may feel itchy, but it will not be painful. The rash generally starts at the flexion of the elbow and other surfaces. It appears next on the trunk and gradually spreads out to the arms and legs. The palms, soles and face are usually left uninvolved by the rash. The face, however, is usually flushed, most prominently in the cheeks, with a ring of paleness around the mouth. After the rash spreads, it becomes more pronounced in creases in the skin, such as the skin folds in the inguinal and axillary regions of the body. Also in those areas, Pastia's Lines may appear: petechiae arranged in a linear pattern. Within 1 week of onset, the rash begins to fade followed by a longer process of desquamation, or shedding of the outer layer of skin. This lasts several weeks. The desquamation process usually begins on the face and progresses downward on the body. After the desquamation, the skin will be left with a sunburned appearance.

Mouth

Throat of a child with a positive throat culture for streptococcal pharyngitis

The streptococcal pharyngitis, which is the usual presentation of scarlet fever in combination with the characteristic rash, commonly involves the tonsils. The tonsils will appear swollen and reddened. The palate and uvula are also commonly affected by the infection. The involvement of the soft palate can be seen as tiny red and round spots known as Forchheimer spots.

Variable presentations

The features of scarlet fever can differ depending on the age and race of the person. Children less than 5 years old can have atypical presentations. Children less than 3 years old can present with nasal congestion and a lower grade fever. Infants may present with symptoms of increased irritability and decreased appetite.

Children who have darker skin can have a different presentation, as the redness of the skin involved in the rash and the ring of paleness around the mouth can be less obvious. Suspicion based on accompanying symptoms and diagnostic studies are important in these cases.

Course

Following exposure to streptococcus, onset of symptoms occur 12 hours to 7 days later. These may include fever, fatigue, and sore throat. The characteristic scarlatiniform rash appears 12–48 hours later. During the first few days of the rash development and rapid generalization, the Pastia's Lines and strawberry tongue are also present. The rash starts fading within 3–4 days, followed by the desquamation of the rash, which lasts several weeks to a month. If the case of scarlet fever is uncomplicated, recovery from the fever and clinical symptoms, other than the process of desquamation, occurs in 5–10 days.

Complications

The complications, which can arise from scarlet fever when left untreated or inadequately treated, can be divided into two categories: suppurative and nonsuppurative.

Suppurative complications: These are rare complications that arise either from direct spread to structures that are close to the primary site of infection, or spread through the lymphatic system or blood. In the first case, scarlet fever may spread to the pharynx. Possible problems from this method of spread include peritonsillar or retropharyngeal abscesses, cellulitis, mastoiditis or sinusitis.

In the second case, the streptococcal infection may spread through the lymphatic system or the blood to areas of the body further away from the pharynx. A few examples of the many complications that can arise from those methods of spread include endocarditis, pneumonia, or meningitis.

Nonsuppurative complications: These complications arise from certain subtypes of group A streptococci that cause an autoimmune response in the body through what has been termed molecular mimicry. In these cases, the antibodies which the person's immune system developed to attack the group A streptococci are also able to attack the person's own tissues. The following complications result, depending on which tissues in the person's body are targeted by those antibodies.

• Acute rheumatic fever: This is a complication that results 2–6 weeks after a group A streptococcal infection of the upper respiratory tract. It presents in developing countries, where antibiotic treatment of streptococcal infections is less common, as a febrile illness with several clinical manifestations, which are organized into what is called the Jones criteria. These criteria include arthritis, carditis, neurological issues, and skin findings. Diagnosis also depends on evidence of a prior group A streptococcal infection in the upper respiratory tract (as seen in streptococcal pharyngitis and scarlet fever). The carditis is the result of the immunologic response targeting the person's heart tissue, and it is the most serious sequelae that develops from acute rheumatic fever. When this involvement of the heart tissue occurs, it is called rheumatic heart disease. In most cases of rheumatic heart disease, the mitral valve is affected, ultimately leading to mitral stenosis.
• Poststreptococcal glomerulonephritis: This is inflammation of the kidney, which presents 1–2 weeks after a group A streptococcal pharyngitis. It can also develop after an episode of Impetigo or any group A streptococcal infection in the skin (this differs from acute rheumatic fever which only follows group A streptococcal pharyngitis). It is the result of the autoimmune response to the streptococcal infection affecting part of the kidney. Persons present with what is called acute nephritic syndrome, in which they have high blood pressure, swelling, and urinary abnormalities. Urinary abnormalities include blood and protein found in the urine, as well as less urine production overall.
• Poststreptococcal reactive arthritis: The presentation of arthritis after a recent episode of group A streptococcal pharyngitis raises suspicion for acute rheumatic fever, since it is one of the Jones criteria for that separate complication. But, when the arthritis is an isolated symptom, it is referred to as poststreptococcal reactive arthritis. This arthritis can involve a variety of joints throughout the body, unlike the arthritis of acute rheumatic fever, which primarily affects larger joints such as the knee joints. It can present less than 10 days after the group A streptococcal pharyngitis.

