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Joseph M Lam† An is any eruptive skin that may be associated with fever or other systemic symptoms. Causes include infectious , 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.

An exanthem is any eruptive skin rash that 10–12 days, and clinical disease begins with may be associated with fever or other systemic symptoms of fever, conjunctivitis, rhinorrhea, symptoms. Causes include infectious patho- sore throat and a dry cough. Koplik spots (gray– gens, medication reactions and, occasionally, a white on the buccal mucosa) may be seen combination of both. during this prodromal phase. Approximately Over 100 years ago, a group of characteristic 3–4 days after the prodromal symptoms, the childhood eruptions were described and num- typical exanthem of coalescing erythematous bered from one to six [1,2]: , , macules and papules erupts, beginning behind , infectiosum and infan- the ears and in the hairline area, and spreads over tum. The origin of the fourth classic childhood the rest of the skin over a period of a few days. eruption, formerly referred to as Dukes’ disease, The eruption typically resolves in the same order is controversial. It may represent misdiagnosed as its appearance, and will often desquamate. cases of rubella or scarlet fever, rather than a The differential diagnosis includes other distinct illness. maculopapular exanthems, such as rubella, Viral exanthems are common in childhood. toxic shock syndrome, roseola, parvovirus B-19 The words ‘exanthema’ and ‘anthos’ mean infection and drug eruptions. Complications of ‘breaking out’ and ‘flower’ in Greek, respectively. measles include transient immunosuppression, Similarly, a child breaking out with a viral exan- acute postinfectious encephalitis and subacute them may be likened to a flower bursting into sclerosing panencephalitis (SSPE). Transient bloom. In children, exanthems are most often immunosuppression occurs during the ill- related to infection [3] and, of these, viral infec- ness and lasts for approximately 6 weeks [1] . tions are the most common. Determining the During this time, an infected individual is at cause of an exanthem is based on the character- risk for secondary bacterial infections, such istic morphology, distribution and time course as otitis media, pneumonia or gastroenteritis. of the eruption, as well as a careful assessment Postinfectious encephalitis occurs in approxi- of infectious contacts, immunization status and mately one in 1000 patients, and manifests aspects of the physical examination. Although approximately 1 week after the onset of the not always diagnostic, the morphology and exanthem [4]. Symptoms present during, or configuration of cutaneous lesions are of con- shortly after, acute infection, and include head- †Departments of Paeditrics & , University of British siderable importance to the classification and ache, fever and seizures. A lesser-known entity, Columbia, 1803–1805 West Broadway, diagnosis of viral exanthems. For the purpose known as measles inclusion-body encephalitis, Vancouver, BC, V5Z 1K1, Canada Tel.: +1 604 876 4433 of this article, we will characterize common can affect immunocompromised patients from Fax: +1 604 876 4431 [email protected] and uncommon viral exanthems, based on their weeks to months after acute infection [5]. SSPE morphology, and will discuss current advance- affects approximately one in 100,000 patients, ments in understanding and treatment of these and manifests as a slow, progressive disease, Keywords viral diseases. which can present months or even years after resolution of the acute infection. The onset of • dermatology • exanthem • Macular & maculopapular exanthems SSPE is insidious, and psychiatric manifesta- Measles tions are prominent. Subsequently, myoclonic Measles is caused by a ssRNA virus belonging to seizures usually lead to a final stage of akinetic part of the family, Morbillivirus. mutism. In total, 95% of individuals with It has an of approximately SSPE die within 5 years of diagnosis [6]. SSPE

