Characterizing viral exanthems - UFRGS

623ISSN 1745-5111Pediatric Health (2010) 4(6), 623–63510.2217/PHE.10.66 © 2010 Future Medicine Ltd

An exanthem is any eruptive skin rash that may be associated with fever or other systemic symptoms. Causes include infectious patho-gens, medication reactions and, occasionally, a combination of both.

Over 100 years ago, a group of characteristic childhood eruptions were described and num-bered from one to six [1,2]: measles, scarlet fever, rubella, erythema infectiosum and roseola infan-tum. The origin of the fourth classic childhood eruption, formerly referred to as Dukes’ disease, is controversial. It may represent misdiagnosed cases of rubella or scarlet fever, rather than a distinct illness.

Viral exanthems are common in childhood. The words ‘exanthema’ and ‘anthos’ mean ‘breaking out’ and ‘flower’ in Greek, respectively. Similarly, a child breaking out with a viral exan-them may be likened to a flower bursting into bloom. In children, exanthems are most often related to infection [3] and, of these, viral infec-tions are the most common. Determining the cause of an exanthem is based on the character-istic morphology, distribution and time course of the eruption, as well as a careful assessment of infectious contacts, immunization status and aspects of the physical examination. Although not always diagnostic, the morphology and configuration of cutaneous lesions are of con-siderable importance to the classification and diagnosis of viral exanthems. For the purpose of this article, we will characterize common and uncommon viral exanthems, based on their morphology, and will discuss current advance-ments in understanding and treatment of these viral diseases.

Macular & maculopapular exanthemsMeaslesMeasles is caused by a ssRNA virus belonging to the Paramyxoviridae family, genus Morbillivirus. It has an incubation period of approximately

10–12 days, and clinical disease begins with symptoms of fever, conjunctivitis, rhinorrhea, sore throat and a dry cough. Koplik spots (gray–white papules on the buccal mucosa) may be seen during this prodromal phase. Approximately 3–4 days after the prodromal symptoms, the typical exanthem of coalescing erythematous macules and papules erupts, beginning behind the ears and in the hairline area, and spreads over the rest of the skin over a period of a few days. The eruption typically resolves in the same order as its appearance, and will often desquamate.

The differential diagnosis includes other maculopapular exanthems, such as rubella, toxic shock syndrome, roseola, parvovirus B-19 infection and drug eruptions. Complications of measles include transient immunosuppression, acute postinfectious encephalitis and subacute sclerosing panencephalitis (SSPE). Transient immunosuppression occurs during the ill-ness and lasts for approximately 6 weeks [1]. During this time, an infected individual is at risk for secondary bacterial infections, such as otitis media, pneumonia or gastroenteritis. Postinfectious encephalitis occurs in approxi-mately one in 1000 patients, and manifests approximately 1 week after the onset of the exanthem [4]. Symptoms present during, or shortly after, acute infection, and include head-ache, fever and seizures. A lesser-known entity, known as measles inclusion-body encephalitis, can affect immunocompromised patients from weeks to months after acute infection [5]. SSPE affects approximately one in 100,000 patients, and manifests as a slow, progressive disease, which can present months or even years after resolution of the acute infection. The onset of SSPE is insidious, and psychiatric manifesta-tions are prominent. Subsequently, myoclonic seizures usually lead to a final stage of akinetic mutism. In total, 95% of individuals with SSPE die within 5 years of diagnosis [6]. SSPE

5(9,(:

Characterizing viral exanthemsJoseph M Lam†

An exanthem is any eruptive skin rash that may be associated with fever or other systemic symptoms. Causes include infectious pathogens, medication reactions and, occasionally, a combination of both. In children, exanthems are most often related to infection and, of these, viral infections are the most common. Some exanthems have very specific morphologies that help identify and characterize the eruption. In this article, we describe common and uncommon viral exanthems, based on their morphology, and review current advancements in understanding and treatment of these exanthems.

†Departments of Paeditrics & Dermatology, University of British Columbia, 1803–1805 West Broadway, Vancouver, BC, V5Z 1K1, Canada Tel.: +1 604 876 4433 Fax: +1 604 876 4431 [email protected]

Keywords

• dermatology • exanthem • virus

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is caused by a persistent infection of the CNS with the virus, and early childhood infection with measles is a risk factor for SSPE.

An unusual variant of measles can be seen in previously vaccinated individuals, infants with maternal IgG antibodies and patients on immu-noglobulin therapy [1]. In this modified form, the prodrome and exanthem are milder and of shorter duration. However, the disease is just as contagious in these individuals. Diagnosis is based on clinical presentation with labora-tory confirmation, if necessary. Measles IgM can usually be detectable after the first 3 days of the exanthem.