Cause

Strep throat spreads by close contact among people, via respiratory droplets (for example, saliva or nasal discharge). A person in close contact with another person infected with group A streptococcal pharyngitis has a 35% chance of becoming infected. One in ten children who are infected with group A streptococcal pharyngitis will develop scarlet fever.

Pathophysiology

Streptococcus pyogenes (pictured)

The rash of scarlet fever, which is what differentiates this disease from an isolated group A strep pharyngitis (or strep throat), is caused by specific strains of group A streptococcus which produce a pyrogenic exotoxin. These toxin-producing strains cause scarlet fever in people who do not already have antitoxin antibodies. Streptococcal pyrogenic exotoxins A, B, and C (speA, speB, and speC) have been identified. The pyrogenic exotoxins are also called erythrogenic toxins and cause the erythematous rash of scarlet fever. The strains of group A streptococcus that cause scarlet fever need specific bacteriophages in order for there to be pyrogenic exotoxin production. Specifically, bacteriophage T12 is responsible for the production of speA. Streptococcal Pyrogenic Exotoxin A, speA, is the one which is most commonly associated with cases of scarlet fever which are complicated by the immune-mediated sequelae acute rheumatic fever and post-streptococcal glomerulonephritis.

These toxins are also known as “superantigens” because they are able to cause an extensive immune response within the body through activation of some of the main cells responsible for the person's immune system. The body responds to these toxins by making antibodies to those specific toxins. However, those antibodies do not completely protect the person from future group A streptococcal infections, because there are 12 different pyrogenic exotoxins possible.

Microbiology

The disease is caused by secretion of pyrogenic exotoxins by the infecting Streptococcus bacteria. Streptococcal pyrogenic exotoxin A (speA) is probably the best studied of these toxins. It is carried by the bacteriophage T12 which integrates into the streptococcal genome from where the toxin is transcribed. The phage itself integrates into a serine tRNA gene on the chromosome.

The T12 virus itself has not been placed into a taxon by the International Committee on Taxonomy of Viruses. It has a double-stranded DNA genome and on morphological grounds appears to be a member of the Siphoviridae.

 

The speA gene was cloned and sequenced in 1986. It is 753 base pairs in length and encodes a 29.244 kiloDalton (kDa) protein. The protein contains a putative 30- amino-acid signal peptide; removal of the signal sequence gives a predicted molecular weight of 25.787 kDa for the secreted protein. Both a promoter and a ribosome binding site (Shine-Dalgarno sequence) are present upstream of the gene. A transcriptional terminator is located 69 bases downstream from the translational termination codon. The carboxy terminal portion of the protein exhibits extensive homology with the carboxy terminus of Staphylococcus aureus enterotoxins B and C1. 

Streptococcal phages other than T12 may also carry the speA gene.

Diagnosis

Although the presentation of scarlet fever can be clinically diagnosed, further testing may be required to distinguish it from other illnesses. Also, history of a recent exposure to someone with strep throat can be useful in diagnosis. There are two methods used to confirm suspicion of scarlet fever; rapid antigen detection test and throat culture.

The rapid antigen detection test is a very specific test but not very sensitive. This means that if the result is positive (indicating that the group A strep antigen was detected and therefore confirming that the person has a group A strep pharyngitis), then it is appropriate to treat the patient with antibiotics. But, if the rapid antigen detection test is negative (indicating that they do not have group A strep pharyngitis), then a throat culture is required to confirm, as the first test could have yielded a false negative result. In the early 21st century, the throat culture is the current "gold standard" for diagnosis.

Serologic testing seeks evidence of the antibodies that the body produces against the streptococcal infection, including antistreptolysin-O and antideoxyribonuclease B. It takes the body 2–3 weeks to make these antibodies, so this type of testing is not useful for diagnosing a current infection. But, it is useful when assessing a person who may have one of the complications from a previous streptococcal infection.

Throat cultures done after antibiotic therapy can show if the infection has been removed. These throat swabs, however, are not indicated, because up to 25% of properly treated individuals can continue to carry the streptococcal infection while being asymptomatic.

