Many viral infections have cutaneous manifestations. The term exanthem is derived from the Greek "exanthema," which means "a breaking out."1 More descriptively, "anthos" refers to a flower blossom and, thus, the term compares a child breaking out with a viral rash to a flower blossoming.2 An enanthem (enanthema) is an internal rash, especially one involving mucous membranes.
The exanthematous diseases of childhood were originally named according to the order in which they were reported: First disease - measles (rubeola); Second disease - scarlet fever; Third disease - rubella; Fourth disease - Duke's disease (not likely a true entity; possibly a scarlet fever variant); Fifth disease - Erythema infectiosum; and Sixth disease - roseola.3 Discussions in the following paragraphs review the four classic viral exanthems as well as others that are confirmed or presumed to be viral.
Measles (rubeola/First disease) is a very highly contagious disease caused by a paramyxovirus. In 2004 the Centers for Disease Control and Prevention (CDC) reported 37 cases of measles in the United States, the lowest number ever recorded.33 Measles is likely to be diagnosed in non-vaccinated groups of immigrants, those who are not immunized due to religious purposes, visitors from other countries (primarily eastern Europe, Asia, and the Middle East), and native-born American aid workers and church groups who have recently traveled to endemic areas. Humans are the natural host and reservoir of the virus. Spread by respiratory droplets, primary replication of the virus occurs in respiratory epithelial cells, with subsequent spread to the local lymph nodes and then to blood with resultant viremia. Upon exposure, the incubation period of measles is 10 to 14 days, after which a prodrome of fever, dry cough, pronounced coryza and rhinoconjunctivitis develops (see Figure Ia). One to two days prior to the onset of cutaneous lesions, an enanthem of gray-white papules develops on the buccal mucosa (Koplik's spots). The typical exanthem is composed of dark red to purple macules and papules that erupt over a period of 2 to 4 days. It often begins on the head (forehead, hairline, and posterior auricular scalp) with a cephalocaudad progression. Individual lesions often progress to confluence (see Figure Ib, page 23) and begin to fade around the fifth day, in the order in which they appeared.4
Figure la. Measles (rubeola) -Characteristic conjunctivitis. (Figures courtesy of Gary A. Dyer, MD)
Patients previously immunized against measles virus who showed a full antiviral response may exhibit atypical clinical manifestations if infected with the wild virus. Such patients may have high fever, cough, and pulmonary infiltrates, with little to no rhinoconjuncttvitis and a variable exanthem. Vesicles, petechiae, purpura, and acrai edema have all been described in association with "atypical measles."
Complications of measles include otitis, pneumonia, encephalitis, myocarditis, and a rare delayed neurodegenerative disorder, subacute sclerosing panencephalitis (SSPE), which begins years after the acute infection. Measles infection also induces a significant transient immunosuppression. Secondary infection and exacerbation of latent tuberculosis resulting from this immunosuppression is a major source of associated morbidity and mortality.5
Suspected cases should be evaluated with swabs of secretions for virus isolation and serologie testing. In patients with poor nutrition or in areas where vitamin A deficiency occurs, supplementation with vitamin A is strongly recommended. Measles vaccine was introduced in 1963 and is from an attenuated live virus. It is typically given along with mumps and rubella vaccines, with an initial dose at 12 to 15 months of age, with second dose given at 4 to 6 years of age. Adverse reactions to the MMR vaccine most commonly include fever (5% to 15%) and rash (5%) and are often due to the measles component.6
RUBELLA (GERMAN MEASLES)