Currently, there is no specific antiviral ther-apy for measles and treatment is symptomatic. More importantly, the longstanding availabil-ity of the measles vaccine makes the disease easily preventable. Despite, this, there is still poor uptake of the vaccine [7–9], owing to, in part, a proposed causal relationship between receipt of the measles–mumps–rubella vaccine and autism, a claim that has been convincingly scientifically refuted [10].

RubellaRubella, or German measles, is caused by an RNA virus in the Togaviridae family. Approximately 50% of infected individuals become symptomatic. After an incubation period of 2–3 weeks, symptomatic patients exhibit prodromal symptoms, which include low-grade fever, headache, sore throat and myalgias. A macular or maculopapular exan-them appears after approximately 2–5 days and spreads in a cephalocaudal pattern. Symmetrical lymphadenopathy is often seen, and often occurs in the postauricular and occipital areas. Arthralgias and arthritis are also common. The most serious complication of rubella is congen-tial rubella syndrome, which classically presents with the triad of deafness, cataracts and cardiac disease [11]. The differential diagnosis includes other maculopapular exanthems, such as mea-sles, roseola, parvovirus B-19 infection and drug eruptions. The diagnosis of rubella can be made with IgM antibody titers. Patients are contagious 1 week prior to the eruption of the rash until a week after the rash resolves. The treatment of rubella is supportive.

Erythema infectiosumErythema infectiosum (EI) is a common child-hood exanthematous illness caused by parvo-virus B19 – a nonenveloped, ssDNA virus belonging to the Parvoviridae family. The name

B19 comes from the bloodbank code, where the original positive serum sample was labeled (i.e., Row B, Sample 19) [12]. It is the only parvo-virus that has been linked directly to disease in humans [13]. Although parovirus B19 infection can have different clinical manifestations (see later), EI is the most commonly recognized.

Erythema infectiosum manifests in three overlapping stages. After an incubation period of 1–2 weeks, patients present with fiery-red facial erythema, which has been described as having a ‘slapped cheeks’ appearance (FIGURE 1). In the second stage, patients develop a reticulate macular or urticarial exanthem 1–4 days after the slapped cheek eruption, and this second rash is mainly seen over the proximal extremities. In the third stage, the exanthem recurs inter-mittently in response to stimuli, such as local irritation, high temperatures and emotional stress [12]. Arthropathy may occur in up to 60% of adults with EI [14], whereas it will only occur in approximately 10% of children with joint symptoms. In children, the arthro pathy affects larger joints, such as the knees, wrists and ankles, and in an asymmetric pattern [12].

The differential diagnosis includes a drug reaction, measles, rubella and enterovirus infec-tion, and roseola infantum. Complications of EI are owing to the affinity of parvovirus B19 for erythroid precursors. Parvovirus B19 infec-tion can suppress red blood cell production, causing transient aplastic crisis, chronic red cell aplasia, hydrops fetalis or congenital anemia. This is even more likely in patients with ill-nesses that have already shortened the lifespan of erythrocytes, such as iron-deficiency ane-mia, HIV, sickle cell disease, thalassemia and sphero cytosis. Although treatment is support-ive, at-risk patients may require transfusions or intravenous immunoglobulin therapy [15,16].

The diagnosis of EI is usually made clinically. An ELISA is commercially available with high sensitivity, although false-positive results may recur owing to crossreaction to other viruses or the rheumatoid factor [17]. PCR can detect viral DNA in clinical samples of urine, respiratory secretions, body tissues and serum [18].

Roseola infantumRoseola infantum is caused by human her-pesvirus (HHV) types 6 and 7, and belongs to the Roseolovirus genus in the subfamily of Betaherpesvirinae [19].

Both HHV-6 and -7 are highly prevalent in the healthy population, and establish latency in macrophages and T lymphocytes. They are

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frequently shed in saliva of healthy donors, and the pathogenic potential of reactivated virus ranges from asymptomatic infection to severe diseases in transplant recipients. By the end of the second year of life, approximately 75% of all children are seropositive for HHV-6 and approximately 24% of all children with HHV-6 infection will manifest clinical symp-toms of roseola [20,21]. HHV-7 infection usually occurs later, with approximately 65% of British children infected by the age of 3 years [22].