Differential diagnosis

• Viral exanthem: Viral infections are often accompanied by a rash which can be described as morbilliform or maculopapular. This type of rash is accompanied by a prodromal period of cough and runny nose in addition to a fever, indicative of a viral process.
• Allergic or contact dermatitis: The erythematous appearance of the skin will be in a more localized distribution rather than the diffuse and generalized rash seen in scarlet fever.
• Drug eruption: These are potential side effects of taking certain drugs such as penicillin. The reddened maculopapular rash which results can be itchy and be accompanied by a fever.
• Kawasaki disease: Children with this disease also present a strawberry tongue and undergo a desquamative process on their palms and soles. However, these children tend to be younger than 5 years old, their fever lasts longer (at least five days), and they have additional clinical criteria (including signs such as conjunctival redness and cracked lips), which can help distinguish this from scarlet fever.
• Toxic shock syndrome: Both streptococcal and staphylococcal bacteria can cause this syndrome. Clinical manifestations include diffuse rash and desquamation of the palms and soles. It can be distinguished from scarlet fever by low blood pressure, lack of sandpaper texture for the rash, and multi-organ system involvement.
• Staphylococcal scalded skin syndrome: This is a disease that occurs primarily in young children due to a toxin-producing strain of the bacteria Staphylococcus aureus. The abrupt start of the fever and diffused sunburned appearance of the rash can resemble scarlet fever. However, this rash is associated with tenderness and large blister formation. These blisters easily pop, followed by causing the skin to peel.
• Staphylococcal scarlet fever: The rash is identical to the streptococcal scarlet fever in distribution and texture, but the skin affected by the rash will be tender.

Prevention

One method is long-term use of antibiotics to prevent future group A streptococcal infections. This method is only indicated for people who have had complications like recurrent attacks of acute rheumatic fever or rheumatic heart disease. Antibiotics are limited in their ability to prevent these infections since there are a variety of subtypes of group A streptococci that can cause the infection.

The vaccine approach has a greater likelihood of effectively preventing group A streptococcal infections because vaccine formulations can target multiple subtypes of the bacteria. A vaccine developed by George and Gladys Dick in 1924 was discontinued due to poor efficacy and the introduction of antibiotics. Difficulties in vaccine development include the considerable strain variety of group A streptococci present in the environment and the amount of time and number of people needed for appropriate trials for safety and efficacy of any potential vaccine. There have been several attempts to create a vaccine in the past few decades. These vaccines, which are still in the development phase, expose the person to proteins present on the surface of the group A streptococci to activate an immune response that will prepare the person to fight and prevent future infections.

There used to be a diphtheria scarlet fever vaccine. It was, however, found not to be effective. This product was discontinued by the end of World War II.

Treatment

Antibiotics to combat the streptococcal infection are the mainstay of treatment for scarlet fever. Prompt administration of appropriate antibiotics decreases the length of illness. Peeling of the outer layer of skin, however, will happen despite treatment. One of the main goals of treatment is to prevent the child from developing one of the suppurative or nonsuppurative complications, especially acute rheumatic fever. As long as antibiotics are started within nine days, it is very unlikely for the child to develop acute rheumatic fever. Antibiotic therapy has not been shown to prevent the development of post-streptococcal glomerulonephritis. Another important reason for prompt treatment with antibiotics is the ability to prevent transmission of the infection between children. An infected individual is most likely to pass on the infection to another person during the first 2 weeks. A child is no longer contagious (able to pass the infection to another child) after 24 hours of antibiotics.

The antibiotic of choice is penicillin V which is taken by mouth in pill form. Children who are not able to take pills can be given amoxicillin which comes in a liquid form and is equally effective. Duration of treatment is 10 days. Benzathine Penicillin G can be given as a one time intramuscular injection as another alternative if swallowing pills is not possible. If the person is allergic to the family of antibiotics which both penicillin and amoxicillin are a part of (beta-lactam antibiotics), a first generation cephalosporin is used. Cephalosporin antibiotics, however, can still cause adverse reactions in people whose allergic reaction to penicillin is a Type 1 Hypersensitivity reaction. In those cases it is appropriate to choose clindamycin or erythromycin instead. Tonsillectomy, although once a reasonable treatment for recurrent streptococcal pharyngitis, is not indicate, as a person can still be infected with group A streptococcus without their tonsils.

Antibiotic resistance

A drug-resistant strain of scarlet fever, resistant to macrolide antibiotics such as erythromycin, but retaining drug-sensitivity to beta-lactam antibiotics such as penicillin, emerged in Hong Kong in 2011, accounting for at least two deaths in that city—the first such in over a decade. About 60% of circulating strains of the group A streptococcus that cause scarlet fever in Hong Kong are resistant to macrolide antibiotics, says Professor Kwok-yung Yuen, head of Hong Kong University's microbiology department. Previously, observed resistance rates had been 10–30%; the increase is likely the result of overuse of macrolide antibiotics in recent years.

Epidemiology

Scarlet fever occurs equally in both males and females. Children are most commonly infected, typically between 5–15 years old. Although streptococcal infections can happen at any time of year, infection rates peak in the winter and spring months, typically in colder climates.

