Human herpesvirus (HHV) can cause a variety of viral exanthems, including vesicular, maculopapular, morbilliform, urticarial, scarlatiniform or purpuric rashes. Distinct patterns and persistent reactivation of latent herpesviruses [Epstein–Barr virus (EBV), cytomegalovirus and HHV-6] have also been observed following drug-induced hypersensitivity syndrome/Stevens–Johnson syndrome [1,15▪▪,36▪].
Acute cytomegalovirus infection does not generally cause an exanthema, although it was the proposed cause in 4% of patients presenting with atypical exanthems as determined by serology and polymerase chain reaction; EBV was identified in another 8% [1,17–19,38]. Acute EBV infection may be associated with a maculopapular rash lasting up to a week that begins on the trunk and arms before spreading to the forearms and face [7▪▪]. It may be associated with an enanthem.
Roseola infantum is a febrile illness predominantly caused by HHV-6 and occasionally HHV-7. It typically occurs in early childhood and presents with a febrile illness followed by rose-pink macules and papules on the neck, proximal extremities, trunk and occasionally on the face. An enanthem may be present. Using serology, HHV-6 was the most common cause in a prospective study of rash and febrile illness amongst patients less than 40 years of age presenting to clinics or hospitals .
Despite the availability of highly effective vaccines, reports of measles and rubella are increasing.
Measles incidence is rising, particularly in areas of low prevalence from imported cases where measles is endemic [42–44]. During 2011, more than 26 000 measles cases were reported in 36 European countries . The USA has seen 20 outbreaks with 603 cases of measles in 2014 (until October 31) . Following an influenza-like prodrome, Koplik spots usually precede a cephalocaudal morbilliform rash that appears 3–5 days after the onset of symptoms (Fig. 5).
With increased travel and population movements, imported viral infections with secondary local transmission are of great concern and outbreaks in susceptible populations may present containment issues.
Of the 754 recognized arboviruses, only Chikungunya, dengue, Japanese encephalitis and yellow fever viruses have evolved to primarily use humans as hosts. This implies that a large reservoir of other arboviruses in animals may affect humans. Table 3 details the clinical presentations, geographical distribution and diagnostic tests available.
Exanthems in alphavirus infections may appear anytime during the course of illness. Characteristic features include the cephalocaudal spread of rash in Barmah Forest virus (BFV) infection, and palmoplantar involvement in Ross River, Barmah Forest and Chikungunya virus.
Chikungunya has spread to the Caribbean and Americas following large outbreaks in the Indian Ocean islands, Indian subcontinent and Europe [55–60]. The expansion of geographical areas of Chikungunya-competent vectors through climate change, and the spread of the virus into new vector species such as Aedes albopictus following importation from endemic areas have been responsible for the ongoing transmission of infection. Chikungunya virus rash is usually morbilliform, with or without acral and facial oedema, mucosal, genital and intertriginous ulceration. Vesiculobullous eruptions are more likely to occur in children.
Murray Valley encephalitis was first recognized in the Australian states of Victoria and South Australia in 1951. First isolated in Japan, Japanese encephalitis virus is now the leading cause of viral encephalitis worldwide. Most infections are subclinical or mild, with fever and an erythematous macular and/or papular rash that is more pronounced on the extremities [62,75].
The filoviruses responsible for viral haemorrhagic fevers include Ebola, Marburg and Lassa viruses. Ebola virus disease in West Africa has captured public attention with the largest recorded epidemic in 2014. Rash occurs in more than half of patients with Marburg virus infection after 4–5 days of symptom onset, but is uncommon in Ebola or Lassa virus infection. It develops over the upper limbs, face and trunk and resolves over days with desquamation and alopecia. It may be associated with enanthema involving the tonsils and palate with ‘tapioca granules’ on the soft palate with gingivitis, glossitis and fissuring [76–79].
Hepatitis B and C are uncommon causes of viral exanthema. Manifestations are summarized in Table 4[35▪▪,82]. Treatment includes targeted antiviral therapy, and steroids and plasma exchange may have a role in the presence of serum sickness or vasculitis. Acute hepatitis E may also be associated with a rash .
Smallpox was last reported in Somalia in 1977, but has gained notoriety as a potential agent of bioterrorism. It is highly contagious and carries a 30% mortality rate in unvaccinated populations. Smallpox causes a characteristic maculopapular rash that progresses to raised fluid-filled blisters, pustules and pocks. Scabs appear 10–14 days after onset of rash and fall off, leaving areas of hypopigmentation. Scarring may persist lifelong. Unlike pocks from VZV, pocks from smallpox usually occur in the limbs with palmoplantar involvement and are in the same stage of development.
Where available, nucleic acid testing (NAT) on specimens including blood, fluid and tissues is generally the most sensitive and specific test, but specimen quality, storage and transport can affect the performance of NAT. Viraemia generally predates the onset of symptoms, but NAT of blood samples may be falsely negative if the period of viraemia is brief. In addition to qualitative assays, quantitative NAT, if available, can provide an assessment of disease progression and prognosis and guide treatment response. Antiviral resistance can also be detected using NAT. NAT is also useful for epidemiological purposes, which allows monitoring of phylogenetic secular trends and assay performance [34▪▪].
Immunofluorescence antigen detection is still used for the rapid diagnosis of HSV and VZV infections. Viral cultures are slow, time consuming, labour intensive and lack sensitivity, but remain the ‘gold-standard’ for diagnosis, which NAT assays are validated against.
Skin biopsies are not generally performed in viral exanthems as histological examination usually does not provide a definitive aetiological diagnosis. If the differential diagnosis includes a drug as the cause of the exanthem, then a skin biopsy should be performed as this may help elucidate the diagnosis. However, HHV infections have characteristic features including multinucleation, nuclei enlargement, nucleoli and intranuclear inclusions. Immunohistochemistry using specific monoclonal antibodies may also identify specific viruses [85▪▪,86▪▪].
The management of viral exanthems is largely supportive in the absence of specific antiviral therapy. Topical therapies such as steroid creams do not improve the natural history. Analgesia can be offered systemically, or via topical and viscous forms for painful enanthems and smaller areas of rash. Infection control measures remain an important strategy to limit further transmission of infection.
Viral exanthems are becoming more common with declining vaccination rates, increasing population and vector movements and emerging novel viruses. Vector control remains pivotal in preventing arboviral infections, and we eagerly await outcomes of Ebola, Chikungunya, dengue, HCV and enterovirus-A71 vaccination trials. New immunosuppressive treatments have led to higher rates of reactivation of latent viruses, and clinicians should be alert to atypical presentations of established viruses.
We have outlined pathognomonic features of endemic viruses causing exanthems and key epidemiological clues that are important where rash morphology is nonspecific. Diagnosis is generally secured via serology or NAT. Prevention and control measures are crucial in management.
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