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is caused by a persistent infection of the CNS B19 comes from the bloodbank code, where with the virus, and early childhood infection the original positive serum sample was labeled with measles is a risk factor for SSPE. (i.e., Row B, Sample 19) [12] . It is the only parvo- An unusual variant of measles can be seen in virus that has been linked directly to disease in previously vaccinated individuals, infants with humans [13] . Although parovirus B19 infection maternal IgG and patients on immu- can have different clinical manifestations (see noglobulin therapy [1] . In this modified form, later), EI is the most commonly recognized. the prodrome and exanthem are milder and of Erythema infectiosum manifests in three shorter duration. However, the disease is just overlapping stages. After an incubation period as contagious in these individuals. Diagnosis of 1–2 weeks, patients present with fiery-red is based on clinical presentation with labora- facial erythema, which has been described as tory confirmation, if necessary. Measles IgM having a ‘slapped cheeks’ appearance (FIGURE 1). can usually be detectable after the first 3 days In the second stage, patients develop a reticulate of the exanthem. macular or urticarial exanthem 1–4 days after Currently, there is no specific antiviral ther- the slapped cheek eruption, and this second rash apy for measles and treatment is symptomatic. is mainly seen over the proximal extremities. More importantly, the longstanding availabil- In the third stage, the exanthem recurs inter- ity of the measles vaccine makes the disease mittently in response to stimuli, such as local easily preventable. Despite, this, there is still irritation, high temperatures and emotional poor uptake of the vaccine [7–9], owing to, in stress [12] . Arthropathy may occur in up to part, a proposed causal relationship between 60% of adults with EI [14], whereas it will only receipt of the measles––rubella vaccine occur in approximately 10% of children with and autism, a claim that has been convincingly joint symptoms. In children, the arthro pathy scientifically refuted [10] . affects larger joints, such as the knees, wrists and ankles, and in an asymmetric pattern [12] . Rubella The differential diagnosis includes a drug Rubella, or German measles, is caused by reaction, measles, rubella and enterovirus infec- an RNA virus in the Togaviridae family. tion, and roseola infantum. Complications of Approximately 50% of infected individuals EI are owing to the affinity of become symptomatic. After an incubation for erythroid precursors. Parvovirus B19 infec- period of 2–3 weeks, symptomatic patients tion can suppress production, exhibit prodromal symptoms, which include causing transient aplastic crisis, chronic red cell low-grade fever, headache, sore throat and aplasia, or congenital . myalgias. A macular or maculopapular exan- This is even more likely in patients with ill- them appears after approximately 2–5 days and nesses that have already shortened the lifespan spreads in a cephalocaudal pattern. Symmetrical of erythrocytes, such as iron-deficiency ane- is often seen, and often mia, HIV, , thalassemia and occurs in the postauricular and occipital areas. sphero cytosis. Although treatment is support- Arthralgias and are also common. The ive, at-risk patients may require transfusions or most serious complication of rubella is congen- intravenous [15,16] . tial rubella syndrome, which classically presents The diagnosis of EI is usually made clinically. with the triad of deafness, cataracts and cardiac An ELISA is commercially available with high disease [11] . The differential diagnosis includes sensitivity, although false-positive results may other maculopapular exanthems, such as mea- recur owing to crossreaction to other or sles, roseola, parvovirus B-19 infection and the rheumatoid factor [17] . PCR can detect viral drug eruptions. The diagnosis of rubella can DNA in clinical samples of urine, respiratory be made with IgM titers. Patients are secretions, body tissues and serum [18] . contagious 1 week prior to the eruption of the rash until a week after the rash resolves. The Roseola infantum treatment of rubella is supportive. Roseola infantum is caused by human her- pesvirus (HHV) types 6 and 7, and belongs Erythema infectiosum to the genus in the subfamily Erythema infectiosum (EI) is a common child- of [19] . hood exanthematous illness caused by parvo- Both HHV-6 and -7 are highly prevalent in virus B19 – a nonenveloped, ssDNA virus the healthy population, and establish latency belonging to the family. The name 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 Figure 1. A child with the classic ‘slapped that last 3–5 days. This is followed by the acute cheek’ appearance of erythema onset of a rosey pink, nonpruritic macular rash, infectiosum. predominantly on the neck and trunk. Owing to the presence of high fevers, patients are often to the antibiotic after the EBV infection will worked up for an occult bacterial infection. not trigger a similar response. However, since Roseola infection can cause leukopenia [23] antimicrobial therapy is not necessary for infec- and, rarely, thrombocytopenia and hepatitis [22]. tious mononucleosis, the antibiotic should be Patients generally recover without sequelae. discontinued during the acute EBV infection. However, approximately 22% of patients with Although approximately 7% of mononucl- roseola may develop febrile seizures [24]. The dif- eosis-like illnesses are caused by cytomegalo- ferential diagnosis includes measles, rubella and virus (CMV), CMV does not appear to give other viral exanthems. this drug-related exanthem [28]. The diagnosis of roseola is made clinically. Laboratory diagnosis of HHV-6 and -7 infec- Vesicular & pustular exanthems tions is difficult owing to the limited availabil- Varicella & herpes zoster ity of antibody tests, problems with antigenic Varicella is caused by varicella-zoster virus crossreaction and lack of understanding of the (VZV), an enveloped dsDNA virus responsi- clinical relevance and epidemiology of these two ble for varicella () and herpes zoster viruses. However, the development of standard- (). VZV is one of eight herpesviruses ized quantitative real-time PCR, and the use of known to infect humans, and is associated with antibody tests based on recombinant , vesicular lesions, infection of neuronal tissue may aid in the diagnosis of HHV-6 and -7 and latent infection of dorsal root ganglia. infection in the future [22]. Primary infection causes varicella, after which, the virus becomes latent. Epstein–Barr virus & aminopenicillins The transmission of VZV does not require Epstein–Barr virus (EBV) is a member of the skin-to-skin contact, and is more commonly Herpesvirus family, belonging to the genus transmitted by respiratory secretions via an aer- . While only approximately osol route [29]. When a susceptible individual is 5–10% of children infected with EBV manifest exposed to VZV, the virus initially undergoes an exanthem [2], if amoxicillin or ampicillin is primary replication, beginning 3–4 days after administered, a characteristic bright-red mor- exposure, and occurring in the oropharynx and billiform eruption almost always occurs [25–27]. regional lymph nodes. This is followed by a This eruption begins 5–9 days after exposure primary viremia. A secondary viremia occurs to the medication, starting on the trunk before 10–21 days after exposure and, during this becoming generalized as confluent macules and time period, patients manifest with prodromal papules. The eruption most likely results from symptoms of fever, malaise and myalgias. The ampicillin–antibody immune complexes as a exanthem begins soon after as erythematous consequence of polyclonal B-cell activation. pruritic macules, which develop into papules This consistently occurs in adolescents and and fluid-filled vesicles, described as ‘dewdrops adults with infectious mononucleosis admin- on a rose petal’. The lesions usually begin in istered ampicillin, but resolves without specific the hairline and spread in a cephalocaudal measures. This reaction is not considered a ‘true’ pattern, involving the scalp and mucous mem- drug allergy and, in most children, re-exposure branes. The vesicles crust over, typically within