Rubella (German measles/Third disease) derives its name from the Latin, meaning "little red." It was first described as a distinct disease in the German literature in the early 180Os and, thus, earned the moniker "German measles." Importantly, in March 2005 the CDC announced the elimination of endemic rubella and congenital rubella syndrome in the United States.7 However, rubella still occurs in other parts of the world and may be imported into the United States. The causative agent is a single-stranded RNA virus (togavirus)8 spread via respiratory droplets, and is moderately contagious. Infections usually occur in late winter to early spring. Humans are the only host. Upon infection of upper respiratory tract epithelial cells and replication in the local lymphoid organs, a subsequent viremia occurs after 5 to 7 days with dissemination of the virus. Infected patients shed virus from 7 days prior to the exanthem to 7 days after, although they are most contagious at time of the exanthem.9
Infection with rubella is typically mild and can be subclinical, especially in children. The incubation period is 16 to 18 days, after which a prodrome exhibiting fever, headache, malaise, lymphadenopathy, and upper respiratory symptoms may occur lasting 1 to 5 days. An enanthem of erythematous papules on the soft palate (Forschheimer's spots) is described but is not diagnostic. The relatively nonspecific exanthem occurs 7 to 10 days after infection (3 to 4 weeks after exposure) and is characterized by occasionally pruritic erythematous macules and papules on the face, which spread in a cephalocaudad fashion. Tender lymphadenopathy, especially in the occipital, posterior auricular, and cervical regions is often present, may last for several weeks, and can be a helpful clinical finding. As its name implies, the exanthem of rubella is usually fainter than measles, and individual lesions do not tend to coalesce (see Figure 2). The exanthem fades in 2 to 3 days in the order it appeared in association with development of the humoral immune response, signaling the end of the viremic phase. Arthralgia and arthritis, most often of the fingers, wrists, and knees, occurs most commonly in postpubertal females (up to 60%). Symptoms last 3 to 4 days (occasionally longer) and may fluctuate. Occasionally hepatitis, myocarditis, pericarditis, hemolytic anemia, neuritis, encephalitis, or thrombocytopenic purpura are noted.10
Congenital rubella syndrome is the most devastating potential outcome of rubella infection. Viremia in a pregnant woman naive to rubella virus leads to placental infection allowing for infection of the fetus. This is most likely during the first 16 weeks (especially the first 10 weeks) of pregnancy. Up to 85% of infants infected in first trimester will be affected and will develop features of congenital rubella. Infection after the first trimester puts the fetus at very low risk. The most common findings of congenital rubella syndrome are sensorineural deafness, cataracts, congenital heart disease, and CNS abnormalities.
The clinical diagnosis of rubella is unreliable, and laboratory confirmation of suspected cases should be sought. The presence in serum of anti-rubella IgM or a four-fold increase in IgG strongly suggests recent infection. Rubella vaccination is highly effective, with a single dose of live attenuated virus vaccine generating an effective lifelong response in >97% of patients. Females of childbearing age should be vaccinated unless there is proof of immunity. The vaccine is contraindicated in pregnant women (although data suggest it is safe), and vaccinated women should avoid pregnancy for 3 months after immunization.
figure Ib-MeaslesfrubeolaJ-Deeplyerythematousexanthemofmaculopapular lesions evolving in cephalocaudad fashion progressing to confluence.
Figure 2. Rubella - Characteristic exanthem of erythematous maculopapular lesions with minimal progression to confluence.
Enteroviruses and Associated Exanthems
parvovi rus b19
parvovirus b 19, the only parvovirus known to infect humans, is a small, single stranded nonenveloped dna virus. infections are more common in winter and spring, possibly following a 6 year cycle.11 spread is typically via respiratory droplets, although transmission via blood products and vertically from mother to fetus can occur. Infection is most common in school-aged children. Seroprevalence for parvovirus B 19 increases with age, and by 15 years old >50% of adolescents have anti-parvovirus antibodies.
Figure 3a. Fifth disease - Characteristic "slapped cheeks" of erythema infectiosum. Note lacy reticulate erythematous eruption of the extremities typical of later stages of Fifth disease.
