Sixth disease

Roseola infantum / exanthem subitum

Epidemiology

• Primarily affects children aged 6 to 24 months; >90% of cases occur before age 3.
• Nearly all children are seropositive for HHV-6 by age 2.
• Transmission occurs via salivary secretions, often from asymptomatic adults.
• Peak infectivity is during febrile phase, before rash onset.

Synonyms of sixth disease: Exanthem subitum, Roseola infantum, Roseola infantalis, roseaola, rose rash, sudden rash, rose rash of infants, 3-day fever, sixième maladie, sixth disease, reddish disease, baby rash, baby measles, wind measles, false measles, measles brother

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Clinical Manifestations

Febrile Phase:

• High-grade fever (≥39.5°C) lasting 3–5 days
• May be accompanied by mild coryza, irritability, diarrhoea, or bulging fontanelle
• Febrile seizures occur in up to 15% of cases in children aged 6–18 months

Exanthematous Phase:

• Begins as fever subsides, often within hours (subitum)
• Pale pink, almond-shaped macules first appear on trunk and neck
• Spreads centrifugally to face and extremities
• Lesions may become confluent; rash resolves within 48 hours without scaling or pigmentation

Diagnosis

• Primarily clinical, based on classic biphasic pattern of fever then rash
• Serologic or PCR testing rarely required except in immunocompromised hosts

Treatment

• Supportive only – antipyretics for fever, fluids for hydration
• No antivirals or antibiotics required
• Education about benign course and febrile seizure precautions helpful for caregivers

Differential Diagnosis

• Measles (longer prodrome, Koplik spots, descending rash)
• Rubella (longer-lasting rash, tender lymphadenopathy)
• Fifth disease (slapped cheek and lacy rash)
• Scarlet fever (sandpaper rash, pharyngitis)
• Drug eruptions

Complications

• Febrile seizures are most common complication
• Rare neurologic sequelae include encephalitis and status epilepticus (especially in immunocompromised)
• HHV-6 can remain latent and may reactivate in transplant recipients

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History of Sixth disease

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.

1800s – 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 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, restlessness…

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 (1867–1956), a St. Louis paediatrician, published “A disease resembling scarlet fever,” describing 14 cases of a mysterious febrile illness in infants followed by a sudden rash. He used the name “roseola infantilis” and distinguished it from rubella and scarlet fever:

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 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 – Borden S. Veeder (1877–1954) formally introduced the term exanthem subitum (“sudden rash”) after reviewing 84 cases. He emphasized the abrupt transition from fever to rash and advocated for its recognition as a distinct entity. Rejecting 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 French paediatrician, referred to the illness as la sixième maladie (sixth disease), proposing the now familiar numbered classification among childhood exanthems.

1949 – Berenberg and Rappaport provided detailed clinical descriptions confirming Zahorsky’s findings. They highlighted the age range, fever-to-rash transition, and frequent misdiagnosis as measles or scarlet fever.

1988 – Yamanishi et al in Japan isolated human herpesvirus 6 (HHV-6) from the peripheral blood mononuclear cells of infants with exanthem subitum. This discovery confirmed the viral aetiology and clarified transmission.

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

1990s – HHV-7 was subsequently identified as a less common causative agent, often implicated in similar presentations or reactivations in immunocompromised patients.

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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. 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