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4–5 days of the onset of the initial lesion. The adults. Reactivation is probably due to declin- average number of lesions is approximately ing cell-mediated immunity, which explains 300–400 [30]. the increased incidence in the elderly and in Older lesions crust over as newer lesions immunocompromised patients. form, and so giving a polymorphous appear- Since varicella is usually a benign, mild, self- ance to the exanthem. Lesions may heal with limiting disease in most immuno competent hypo pigmentation and scarring. The differen- individuals, oral acyclovir (ACV) is not rou- tial diagnosis includes pityriasis lichenoides, tinely recommended. However, since adoles- arthropod bites, virus (HSV) cents and young adults are at a moderately infection and . The most common high risk for developing severe illness, oral complication of varicella in immunocompe- ACV should be administered for 5 days, ide- tent children is bacterial superinfection, usually ally starting within 24 h of the development of due to group A Streptococcus or Staphylococcus a varicella rash [32]. aureus. Neurological complications can also Intravenous ACV is used for patients at seri- occur, and these include meningitis, meningo- ous risk for, or who have, a severe or potentially encephalitis, cerebellar ataxia, transverse myeli- severe VZV infection, such as immunocompro- tis and Guillain–Barre syndrome. Other com- mised patients. The recommended duration of plications include arthritis, glomerulonephritis, ACV therapy is 7 days, or until no new lesions myo carditis, thrombocytopenia and purpura have appeared for 48 h [33]. Ideally, therapy fulminans. Immunocompromised patients should be started within 24 h of onset, but are at risk for severe and protracted varicella, ACV can still be effective up to 72 h after the multiorgan involvement and hemorrhagic appearance of the skin lesions. varicella [31]. Fever should be controlled with acetami- The other common clinical manifesta- nophen. The use of aspirin may predispose to tion of VZV infection is herpes zoster (shin- Reye syndrome, and ibuprofen may pre dispose gles) (FIGURE 2). VZV becomes latent in dorsal to group A Streptococcus infection. The live- root ganglia cells until reactivation, at which attenuated has been useful time, the virus travels back to the skin along in decreasing the incidence of VZV infec- the sensory nerve, manifesting as a unilateral tion [34,35]. Zoster appears to be less of a problem vesicular skin eruption involving one to three after immunization than after natural infec- dermatomes. Skin vesicles may be painful or tion. To avoid breakthrough varicella, individu- pruritic, especially in adults. Zoster gener- als should be vaccinated twice, once at an age ally is a milder disease in children than in 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 specific 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 herpeticum (also known as HSV- associated Kaposi varicelliform eruption) is a severe form of disseminated cutaneous HSV Figure 2. A child with vesicles on an erythematous base in a infection, which occurs primarily in individuals dermatomal pattern. with atopic and skin diseases, such as