Parvovirus B 19 uses the erythrocyte P antigen (globoside) as its receptor, explaining its strong tropism for erythrocyte progenitor cells (globoside is also present on placenta and fetal myocardium). Patients who are genetically deficient in globoside appear resistant to parvovirus B 19 infection.12 Initial respiratory tract infection and replication are followed by viremia after 4 to 14 days, which ends with the appearance of antiB19 IgM. IgG appears approximately 1 week after IgM and coincides with the rash and arthralgias.
ERYTHEMA INFECTIOSUM (FIFTH DISEASE)
The classic exanthem of parvovirus B 19 infection is erythema infectiosum or "Fifth disease." It is most common between 4 to 10 years of age and typified by bright red macular erythema of the cheeks with sparing of the nasal ridge and perioral areas (Figure 3a). Erythematous macules and papules appear 1 to 4 days later evolving into lacy reticulate erythema, most noticeable on the extremities. This lasts for 1 to 3 weeks or longer. The generalized exanthem may intensify with increased body temperature, and parents should be cautioned that this does not reflect recrudescence of the disease. Associated findings include arthralgia or arthritis in up to 10% of patients. It typically involves the small joints of the hands, wrists, knees, or ankles, is self limited, and is more common in adults, especially women.13 Fetal infection with parvovirus B 19 can lead to anemia with subsequent fetal hydrops, spontaneous miscarriage, and even stillbirth. The second trimester is the period of highest risk especially between 20 and 28 weeks. The risk of transplacental infection in women infected during pregnancy is about 30%, and the risk of fetal loss with infection is 8% to 10%. 14'15 Up to 60% of adult females are immune to parvovirus B 19, and while the overall risk, even in infected pregnancies, is low, parvovirus B19 remains the most common cause of hydrops fetalis. Because of the slow turnover of red blood cells in the normal host, the transient anemia and reticulocytopenia induced by parvovirus B 19 are not normally problematic. However, patients with conditions causing increased RBC destruction or decreased production (sickle cell anemia/ thalassemia/hereditary spherocytosis) can have aplastic episodes.
PAPULAR PURPURIC GLOVES AND SOCKS SYNDROME (PPGS)
An additional exanthem most commonly caused by parvovirus B 19 is papular purpuric gloves and socks syndrome (PPGS). Additional reported causes of this exanthem include Coxsackievirus B6, HHV6, hepatitis B, and Epstein-Barr virus. This characteristic exanthem occurs in young adults, especially in the spring and summer. Prodromal symptoms such as fever, anorexia, and arthralgia are mild. An enanthem exhibiting oral erosions, vesicles, swollen lips, and petechiae of the hard palate, pharynx, and tongue may be present. The exanthem is characterized by edema and erythema of both hands and feet with associated petechiae and purpura (see Figure 3b). The eruption may extend onto the dorsal surfaces but is sharply marginated at the wrists and ankles. Burning and pruritus are frequent. Treatment is symptomatic, and the eruption typically resolves over 1 to 2 weeks. In contrast to erythema infectiosum, in which the viremic (and, thus, infectious) phase of the illness ends prior to the development of the exanthem, it appears that PPGS patients develop mucocutaneous lesions, while viremic and patients are considered infectious when the exanthem is present.16
When confirmation of parvovirus B 19 infection is required, serologie studies for the presence of anti-parvovirus B 19 IgM are preferred, because positive results indicate infection within the past 2 to 4 months. Treatment is symptomatic, and nonsteroidal anti-inflammatory drugs may help the arthropathy. Supportive transfusions are utilized when necessary. In cases of persistent infection in the immunocompromised, intravenous immunoglobulin has been utilized and can precipitate the rash and joint symptoms of erythema infectiosum.
