Exanthems commonly accompany viral infections, but may also be caused by other infectious and noninfectious aetiologies. Although exposure to viruses may occur at mucosal surfaces or abraded skin sites, the presence of a rash in viral infections is generally not due to viral replication per se, but a hypersensitivity reaction to the virus. Viral exanthems may or may not be pruritic, and may be the first symptom or develop during the course of infection. In addition, they can occur during primary infection or following reactivation of a latent virus.
The spectrum of viral causes of exanthems and enanthems (in which mucous membranes are also involved) has increased with emergence of novel viruses and advances in laboratory diagnostic methods. Although some exanthems and enanthems may be nonspecific, others can be pathognomonic . Pattern recognition and knowledge of epidemiology is pivotal in differentiating the likely pathogen and predicting the natural course and public health importance of cases (Fig. 1). In the absence of a specific pattern, arthropod exposure, travel and vaccination history may provide clues to the differential diagnoses. However, atypical patterns of exanthems can occur in immunocompromised patients or following vaccination. Herein, we describe common causes of viral exanthems and outline an approach to guide further investigation and management.
Syndromic rashes in viral infections can generally involve hands, feet and mouth; ‘gloves and socks’; and the face, limbs and buttocks with truncal sparing (Gianotti–Crosti syndrome).
Hand, foot and mouth disease
The enteroviruses have recently been reclassified (Table 1). Hand, foot and mouth disease (HFMD) is the commonest manifestation of human enterovirus infections (Table 2[2–14]), which are a major cause of rash and fever [1,15▪▪] (Fig. 2).
Palmoplantar vesicular lesions and painful oral erosions (Fig. 2b) with the involvement of the buttocks/perineum may be seen. Less commonly, onychomadesis (painless spontaneous nail shedding) occurs after HFMD [17–19]. A more fulminant progression of HFMD associated with enterovirus-A71 has been recently described, resulting in the death of 170 children in an outbreak in Vietnam in 2011 [1,20,21].
Coxsackie virus-A6 is increasingly recognized to cause HFMD with atypical presentations in children [2–6,22–24]. In addition to hand, foot and buttock involvement, rash may be present periorally, truncally or with a predilection for areas of active atopic dermatitis, termed ‘eczema coxsackium’. Other reported morphologies include vesiculobullous eruption on the trunk, Gianotti–Crosti-like eruption, and petechial and purpuric eruptions [1,7▪▪,8,18–22,25–29]. Desquamation occurs in approximately 50% of cases, and rarely, a more severe form of infection occurs in the absence of rash [2–6,9,17,22–24].
In 2014, there has been a nationwide outbreak of enterovirus-D68 in the USA. Although respiratory illnesses are the predominant feature of enterovirus-D68 infections, rash may also be present [10,30].
Papular-purpuric ‘gloves and socks’ syndrome
Papular-purpuric ‘gloves and socks’ syndrome is most commonly associated with parvovirus B19 infection (Fig. 3). It is transmitted via respiratory droplets, blood products or in utero. The appearance of B19-specific immunoglobulin G coincides with onset of the rash, which is commonly pruritic [2,10]. Clinically, it can manifest as erythema infectiosum (Fig. 4), papular–purpuric ‘gloves and socks’ syndrome or purpuric exanthems. Unusual presentations include flagellate erythema [11,31]. Parvovirus is generally not infectious after the onset of the rash.
Gianotti–Crosti syndrome commonly occurs in children and resolves over 3–4 weeks [12–14,32,33]. It was initially described in children with hepatitis B infection, but has subsequently been associated with many other viral and bacterial infections [1–14,34▪▪,35▪▪].
OTHER ENDEMIC VIRUSES – HUMAN HERPESVIRUSES
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▪].
Herpes simplex virus
Herpes simplex virus (HSV)-1 and 2 typically produce vesicular lesions in the oral-labial or genital regions, although primary infection may cause a maculopapular rash. Vesicles may involve single or multiple anatomical sites following autoinoculation or in disseminated disease. Eczema herpeticum in patients with atopic dermatitis, herpes gladiatorum in athletes and erythema multiforme are also associated with HSV infection.
Varicella zoster virus
Primary and secondary varicella zoster virus (VZV) infection produces a classical and easily recognizable rash that is diffuse and dermatomal, respectively. However, herpes zoster may manifest as dermatomal pain or encephalitis in the absence of a rash (zoster sine herpete) [16,37▪▪], making the diagnosis more challenging. VZV is now vaccine preventable.
Cytomegalovirus and Epstein–Barr virus
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.