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, Darier disease or traumatic burns. Defective cytokine secretion and decreased cell-mediated immunity in skin affected by 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, Figure 3. A child with clustered zoster and impetigo. Complications include vesiculopustules and punched-out viremia, secondary bacterial superinfection erosions. and keratoconjunctivitis. In some cases, it may progress to fulminating life-threatening infec- distinguish HFMD from other causes of child- tion, and mortality rates were as high as 75% hood exanthems, although cases without oral before antiviral drugs were available [40]. lesions have been described. In the oral cavity, The diagnosis is made clinically, but may the hard palate, tongue and buccal mucosa are be confirmed by a Tzanck smear (looking for most commonly affected. The differential diag- multinucleated giant cells), a fluorescent anti- nosis includes , varicella, body smear or culture of a vesicular lesion. HSV infection and . The treatment involves systemic ACV. More Most HFMD cases are self-limiting, and severe involvement may require hospitalization only required supportive treatment. Rarely, and the use of intravenous antivirals. In addi- there may be a neurological or cardiopulmo- tion, it is recommended that topical steroids nary complication, such as meningoencepha- and moisturizers be continued to repair the litis or . Uncomplicated HFMD skin barrier. usually resolves in 5–7 days. The case–fatality rate for HFMD ranges from 0.06 to 0.11% [42]. Hand–foot–mouth disease In particular, enterovirus 71 infection has been Hand–foot–mouth disease (HFMD) is a dis- associated with fatal outcomes. tinct monomorphous exanthem caused by The diagnosis of HFMD is usually made viruses of the Picornaviridae family in the on clinical grounds. Confirmation is possible Enterovirus genus. Although the enteroviruses via isolating the virus from the vesicles, naso- can cause an assortment of virus-mediated pharyngeal secretions, cerebrospinal fluid, exanthems, HFMD is a recognizable and com- blood or biopsy materials. Therapy is pri- mon clinical manifestation. The most com- marily supportive. Children are particularly mon is the Coxsackie A16 virus, but infectious until the have disappeared. other Coxsackie viruses and enteroviruses have Exclusion from school or childcare is not practi- been implicated as well. In particular, human cal, as the virus may be present in the feces for enterovirus 71 appears to be responsible for several weeks. recent epidemics of HFMD in the Asia–Pacific region [41]. Acute generalized The infection has a typical incubation period exanthematous pustulosis of 3–7 days. The main manifestations are fever, Acute generalized exanthematous pustulosis lymphadenopathy, followed by the appearance (AGEP) is an eruption characterized by the of 2–8-mm painful oval, gray vesicles on the acute onset of fever and multiple nonfollicular palmar and plantar skin, buccal mucosa and pinpoint sterile papulopustules, which overlie tongue after 1–2 days. The vesicles are often the generalized erythroderma (FIGURE 4). AGEP arranged parallel to the dermatoglyphs, and was first in the literature in 1980, when Beylot may have a surrounding red halo. Papular and et al. described pustular eruptions with the char- vesicular lesions can also occur on other parts acteristics of acute onset after a bout of infec- of the body, and the buttocks may often exhibit tion and/or drug ingestion in patients without a a nonspecific eruption prior to the onset of the history of , evolution toward spontane- vesicular exanthem. The oral helps to ous healing after a single attack, and existence

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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 [44]. The diagnosis is made clinically, and therapy is supportive. The differential diagnosis includes pustular psoriasis, pustulosa and . No definitive treatment exists, but it is important to recognize AGEP clinically and histologically and remove any potential offending medications.

Papular exanthems Papular acrodermatitis of childhood Papular acrodermatitis of childhood (PAC), also known as Gianotti–Crosti syndrome (GCS), is Figure 4. Sterile nonfollicular pustules with a unique cutaneous disorder characterized by underlying erythema. the abrupt onset of an erythematous papular exanthem found on the extremities, buttocks of a marked dermal in addition to and face (FIGURE 5). It is a relatively common der- nonfollicular subcorneal pustules on histologic matosis, seen worldwide, primarily affecting examination [43]. Roujeau et al. proposed the children between 2 and 6 years of age. following criteria for the diagnosis of AGEP: Papular acrodermatitis of childhood was first the presence of numerous, small, nonfollicu- described by Gianotti in 1953, in a young child lar pustules arising on a widespread edematous with a monomorphous erythematous papular erythema, fever exceeding 38°C, pathologic rash confined to the extensor surfaces of the findings of subcorneal and/or intraepithelial arms and legs [48]. After finding hepatitis B sur- spongiform pustules, blood neutrophil count 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, (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, Figure 5. Lichenoid monomorphic papules elbows and knees are usually spared; lesions on the extensor upper extremity. typically fade within 3–4 weeks.

