Scarlet fever

Scarlet fever typically presents with a sudden onset of sore throat, fever, and malaise. Headache, nausea, vomiting and abdominal pain may also be present. Scarlet fever usually follows from a group A streptococcal infection that involves a strep throat, such as streptococcal tonsillitis or more usually streptococcal pharyngitis. Often these can present together, known as pharyngotonsillitis. The signs and symptoms are therefore those of a strep throat but these are followed by the inclusion of the characteristic widespread rash. The rash usually appears one to two days later, but may appear before or up to seven days following feeling ill. The tonsils may appear red and enlarged and are typically covered in exudate. Rash The characteristic rash has been denoted as "scarlatiniform", and it appears as a diffuse redness of the skin with small bumps resembling goose bumps. It typically appears as small flat spots on the neck or torso before developing into small bumps that spread to the arms and legs. It tends to feel rough like sandpaper. The cheeks might look flushed with a pale area around the mouth. These are lines of petechiae, appearing as pink/red areas located in arm pits and elbow pits. Variable presentations Children younger than five years old may have atypical presentations and many of the common signs and symptoms may be missing or different. Children younger 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. 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 sequela 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. The link to rheumatic fever and heart disease is a particular concern in Australia, because of the high prevalence of these diseases in Aboriginal and Torres Strait Islander communities. • 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==

'' 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 that produce a streptococcal pyrogenic exotoxin, These toxin-producing strains cause scarlet fever in people who do not already have antitoxin antibodies. Streptococcal pyrogenic exotoxins – SPEs A, B, C, and F have been identified. The pyrogenic exotoxins, also called erythrogenic toxins, cause the erythematous rash of scarlet fever. Streptococcal Pyrogenic Exotoxin A, speA, is the one most commonly associated with cases of scarlet fever that are complicated by the immune-mediated sequelae of acute rheumatic fever and post-streptococcal glomerulonephritis. Although the body responds to the toxins it encounters by making antibodies, those antibodies will only protect against that particular subset of toxins. They will not necessarily completely protect a person from future group A streptococcal infections, because there are 12 different pyrogenic exotoxins that may be produced by the disease, and future infections may produce a different subset of those toxins. 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. In the early 21st century, the throat culture is the current "gold standard" for diagnosis. • Kawasaki disease: Children with this disease also present with a strawberry tongue and undergo a desquamative process on their palms and soles. However, these children tend to be younger than five 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. 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. A child is no longer contagious (able to pass the infection to another child) after 24 hours of antibiotics. 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. About 60% of circulating strains of the group A streptococcus that cause scarlet fever in Hong Kong are resistant to macrolide antibiotics, according to Professor Yuen Kwok-yung, 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. There was also an outbreak in the UK in 2014, and the National Health Service reported a 68% increase in the number of S. pyogenes identified in laboratory reports between 2014 and 2018. New research published in October 2020 indicates that the bacterium appears to be getting more robust after being infected with viruses, They found three new genes, acquired from viruses, which cause development of "superantigens" targeting white blood cells, resulting in a more virulent strain of the bacterium. A vaccine that will protect against the 180 to 200 types of bacteria causing the disease has been worked on for over 20 years, but {{as of ==Epidemiology==

Scarlet fever occurs equally in both males and females. 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 reason for these 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%. Further increases in the reporting of scarlet fever cases have been noted in England during the 2021–2022 season (September to September) and so far also in the season 2022–2023. The World Health Organization has reported an increase in scarlet fever (and iGAS – invasive GAS cases) in England, and other European countries during this time. Increases have been reported in France and Ireland. In the US, cases of scarlet fever are not reported, but as of December 2022, the CDC was looking at a possible increase in the numbers of invasive GAS infections reported in children. In late December 2022, the CDC's Health Alert Network issued an advisory on the reported increases in invasive GAS infections. ==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 unambiguous 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 from measles. 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. Also in 1884, the world's first convalescent home for people with scarlet fever was opened at Brockley Hill, Stanmore, founded by Mary Wardell. 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, 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 Rebecca 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 Cantacuzène (Ioan Cantacuzino) and Bonciu. There was a widespread epidemic of scarlet fever in 1922. Among the victims of this epidemic was Agathe Whitehead. An antitoxin for scarlet fever was developed in 1924. The discovery of penicillin and its subsequent widespread use significantly reduced the mortality of this once-feared disease. The first toxin which causes this disease was cloned and sequenced in 1986 by Weeks and Ferretti. Cases were also reported to be increasing after the easing of restrictions due to the COVID pandemic that started in 2020. The Dick test The Dick test, developed in 1924 by George F. Dick and Gladys Dick, was used to identify those susceptible to scarlet fever. The Dick test involved injecting a diluted strain of the streptococci known to cause scarlet fever; a reaction in the skin at the injection site identified people susceptible to developing scarlet fever. The reaction could be seen four hours after the injection, but was more noticeable after 24 hours. If no reaction was seen in the skin, then the person was assumed not to be at risk from the disease, having developed immunity to it. File:Über die Nierenveränderungen bei Scharlach (1891).jpg|Otto Kalischer wrote a doctoral thesis on scarlet fever in 1891. File:Poster - "Regulation of the Milk Supply" (FDA 178) (8211297109).jpg|A 1930s American poster attempting to curb the spread of such diseases as scarlet fever by regulating milk supply File:Gladys Rowena Henry Dick (1881-1963).jpg|Gladys Henry Dick (pictured) and George Frederick Dick developed an antitoxin and vaccine for scarlet fever in 1924 which were later eclipsed by penicillin in the 1940s. ==References==