In roseola, after an incubation period of 5–15 days, infected children develop high fevers that last 3–5 days. This is followed by the acute onset of a rosey pink, nonpruritic macular rash, predominantly on the neck and trunk. Owing to the presence of high fevers, patients are often worked up for an occult bacterial infection.

Roseola infection can cause leukopenia [23] and, rarely, thrombocytopenia and hepatitis [22]. Patients generally recover without sequelae. However, approximately 22% of patients with roseola may develop febrile seizures [24]. The dif-ferential diagnosis includes measles, rubella and other viral exanthems.

The diagnosis of roseola is made clinically. Laboratory diagnosis of HHV-6 and -7 infec-tions is difficult owing to the limited availabil-ity of antibody tests, problems with antigenic crossreaction and lack of understanding of the clinical relevance and epidemiology of these two viruses. However, the development of standard-ized quantitative real-time PCR, and the use of antibody tests based on recombinant proteins, may aid in the diagnosis of HHV-6 and -7 infection in the future [22].

Epstein–Barr virus & aminopenicillinsEpstein–Barr virus (EBV) is a member of the Herpesvirus family, belonging to the genus Lymphocryptovirus. While only approximately 5–10% of children infected with EBV manifest an exanthem [2], if amoxicillin or ampicillin is administered, a characteristic bright-red mor-billiform eruption almost always occurs [25–27]. This eruption begins 5–9 days after exposure to the medication, starting on the trunk before becoming generalized as confluent macules and papules. The eruption most likely results from ampicillin–antibody immune complexes as a consequence of polyclonal B-cell activation. This consistently occurs in adolescents and adults with infectious mononucleosis admin-istered ampicillin, but resolves without specific measures. This reaction is not considered a ‘true’ drug allergy and, in most children, re-exposure

to the antibiotic after the EBV infection will not trigger a similar response. However, since antimicrobial therapy is not necessary for infec-tious mononucleosis, the antibiotic should be discontinued during the acute EBV infection.

Although approximately 7% of mononucl-eosis-like illnesses are caused by cytomegalo-virus (CMV), CMV does not appear to give this drug-related exanthem [28].

Vesicular & pustular exanthemsVaricella & herpes zosterVaricella is caused by varicella-zoster virus (VZV), an enveloped dsDNA virus responsi-ble for varicella (chickenpox) and herpes zoster (shingles). VZV is one of eight herpesviruses known to infect humans, and is associated with vesicular lesions, infection of neuronal tissue and latent infection of dorsal root ganglia. Primary infection causes varicella, after which, the virus becomes latent.

The transmission of VZV does not require skin-to-skin contact, and is more commonly transmitted by respiratory secretions via an aer-osol route [29]. When a susceptible individual is exposed to VZV, the virus initially undergoes primary replication, beginning 3–4 days after exposure, and occurring in the oropharynx and regional lymph nodes. This is followed by a primary viremia. A secondary viremia occurs 10–21 days after exposure and, during this time period, patients manifest with prodromal symptoms of fever, malaise and myalgias. The exanthem begins soon after as erythematous pruritic macules, which develop into papules and fluid-filled vesicles, described as ‘dewdrops on a rose petal’. The lesions usually begin in the hairline and spread in a cephalocaudal pattern, involving the scalp and mucous mem-branes. The vesicles crust over, typically within

Characterizing viral exanthems – 5(9,(:

Figure 1. A child with the classic ‘slapped cheek’ appearance of erythema infectiosum.


4–5 days of the onset of the initial lesion. The average number of lesions is approximately 300–400 [30].

Older lesions crust over as newer lesions form, and so giving a polymorphous appear-ance to the exanthem. Lesions may heal with hypo pigmentation and scarring. The differen-tial diagnosis includes pityriasis lichenoides, arthropod bites, herpes simplex virus (HSV) infection and impetigo. The most common complication of varicella in immunocompe-tent children is bacterial superinfection, usually due to group A Streptococcus or Staphylococcus aureus. Neurological complications can also occur, and these include meningitis, meningo-encephalitis, cerebellar ataxia, transverse myeli-tis and Guillain–Barre syndrome. Other com-plications include arthritis, glomerulonephritis, myo carditis, thrombocytopenia and purpura fulminans. Immunocompromised patients are at risk for severe and protracted varicella, multiorgan involvement and hemorrhagic varicella [31].

The other common clinical manifesta-tion of VZV infection is herpes zoster (shin-gles) (FIGURE 2). VZV becomes latent in dorsal root ganglia cells until reactivation, at which time, the virus travels back to the skin along the sensory nerve, manifesting as a unilateral vesicular skin eruption involving one to three dermatomes. Skin vesicles may be painful or pruritic, especially in adults. Zoster gener-ally is a milder disease in children than in

adults. Reactivation is probably due to declin-ing cell-mediated immunity, which explains the increased incidence in the elderly and in immunocompromised patients.