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The diagnosis is made clinically, and a recent Box 1. Proposed diagnostic criteria for papular acrodermatitis study proposed clinical criteria for the diagno- of childhood. sis of PAC (BOX 1) [51,52]. The differential diag- nosis includes varicella, Henoch–Schönlein Positive clinical features purpura, arthopod bites, and MC. • Monomorphous, flat-topped, pink-brown papules or papulovesicles 1–10 mm in Treatment is usually unnecessary as the disease diameter on at least three of the following four sites: cheeks, buttocks, extensor is self-limiting. surfaces of the forearms, and extensor surfaces of the legs • Symmetrical distribution Molluscum contagiosum • Duration of at least 10 days Molluscum contagiosum is a highly contagious Negative clinical features viral infection of the mucous membranes and • Extensive truncal lesions skin, commonly seen in children. It is caused • Scaly lesions by a poxvirus of the genus Molluscipoxvirus. It Data taken from [52]. usually presents as pearly umbilicated skin- colored dome-shaped papules, which usually clearance of MC infection, and these include range from 2 to 8 mm in size (FIGURE 6). In topical imiquimod, oral cimetidine and intral- approximately 30% of patients, an eczematous esional Candida antigen [56]. Antivirals, such as reaction may encircle lesions [53]. Patients with cidofovir, have been used in pediatric patients immunodeficiency, including AIDS and leuke- with HIV-1 for the treatment of disseminated mia, may be more likely to develop extensive MC recalcitrant to conventional therapy [57,58]. disease [54]. MC is transmitted by close physical contact, fomites and autoinoculation. Shared Other viral exanthems bathtubs, pools and towels may facilitate spread Papular purpuric glove & socks of the MC virus. syndrome & parvovirus-induced The diagnosis is made clinically, but Wright petechial syndromes or Giemsa staining of cells expressed from the Papular purpuric glove and socks syndrome central core of lesions will reveal characteristic (PPGSS) is a distinctive exanthem, which is intracytoplasmic inclusions. A Tzanck stain can usually caused by parovovirus B19. While also be done to highlight the typical pattern other viruses, such as CMV, EBV, measles and of numerous discrete ovoid intracytoplasmic HHV-6, have also been considered as causative inclusion bodies, known as molluscum bodies. agents for PPGSS [59], most studies employ- The differential diagnosis includes juvenile ing seroconversion, viral DNA detection and 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 Figure 6. Pearly umbilicated skin-colored as lactic acid or topical retinoids. Immune- dome-shaped papules over the enhancing agents speed up the immune posterior leg.

