Sixth 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).

The sixth paediatric rash looked similar, but had an unusual and consistent clinical course which ultimately provided its name exanthem subitum or ‘sudden rash’. In 1909, John Zahorsky accurately described the rash as roseola infantum; Borden Veeder opined exanthem subitum in 1921; and Jules-René Dreyfus attributed the term ‘la sixième maladie‘ (sixth disease) in 1936.

Clinical manifestations of sixth disease

Roseola infantum (exanthem subitum) is a viral illness that mostly affects infants and toddlers. Infected children have a prodromal high fever, with few or minor symptoms, which disappears after 3 to 5 days and is followed by morbilliform rash which can sometimes be confused with measles or rubella.

Most children appear inappropriately well for the degree of pyrexia, but may experience anorexia, vomiting, coryzal symptoms and rarely hepatomegaly. Febrile convulsions or general cerebral irritability may occur during the febrile phase.

The rash begins ‘suddenly’ (subitum) as the fever disappears. Pale pink, almond-shaped macules appear first on the trunk and neck, and later on the face, arms and legs. They become confluent, and then fade in a few hours to 2 days without scaling or pigmentation.

Recovery is complete.

Epidemiology

95% of cases occur before the age of 3 with most between 6 and 15 months

Roseola is most infectious while the child is unwell – from the start of the fever up to the time before the rash appears.

Roseola is caused by infection with human herpesvirus 6 (HHV-6), or, less frequently, by human herpesvirus 7 (HHV-7). These are Roseolovirus a genus of virus in the order Herpesvirales, and the family Herpesviridae.

History

Early descriptions of roseola aestiva (Latin: summer) occurring in the warmer months, provide the first attempts to differentiate the more common exanthems of childhood.

The roseola aestiva is sometimes preceded by chilliness, alternating with flushes of heat, by slight pains in the head and limbs, faintness, lassitude, restlessness, and incapacity of close attention. The rash appears on the third, four, fifth, sixth, or seventh day after the commencement of these symptoms. It is distributed first on the face and neck and afterwards, in the course of a day or two, over the whole body 

Willan 1809

Again, in a yet more marked form, which frequently but by no means exclusively, occurs in warm weather, when it is styled roseola aestiva and autumnalis, the eruption is symptomatic of a more definite constitutional disturbance. It begins with more or less chilliness, alternating with heat, with loss of strength and spirits, with headache, restless ness, sometimes mild delirium, and even…with slight convulsive phenomena.

After these symptoms have continued for two, three, four, or even six or seven days, the eruption appears first upon the face and neck, whence it extends in twenty-four or forty-eight hours to the rest of the body. The rash resembles very closely, in some cases exactly, that of measles; but the catarrhal symptoms are absent.

Roseola aestiva might be readily mistaken by a careless observer for measles or scarlatina, especially the former.

Meigs 1853

1909 – John Zahorsky Jr (1871-1963) described a febrile exanthem which he termed roseola infantum, in 15 infants and young children, in a presentation to the to the St Louis Pediatric society. The disease was characterized by a relatively asymptomatic febrile course of three to five days, followed by the appearance of a morbilliform rash.

I feel convinced that there is a symptom-complex, a febrile erythema, occurring mostly in infants, which deserves a place outside of the erythema group of skin diseases, and to which the name roseola infantilis was given by the older writers, who however, did not differentiate this disease from rubella and other skin diseases.

These are the striking and characteristic symptoms; a prodromal fever lasting from two to five days, disappearance of the general symptoms with the appearance of the rash, and a morbilliform eruption.

Zahorsky 1910

The patient is almost always a child under 3 years of age who suddenly becomes ill with a high fever. The physician is called and on an examination of the patient finds nothing to account for the fever. The fever continues, but no diagnosis can be made on the second, third or even fourth day. Then the temperature drops to normal or nearly so and the child, who has been drowsy and irritable, sits up and commences to play. Coincident with the decline in the temperature a morbilliform rash appears on the face and neck and rapidly spreads over the body. The eruption disappears in twenty-four to forty-eight hours. There are no complications nor sequelae. No desquamation follows the disappearance of the rash.

