Second disease

History of the numbered diseases

In 1900, Clement Dukes (1845-1925) attempted to number the paediatric exanthems to help differentiate the variably described and inaccurately labelled rashes of childhood. He noted sub-groups of these rashes and divided them based on clinical presentation into: measles (first), scarlet fever (second), rubella (third), and Filatov-Dukes (fourth). In 1905, Léon Cheinisse added erythema infectiosum (fifth), and in 1910 John Zahorsky added roseola infantum (sixth).

Scarlet fever is an infectious-contagious bacterial illness that often presents as diffuse erythematous rash in the setting of a sore throat (streptococcal pharyngitis) or school sores (impetigo) in children under 10 years of age. It is caused by Group A beta-haemolytic streptococci (GABHS), primarily Streptococcus pyogenes, integrated with a bacteriophage producing a specific type of erythrogenic toxin.

Clinical manifestations

Scarlet fever often presents with a sudden fever; sore throat; cervical lymphadenopathy; headache; nausea; vomiting; anorexia; myalgia and malaise. Coryzal symptoms are usually absent.

• Pharyngitis: tonsillopharyngeal erythema, exudates, and petechial macules of the palate (strep throat)
• Rash: appears 24-48 hours after the start of the fever; usually starts on the neck, chest, axilla and groin before spreading to the rest of the body over 24 hours. Diffuse fine, red and bumpy like sandpaper; confluent areas described as ‘sunburn with goose pimples‘; the rash blanches on pressure. The erythematous macropapular rash typically lasts five to six days. Once the rash fades, the skin may desquamate (especially over the hands, feet, toes, and fingers) and the peeling may last up to 6 weeks.
• Filatov mask: the sandpaper like rash does not usually appear on the face. Instead facial flushing with circumoral pallor is common. Absence of erythema in the perioral region, between nasolabial folds (Filatov triangle).
• Pastia sign: pink or red lines produced by confluent petechiae in the skin folds of the upper and lower limbs; particularly the creases of the the antecubital fossa, axilla, and groin. May appear prior to the appearance of the rash and persist as pigmented lines following desquamation. [Pastia–Grozovici sign; Pastia lines; Thomson sign]
• Strawberry tongue: initially the tongue often has a white coating with red and oedematous papillae projecting through (white strawberry tongue). By fifth day, the coating peels off, leaving behind a red, glistening tongue studded with prominent papillae (red strawberry tongue).

Diagnosis

Scarlet fever is diagnosed based on the clinical presentation in conjunction with results of laboratory testing.

• Throat and tonsil swab culture or a rapid GABHS antigen detection test.
• Antistreptococcal serologies: Antistreptolysin O assay or Antideoxyribonuclease B assay. Streptococcal serology helps in the diagnosis of post infectious complications which most often occur 2–3 weeks after the acute infection, when culture of the causative bacterium is usually no longer possible

Treatment

Antimicrobial treatment rapidly alleviates symptoms and is the primary mode of prevention for the subsequent occurrence of acute rheumatic fever, especially if antimicrobial therapy is commenced within 9 days from the onset of symptoms of GABHS pharyngitis.

The drug of choice for treatment of scarlet fever is penicillin V or penicillin G where compliance an issue. In penicillin-allergic patients clarithromycin, azithromycin or clindamycin may be used. For patients with non–type I hypersensitivity to penicillins, cephalosporins can be used.

Differential diagnosis

The scarlatiniform eruption is seen in other infectious diseases, such as the early stages of viral hepatitis, infectious mononucleosis, Kawasaki disease, toxic shock syndrome (TSS), measles, and rubella.

Drug-associated eruptions may also mimic scarlet fever such as sulfonamides, penicillin, streptomycin, quinine, and atropine. Drug eruptions are more likely to produce mucosal erosions and crusts, which can be a helpful distinguishing sign.

Complications

Before the ready availability of antibiotics, scarlet fever was a major cause of death with significant late complications including as poststreptococcal glomerulonephritis (PSGN); and acute rheumatic fever (ARF), which leads to rheumatic heart disease.

Complications of GABHS include pneumonia, pericarditis, meningitis, hepatitis, glomerulonephritis, and rheumatic fever.

PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections). is a controversial hypothetical diagnosis for a subset of children in whom GABHS may trigger an autoimmune response exacerbating symptoms of certain childhood disorders, such as OCD, tic disorders, Tourette syndrome and ADHD.