Since varicella is usually a benign, mild, self-limiting disease in most immuno competent individuals, oral acyclovir (ACV) is not rou-tinely recommended. However, since adoles-cents and young adults are at a moderately high risk for developing severe illness, oral ACV should be administered for 5 days, ide-ally starting within 24 h of the development of a varicella rash [32].

Intravenous ACV is used for patients at seri-ous risk for, or who have, a severe or potentially severe VZV infection, such as immunocompro-mised patients. The recommended duration of ACV therapy is 7 days, or until no new lesions have appeared for 48 h [33]. Ideally, therapy should be started within 24 h of onset, but ACV can still be effective up to 72 h after the appearance of the skin lesions.

Fever should be controlled with acetami-nophen. The use of aspirin may predispose to Reye syndrome, and ibuprofen may pre dispose to group A Streptococcus infection. The live-attenuated varicella vaccine has been useful in decreasing the incidence of VZV infec-tion [34,35]. Zoster appears to be less of a problem after immunization than after natural infec-tion. To avoid breakthrough varicella, individu-als should be vaccinated twice, once at an age of 12–15 months and again at 4–6 years [36]. The varicella vaccine has been combined with the measles–mumps–rubella vaccine, and was licensed by the US FDA in September 2005 for use in children 12 months through to 12 years of age. [37].

The diagnosis of VZV infection is usu-ally made by history and clinical findings. Laboratory confirmation can be conducted by demonstrating the presence of specif ic viral antigens in skin scrapings by immuno-fluorescence using a commercial monoclonal antibody to VZV conjugated to fluorescein, or by PCR. These diagnostic methods are highly sensitive and rapid [38]. Serological testing is unreliable to detect acute infection but can confirm the diagnosis retrospectively [38].

Eczema herpeticumEczema herpeticum (also known as HSV-associated Kaposi varicelliform eruption) is a severe form of disseminated cutaneous HSV infection, which occurs primarily in individuals with atopic dermatitis and skin diseases, such as

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Figure 2. A child with vesicles on an erythematous base in a dermatomal pattern.


pemphigus, Darier disease or traumatic burns. Defective cytokine secretion and decreased cell-mediated immunity in skin affected by atopic dermatitis appear to play a role in the pathogenesis of eczema herpeticum [39]

Patients present with monomorphic umbili-cated vesiclulopustules, which progress to form punched-out erosions in areas of active der-matitis (FIGURE 3). The upper body is the most common site of infection, with a predilection for the head and neck. Fever and malaise are often present.

The differential diagnosis includes varicella, zoster and impetigo. Complications include viremia, secondary bacterial superinfection and keratoconjunctivitis. In some cases, it may progress to fulminating life-threatening infec-tion, and mortality rates were as high as 75% before antiviral drugs were available [40].

The diagnosis is made clinically, but may be confirmed by a Tzanck smear (looking for multinucleated giant cells), a fluorescent anti-body smear or culture of a vesicular lesion. The treatment involves systemic ACV. More severe involvement may require hospitalization and the use of intravenous antivirals. In addi-tion, it is recommended that topical steroids and moisturizers be continued to repair the skin barrier.

Hand–foot–mouth diseaseHand–foot–mouth disease (HFMD) is a dis-tinct monomorphous exanthem caused by viruses of the Picornaviridae family in the Enterovirus genus. Although the enteroviruses can cause an assortment of virus-mediated exanthems, HFMD is a recognizable and com-mon clinical manifestation. The most com-mon pathogen is the Coxsackie A16 virus, but other Coxsackie viruses and enteroviruses have been implicated as well. In particular, human enterovirus 71 appears to be responsible for recent epidemics of HFMD in the Asia–Pacific region [41].

The infection has a typical incubation period of 3–7 days. The main manifestations are fever, lymphadenopathy, followed by the appearance of 2–8-mm painful oval, gray vesicles on the palmar and plantar skin, buccal mucosa and tongue after 1–2 days. The vesicles are often arranged parallel to the dermatoglyphs, and may have a surrounding red halo. Papular and vesicular lesions can also occur on other parts of the body, and the buttocks may often exhibit a nonspecific eruption prior to the onset of the vesicular exanthem. The oral enanthem helps to

distinguish HFMD from other causes of child-hood exanthems, although cases without oral lesions have been described. In the oral cavity, the hard palate, tongue and buccal mucosa are most commonly affected. The differential diag-nosis includes aphthous stomatitis, varicella, HSV infection and herpangina.

