Atypical viral exanthems:
New rashes and variations on old themes

By K. Robin Carder, MD, and William L. Weston, MD

A viral skin eruption that doesn't follow a familiar or classic pattern can confuse the diagnosis, leading to unnecessary tests when only reassurance is needed. This practical guide to recently identified, less known, and atypical viral rashes of childhood takes the mystery out of your evaluation.

Viral skin eruptions are familiar to pediatricians and dermatologists alike. Yet such eruptions can be a source of great confusion.

Consider the child who is brought to you with a "rash." She (or he) may have a concurrent fever or other nonspecific symptoms such as an upper respiratory infection, sore throat, malaise, or lymphadenopathy. Or she may have only the rash without a history of associated illness. As clinicians, we are accustomed to and comfortable with certain patterns. We easily recognize an eruptive, pink, papular rash following a high fever as roseola or exanthem subitum. Red, "slapped" cheeks followed by a reticulate erythema on the extremities suggest erythema infectiosum (fifth disease). We would still recognize red macules and distinct pink-red papules in a child with high fever, coryza, and conjunctivitis as measles, even though effective vaccination has made measles uncommon.

But it is the eruption that does not follow a recognized or classic pattern that makes us uncomfortable. Sometimes an eruption follows a classic pattern—but the child is the wrong age. At other times, the lesions look familiar, but their distribution is unusual—they appear on only one side of the body, for example.

We examine the child with the unfamiliar eruption and try to assemble the pieces of the puzzle, aware that the parents are concerned and looking to us for help, reassurance, and a diagnosis. We think through a differential diagnosis, but it raises more questions than answers. Should we order laboratory studies? Perform a skin biopsy? Prescribe antibiotics or a topical steroid?

The goal of this review is to remove some of the mystery from the evaluation of viral eruptions. Realizing that most diagnostic dilemmas do not involve more common eruptions, we focus on recently identified and less-known viral skin conditions (Table 1). We also consider unusual or atypical presentations of more familiar viral eruptions. We describe the clinical signs and symptoms of each condition, review helpful laboratory or histologic studies, and, most important, offer a differential diagnosis to help distinguish between similar eruptions.

TABLE 1
New or atypical viral exanthems

Asymmetric periflexural exanthem of childhood (APEC)

Gianotti-Crosti syndrome

Papular-purpuric gloves-and-socks syndrome

STAR complexes

Atypical pityriasis rosea
  Inverse
  Vesicular
  Purpuric, erythema multiforme-like, urticarial

Infectious mononucleosis in toddlers

Asymmetric periflexural exanthem of childhood

Taïeb and colleagues first described asymmetric periflexural exanthem of childhood (APEC), also called unilateral laterothoracic exanthem, in 1986 (Table 2).¹ Two published case series have evaluated the characteristics of this eruption.^1,2 Both found a female predominance. The condition also appears to be seasonal, with peak occurrence in the spring. As the name implies, the exanthem affects young children, between 1 and 4 years of age, with a mean age of onset of 2 years. Interestingly, two familial cases have been described.²

TABLE 2
Asymmetric periflexural exanthem of childhood

Etiology is unclear*

Female predominance

Peak occurrence in spring

Mean age of onset is 2 yr

Progression of skin lesions is typical
  Week 1: Unilateral erythematous papular eruptions near the axilla
  Week 2: Centrifugal spread, morbilliform or eczematous, asymmetric
  Week 3: Lesions resolve
  Week 4: Residual skin dryness only

Variable constitutional symptoms
  Regional lymphadenopathy
  Pruritus
  Fever
  Rhinopharyngitis, diarrhea, vomiting, otitis

Spontaneous resolution in 3­6 wk

Biopsy is nonspecific

No treatment available; antibiotics and topical steroids are not helpful

*Most likely viral

The initial eruption is strikingly unilateral. Classically, a pink-red papular eruption appears first in the area of the axilla, on one side of the body only (Figure 1); the left side was affected more often in one series.² Less often, the lesions appear first on the thigh, flank, or inguinal fold. The palms, soles, and face are always spared. Occasionally, the lesions are serpiginous (circinate) with central blue-gray coloration.

By the end of the first week, the eruption spreads centrifugally, away from the axilla, and may become bilateral or generalized. Despite the spread, the papules remain asymmetric with greater involvement of the originally affected side. After the first week, the lesions may appear more scarlatiniform, morbilliform, or eczematous. By the third week, the pink-red lesions resolve, leaving only residual dry skin at week four. The eruption resolves spontaneously in three to six weeks in most cases, although one case was reported to have persisted for four months.¹ No lasting sequelae have been reported after the lesions resolve.

Most children are otherwise asymptomatic, although half may experience mild or moderate itching. Localized lymphadenopathy may develop in the area where the eruption began. Some children have fever, sore throat, otitis, vomiting, or diarrhea at or near the time of the eruption.