The morbidity and mortality of scarlet fever has declined since the 18th and 19th century when there were epidemics caused by this disease. Around 1900 the mortality rate in multiple places reached 25%. The improvement in prognosis can be attributed to the use of penicillin in the treatment of this disease. The frequency of scarlet fever cases has also been declining over the past century. There have been several reported outbreaks of the disease in various countries in the past decade. The reason for these recent increases remains unclear in the medical community. Between 2013 and 2016 population rates of scarlet fever in England increased from 8.2 to 33.2 per 100,000 and hospital admissions for scarlet fever increased by 97%.

History

It is unclear when a description of this disease was first recorded. Hippocrates, writing around 400 BC, described the condition of a person with a reddened skin and fever.

The first description of the disease in the medical literature appeared in the 1553 book De Tumoribus praeter Naturam by the Sicilian anatomist and physician Giovanni Filippo Ingrassia, where he referred to it as rossalia. He also made a point to distinguish that this presentation had different characteristics to measles. It was redescribed by Johann Weyer during an epidemic in lower Germany between 1564 and 1565; he referred to it as scalatina anginosa. The first unequivocal description of scarlet fever appeared in a book by Joannes Coyttarus of Poitiers, De febre purpura epidemiale et contagiosa libri duo, which was published in 1578 in Paris. Daniel Sennert of Wittenberg described the classical 'scarlatinal desquamation' in 1572 and was also the first to describe the early arthritis, scarlatinal dropsy, and ascites associated with the disease.

In 1675 the term that has been commonly used to refer to scarlet fever, "scarlatina", was written by Thomas Sydenham, an English physician.

In 1827, Richard Bright was the first to recognize the involvement of the renal system in scarlet fever.

The association between streptococci and disease was first described in 1874 by Theodor Billroth, discussing people with skin infections. Billroth also coined the genus name Streptococcus. In 1884 Friedrich Julius Rosenbach edited the name to its current one, Streptococcus pyogenes, after further looking at the bacteria in the skin lesions. The organism was first cultured in 1883 by the German surgeon Friedrich Fehleisen from erysipelas lesions.

Also in 1884, the German physician Friedrich Loeffler was the first to show the presence of streptococci in the throats of people with scarlet fever. Because not all people with pharyngeal streptococci developed scarlet fever, these findings remained controversial for some time. The association between streptococci and scarlet fever was confirmed by Alphonse Dochez and George and Gladys Dick in the early 1900s.

Nil Filatov (in 1895) and Clement Dukes (in 1894) described an exanthematous disease which they thought was a form of rubella, but in 1900, Dukes described it as a separate illness which came to be known as Dukes' disease, Filatov's disease, or fourth disease. However, in 1979, Keith Powell identified it as in fact the same illness as the form of scarlet fever which is caused by staphylococcal exotoxin and is known as staphylococcal scalded skin syndrome.

Scarlet fever serum from horses' blood was used in the treatment of children beginning in 1900 and reduced mortality rates significantly.

In 1906, the Austrian pediatrician Clemens von Pirquet postulated that disease-causing immune complexes were responsible for the nephritis that followed scarlet fever.

Bacteriophages were discovered in 1915 by Frederick Twort. His work was overlooked and bacteriophages were later rediscovered by Felix d'Herelle in 1917. The specific association of scarlet fever with the group A streptococci had to await the development of Lancefield's streptococcal grouping scheme in the 1920s. George and Gladys Dick showed that cell-free filtrates could induce the erythematous reaction characteristic of scarlet fever, proving that this reaction was due to a toxin. Karelitz and Stempien discovered that extracts from human serum globulin and placental globulin can be used as lightening agents for scarlet fever and this was used later as the basis for the Dick test. The association of scarlet fever and bacteriophages was described in 1926 by Cantucuzene and Boncieu.

An antitoxin for scarlet fever was developed in 1924.

The first toxin which causes this disease was cloned and sequenced in 1986 by Weeks and Ferretti. The discovery of penicillin and its subsequent widespread use has significantly reduced the mortality of this once feared disease. Reports of cases of scarlet fever have been on the rise in countries including England, Wales, South Korea, Vietnam, China, and Hong Kong in recent years. Researchers are unsure as to what has caused the spike in cases of the disease.

The Dick test

The Dick test, invented in 1924 by George F. Dick and Gladys Dick, was used to identify those susceptible to scarlet fever. The Dick test consisted of injecting a diluted strain of the streptococci known to cause scarlet fever into a person's skin. A local reaction in the skin at the site of injection appeared in people who were susceptible to developing scarlet fever. This reaction was most notable around 24 hours after the injection but could be seen as early as 4–6 hours. If there is no reaction seen in the skin, then that person was assumed to have already developed immunity to the disease and was not at risk of developing it.