The use of penicillin and subsequent development of rash has been recently challenged in a prospective study of 184 patients with acute EBV infection [39,40]. Most of the 103 patients who received antibiotics were prescribed amoxicillin, and the presence of rash in those given penicillin derivatives was not significantly different from those that were not exposed.
Human herpesvirus-6 and human herpesvirus-7
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 .
VACCINE-PREVENTABLE VIRAL INFECTIONS
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).
There have been recent rubella outbreaks in Japan, China, India and Tunisia [12,47▪,48,49]. A 5-day prodrome of fever, headache and upper respiratory tract symptoms is associated with cephalocaudal progression of a maculopapular rash (Fig. 6). Infected individuals should be quarantined until 4 days after the rash subsides.
Although rash is uncommon in influenza, cutaneous manifestations have been reported with influenza A (H1N1)pdm09, A/H7N9 and influenza B [50–53]. A confluent maculopapular rash that spares the face and palmoplantar surfaces has been observed in influenza A (H1N1)pdm09 infection . Influenza should remain in the differential diagnosis of children with fever and rash, particularly in the presence of respiratory symptoms during the influenza season.
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.
Ross River and Barmah Forest virus
Ross River virus and BFV are endemic in Australia, with occasional outbreaks in the Pacific [11,61,62]. BFV is characterized by a rash in 90% of cases, whereas Ross River virus infection is more commonly associated with arthritis. However, around 40% of patients develop a rash [11,62,63▪,64–66]. The rash seen in BFV infection appears with the onset of illness and has cephalocaudal spread. It may be maculopapular, purpuric or vesicular [62–64].
The flaviviruses are structurally similar and serology may be cross-reactive (Table 3).
Dengue and Zika virus
Dengue virus transmission overlaps with that of Chikungunya virus and coinfection can occur. A faint morbilliform or scarlatiniform rash with islands of sparing occurs in 50% of individuals. Minor haemorrhagic lesions can occur. The rash rarely persists beyond 2 weeks . Although secondary dengue carries a greater risk of dengue haemorrhagic fever, severe dengue also occurs with primary infections and some strains appear to diminish in severity with subsequent infection [68▪▪,69–71]. Zika virus is a flavivirus with an indistinguishable presentation from dengue infection. Outbreaks of Zika, dengue and Chikungunya have increased in frequency in recent years, particularly in the Pacific [60,72,73].
West Nile virus
Cutaneous manifestations in West Nile virus occur in 25% of patients and nonspecific erythematous macular or papular eruptions affecting the extremities predominate .
Murray Valley and Japanese encephalitis
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].
In HIV infections, rash may be due to HIV per se, or from other infectious and noninfectious causes. HIV seroconversion illness may be associated with a generalized maculopapular rash, although this usually affects the palms and soles of the feet, with papules and nodules present on the trunk. Secondary syphilis should also be excluded. In HIV infection, HHV-8 can cause Kaposi's sarcoma, which may present as variegated macules, plaques or nodules. Multicentric Castleman's disease associated with HHV-8 infection can also result in a recurrent maculopapular rash of the limbs and trunk without mucosal involvement [69,80]. Other dermatoses in established HIV infection include papulo-pruritic eruptions, eosinophilic folliculitis, infective folliculitis, necrotizing vasculitis and drug reactions; skin biopsy is useful to differentiate these entities .
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.
New zoonotic viruses
A recent report describes Sosuga virus as the cause in a wildlife biologist who developed fever and a maculopapular exanthema after travel to South Sudan and Uganda [84▪]. This paramyxovirus is a rubella-like virus similar to others derived from fruit bats. Associated with an enanthem, the exanthema progressed to a petechial rash over sites of trauma or pressure. She recovered after 2 weeks.
Laboratory confirmation of viral exanthems is commonly made by virus-specific serology. The advantages of serology include its noninvasive nature and minimal sample degradation if transported and stored appropriately. Pathogen-specific immunoglobulin M is suggestive of an acute infection, but false-positive results can occur because of cross-reactivity with other viruses. Immunoglobulin G seroconversion (or a four-fold or greater rise in antibody titres between acute and convalescent sera) is regarded as definitive evidence of infection, but confirmation of infection may be delayed and a convalescent sera is not always collected. Measuring immunoglobulin G avidity to determine the maturity of the immunoglobulin G response may differentiate acute from previous infection. High immunoglobulin G avidity is indicative of previous infection, but low immunoglobulin G avidity is not necessarily suggestive of an acute infection as high avidity can take years to develop.
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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Conflicts of interest
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