The cause of APEC remains unknown. A viral etiology has been suggested because of the young age group, seasonal occurrence, reports of familial involvement, and occasional lymphadenopathy and fever.² In the two case series, laboratory tests did not show evidence of infection. Tests performed included complete blood cell count, liver function tests, throat cultures, and tests for Epstein-Barr virus (EBV), cytomegalovirus (CMV), parvovirus B19, hepatitis, coxsackievirus, Borrelia burgdorferi, toxoplasmosis, Spiroplasma (one case tested positive with a low titer¹), Mycoplasma, and Rickettsia.

Skin biopsy findings are nonspecific. Histology reveals only epidermal spongiosis, exocytosis of mononuclear cells, and perivascular and periappendageal inflammation.² Because laboratory and histologic studies are nonspecific, diagnosis is based on clinical findings alone.

Although oral antibiotics and topical steroids have been given to treat APEC, they do not appear to alter the course of the illness.^1,2 In both case series mentioned, the time to resolution of lesions in treated and untreated children did not vary. Therefore, no treatment is indicated other than, perhaps, an oral antihistamine to relieve itching.

The unilateral onset of this eruption is unique. Eczematous conditions, such as allergic contact dermatitis or atopic dermatitis, can be unilateral, but they are much more pruritic, often weep or crust, and respond well to topical steroid therapy. The more morbilliform lesions of APEC may mimic miliaria, Gianotti- Crosti syndrome, or roseola, but differ in their unilateral distribution. Also, miliaria typically occurs on the face, an area spared by APEC. Gianotti-Crosti syndrome is localized to the face and extremities, whereas roseola is more generalized and transient (often fading within 24 hours). APEC also may mimic pityriasis rosea, but pityriasis rosea occurs more often in older children, is often preceded by a "herald" patch, and has larger, symmetrically distributed lesions that follow skin folds.

Gianotti-Crosti syndrome

The self-resolving eruption of Gianotti-Crosti syndrome (Table 3) was first described by Gianotti in Italy in 1955. Soon thereafter, he described an association between the syndrome and hepatitis B infection. Gianotti defined the association of the classic skin eruption with hepatitis B infection as true Gianotti- Crosti syndrome or papular acrodermatitis of childhood.^3,4

TABLE 3
Gianotti-Crosti syndrome

Etiology is a viral infection (see Table 4) or sequela of vaccination

Slight male predominance

More common in spring, early summer

Mean age of onset is 2 yr*

Skin eruptions
  Flat-topped, red-to-purpuric papules and papulovesicles
  Symmetric on face, buttocks, extensors (elbows and knees)

Variable constitutional symptoms
  Lymphadenopathy (axillary, inguinal)
  Low-grade fever
  Pruritus (uncommon)

Spontaneous resolution in 3 or 4 wk

Biopsy is nonspecific

Laboratory findings
  Transient elevation of hepatic enzymes (if patient is hepatitis B­positive)
  Evaluation to determine infectious cause

Treatment is symptomatic (oral antihistamine for pruritus)

*Also reported in adults

Similar cases were later described after infection with nonhepatitis viruses and were termed papulovesicular acrolocated syndrome because they were thought to differ clinically from classic Gianotti- Crosti. The clinical findings associated with hepatitis B infection have since been shown not to differ significantly from those that follow infection with other viruses.⁵ Most people now believe that all such cases should be designated as Gianotti-Crosti syndrome.^3­5

Gianotti-Crosti syndrome is typically a disease of young children. Caputo and colleagues reviewed more than 300 cases and found the mean age of onset to be 2 years (range, 6 months to 14 years).⁵ They also found that the condition was somewhat more common in boys and during the spring and early summer.

Onset is characterized by the appearance of monomorphous, 2- to 5-mm, red to red-brown, flat-topped papules (Figure 2). Lesions may also be flesh-colored or papulovesicular (blister-like papules). Occasionally, they appear purpuric on the lower extremities or edematous. The papules are distributed symmetrically on the face, buttocks, and extensor extremities (especially the cheeks, ears, elbows, and knees). The eruption typically begins on the legs and buttocks, then spreads upward toward the face within the first week. The flexor surfaces of the extremities and trunk are usually spared. Occasionally, the lesions are more widespread but remain dense on the extensor surfaces. Some lesions may demonstrate the Koebner phenomenon (accentuation in areas of trauma) early in the course of the eruption.