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immunohistochemistry still strongly support Classically, begins as an ery- parvovirus B19 as the main etiologic agent of thematous, scaly patch on the trunk, known as PPGSS [60]. a herald patch. This large lesion is commonly In 1990, Harms et al. first described PPGSS [61]. 2–10 cm in diameter, ovoid, erythematous and Clinically, it is characterized by symmetric, pain- slightly raised, with a typical collarette of scale ful erythema, and edema of the hands and feet at the margin. At times, the herald patch may be that later progresses to a petechial rash. Edema absent or overlooked. In one series, only 17% of and erythema can be observed on the buccal and patients referred to a dermatology clinic reported genital mucosa, and on the inner aspect of the a herald patch [72]. Days to weeks later, numerous thighs (FIGURE 7). Unlike EI, patients with PPGSS smaller scaly papulosquamous plaques develop are contagious when they exhibit the exanthem. on the trunk along the lines of skin cleavage with Other distinctive localized forms of a collarette of scale (FIGURE 8). The plaques usually parvovirus- related petechiae and purpura have spare the face, scalp and distal extremities. been described, and given names such as ‘bath- In children, pityriasis rosea may affect the face ing suit’ and ‘acropetechial’ syndrome [60,62,63]. and extremities other than the trunk, and this Parvovirus B19 has been described recently to is referred to as inverse pityriasis rosea. In par- cause generalized petechiae [64–66]. The differ- ticular, dark-skinned children seem to have more ential diagnosis includes allergic contact derma- frequent facial and scalp involvement [67]. In titis, rickettsial infections and . addition, vesicular, pustular, urticarial and hem- Treatment is symptomatic, and diagnosis can be orrhagic variants have also been described [67]. made clinically or serologically. The differential diagnosis includes tinea cor- poris, guttate psoriasis, pityriasis lichenoides Pityriasis rosea and . Pityriasis rosea is an acute self-limiting and dis- The rash of pityriasis rosea typically lasts tinctive exanthem, characterized by oval ery- approximately 5 weeks, and resolves by 8 weeks thematous-squamous lesions of the trunk and in more than 80% of patients [73]. Clearance limbs, which usually spares the face, scalp, palms usually occurs within 6 weeks, and lesions may and soles. It is thought to be virally induced fade with residual hypopigmetation. Diagnosing because of features such as an associated prodro- pityriasis rosea is nearly always made by his- mal symptoms and seasonal clustering of cases. tory and physical examination alone. In cer- Pityriasis rosea derives its name from pityriasis tain atypical cases, a skin biopsy may prove meaning bran-like, and rosea meaning pink. It useful in differentiating pityriasis rosea from has been linked to HHV-6 and HHV-7 [67–69], other exanthems. but this association has been disputed [70,71]. 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 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 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 Figure 7. Petechiae coalescing into purpura over the upper thighs. and is often seen over the hands and feet. The

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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 exanthem Figure 8. Pink papulosquamous plaques Unilateral laterothoracic exanthem (ULTE) is an with a collarette of scale over the trunk. eruption that begins unilaterally in the axillae or groin, and spreads centrifugally (FIGURE 9). It has a virus and influenza virus in the winter [93]. The prolonged course and usually resolves within 4–6 exanthem usually consists of erythematous weeks. ULTE was first described as a new clini- macules and papules, but may be urticarial [94,95]. cal entity by Bodemer and de Prost in 1992 [83], but, in the past has been described under dif- Conclusion & future perspective ferent names from as early as 1962 [84,85]. In the Our understanding of certain viral exanthems has literature, ULTE has other designations, such as expanded significantly since the original descrip- asymmetric periflexural exanthem and unilateral tion of the classic exanthems of childhood. Many mediothoracic exanthem [86,87]. viral diseases, such as measles, rubella and varicella, Clinically, ULTE is usually preceded by an are now preventable with vaccination. However, upper respiratory or gastrointestinal prodrome, our understanding and recognition of new viral- and is characterized by a unilateral and local- associated exanthems continues to expand. In the ized exanthem, often in the axillary region case of papular acrodermatitis of childhood, what (FIGURE 9), which spreads in a centrifugal pattern, was once thought to be a manifestation of hepa- sometimes reaching the contralateral side. The titis B is now recognized to be a manifestation of mucous membranes, face, palms and soles are a number of infectious agents, including viruses. generally spared. In the case of acute generalized exanthematous 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 . The diagnosis is made clinically and treatment is supportive.

Nonspecific viral exanthem A 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 , adeno- Figure 9. Erythematous papules over the virus, parainfluenza virus, respiratory syncytial left axillae and upper left trunk.

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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 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.

pustulosis, what was once thought to be a drug- striatus. Improving laboratory testing in combina- induced exanthem is now recognized to have viral tion with continual clinical sleuthing may pro- triggers. In the case of parvovirus B19, the ability to vide clues to the role of viruses in these and other detect the virus in seronegative patients using PCR exathematous disease in childhood. has been useful in linking the virus to erythema infectiousum, as well as other manifestations, such Financial & competing interests disclosure as PPGSS and generalized petechiae. The author has no relevant affiliations or financial involve- There are still cases of exanthematous disease ment with any organization or entity with a financial interest where the roles of viruses have yet to be fully elu- in or financial conflict with the subject matter or materials cidated. These include the association of HHV-6 discussed in the manuscript. This includes employment, con- and -7 reactivation in drug hypersensitivity syn- sultancies, honoraria, stock ownership or options, expert drome, the role of viral triggers in Kawasaki syn- testimony, grants or patents received or pending, or royalties. drome and the role of viruses in dermatological No writing assistance was utilized in the production of conditions with seasonal clustering, such as lichen this manuscript.

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