History of second disease – scarlet fever

1553 – The first significant description of scarlet fever in medical literature was recorded by Giovanni Filippo Ingrassias (1510-1580), first professor at Naples and celebrated anatomist. In his book entitled De tumoribus praeter naturam, tomus primus, he differentiated measles and chickenpox from scarlet fever.

Moreover measles purges mixed bile blood or mucus. Besides both these kinds I have seen everywhere, one of which is commonly called Rossaniam or Rossaliam, the other crystallos [chickenpox] which since, as is known, reddish pustules break out and are dispersed over the whole body, the size of a pea, more or less, white and of a shiny crystal appearance which when they are opened one sees an aqueous fluid escape. The other indeed, is called rossaniam because there are dispersed over the entire body spots very large and small, fiery and red, scarcely raised sufficient to be worthy of mention; the appearance distinct from erysipelas, so that the whole body appears as if on fire [red hot].

Some there are, who think that measles is the same as rossalia, but we have often seen that the two affections are distinct, trusting in our own eyes and not merely in the description of others

Ingrassias 1553

1565 – According to most scholars, Johann Weyer of the Netherlands was the first to describe a sore throat occurring during epidemics of scarlatina anginosa

1635 – Daniel Sennert (1572-1637) described an epidemic which occurred at Wittenberg in the beginning of the seventeenth century. He identified it with the rossalia of Ingrassias, and described the eruption in similar terms (universum corpus rubrum et quasi apparet ac si universali erysipelate laboraret).

Sennert was the first writer to mention scarlatinal desquamation (epidermide squamarum instar decidente); the early arthritis (in declinatione materia ad articulos transfertur ac dolorem et ruborem ut in arthriticis excitat); and post-scarlatinal oedema and ascites (mox pedes ad talos et suras usque intumescunt). 

On a side note, Sennert probably owes much of the description to his son-in-law, Michael Döring (1582-1644) who observed an epidemic of ‘die Deittelen‘ in Poland during 1625, also noting the desquamation, rheumatoid pains, and anasacra characteristic of the disease. Döring wrote to Sennert in 1625 (letter 88) and 1628 (letter 18) recorded in “Centuria I epistolarum medicinalium” where he provided a long and accurate account of scarlet fever.

1675 – The term “scarlatina” is supposed to have been introduced into medical literature by Thomas Sydenham (1624-1689) as ‘Febre Scarlatina‘ first in ‘Medical Observations, then in ‘Processus integri in morbis ferè omnibus curandis’ published after his death in 1693.

Scarlet fever may appear at any season. Nevertheless it oftenest breaks out towards the end of the summer, when it attacks whole families at once, and more especially the infant part of them. The patients feel rigors and shivering just as they do in other fevers. The symptoms, however, are moderate. Afterwards, however, the whole skin becomes covered with small red maculae thicker than those of measles, as well as broader, and redder and less uniform. These last for two or three days and then disappear. The cuticle peels off and branny scales remain lying on the surface like meal. They appear and disappear two or three times

Sydenham 1693

Note: the term was probably in common use earlier; see Diary of Samuel Pepys November 10th, 1664 “My little girle Susan is fallen sicke of the meazles, we fear, or, at least, of a Scarlett fevour.“

1826 – Scarlet fever was generally regarded as a distinct disease from measles. However, there was a tendency to confuse the sore throat and mouth ulceration with angina maligna. This was not established as a distinct disease until 1826 when Pierre-Fidèle Bretonneau (1778-1862) provided the distinction, and the name “diphthérite“. Armand Trousseau (1801-1867) emphasised the last distinguishing feature by the aphorism “La scarlatine n’aime pas le larynx”

1836 – Richard Bright (1759-1858) in discussing the causes of the archaic term Bright’s disease (glomerulonephritis), stated that “scarlatina has apparently laid the foundation for the future mischief.” [source]

1874 – Austrian surgeon, Theodor Billroth (1829-1894) provided the first description of streptococcal infection when he described the organism in cases of erysipelas and wound infections. He described “small organisms (Kettenkokken) as found in either isolated or arranged in pairs, sometimes in chains of four to twenty or more links (Streptococcus; Gr. strepto, a chain, and coccus, a berry).”

1879, Louis Pasteur (1822-1895) isolated the microorganism from the uteruses and blood of women with puerperal fever and demonstrated that streptococcus was the agent responsible for the disease which had the highest mortality rates for women and newborns at the time.