The eruption resolves spontaneously over three to four weeks with residual desquamation, but may persist for as long as two months.^3,4 Pruritus is uncommon.³

Variable constitutional symptoms may accompany Gianotti-Crosti syndrome. In one series, nonspecific viral symptoms such as fever, cough, rhinitis, and other upper respiratory tract symptoms preceded the eruption in six of seven cases.⁴ Lymphadenopathy, especially axillary and inguinal, occurred in approximately half of the children, and splenomegaly was noted in two (one of whom was the child who did not have viral symptoms). Each of the seven children had at least one associated sign or symptom. Hepatomegaly is noted more often in hepatitis B­associated cases, but more serious hepatitis-related sequelae seldom occur.³

The association of Gianotti- Crosti syndrome with hepatitis B virus is strongest in Italy and Japan and most often involves the ayw subtype of the virus; less often, the adw or adr subtype is involved.³ Hofmann and colleagues detected hepatitis B virus in none of seven affected patients in Germany, but found evidence of EBV virus in five of them.⁴ No clear viral etiology was found in the remaining two patients, but both had received immunizations (polio and DTP plus polio) two to three weeks before onset of the eruption. Several viral and bacterial infections and several immunizations have been implicated in the etiology of Gianotti-Crosti syndrome (Table 4). In Europe and North America, EBV appears to be most often associated with Gianotti- Crosti.⁴

TABLE 4
Associations with Gianotti-Crosti syndrome

Viral infections

Adenovirus
Coxsackievirus
Cytomegalovirus
Echovirus
Enterovirus
Epstein-Barr virus (most common)
Hepatitis A, B, and C
Human immunodeficiency virus
Parainfluenza virus
Parvovirus B19
Poliovirus
Respiratory syncytial virus
Rotavirus
Rubella

Bacterial infections
Group A ß-hemolytic streptococcus
Mycobacterium avium-intracellulare (with HIV)

Immunizations
Diphtheria
Influenza
Pertussis
Polio
Tetanus
Vaccinia

Laboratory findings are not characteristic, with the exception of transiently elevated levels of hepatic enzymes in cases associated with hepatitis B virus. Because hepatitis B­ induced cases are rare outside Italy and Japan, possibly as a result of early vaccination, evaluation for hepatitis B is often unnecessary. Reserve testing of the hepatitis B surface antigen level for patients with a history of hepatitis B exposure, systemic symptoms (hepatomegaly, splenomegaly, diarrhea), elevated hepatic enzyme levels, or Italian or Japanese heritage. If lymphadenopathy, fever, or sore throat is present, testing for EBV, which is more likely to be the causative agent in Europe and North America, is recommended.

Biopsy is unwarranted because the histopathology of Gianotti-Crosti syndrome is nonspecific. Findings include hyperkeratosis, acanthosis, and focal parakeratosis of the epidermis. Perivascular inflammation can be seen in the superficial dermis.³

The distribution and appearance of lesions in Gianotti-Crosti syndrome are characteristic, and the diagnosis is largely clinical. The lesions, when purpuric, may occasionally be confused with those of Henoch-Schönlein purpura. In Henoch-Schönlein purpura, however, the lesions typically do not involve the face and arms, and gastrointestinal, renal, and joint symptoms are often present.

Lichenoid eruptions also may resemble those of Gianotti-Crosti syndrome. The lesions of lichenoid drug eruptions tend to occur on areas exposed to the sun, however, and are uncommon on the buttocks. They also persist until the offending medication is discontinued (see "Is it a drug rash or a viral eruption?".). Pityriasis lichenoides et varioliformis acuta (PLEVA) is characterized by recurrent crops of crusted lesions over weeks to months—unlike Gianotti-Crosti, in which lesions are not crusted and resolve within one month without recurrence.

As with asymmetric periflexural exanthem, treatment of Gianotti- Crosti syndrome is indicated only if the child is symptomatic. Oral antihistamines relieve itching; topical steroids also have been used to control itching but do not usually improve the appearance of the skin or shorten the duration of the skin lesions.³ In fact, topical steroids occasionally exacerbate the eruption, causing an abrupt increase in the number of skin lesions.⁶ For this reason, steroids are generally discouraged.

If hepatitis B virus or EBV is present, precautions should be taken to prevent spread of infection. Obtain a history of the patient's contacts, and, if indicated, evaluate them for evidence of infection.

Papular-purpuric gloves- and-socks syndrome

Also known as petechial glove-and-sock syndrome, papular-purpuric gloves-and-socks syndrome (Table 5) was first described by Harms and colleagues in 1990.⁷ They reported a distinct pruritic, erythematous, petechial eruption of the hands and feet that appeared suddenly, then spontaneously regressed within days of onset. Since then, many more cases have been reported.