Most HFMD cases are self-limiting, and only required supportive treatment. Rarely, there may be a neurological or cardiopulmo-nary complication, such as meningoencepha-litis or myocarditis. Uncomplicated HFMD usually resolves in 5–7 days. The case–fatality rate for HFMD ranges from 0.06 to 0.11% [42]. In particular, enterovirus 71 infection has been associated with fatal outcomes.

The diagnosis of HFMD is usually made on clinical grounds. Confirmation is possible via isolating the virus from the vesicles, naso-pharyngeal secretions, cerebrospinal f luid, blood or biopsy materials. Therapy is pri-marily supportive. Children are particularly infectious until the blisters have disappeared. Exclusion from school or childcare is not practi-cal, as the virus may be present in the feces for several weeks.

Acute generalized exanthematous pustulosisAcute generalized exanthematous pustulosis (AGEP) is an eruption characterized by the acute onset of fever and multiple nonfollicular pinpoint sterile papulopustules, which overlie the generalized erythroderma (FIGURE 4). AGEP was first in the literature in 1980, when Beylot et al. described pustular eruptions with the char-acteristics of acute onset after a bout of infec-tion and/or drug ingestion in patients without a history of psoriasis, evolution toward spontane-ous healing after a single attack, and existence

Characterizing viral exanthems – 5(9,(:�

Figure 3. A child with clustered vesiculopustules and punched-out erosions.


of a marked dermal vasculitis in addition to nonfollicular subcorneal pustules on histologic examination [43]. Roujeau et al. proposed the following criteria for the diagnosis of AGEP: the presence of numerous, small, nonfollicu-lar pustules arising on a widespread edematous erythema, fever exceeding 38°C, pathologic findings of subcorneal and/or intraepithelial spongiform pustules, blood neutrophil count

above 7000 per mm3 and acute course with spontaneous resolution of the pustules in less than 15 days [44]. Although medications are often implicated in adult cases of AGEP, a small series of pediatric patients suggested a viral trigger in 80% of affected patients [45]. Viral infections found to be associated with AGEP include enterovirus [44,46], adenovi-rus [44], EBV [44], CMV [44,47] and hepatitis B virus [44]. The diagnosis is made clinically, and therapy is supportive. The differential diagnosis includes pustular psoriasis, miliaria pustulosa and folliculitis. No definitive treatment exists, but it is important to recognize AGEP clinically and histologically and remove any potential offending medications.

Papular exanthemsPapular acrodermatitis of childhoodPapular acrodermatitis of childhood (PAC), also known as Gianotti–Crosti syndrome (GCS), is a unique cutaneous disorder characterized by the abrupt onset of an erythematous papular exanthem found on the extremities, buttocks and face (FIGURE 5). It is a relatively common der-matosis, seen worldwide, primarily affecting children between 2 and 6 years of age.

Papular acrodermatitis of childhood was first described by Gianotti in 1953, in a young child with a monomorphous erythematous papular rash confined to the extensor surfaces of the arms and legs [48]. After finding hepatitis B sur-face antigen in the serum of affected children, it was believed that PAC was solely a manifesta-tion of hepatitis B infection [49]. However, sub-sequently, EBV has become recognized as the most common viral agent associated with GCS in the USA [50]. However, many other viruses and infectious agents have been associated with PAC, and these include hepatitis A virus, CMV, human herpesvirus, Coxsackie virus A16, B4 and B5, rotavirus, parvovirus B19, molluscum contagiosum (MC), respiratory syncytial virus, mumps virus, and parainfluenza virus type 1 and 2 [48].

The pathogenesis of GCS is still unclear but probably reflects a recognizable reactive pat-tern in response to diverse infectious stimuli. Clinically, PAC usually presents with symmetri-cal monomorphous papular or papulovesicular exanthem over the cheeks, extensor aspects of the extremities and gluteal areas. Occasionally, the papules coalesce into larger plaques and become hemorrhagic or form scales. The trunk, elbows and knees are usually spared; lesions typically fade within 3–4 weeks.

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Figure 4. Sterile nonfollicular pustules with underlying erythema.

Figure 5. Lichenoid monomorphic papules on the extensor upper extremity.


The diagnosis is made clinically, and a recent study proposed clinical criteria for the diagno-sis of PAC (BOX 1) [51,52]. The differential diag-nosis includes varicella, Henoch–Schönlein purpura, arthopod bites, scabies and MC. Treatment is usually unnecessary as the disease is self-limiting.

