Viral Exanthems

A viral exanthem is a widespread skin eruption that accompanies a systemic viral infection, and an enanthem is its counterpart on the mucous membranes. The skin is reached in one of two ways, and the distinction shapes the whole clinical picture. Some viruses replicate directly in the epidermis and produce localised crops of lesions with few systemic symptoms, as with the human papillomaviruses, the poxviruses and recurrent herpes simplex. Others cause a generalised rash as part of a wider systemic illness, as with the childhood exanthemata, where the rash often reflects the host immune response to virus in the skin and small vessels rather than direct destruction.

Two consequences follow. First, virus is shed from the fluid of vesicular lesions but not from a maculopapular rash, which matters for both diagnosis and infection control. Second, the rash is rarely diagnostic on its own, because maculopapular eruptions are also produced by drugs, bacteria, rickettsiae and many other causes, so the whole clinical syndrome must be read together.

This article covers the exanthems and localised skin lesions. The genital and mucosal lesions of herpes simplex and human papillomavirus are sexually transmitted and are handled with the other viral sexually transmitted infections; the haemorrhagic rashes of the viral haemorrhagic fevers are covered with those diseases.

Classifying the rashes

Rashes are grouped by the morphology of the individual lesion, which narrows the viral differential.

Morphology	Viruses
Maculopapular	Measles, rubella, parvovirus B19, HHV-6 and HHV-7, many enteroviruses (echoviruses, coxsackieviruses), EBV, CMV, dengue, Zika, chikungunya and other arboviruses, hepatitis B
Vesicular	Varicella-zoster virus, herpes simplex viruses, coxsackieviruses and enterovirus 71
Vesiculopustular	Mpox (monkeypox) virus, cowpox, vaccinia
Nodular	Human papillomaviruses, molluscum contagiosum, orf, milker’s nodule, tanapox

Macules are flat coloured spots and papules are raised but contain no expressible fluid; vesicles are blisters of clear fluid; pustules contain pus; and nodules are solid raised lesions. Two classic prototypes anchor the maculopapular group: the morbilliform rash of measles, of large blotchy macules that coalesce, and the rubelliform rash of rubella, of finer discrete pink macules. Numerous unrelated viruses, above all the enteroviruses, produce rashes that mimic one or other prototype.

The maculopapular exanthems

The classic childhood exanthems are traditionally numbered, and four of the historic “six diseases” are viral maculopapular rashes (the second and fourth were bacterial).

Exanthem	Agent	Incubation	Key features
Measles (first disease)	Measles virus	10 to 14 days	Prodrome of fever, cough, coryza, conjunctivitis; Koplik spots; rash spreads head to trunk to limbs
Rubella (third disease)	Rubella virus	14 to 21 days	Mild; posterior auricular and suboccipital lymphadenopathy; teratogenic in pregnancy
Erythema infectiosum (fifth disease)	Parvovirus B19	4 to 14 days	“Slapped cheek” then lacy limb rash; arthropathy in adults; aplastic crisis, hydrops
Roseola (sixth disease)	HHV-6, HHV-7	9 to 10 days	High fever then rash as fever breaks; can trigger febrile seizures

Measles is a highly contagious infection spread by respiratory droplets and aerosols. After an incubation of about 10 to 14 days comes a prodrome of fever, cough, coryza and conjunctivitis, and the pathognomonic Koplik spots on the buccal mucosa, before the morbilliform rash spreads from the forehead and behind the ears down to the trunk, limbs, palms and soles. The rash is a hypersensitivity reaction, so children with defective cell-mediated immunity can have measles without a rash, which hinders diagnosis. Complications include otitis media, diarrhoea, pneumonia (the commonest serious complication) and encephalitis, and are more frequent and severe in the immunocompromised and the malnourished. Measles remains a major global killer, with over half of deaths in Africa.

Rubella, or German measles, is milder and is asymptomatic in about half of cases. After an incubation of 14 to 21 days a low-grade prodrome is followed by a fine pink rash and characteristic posterior auricular and suboccipital lymphadenopathy, with arthropathy common in adult women. The clinical illness is trivial, but rubella in early pregnancy causes the congenital rubella syndrome, so its control is a matter of protecting the fetus rather than the patient.