TABLE 5
Papular-purpuric gloves-and-socks syndrome

Etiology is a viral infection (parvovirus B19)

Most often affects Caucasian children and young adults (9­45 yr), male and female

More common in spring and summer

Skin eruption
  Pruritic or tender erythema and edema of hands and feet
  Progression to confluent petechiae (palmoplantar and dorsal surfaces)
  Sharp demarcation at wrists and ankles
  Enanthem (petechiae, aphthae, erosions, edema, vesicles)
  Occasional lesions of face, buttocks, extremities, groin, trunk

Variable constitutional symptoms
  Lymphadenopathy
  Transient fever (to 39° C)
  Arthritis, arthralgia
  Anorexia or myalgia
  Respiratory or gastrointestinal symptoms

Spontaneous resolution in 1­2 wk

Biopsy is nonspecific

Laboratory results
  Anemia, leukopenia, or thrombocytopenia
  Elevated AST
  Determine viral cause
    Presence of parvovirus B19 IgM or IgG antibodies
    Polymerase chain reaction of skin or serum for parvovirus B19 DNA

No treatment available

Children and young adults (9 to 45 years of age) are affected most often,⁸ although the eruption has been reported in children as young as 22 months.⁹ Most cases involve Caucasians, males and females, and tend to occur in the spring and summer.⁸

The typical presentation begins with a progressive redness and swelling of the hands and feet,^8-10 often accompanied by itching or tenderness. Onset is sudden and redness is strikingly symmetric. The eruption progresses to numerous, confluent petechiae on the palmoplantar and dorsal surfaces of the hands and feet over the first few days (Figure 3). A characteristically sharp demarcation at the ankles and wrists can be noted. Often, petechial or purpuric lesions appear on the trunk, extremities (especially the inner aspect of the thighs), groin, genitalia, and face. A characteristic enanthem—erosions, vesicles, petechiae, diffuse redness, edema, or aphthae—may occur on the oral mucosa, including the tongue, lips, and palate. The cutaneous lesions resolve spontaneously in one or two weeks with only residual fine desquamation on affected areas.

Systemic findings are occasionally noted before or during the eruption of papular-purpuric gloves- and-socks syndrome.^8­10 Signs and symptoms may include lymphadenopathy, transient fever (to 39° C), sore throat, myalgias, anorexia, diarrhea, malaise, and upper respiratory symptoms.

Laboratory findings are variable but tend to be mild and transient. The most commonly noted laboratory changes are leukopenia, thrombocytopenia, anemia, and elevation of serum aspartate aminotransferase (AST).^8,10

Skin biopsy findings are nonspecific. Histopathology reveals an interstitial perivascular lymphocytic infiltrate, focal vacuolization of the basal layer, and extravasated red cells. No evidence of vasculitis has been reported.^8,11

Most cases of papular-purpuric gloves-and-socks syndrome are thought to be associated with human parvovirus B19 infection.^8,10,11 Parvovirus seroconversion can be demonstrated by a rise in the parvovirus B19 IgM and IgG antibody levels using enzyme-linked immunosorbent assay (ELISA), but these changes often are not seen until a week or more after onset of the eruption.⁸ A polymerase chain reaction (PCR) assay for parvovirus B19 DNA permits earlier detection.⁸ Parvovirus B19 is known to be associated with several other conditions, including erythema infectiosum (fifth disease), transient aplastic crisis (in those with hemolytic anemia), chronic anemia (in immunodeficient patients), fetal hydrops, arthropathy, and purpura, including cases of Henoch-Schönlein purpura.^8,11,12

Parvovirus B19 may not be the only cause of papular-purpuric gloves-and-socks syndrome, however. Cases have been reported in association with coxsackie B6 infection¹¹ and with simultaneous human herpesvirus 7 and parvovirus B19 infection.¹³

The clinical course is typically mild and self-limited. All signs and symptoms resolve spontaneously within one or two weeks.^8­11 Recurrences have not been reported.⁸ No treatment is indicated as the symptoms tend to be mild and transient.

Keep in mind this important difference in the immune response to parvovirus infection associated with papular-purpuric gloves-and- socks syndrome compared with erythema infectiosum: In erythema infectiosum, the eruption appears after the IgM-IgG immune response and clearance of the viremia.⁸ Affected children are therefore no longer contagious and do not need to be isolated. In contrast, the eruption of papular-purpuric gloves- and-socks syndrome often appears before the immune response (the patient is seronegative for parvovirus B19 at onset of the eruption). Because viral shedding may still be present, appropriate infectious precautions must be taken until IgM antibodies to parvovirus B19 are noted.⁸

Early papular-purpuric gloves- and-socks syndrome may be difficult to distinguish from acral erythema. The latter, however, is associated with chemotherapy, tends to affect the palms and soles only (not the dorsal surfaces), and does not produce petechiae. Erythema multiforme also may produce palmoplantar lesions, but the lesions appear target-like (larger erythematous macules with dusky centers) and are more widely distributed. Also, patients with erythema multiforme often have a history of a preceding herpes simplex infection.