Molluscum contagiosumMolluscum contagiosum is a highly contagious viral infection of the mucous membranes and skin, commonly seen in children. It is caused by a poxvirus of the genus Molluscipoxvirus. It usually presents as pearly umbilicated skin-colored dome-shaped papules, which usually range from 2 to 8 mm in size (FIGURE 6). In approximately 30% of patients, an eczematous reaction may encircle lesions [53]. Patients with immunodeficiency, including AIDS and leuke-mia, may be more likely to develop extensive disease [54]. MC is transmitted by close physical contact, fomites and autoinoculation. Shared bathtubs, pools and towels may facilitate spread of the MC virus.

The diagnosis is made clinically, but Wright or Giemsa staining of cells expressed from the central core of lesions will reveal characteristic intracytoplasmic inclusions. A Tzanck stain can also be done to highlight the typical pattern of numerous discrete ovoid intracytoplasmic inclusion bodies, known as molluscum bodies.

The differential diagnosis includes juvenile xanthogranuloma, verruca plana, milia and papular urticaria. Lesions usually resolve spon-taneously, but this process may take years, with more prolonged illness in the immunocom-promised patient. Reasons for actively treating MC may include alleviating discomfort and itching, limitating spread to other areas and people, preventing scarring and superinfection, and eliminating the social stigma of visible lesions. No single intervention has been shown to be convincingly effective in the treatment of MC [55]. Treatment options include destructive, immune-enhancing or antiviral modalities.

Gentle local destruction is the typical approach for treating MC, and cantharidin is a safe and effective therapy for MC in children; it is extremely effective and well tolerated, with high parental satisfaction if used in experienced hands [53]. Benefits include painless application and high efficacy rates of up to 90% [54]. Other destructive therapies include curettage, liquid-nitrogen cryotherapy and peeling agents, such as lactic acid or topical retinoids. Immune-enhancing agents speed up the immune

clearance of MC infection, and these include topical imiquimod, oral cimetidine and intral-esional Candida antigen [56]. Antivirals, such as cidofovir, have been used in pediatric patients with HIV-1 for the treatment of disseminated MC recalcitrant to conventional therapy [57,58].

Other viral exanthemsPapular purpuric glove & socks syndrome & parvovirus-induced petechial syndromesPapular purpuric glove and socks syndrome (PPGSS) is a distinctive exanthem, which is usually caused by parovovirus B19. While other viruses, such as CMV, EBV, measles and HHV-6, have also been considered as causative agents for PPGSS [59], most studies employ-ing seroconversion, viral DNA detection and

Box 1. Proposed diagnostic criteria for papular acrodermatitis of childhood.

Positive clinical features• Monomorphous, flat-topped, pink-brown papules or papulovesicles 1–10 mm in

diameter on at least three of the following four sites: cheeks, buttocks, extensor surfaces of the forearms, and extensor surfaces of the legs

• Symmetrical distribution• Duration of at least 10 days

Negative clinical features• Extensive truncal lesions• Scaly lesions

Data taken from [52].


Figure 6. Pearly umbilicated skin-colored dome-shaped papules over the posterior leg.


immunohistochemistry still strongly support parvovirus B19 as the main etiologic agent of PPGSS [60].

In 1990, Harms et al. first described PPGSS [61]. Clinically, it is characterized by symmetric, pain-ful erythema, and edema of the hands and feet that later progresses to a petechial rash. Edema and erythema can be observed on the buccal and genital mucosa, and on the inner aspect of the thighs (FIGURE 7). Unlike EI, patients with PPGSS are contagious when they exhibit the exanthem.

Other distinctive localized forms of parvovirus- related petechiae and purpura have been described, and given names such as ‘bath-ing suit’ and ‘acropetechial’ syndrome [60,62,63]. Parvovirus B19 has been described recently to cause generalized petechiae [64–66]. The differ-ential diagnosis includes allergic contact derma-titis, rickettsial infections and Kawasaki disease. Treatment is symptomatic, and diagnosis can be made clinically or serologically.

Pityriasis roseaPityriasis rosea is an acute self-limiting and dis-tinctive exanthem, characterized by oval ery-thematous-squamous lesions of the trunk and limbs, which usually spares the face, scalp, palms and soles. It is thought to be virally induced because of features such as an associated prodro-mal symptoms and seasonal clustering of cases. Pityriasis rosea derives its name from pityriasis meaning bran-like, and rosea meaning pink. It has been linked to HHV-6 and HHV-7 [67–69], but this association has been disputed [70,71].