Erythema infectiosum, fifth disease, is caused by parvovirus B19. After an incubation of about 4 to 14 days the child develops the “slapped cheek” appearance, flushed cheeks with circumoral pallor, then a lacy reticular rash on the limbs as it fades. The rash is immune-mediated and appears late, around 17 to 18 days after infection, by which time the child is no longer infectious. The same virus causes transient aplastic crisis in people with chronic haemolysis, persistent anaemia in the immunocompromised, and non-immune hydrops fetalis after infection in pregnancy, and adults, especially women, often develop arthralgia.

Roseola infantum, exanthem subitum or sixth disease, is caused by HHV-6 and HHV-7, which infect nearly all children by the age of two. After an incubation of about 9 to 10 days the infant has several days of high fever, which may provoke a febrile seizure, and then, as the fever breaks, a rose-pink rash appears on the trunk. The illness is self-limited.

Two other patterns complete the group. About a third of cases of infectious mononucleosis due to EBV or CMV carry a maculopapular rash, and a florid rash follows if the patient is given ampicillin or amoxicillin. Dozens of enteroviruses (notably echoviruses 4, 9 and 16 and coxsackieviruses A9, A16 and B5) cause ephemeral, non-pruritic maculopapular rashes, usually in children during late-summer epidemics, and many arboviruses (dengue, chikungunya, Zika and others) produce a maculopapular or scarlatiniform rash.

The vesicular exanthems

Varicella (chickenpox) is the primary infection with varicella-zoster virus. After an incubation of about 14 to 16 days a brief prodrome is followed by an itchy rash that appears in crops, concentrated first on the trunk and spreading centrifugally, with lesions at different stages at any one time, macule to papule to vesicle to pustule to crust. The lesions being at different stages of evolution distinguished chickenpox from smallpox, in which all lesions were synchronous. Varicella is usually benign in healthy children but causes significant morbidity and mortality in adults, in pregnancy and in the immunocompromised, through pneumonia, encephalitis and disseminated disease. Bacterial superinfection with Staphylococcus aureus or Streptococcus pyogenes is the commonest skin complication.

Herpes zoster (shingles) is reactivation of latent varicella-zoster virus, occurring in about 20% of immunocompetent people and up to half of the immunocompromised, its risk rising with age and immunosuppression. The vesicular rash is confined to one or a few dermatomes with associated neuritis, and its major complication is postherpetic neuralgia, pain persisting beyond 8 to 12 weeks that can be severe and treatment-resistant. Ophthalmic zoster threatens sight and the Ramsay Hunt syndrome causes facial palsy; dissemination beyond the dermatome signals immunocompromise and possible visceral spread.

Hand-foot-and-mouth disease is caused by coxsackievirus A16 and enterovirus 71. After a short incubation of 3 to 6 days it produces vesicles on the palms, soles and buccal mucosa, while the related herpangina gives vesicles and ulcers on the soft palate and tonsils. Both are self-limited, though enterovirus 71 can cause severe neurological and systemic disease. The recurrent vesicular lesions of herpes simplex on the lip or skin belong to the same morphological group.

Poxvirus skin infections

The poxviruses produce distinctive skin lesions ranging from vesiculopustular eruptions to discrete nodules. Smallpox, eradicated in 1980, produced a synchronous centrifugal vesiculopustular rash with about 30% mortality, and its distinction from chickenpox by the uniform stage of the lesions was historically important.

Mpox (monkeypox) resembles a milder smallpox. After an incubation of about 10 to 14 days come a prodrome of fever, malaise and prominent lymphadenopathy, then a rash that begins on the trunk and spreads peripherally, and may involve the palms, soles and mucous membranes, with mortality around 10%. The lymphadenopathy that is absent in smallpox helps distinguish the two, though the poxviruses can be told apart reliably only by PCR. There is no proven specific treatment, but smallpox vaccination is highly protective.

The remaining poxvirus lesions are localised and nodular. Molluscum contagiosum gives 3 to 6 mm dome-shaped papules with central umbilication, spread by skin contact in children and sexually in adults, and becomes florid with hundreds of lesions in advanced HIV. Orf (contagious ecthyma) and milker’s nodule are occupational parapoxvirus infections acquired from sheep and goats or from cattle respectively, producing solitary nodules on the hands that heal spontaneously over weeks. Vaccinia, the smallpox vaccine virus, can cause inoculation lesions and rare severe complications.