Palmar erythema and edema are classic findings in Kawasaki disease, but Kawasaki disease typically affects a much younger age group, and the associated erythema does not exhibit blanching as occurs with gloves-and-socks syndrome. Conjunctivitis, mucosal erythema, and prolonged high-grade fever, typical of Kawasaki disease, are absent in papular-purpuric gloves-and-socks syndrome.

The purpura and petechiae of gloves-and-socks syndrome could also mimic meningococcemia or Rocky Mountain spotted fever. Meningococcemia, however, presents with headache, prominent flu-like symptoms, hypotension, more generalized gray-purple skin lesions, and gram-negative diplococci on examination of a skin or blood smear. History of a tick- bite, headache, periorbital edema, and generalization of lesions would favor Rocky Mountain spotted fever.

STAR complex

This symptom complex comprises a Sore throat, elevated Temperature, Arthritis, and Rash.¹⁴ Rather than a specific illness with a specific cause, it is a group of symptoms shared by many conditions. Most of these conditions are caused by a virus and are self-limited, but it is important to distinguish them from chronic diseases, such as juvenile rheumatoid arthritis, which also may present with the STAR complex.

Jundt and Creager described 20 patients between 3 and 48 years of age with this complex.¹⁴ Most were seen between January and March. Several temperature spikes a day, to 41° C, were noted. Sore throat or a nonexudative pharyngitis occurred intermittently over a period of one to 102 days. Cultures for streptococci were negative in all cases.

The arthritis tended to be migratory and polyarticular, most often affecting the knees, ankles, and metacarpophalangeal and proximal interphalangeal joints of the hands. The intensity of individual joint pain was moderate or severe and lasted hours or days.

All affected patients experienced a recurrent pruritic, urticarial rash lasting minutes or hours at a time. The eruption most often appeared on the trunk and proximal extremities. Several patients also developed an erythema multiforme-like rash, and a few had facial swelling or lesions resembling erythema marginatum. Skin biopsy was nonspecific, but showed findings consistent with urticaria.

More than half the patients in the series had a normocytic anemia and low-titer (1:160 or less) antinuclear antibody (ANA) positivity.¹⁴ Leukocytosis, including leukemoid reactions in two patients, was greater and of longer duration in patients with more severe symptoms.

The STAR complex can occur in association with several viral syndromes (Table 6). Parvovirus and rubella were detected most often.¹⁴ It is important to realize, however, that symptoms, including fever and joint pain, may persist for weeks or months even when the etiology is viral. Be careful not to label such children as having juvenile rheumatoid arthritis (JRA). In general, JRA has a more chronic course of symmetric arthritis involving large joints. The skin eruption of JRA consists of transient, pink-red papules on the trunk, and the ANA is often strongly positive (greater than 1:160).

TABLE 6
Viral causes of the STAR complex

Adenovirus
Coxsackievirus
Echovirus
Epstein-Barr virus
Hepatitis B
Parvovirus*
Rubella*

*Most common

Treatment of viral infection-associated STAR complex is symptomatic only. Most patients respond well to acetaminophen or another nonsteroidal anti-inflammatory drug for fever and joint pain. Antihistamines may be given for pruritus. Antibiotics have not proved to be effective.¹⁴ Methotrexate has been used with some benefit to treat a few patients with prolonged or severe arthritis.

Pityriasis rosea

Although pityriasis rosea is a common and familiar eruption, it continues to cause diagnostic dilemmas. Most of us recognize the pink, oval-shaped, scaly plaques that lie along the skin tension lines in a "Christmas tree" pattern and are preceded by a larger "herald patch." This is the classic presentation. Many variations of pityriasis rosea exist, however, both in type and pattern of lesions (Table 7), making recognition of the eruption more difficult.

TABLE 7
Atypical presentations of pityriasis rosea

Lesions
Erythema multiforme-like
Exfoliative dermatitis
Hemorrhagic or purpuric
Papular or lichenoid
Pityriasis gigantea
Urticarial
Vesicular, pustular, or bullous

Patterns
Inverse
Localized
Unilateral

Pityriasis rosea typically affects people between 10 and 35 years of age, although cases have been reported in infants under 1 year and adults over 80 years.¹⁵ It can occur in any season but appears to be less common in the summer.¹⁵ Only 5% of patients report a prodrome of headache, fever, gastrointestinal symptoms, or malaise.¹⁵ It has been estimated that only 80% of patients exhibit a herald patch and classic pattern of lesions.¹⁶ Twenty percent of all patients have no herald patch, and 5% have more than one patch (Figure 4).¹⁵

The typical herald patch is a single, pink-red, scaly plaque on the trunk (most common), neck, or extremities. It is often annular and may precede the generalized eruption by days or weeks. As a result, the herald patch may be mistaken for tinea corporis or nummular eczema.