ROSEOLA INFANTUM (EXANTHEM SUBITUM/SIXTH DISEASE)
This characteristic exanthem is caused by human herpesvirus 6 (HHV-6) or 7 (HHV-7).17 These viruses are trophic for CD4+ T lymphocytes in which they replicate and may disseminate widely. Like all herpesviridae, latency is established. Both viruses may persist in salivary glands, peripheral blood mononuclear cells, and likely the genital tract.18 Additionally, HHV-6 commonly establishes latency in the brain.19'20 Interestingly, HHV-6 (and not HHV-7) is capable of site-specific integration into human chromosomes, and congenital infection (with HHV-6 DNA detected before third day after birth) may be acquired chromosomally from parents. Most infections occur between 6 months and 3 years of age, with a peak at 6 to 7 months. Over 90% of children are seropositive for HHV-6 by 12 months of age and the remainder by 3 years. HHV-7 infection occurs slightly later than HHV-6.21 HHV-6 infection is most common in the spring and is spread via respiratory droplets. With HHV-6, after a 9- to 10-day incubation period, a prodrome characterized by high fever (40 to 45 degrees C) develops. This may last for 3 to 5 days, and infants appear otherwise well. Up to 10% have febrile seizures, and up to 33% of febrile seizures before age 2 are caused by HHV-6 infection.22 Neonatal infections exhibit variable clinical findings, while children over 6 months old are more likely to have high fever.23 Approximately 50% of primary infections may be afebrile. An enanthem composed of red papules on the soft palate and uvula (Nagayama's spots) is described. Additionally uvulo-palatoglossal junctional ulcers reportedly have high positive and negative predictive values.24 With defervescence the typical exanthem appears, composed of rose pink macules and papules on the trunk, neck, proximal extremities, and occasionally the face (see Figure 4a, page 26). This fades in a few days. Patients are viremic from 2 days prior to the fever until the time of defervescence and rash onset The exanthem may be accompanied by mild upper respiratory symptoms, tympanic membrane injection, neurologic involvement, and cervical/occipital lymphadenopathy. HHV 6 may reactivate in the first weeks to months following organ or bone marrow transplant and the nonspecific clinical features in this setting may mimic acute graft versus host disease. Patients with HIV-I infection may be more susceptible to HHV-6 infection because the viruses co-infect CD4+ T cells. Diagnostic testing is currently limited to research laboratories, and treatment is supportive with antipyretics.
Figure 3b. Papular purpuric gloves and socks syndrome. Note petechial exanthem limited to distal lower extremities.
HHV-6 and HHV-7 have also been implicated in the development of pityriasis rosea, but this association requires further confirmation. Other viruses have been implicated in this disorder also. The characteristic exanthem often begins with a herald patch, a pink, scaly, oval patch typically located on the trunk or proximal extremities, often after a mild prodrome of fever, malaise, headache, and arthralgias. Over the next several days to weeks, a secondary eruption develops, composed of round to oval salmon-colored plaques in a Christmas-tree pattern, especially on the trunk (see Figure 4b, page 26). These lesions typically exhibit a fine collaret of scale. An "inverse" pattern of pityriasis rosea may occur, with most lesions located on the face, axilla, and groin with relative truncal sparing. About 25% of patients complain of pruritus. Lesions typically resolve in 2 to 12 weeks but can persist for more than 5 months.25 Secondary syphilis must be considered in the differential for sexually active patients or those with palmoplantar involvement. Treatment is supportive, and topical steroids exhibit variable efficacy. Both ultraviolet light and oral erythromycin have shown benefit in some reports.26
Figure 4a. Roseola -Characteristic fine maculopapu lar eruption with onset after defervescence after 4 days of high fever.
Figure 4b. Pityriasis rosea - Note Herald patch on lower right abdomen and secondary erythematous papulosquamous patches on abdomen.