Classically, pityriasis rosea begins as an ery-thematous, scaly patch on the trunk, known as a herald patch. This large lesion is commonly 2–10 cm in diameter, ovoid, erythematous and slightly raised, with a typical collarette of scale at the margin. At times, the herald patch may be absent or overlooked. In one series, only 17% of patients referred to a dermatology clinic reported a herald patch [72]. Days to weeks later, numerous smaller scaly papulosquamous plaques develop on the trunk along the lines of skin cleavage with a collarette of scale (FIGURE 8). The plaques usually spare the face, scalp and distal extremities.

In children, pityriasis rosea may affect the face and extremities other than the trunk, and this is referred to as inverse pityriasis rosea. In par-ticular, dark-skinned children seem to have more frequent facial and scalp involvement [67]. In addition, vesicular, pustular, urticarial and hem-orrhagic variants have also been described [67]. The differential diagnosis includes tinea cor-poris, guttate psoriasis, pityriasis lichenoides and syphilis.

The rash of pityriasis rosea typically lasts approximately 5 weeks, and resolves by 8 weeks in more than 80% of patients [73]. Clearance usually occurs within 6 weeks, and lesions may fade with residual hypopigmetation. Diagnosing pityriasis rosea is nearly always made by his-tory and physical examination alone. In cer-tain atypical cases, a skin biopsy may prove useful in differentiating pityriasis rosea from other exanthems.

Although some studies have shown improve-ment with systemic erythromycin and systemic ACV [74,75], treatment is generally supportive. There is some evidence for narrow-band ultra-violet-B phototherapy [76,77]. Topical steroids may be used for associated pruritus [78].

Erythema multiformeErythema multiforme (EM) is a relatively uncom-mon disorder, characterized by the abrupt onset of multiple target skin lesions. It is frequently recurrent, and some individuals have monthly episodes. HSV appears to be responsible for precipitating most cases of EM episodes in chil-dren [79,80]. Other infectious agents and medica-tion have also been implicated [81]. The EM skin lesions characteristically occur 1–10 days after an episode of herpes labialis or genitalis, and appear as ‘target’ lesions, characterized by a central dusky zone surrounded by an inner ring of pale edema, and an outer ring of erythema. The central area may also be vesicular. The eruption is symmetric and is often seen over the hands and feet. The

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Figure 7. Petechiae coalescing into purpura over the upper thighs.


individual lesions may remain fixed for approxi-mately 1 week, and the entire episode may last for 2–3 weeks. The differential diagnosis includes annular urticaria, acute hemorrhagic edema of infancy, urticarial vasculitis and Stevens–Johnson syndrome. The diagnosis can usually be made clinically, and patients are treated symptomati-cally. Childhood HSV-associated EM may be unresponsive to treatment with oral steroids or oral or topical ACV. Frequent recurrences of EM may be treated with prophylactic ACV [82].

Unilateral laterothoracic exanthemUnilateral laterothoracic exanthem (ULTE) is an eruption that begins unilaterally in the axillae or groin, and spreads centrifugally (FIGURE 9). It has a prolonged course and usually resolves within 4–6 weeks. ULTE was first described as a new clini-cal entity by Bodemer and de Prost in 1992 [83], but, in the past has been described under dif-ferent names from as early as 1962 [84,85]. In the literature, ULTE has other designations, such as asymmetric periflexural exanthem and unilateral mediothoracic exanthem [86,87].

Clinically, ULTE is usually preceded by an upper respiratory or gastrointestinal prodrome, and is characterized by a unilateral and local-ized exanthem, often in the axillary region (FIGURE 9), which spreads in a centrifugal pattern, sometimes reaching the contralateral side. The mucous membranes, face, palms and soles are generally spared.

The etiology is unknown, but the frequent early age of onset, the seasonal pattern, the associated prodrome, the lack of response to systemic antibiotics and the possibility of famil-ial cases suggest an infectious cause. Infectious agents linked with the eruption of ULTE include parainfluenza 2 and 3, adenovirus [88], parvo-virus B19 [89], and HHV-6 and -7 [90]. Recently, primary EBV infection has been linked with ULTE [90,91]. ULTE probably represents a distinct cutaneous reaction to several infectious agents.

The eruption usually lasts 4–6 weeks, although some cases can persist for more than 8 weeks [88,92]. The differential diagnosis includes pityriasis rosea, papular acrodermatitis of childhood and allergic contact dermatitis. The diagnosis is made clinically and treatment is supportive.