Zahorsky 1913

1921 – Veeder and Hempelmann helped confirm this syndrome as as specific pathological entity and suggested the name exanthem subitum. The name roseola being very similar to the rubeola (measles) and rubella (German measles).

We suggest the name “exanthem subitum” as being descriptive of the most striking clinical symptom, namely, the sudden, unexpected appearance of the eruption on the fourth day.

The absence of all catarrhal symptoms and Koplik spots, the character and development of the eruption, and the noncommunicability distinguish the disease from rubeola (measles, first disease).

The absence of angina, the onset and course of the fever, the blood picture, the type and course of the eruption and absence of desquamation distinguish the disease clearly and readily from scarlet fever (second disease)

The onset, high fever, late appearance and type of the rash, and absence of postcervical adenopathy, distinguish the condition from rubella (German measles, third disease).

We believe that we are dealing with a distinct clinical entity which deserves a separate place in medical nosology and a place in our textbooks of pediatrics

Veeder BS, Hempelmann TC 1921

1936 – Jules-René Dreyfus (1907-1985) a pediatrician from Berne, appears to be the first to officially document the disease as la sixième maladie (sixth disease)

1988 – Yamanishi et al isolated human herpesvirus-6 (HHV-6) from the peripheral blood lymphocytes of patients with exanthem subitum suggesting that HHV-6 is the cause sixth disease

A virus was isolated from the peripheral blood lymphocytes of patients with exanthem subitum, cultured successfully in cord blood lymphocytes, and shown to be antigenically related to human herpesvirus-6 (HHV-6). Morphological features, as studied by thin-section electronmicroscopy, resembled those of herpes group viruses. Convalescent-phase serum samples, tested against the new viral antigen and HHV-6 antigen, showed seroconversion. The results strongly suggest that the newly isolated virus is identical or closely related to HHV-6 and the causal agent for exanthem subitum.

Yamanishi et al 1988

Associated Persons

• Marco Aurelio Severino (1580-1656)
• Robert Willan (1757-1812)
• John Forsyth Meigs (1818-1882)
• Clement Dukes (1845-1925)
• John Zahorsky Jr (1871-1963)
• Jules-René Dreyfus (1907-1985)

References

Historical references

• Severino MA. Roseolis vocatis saltantibus and Quaestio V In: De recondita abscessuum natura, libri VIII. Variis additamentis adaucti. Accesserunt clarissimorum virorum judicia super hunc tractatum. 1643
• Willan R. Roseola. In: On cutaneous diseases. Philadelphia: Kimber and Conrad 1809: 328-341.
• Meigs JF. Roseola. In: A practical treatise on the diseases of children. Philadelphia: Lindsay & Blakiston 1853: 616.
• Zahorsky J. Roseola Infantilis, Pediatrics. 1910; 22: 60-64
• Zahorsky J. Roseola Infantum, JAMA. 1913; 61(16): 1446-1450
• Veeder BS, Hempelmann TC. A febrile exanthem occurring in childhood: (exanthem subitum). JAMA. 1921; 77(23): 1787–1789.
• Dreyfus J-R. La fièvre de trois jours des jeunes enfants avec exanthème critique et granulocytopénie. [Sixième maladie]. La Presse Médicale,  1936; 58: 1162-1164

Eponymous term review

• Berenberg W, Wright S, Janeway CA. Roseola Infantum (Exanthem Subitum). New England Journal of Medicine, 1949; 241(7): 253-259. 
• Monnet P. [Sixth disease]. Clinique (Paris). 1962 Mar;57:137-46.
• Shapiro L. The numbered diseases: first through sixth. JAMA. 1965 Nov 8;194(6):680.
• Fourth, fifth, and sixth. Br Med J. 1974 Nov 23;4(5942):429.
• Yamanishi K, Okuno T, Shiraki K, Takahashi M, Kondo T, Asano Y, Kurata T. Identification of human herpesvirus-6 as a causal agent for exanthem subitum. Lancet. 1988 May 14;1(8594):1065-7.
• Altschuler EL. Oldest description of roseola and implications for the antiquity of human herpesvirus 6. Pediatr Infect Dis J. 2000 Sep;19(9):903
• Mullins TB, Krishnamurthy K. Roseola Infantum. Stat Pearls

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