The classic eruption of pityriasis rosea consists of multiple, 1 cm, thin, pink, oval, slightly scaly plaques on the trunk, proximal extremities, and, occasionally, the neck and face. The lesions characteristically follow the skin tension lines in a fir tree pattern, best observed on the trunk. The pattern can vary considerably, however.

One of the most common pattern variants is called inverse pityriasis rosea. In this variant, the lesions appear on the face and extremities—the sun-exposed areas typically spared in the classic form of the eruption. The lesions of inverse pityriasis rosea are often more papular than the classic lesions and can be confused with Gianotti-Crosti syndrome, which has a similar distribution of papules on the face and extremities. Occasionally, the eruption may appear on one side of the body, similar to asymmetric periflexural exanthem.¹⁶ Less often, pityriasis rosea may be localized. In some cases, lesions are limited to the face, neck, and shoulders.¹⁵ Some adults have a few, larger plaques that are more localized and persistent. This variant is referred to as pityriasis circinata et marginata of Vidal.¹⁵

Many times, the lesions themselves, rather than their distribution, assume a different appearance. The papular variant (Figure 5) is most common and tends to occur in children, pregnant women, and dark-skinned people.¹⁵ In this form, more classic plaques are interspersed with smaller, pink-brown, rough papules. Older lesions may appear more flat and thickened (lichenoid), resembling pityriasis lichenoides et varioliformis acuta, lichen planus, or a lichenoid drug eruption.

Sometimes, the lesions appear purpuric or hemorrhagic (Figure 6). It is important to recognize this variation to avoid a lengthy and expensive evaluation for hematologic disorders. The variant lesions appear as flat, purple-brown macules and may also show "cayenne pepper" spotting or petechiae similar to the lesions of pigmented purpura, a benign capillaritis which typically affects the lower extremities.¹⁷

Vesicular or bullous pityriasis rosea occurs in infants and children.¹⁵ The lesions resemble the small blisters along the fingers and toes seen in dyshidrotic eczema and may either precede the classic eruption of pityriasis rosea or occur simultaneously.¹⁸ Rarely, pityriasis rosea appears urticarial,¹⁵ erythema multiforme-like (target lesions),¹⁹ or large and plaque-like on the trunk ("pityriasis rosea gigantea").¹⁵ The plaques also may coalesce to create an exfoliative dermatitis.¹⁵

Oral lesions and nail changes may occur in pityriasis rosea but are seldom mentioned. One study noted oral lesions in 9% of cases.²⁰ The type of oral lesion varies. Petechial hemorrhages and erosions are most common, followed by red macules or plaques.²⁰ Although not common, dystrophic nail changes are seen in some cases. The nail findings and typical oval plaques of pityriasis rosea can be easily confused with guttate psoriasis, but the thicker, white, mica- like scales of psoriasis are lacking in pityriasis rosea.

Certain laboratory studies can help differentiate pityriasis rosea and other conditions. A negative potassium hydroxide preparation of a skin scraping helps rule out tinea corporis. Serologic studies for syphilis can be useful when secondary syphilis is a consideration. Skin biopsy can aid in identifying purpuric pityriasis rosea, which shows extravasated red blood cells in addition to the typical lymphocytic infiltrate, spongiosis, and focal parakeratosis.¹⁵ A medication history can be useful because pityriasis rosea-like eruptions have been associated with several medications, including barbiturates, captopril, clonidine, gold, isotretinoin, metronidazole, and penicillamine.¹⁵

Pityriasis rosea has recently been linked to human herpesvirus 7 infection.²¹ The eruption is self-limited and typically resolves in four to eight weeks. In cases that last beyond eight weeks, consider a diagnosis of pityriasis lichenoides chronica. Most cases of pityriasis rosea are asymptomatic, but some patients experience mild itching. In general, no therapy is needed, although ultraviolet B radiation (either phototherapy or sunlight) early in the course of the eruption hastens resolution of the lesions and may relieve itching.^15,22

Infectious mononucleosis

Although infectious mononucleosis, with its triad of fever, pharyngitis, and lymphadenopathy, is considered a disease of teens and young adults, a slightly different presentation worth mentioning occurs in young children.