Nonspecific viral exanthemA number of viruses can cause an exanthem associ-ated with an upper respiratory or gastro intestinal infection. These include the nonpolio enteroviruses in the summer months, and rhinovirus, adeno-virus, parainfluenza virus, respiratory syncytial

virus and influenza virus in the winter [93]. The exanthem usually consists of erythematous macules and papules, but may be urticarial [94,95].

Conclusion & future perspectiveOur understanding of certain viral exanthems has expanded significantly since the original descrip-tion of the classic exanthems of childhood. Many viral diseases, such as measles, rubella and varicella, are now preventable with vaccination. However, our understanding and recognition of new viral-associated exanthems continues to expand. In the case of papular acrodermatitis of childhood, what was once thought to be a manifestation of hepa-titis B is now recognized to be a manifestation of a number of infectious agents, including viruses. In the case of acute generalized exanthematous

Characterizing viral exanthems – 5(9,(:�

Figure 9. Erythematous papules over the left axillae and upper left trunk.

Figure 8. Pink papulosquamous plaques with a collarette of scale over the trunk.


pustulosis, what was once thought to be a drug-induced exanthem is now recognized to have viral triggers. In the case of parvovirus B19, the ability to detect the virus in seronegative patients using PCR has been useful in linking the virus to erythema infectiousum, as well as other manifestations, such as PPGSS and generalized petechiae.

There are still cases of exanthematous disease where the roles of viruses have yet to be fully elu-cidated. These include the association of HHV-6 and -7 reactivation in drug hypersensitivity syn-drome, the role of viral triggers in Kawasaki syn-drome and the role of viruses in dermatological conditions with seasonal clustering, such as lichen

striatus. Improving laboratory testing in combina-tion with continual clinical sleuthing may pro-vide clues to the role of viruses in these and other exathematous disease in childhood.

Financial & competing interests disclosureThe author has no relevant affiliations or financial involve-ment with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, con-sultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

BibliographyPapers of special note have been highlighted as:• of interest•• of considerable interest

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•• Excellent review on various viral exanthems.

2. Fölster-Holst R, Kreth HW: Viral exanthems in childhood – infectious (direct) exanthems. Part 1: classic exanthems. J. Dtsch Dermatol. Ges. 7(4), 309–316 (2009).

•• Excellent review on various viral exanthems.

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•• Good review that discusses recent advances in the understanding of the measles virus, including measles receptor usage, the cellular basis of immunosuppression, the role of measles in ‘nonviral’ diseases and the controversy surrounding measles vaccine safety.

5(9,(:�– Lam5(9,(:�– Lam

Executive summary

Macular & maculopapular exanthems• Measles, rubella, erythema infectiousum and roseola infantum are part of the six classic childhood exanthems, and have very

distinct and recognizable features.• The eruption when aminopenicillins are administered to patients with Epstein–Barr virus is a bright-red morbilliform eruption that

does not preclude future use of aminopenicillins.

Vesicular & pustular exanthems• Varicella infection is benign and self-limiting, but has the potential to cause life- and limb-threatening complications in

immunocompetent and immunocompromised hosts. The varicella vaccine is now available in combination with the measles–mumps–rubella vaccine.

• Eczema herpeticum is a severe form of disseminated cutaneous herpes simplex virus infection that morphologically presents as monomorphic umbilicated vesiclulopustules, which progress to form punched-out erosions.

• Hand–foot–mouth disease is a distinct monomorphous exanthem that is most commonly caused by the Coxsackie A16 virus and human enterovirus 71. Meningoencephalitis and myocarditis are rare complications, which occur more commonly with human enterovirus 71.

• Although acute generalized exanthematous pustulosis usually occurs following drug ingestion, cases in children may be caused by viral infections.

Papular exanthems• Papular acrodermatitis of childhood is characterized by the abrupt onset of erythematous papules over the extremities, buttocks

and face, with relative sparing of the abdomen and chest. It appears to occur as a response to a number of infectious stimuli.• Therapy for molluscum contagiosum ranges from destructive techniques to observation, as lesions will eventually

resolve spontaneously.

Other viral exanthems• Parovovirus B19 has been linked recently to several petechial and purpuric exanthems, which may be localized to particular areas of

the body. Recently, it has also been implicated in outbreaks of generalized petechiae.• Pityriasis rosea in children may present atypically by involving the face and extremities.• Erythema multiforme is often triggered by herpes simplex virus in children.• Unilateral laterothoracic exanthem is a distinct exanthem, which preferentially affects one side of the body, with a prolonged

clinical course.


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