Roseola Infantum (Exanthema Subitum): Etiology, Pathophysiology, Clinical Manifestations, Diagnosis, Treatment, Prevention

Roseola infantum is one of the most common pathogenic diseases of early childhood and occurs worldwide.

In medical literature, roseola is also referred to as exanthema subitum, three‑day fever, pseudorubella, and the sixth disease.

Clinically, roseola infantum is characterized by high fever lasting approximately three days without specific symptoms, followed by the appearance of a fine maculopapular rash. Most children become infected and recover from roseola before the age of three without complications. Before the characteristic rash appears, diagnosing roseola can be challenging; however, understanding the epidemiology and typical course of the infection can significantly reduce the time to an accurate diagnosis.

Etiology and Epidemiology

In most cases, the causative agent of three‑day fever is human herpesvirus 6 (HHV‑6); less commonly, human herpesvirus 7 (HHV‑7).

More than 90 % of adults worldwide are infected with HHV‑6, and some of them shed the virus in saliva, contributing to transmission. The peak incidence of primary infection occurs between 3 and 9 months of age.

HHV‑6 is divided into two subtypes — HHV‑6A and HHV‑6B — which differ in biological, immunological, epidemiological, and molecular features. HHV‑6B is considered the primary cause of exanthema subitum, whereas HHV‑6A infection is more often seen in adults or immunocompromised individuals. These pathogens belong to the Herpesviridae family and share characteristics typical of other herpesviruses.

Primary infection usually occurs through contact with a caregiver who carries a latent form of the virus. The virus is shed in saliva via respiratory droplets and transmitted through direct contact during sneezing, coughing, laughing, or kissing.

The incubation period averages 5 to 15 days.

Pathophysiology

During primary infection, HHV‑6 most commonly replicates in lymphocytes and salivary gland cells. The virus targets mature CD4+ T‑lymphocytes and exerts an immunomodulatory effect by increasing the activity of natural killer (NK) cells.

In response, the body increases the synthesis of interleukin‑15 (IL‑15), which counteracts the virus’s effects on the immune system. After entering the cell, the virus replicates, and its DNA persists long‑term in peripheral blood mononuclear cells, potentially resulting in lifelong latent infection.

Clinical Manifestations

Classic clinical manifestations of roseola infantum include:

• Fever up to 40 °C (104 °F) or higher lasting 3–5 days, often difficult to control with antipyretics. Despite the high fever, the child may remain relatively active and maintain a good appetite.
• Fine maculopapular rash appearing 3–5 days after fever onset. The rash typically consists of pink, round macules or papules 2–3 mm in diameter that blanch with pressure. It first appears on the trunk and then spreads to the neck and extremities. The rash resolves spontaneously within 2–4 days.

Dorsal Roseola Rash in Children

Abdominal Roseola Rash in Children

Rare manifestations of roseola infantum include:

• Upper respiratory tract inflammation (pharyngitis, pharyngotonsillitis, tracheitis, etc.). Nagayama spots — red macules on the soft palate.
• Otitis media — inflammation of the middle ear.
• Lymphadenopathy — enlargement of peripheral lymph nodes.

Complications:

• Febrile seizures.
• Thrombocytopenia — low peripheral blood platelet count.
• Guillain — Barré syndrome — a polyneuritis developing 1–4 weeks after infection.
• Hepatitis.
• Encephalitis or meningoencephalitis.

Diagnosis of Roseola Infantum

The diagnosis is typically clinical and does not require laboratory testing.

If confirmation of the pathogen is necessary, polymerase chain reaction (PCR) is widely used to detect viral DNA in blood, saliva, or swabs. Serologic testing for antibodies (IgM, IgG) is used less frequently.

Differential diagnosis

Roseola infantum should be differentiated from:

• Measles;
• Rubella;
• Scarlet fever;
• Drug‑induced rash;
• Allergic rash;
• Infectious mononucleosis (caused by Epstein — Barr virus);
• Cytomegalovirus infection;
• Parvovirus B19 infection.

Treatment of Roseola Infantum

In most cases, roseola resolves spontaneously and does not require specialized treatment.
When diagnosing roseola, the clinician should explain to the caregiver when to seek medical attention and how to properly care for the child.

Conditions requiring immediate medical evaluation:

• Altered mental status, excessive drowsiness;
• Persistent fever unresponsive to antipyretics;
• Seizures;
• A hemorrhagic (non‑blanching) rash;
• Vomiting without relief;
• Jaundice of the sclera or skin;
• Changes in urine color;
• Edema.

Symptomatic treatment includes:

• Reducing fever;
• Maintaining nasal hygiene;
• Ensuring adequate fluid intake.

Prevention of Exanthema Subitum in Children

There is no specific prevention (vaccination) for HHV‑6 or HHV‑7.

Nonspecific preventive measures include:

• Limiting contact with individuals who have active roseola;
• Practicing good personal hygiene.

Immunity

After recovering from roseola, individuals develop lifelong serologic immunity. Rare cases of reinfection have been described, more often in immunocompromised individuals.