1884 – Julius Friedrich Rosenbach (1842-1923) examined bacteria isolated from suppurative lesions, and the species was named Streptococcus pyogenes (Gr., pyo, pus, and genes, forming). Initially sub-groups of streptococcus were labelled associated with various diseases such as S.eryespaltis, S. scarlatinae, and S. puerperalis but these were later organised under the single heading of S. pyogenes by Andrewes and Christie in 1932

1900 – Clement Dukes numbered the paediatric exanthems to differentiate the variably described and inaccurately labelled rashes of childhood. He divided them based on clinical presentation into: rubeola (first), scarlet fever (second), rubella (third), and Filatov-Dukes (fourth).

1910 – Romanian physician Constantin Chessec Pastia (1883–1926) described a sign useful in differentiating cases of atypical features of scarlet fever and identifying the disease after the disappearance of the rash.

…an intense, continuous linear exanthem localized in the skin folds of the anterior aspect of the elbow. It is of a deep rose color becoming darker in time and after several days even ecchymotic. The lines vary in number from 2 to 4 usually and the skin between these lines presents the rash the same as on the rest of the body.

This sign is given great diagnostic importance in those cases where the eruption is not quite typical and also in retrospective diagnosis, i.e, when the rash has disappeared but the sign remains.

Pastia 1910

1915 – Frederick Twort (1877-1950), an English bacteriologist, discovered agents that he termed ‘filter-passing viruses‘ which required bacteria for growth. Félix d’Hérelle (1873-1949), a French-Canadian microbiologist, first applied the name ‘bacteriophage‘ (from bacteria and the Greek word phagein, ‘to devour’) to a phage that was able to kill a number of pathogenic bacteria, including streptococci.

1923 – George and Gladys Dick confirmed the association between streptococci and scarlet fever. They showed that cell-free filtrates could induce the erythematous reaction characteristic of scarlet fever, proving that this reaction was due to a toxin. They patented the technique for isolation of streptococci specific to scarlet fever; the preparation of a scarlatinal toxin; the injection of animals to obtain an antitoxin; and the antitoxin itself.

The Dicks successfully inoculated volunteers by swabbing their throats with four-day-old cultures of the haemolytic streptococcus grown from the pus of the finger of a nurse who contracted mild scarlet fever. They also devised the Dick test to determine whether the subject is susceptible or immune to the disease. Larger doses of the toxin was found to provide active immunization.

1926 – Cantacuzène and Bonciu described the association of scarlet fever and bacteriophages

1928 – Rebecca Lancefield (1895-1981) classified organisms into various serological groups and identified the group A streptococcus (GAS), Streptococcus pyogenes, as the organism responsible for most of the haemolytic streptococcal infections in humans

1940 – Penicillin was discovered by a Scottish physician Alexander Fleming (1881-1955) in 1928. Howard Florey (1898-1968) and his team at Oxford showed that Penicillium extract killed different bacteria (Streptococcus pyogenes, Staphylococcus aureus, and Clostridium septique) in culture and effectively cured Streptococcus infection in mice “Penicillin as a chemotherapeutic agent“

1964 – Zabriskie reported on the conversion of a non-toxigenic S. pyogenes strain T25₃ to toxin production by phage T12 isolated from toxigenic strains. The new toxigenic strains were T25₃(T12) lysogens that produced erythrogenic toxin; later termed, streptococcal pyrogenic exotoxin A

1984 – Independently, Weeks and Ferretti and Johnson and Schlievert, demonstrated that T12 phage contained the structural gene for the streptococcal pyrogenic exotoxin A (speA). In subsequent experiments, the speA containing T12 bacteriophage was shown to integrate into a gene that encodes a serine tRNA in the host chromosome.

1998 – Susan Swedo et al first described the PANDAS hypothesis based on observations in clinical case studies at the US National Institute of Mental Health. In subsequent clinical trials where children appeared to have dramatic and sudden OCD exacerbations and tic disorders following infection.