Classic infectious mononucleosis is associated with EBV, but identical symptoms occur with CMV as well as with other types of infection (Table 8). In a study of 124 children with infectious mononucleosis, Lajo and colleagues found that 84% of cases tested positive for EBV and 16% were CMV­positive.²³ Mononucleosis caused by EBV occurred in all age groups but most often between 15 and 25 years. CMV­associated disease was significantly more common in children under 4 years of age. Fever was the most common symptom in both groups. Hepatosplenomegaly, upper airway obstruction, and skin rash were more common with CMV infection. Cervical lymphadenopathy and pharyngitis were more often seen in patients with EBV.²³

TABLE 8
Infectious mononucleosis

Clinical triad
Fever
Lymphadenopathy
Pharyngitis

Associated infections
Adenovirus
Corynebacterium diphtheriae
Coxiella burnetti
Cytomegalovirus*
Epstein-Barr virus*
Group A streptococci
Hepatitis A virus
Human herpesvirus 6
Human immunodeficiency virus
Influenza A and B viruses
Rubella virus
Toxoplasma gondii

*Most common

Infectious mononucleosis often begins with a nonspecific prodrome of headache, fever, fatigue, and malaise. Fever may reach 40° C and can persist for one or two weeks.²⁴ The pharyngitis may be exudative in 30% of cases, and petechiae often appear on the palate.²⁴ Most children with mononucleosis have pharyngotonsillitis.

Ganzel and colleagues followed 109 children admitted to the hospital with classic EBV­associated infectious mononucleosis.²⁵ Notably, one third were under 10 years of age. Of those admitted because of severe pharyngotonsillitis, more than half had moderate or severe airway obstruction; average age was 8 years. Young children were therefore not only hospitalized in large numbers for infectious mononucleosis, but also seemed more likely than older children to develop airway obstruction. Most improved with supportive therapy only.

Only 5% to 15% of patients with infectious mononucleosis have skin findings.^24,26 The eruption is nonspecific and can appear as petechiae, target lesions, urticaria, or red macules and papules. Most, if not all, affected people develop an itchy, red, papular eruption following ampicillin. It is important to realize that this does not indicate an allergy to the medication. Jaundice and eyelid edema occur occasionally.²⁴

Because all patients with infectious mononucleosis have been shown to have splenomegaly on ultrasonography,²⁴ it is advisable for children to avoid contact sports for at least one month after onset of symptoms to prevent splenic rupture. Rupture may, rarely, occur spontaneously without preceding trauma.²⁴ Neurologic complications may occur but are uncommon.

Laboratory studies include appropriate viral antibody titers. It is important to remember, however, that heterophile antibodies are detected less often both early in the course of the disease and in children under 4 years of age. Only half of children under 4 years have a positive heterophile antibody test.²⁴ Nevertheless, specific EBV antibody testing can be performed with accuracy in younger age groups. EBV also may be diagnosed by means of EBV viral capsid antigen (VCA) IgM and IgG antibodies. Findings of leukocytosis, atypical lymphocytosis, and elevated hepatic enzymes may aid in diagnosis as well.

Last, in differentiating streptococcal pharyngitis from infectious mononucleosis, remember that some children are chronic carriers of Streptococcus.²⁴ A positive bacterial culture does not, therefore, eliminate the possibility of infectious mononucleosis, and antibody studies should be repeated if symptoms persist.²⁴

Cutting through the confusion

Diagnosis of viral exanthems is not straightforward. The same virus may cause different clinical presentations, and similar presentations may be caused by more than one virus. Moreover, viral exanthems can mimic bacterial infection or drug eruption, and, conversely, bacterial infection and drug eruption can cause a viral exanthem—all causing great confusion. A detailed history of the progression of the eruption and associated symptoms is crucial in making a correct diagnosis. The history and careful examination of the pattern and type of cutaneous lesions are often the only tools needed to identify the viral syndrome.

By recognizing the atypical viral eruptions discussed here, you may be able to avoid costly and painful laboratory studies in situations in which only reassurance is needed. When further evaluation is warranted, recognizing a given syndrome may help direct the laboratory evaluation and avoid unnecessary tests or consultations.

REFERENCES

1. Taïeb A, Mégraud F, Legrain V, et al: Asymmetric periflexural exanthem of childhood. J Am Acad Dermatol 1993;29:391

2. Bodemer C, de Prost Y: Unilateral laterothoracic exanthem in children: A new disease? J Am Acad Dermatol 1992;27:693

3. Gelmetti C: Gianotti-Crosti syndrome, in Harper J, Oranje A, Prose N (eds): Textbook of Pediatric Dermatology. Oxford, Blackwell Science Ltd, 2000, pp 347­351

4. Hofmann B, Schuppe HC, Adams O, et al: Gianotti-Crosti syndrome associated with Epstein-Barr virus infection. Pediatr Dermatol 1997;14:273

5. Caputo R, Gelmetti C, Ermacora E, et al: Gianotti-Crosti syndrome: A retrospective analysis of 308 cases. J Am Acad Dermatol 1992;26:207

6. Hurwitz S: Clinical Pediatric Dermatology: A Textbook of Skin Disorders of Childhood and Adolescence, ed 2. Philadelphia, WB Saunders Company, 1993, p 130