Pathophysiology

Viruses reach the skin by three routes: direct inoculation (primary herpes simplex, papillomaviruses, most poxviruses), spread from an internal focus (the recurrent lesions of herpes simplex and zoster travelling down sensory nerves from the ganglion), and systemic infection with viraemic dissemination (primary varicella, measles, rubella).

The lesion is produced either by the virus directly or by the host response to it. Viruses that replicate in the epidermis, such as the papillomaviruses and poxviruses, damage the skin directly and characteristically produce a localised lesion. Viruses that replicate elsewhere reach the skin through the bloodstream, and the rash of measles and rubella is thought to be largely a cell-mediated immune response to virus in the skin and endothelium, which is why the immunodeficient child may have measles with no rash at all.

Diagnosis

Most exanthems are diagnosed clinically, but the rash is rarely specific and the differential is wide, so the whole syndrome, the prodrome, the distribution and the evolution of the lesions, must be weighed. Where confirmation is needed the approach depends on the lesion.

For the maculopapular exanthems, serology (specific IgM, or a rising IgG titre) confirms measles, rubella and parvovirus B19, and molecular testing is increasingly used. For vesicular lesions a Tzanck smear shows the multinucleate giant cells of herpes simplex and varicella-zoster, and PCR on vesicle fluid is the most sensitive test, having largely replaced insensitive culture. For suspected enteroviral disease, throat and vesicle swabs (or throat and rectal swabs where there are no vesicles) are taken for RT-PCR. Poxviruses are confirmed by PCR, which is the only reliable way to separate mpox from other poxvirus infections.

The skin as a marker of systemic viral disease

Beyond the exanthems, the skin can be the first clue to a systemic viral infection. Mucocutaneous lesions are often what first raises suspicion of HIV and can mark progression of disease, from the florid molluscum and severe zoster of advancing immunodeficiency to Kaposi sarcoma. Chronic hepatitis C is associated with a range of skin disorders including porphyria cutanea tarda and leukocytoclastic vasculitis of cryoglobulinaemia, and EBV underlies both the rash of infectious mononucleosis and several lymphomas. These associations are signposts to look for the underlying infection.

Management

Most viral exanthems are self-limited and need only symptomatic care. Specific antiviral therapy is reserved for the herpesviruses: aciclovir, valaciclovir or famciclovir for varicella in those at risk (pregnant women, neonates, adults and the immunocompromised, given intravenously in severe disease) and for herpes zoster, where early treatment and adjuncts such as gabapentin reduce postherpetic neuralgia. There is no specific antiviral for measles, rubella, the enteroviral exanthems or parvovirus B19, though intravenous immunoglobulin helps parvovirus B19 infection in the immunocompromised and in aplastic crisis.

Prevention is dominated by vaccination. The measles, mumps and rubella (MMR) vaccine prevents the two most important maculopapular exanthems; live varicella vaccine prevents chickenpox and a zoster vaccine reduces shingles and postherpetic neuralgia in older adults; the human papillomavirus vaccine prevents warts and cancers; and smallpox vaccination is protective against mpox. Varicella-zoster immunoglobulin is used for post-exposure prophylaxis in susceptible pregnant women, neonates and the immunocompromised.

South African context

South Africa immunises against measles through the childhood Expanded Programme on Immunisation. Measles is more severe in HIV-infected children, who have higher rates of hospitalisation and a higher case-fatality rate, and molluscum contagiosum and herpes zoster are common cutaneous markers of untreated HIV. Measles is a notifiable condition, and the National Institute for Communicable Diseases guides the diagnosis and the prevention of secondary cases.

References and recommended reading

• Nawas ZY, Tyring SK. Viral Diseases of the Skin. In: Richman DD, Whitley RJ, Hayden FG, editors. Clinical Virology, 4th edition, Chapter 8. Washington: ASM Press; 2016. The backbone source for the individual exanthems and their clinical features.
• Burrell CJ, Howard CR, Murphy FA. Fenner and White’s Medical Virology, 5th edition. Academic Press / Elsevier; 2017. The source for the morphological classification of viral skin rashes.
• National Department of Health. Expanded Programme on Immunisation (EPI-SA): schedule and programme overview. Pretoria: NDoH; 2024. The current South African reference for the childhood measles vaccine schedule.
• Centre for Respiratory Diseases and Meningitis. Measles. Johannesburg: National Institute for Communicable Diseases; 2022 to 2025. The South African reference for measles surveillance and the prevention of secondary cases.