Associated Persons

• Giovanni Filippo Ingrassias (1510-1580)
• Daniel Sennert (1572-1637)
• Michael Döring (1582-1644)
• Thomas Sydenham (1624-1689)
• Pierre-Fidèle Bretonneau (1778-1862)
• Clement Dukes (1845-1925)
• Constantin Chessec Pastia (1883–1926)
• Frederick Twort (1877-1950
• Félix d’Hérelle (1873-1949)
• Rebecca Lancefield (1895-1981)

References

Historical references

• Ioannis Philippi Ingrassiae. De tumoribus praeter naturam, tomus primus 1553: 194-195
• Danielis Sennerti. De febre maligna cum variolis & morbillis. In: Epitome librorum de febribus. 1635; Liber IV, Cap XII: 212-215
• Sydenham T. ‘Febre Scarlatina‘ In: rocessus integri in morbis ferè omnibus curandis. 1693

Eponymous term review

• Bretonneau P. Des inflammations spéciales du tissu muqueux, et en particulier de la diphtérite, ou inflammation pelliculaire, connue sous le nom de croup, d’angine maligne, d’angine gangréneuse, etc.. [Condensed version: “Extrait du traité de la diphthérite, angine maligne, ou croup épidémique” Archives générales de médecine, 1826; 11: 219-254.
• Billroth T. Untersuchungen über die vegetationsformen von coccobacteria septica und den antheil, welchen sie an der entstehung und verbreitung der accidentellen wundkrankheiten haben. Berlin: G. Reimer. 1874
• Rosenbach FJ. Mikro-organismen bei den Wund-Infections-Krankheiten des Menschen, 1884.
• Pastia CC. La Tribune médicale, 1910; 46: 726
• Taubles GH. Diagnostic value of Pastia’s sign in scarlet fever. Cal State J Med. 1912 Jul;10(7):305-6.
• Twort FW. An investigation on the nature of ultra-microscopic viruses. Lancet 1915; 186(4814): 1241-1243
• d’Herelle F. Sur un microbe invisible antagoniste des bacilles dysentériques. Académie des Sciences, 1915; 373-375.
• d’Herelle F. On an invisible microbe antagonistic to dysentery bacilli. Comptes Rendus Academie des Sciences 1917; 165: 373-375
• Cantacuzène J, Bonciu O. Modifications subies par des streptocoques d’origine non scarlatineuse au contact de produits scarlatineux filtrès. Comptes rendus de l’Académie des Sciences. 1926; 182: 1185–1187.
• Rolleston JD. The history of scarlet fever. Br Med J. 1928 nov 24;2(3542):926-9.
• Andrewes FW, Christie EM. The haemolytic streptococci: their grouping by agglutination. London: H.M. Stationery Office, 1932
• Ruhräh J. Michael Doering ?-1644. American journal of diseases of children, 1933; 46(5.1): 1098.
• Ruhräh J. Giovanni Filippo Ingrassias 1510-1580. Archives of Pediatrics & Adolescent Medicine, 1933; 45(2): 372.
• Ruhräh J. Daniel Sennert 1572-1637. Archives of Pediatrics & Adolescent Medicine, 1933; 46(6): 1393.
• Rolleston JD. Scarlet fever. In: The history of the acute exanthemata: the Fitzpatrick lectures for 1935 & 1936
• Zabriskie JB. The role of temperate bacteriophage in the production of erythrogenic toxin by group a streptococci. J Exp Med. 1964;119(5):761-80.
• Weeks CR, Ferretti JJ. The gene for type A streptococcal exotoxin (erythrogenic toxin) is located in bacteriophage T12. Infect Immun. 1984 Nov;46(2):531-6.
• Johnson LP, Schlievert PM. Group A streptococcal phage T12 carries the structural gene for pyrogenic exotoxin type A. Mol Gen Genet. 1984;194(1-2):52-6.
• Weeks CR, Ferretti JJ. Nucleotide sequence of the type A streptococcal exotoxin (erythrogenic toxin) gene from Streptococcus pyogenes bacteriophage T12. Infect Immun. 1986 Apr;52(1):144-50.
• Swedo SE, Leonard HL, Garvey M, Mittleman B, Allen AJ, Perlmutter S, Lougee L, Dow S, Zamkoff J, Dubbert BK. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: clinical description of the first 50 cases. Am J Psychiatry. 1998 Feb;155(2):264-71.
• Weir E, Main C. Invasive group A streptococcal infections, CMAJ Jul 2006; 175(1): 32
• Steer AC, Smeesters PR, Curtis N. Streptococcal Serology: Secrets for the Specialist. Pediatr Infect Dis J. 2015 Nov;34(11):1250-2.

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