7. Harms M, Feldmann R, Saurat JH: Papular-purpuric "gloves and socks" syndrome. J Am Acad Dermatol 1990;23:8504

8. Vargas-Diez E, Buezo GF, Aragües M, et al: Papular-purpuric gloves-and-socks syndrome. Int J Dermatol 1996; 35:626

9. Mancini AJ: Exanthems in childhood: An update. Pediatr Annals 1998;27:163

10. Halasz CLG, Cormier D, Den M: Petechial glove and sock syndrome caused by parvovirus B19. J Am Acad Dermatol 1992;27:835

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12. Lefrere JJ, Couroucé AM, Muller JY, et al: Human parvovirus and purpura. Lancet 1985;ii:730

13. Ongrádi J, Becker K, Horváth A, et al: Simultaneous infection by human herpesvirus 7 and human parvovirus B 19 in papular-purpuric gloves-and-socks syndrome. Arch Dermatol 2000;136:672

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15. Parsons JM: Pityriasis rosea update: 1986. J Am Acad Dermatol 1986;15:159

16. Repiso T, González-Castro U, Luelmo J, et al: Atypical pityriasis rosea in a 2-year-old. Pediatr Dermatol 1995;12:63

17. Paller AS, Esterly NB, Lucky AW, et al: Hemorrhagic pityriasis rosea: An unusual variant. Pediatrics 1982; 70:357

18. Griffiths A: Vesicular pityriasis rosea. Arch Dermatol 1977;113:1733

19. Friedman SJ: Pityriasis rosea with erythema multiforme-like lesions. J Am Acad Dermatol 1987; 17:135

20. Kay MH, Rapini RP, Fritz KA: Oral lesions on pityriasis rosea. Arch Dermatol 1985;121:1149

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22. Leenutaphong V, Jiamton S: UVB phototherapy for pityriasis rosea: A bilateral comparison study. J Am Acad Dermatol 1995;33:996

23. Lajo A, Borque C, del Castillo F, et al: Mononucleosis caused by Epstein-Barr virus and cytomegalovirus in children: A comparative study of 124 cases. Pediatr Infect Dis J 1994;13:56

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DR. CARDER was a fellow and instructor, department of dermatology, The University of Colorado Health Sciences Center, Denver, when this article was written. She is currently assistant professor, department of dermatology, The University of Texas Southwestern Medical School, Dallas.

DR. WESTON is professor and chairman, Department of Dermatology, The University of Colorado Health Sciences Center, Denver.

Is it a drug rash or a viral eruption?

Differentiating a viral exanthem from a drug-related rash is not always easy. A thorough medication history is important in the evaluation of any skin eruption. Ask not only about prescription drugs but about over-the-counter medications, recent vaccinations, vitamins, and herbal or homeopathic products. Certain medications, such as antibiotics, nonsteroidal antiinflammatory drugs, and anticonvulsants, are generally more likely to cause a skin reaction.

A clear sense of the timing of each medication relative to the time of onset of skin lesions can be very helpful. Medications started after the onset of the eruption are unlikely to be related. Eruptions most often occur in the first week or two after a medication is started, but they can occur after just a few doses or during the first three months of therapy.

Symptoms, signs, and a history of ill contacts at home or school can provide another clue to the cause of the eruption. Fever, malaise, pruritus, and arthralgias may occur in both viral and drug-related conditions. The lack of a symptom, such as itch, or the presence of more specific findings, such as sore throat, may suggest a viral condition. It is important to remember that a viral illness and a drug eruption may occur simultaneously, because most medications are started during an acute illness. In this situation, it may be helpful to ask if the eruption became worse or changed after a certain medication was started.

Attention to the appearance and pattern of the skin lesions is important. In general, drug eruptions tend to be symmetric and generalized but have no characteristic pattern. A morbilliform (measles-like) eruption is most likely to be confused with a viral eruption, often starting on the trunk and spreading to the extremities. Urticarial (hive-like) and vasculitic (purpuric or petechial) drug eruptions also tend to generalize. Typically, viral eruptions are pink or salmon in color, whereas drug eruptions are bright red. As discussed, the lesions of asymmetric periflexural exanthem, papular-purpuric gloves-and-socks syndrome, and pityriasis rosea occur in a characteristic pattern of distribution.

The acral and facial lesions of inverse pityriasis rosea and Gianotti-Crosti syndrome can mimic photosensitive (sun-induced) drug eruptions. Gianotti-Crosti syndrome tends to produce discrete papules that involve the more sun-protected skin on the buttocks, which would be unusual for a photosensitive drug eruption. Pityriasis rosea can be distinguished by its ovoid, slightly scaly papules, which tend to follow skin lines.

Laboratory tests to confirm a viral cause may be useful occasionally. Skin biopsy is not often helpful, however, because findings are nonspecific in many drug eruptions and most viral exanthems.

 

Robin Carder, William Weston. Atypical viral exanthems: New rashes and variations on old themes. Contemporary Pediatrics 2002;2:111.