Varicella-zoster virus (VZV) is a highly contagious member of the herpesvirus family. VZV is very stable, and high levels of virus are detectable in fluid from cutaneous vesicular lesions in patients with both primary varicella (chickenpox) and reactivation (herpes zoster). The virus rarely may also pass transplacentally from mother to fetus. Older patients not previously exposed to the virus, immunocompr orni sed, and pregnant patients often exhibit more severe infections. Primary infection is spread via respiratory droplets. After inhalation of the virus, it infects upper respiratory tract cells. Initial replication in regional lymph nodes is followed by primary viremia 4 to 6 days later. Approximately one week after the primary viremia, a secondary viremia occurs with dissemination of virus to skin and internal organs leading to the typical lesions. Spread to the respiratory tract begins the period of contagiousness. A prodrome of 1 to 2 days of low grade fever, occasionally mild abdominal pain, headache, malaise, anorexia, cough, coryza, sore throat, and pruritus is often present. The typical rash appears in crops, with the number of individual lesions quite variable. Lesions in various stages of development are frequently present. Within households the index case often exhibits fewer lesions with secondary contacts exhibiting more severe infection, probably reflecting a higher infecting dose of virus. The exanthem usually begins on the head and torso and spreads centrifugally. Lesions begin as red macules and progress to become papules, vesicles, and pustules with eventual crusting. Vesicles on an erythematous base exhibit the typical appearance of "dewdrop on a rose petal" (see Figure 5, page 27). An enanthem of erythematous lesions in the oropharynx may occur. New lesions develop over 3 to 5 days with crusting by day 6 and complete healing in several weeks (1 to 4 week range). Congenital varicella is seen in about 2% of children born to nonimmune women who develop varicella in the first or second trimesters of pregnancy. This syndrome exhibits intrauterine growth retardation, central nervous system, limb, ocular, and skin abnormalities. The severity of fetal disease is not related to the extent of maternal disease. In contrast, the development of maternal herpes zoster has not been associated with fetal injury. In mothers developing primary varicella within 5 days before to two days after delivery, the virus is transmitted transplacentally yet there is no passage of maternal antibody. In such cases, infection of the neonate is likely to be severe and widespread, and treatment with acyclovir and varicella-zoster immune globulin (VZIG) or IVIQ, if unavailable, is indicated as mortality can be substantial. Maternal varicella occurring more than 5 days antepartum allows sufficient time for antibody production and transplacental passage. Affected infants typically have a mild illness and do not usually require VZIG or IVIG, although acyclovir has been used. Patients are infectious from 2 days prior to exanthem onset until all lesions are crusted (about 5 days). Patients should be observed for the development of secondary infection of lesions often indicated by rising fever, spreading erythema, or induration/ swelling.27'30
Figure 5. Primary varicella - Umbilicated vesiculopustules on erythematous bases scattered on the trunk
UNILATERAL LATEROTHORACIC EXANTHEM
Unilateral Laterothoracic Exanthem, also called asymmetric periflexural exanthem of childhood, was first described in 1962.31 This distinctive eruption often follows a low-grade fever, diarrhea, or rhinitis. However, a specific virus has not been implicated, and transmission to close contacts has not been routinely documented. Patients are typically 6 months to 10 years of age with most about 2 years old. There is a maleto-female ratio of 1 to 2, and most patients are white. The majority of cases begin in the spring. The characteristic exanthem begins unilaterally, most commonly around an axillary vault, but it can also begin on the trunk, arm, or thigh. Within two weeks, the exanthem becomes bilateral. Individual lesions may be morbilliform or eczematous (see Figure 6). The face, palms, and soles are typically spared. Up to 66% of patients complain of pruritus. Localized lymphadenopathy may be palpated in the most affected axilla. The eruption typically lasts 3 to 6 weeks and resolves without recurrence; however, some cases can last up to 3 to 4 months. Treatment is supportive as topical steroids are of minimal benefit.32
Figure 6. Unilateral laterothoracic exanthem - Eczematous eruption following several days of gastrointestinal illness. Onset in left axilla with gradual spread along left trunk
GIANOTTI-CROSTI SYNDROME (GCS)
Gianotti-Crosti syndrome (GCS), also called papular acrodermatitis of childhood, is a characteristic symmetrical aerai eruption affecting children. Most are between 1 and 6 years of age. GCS was first described in Europe associated with hepatitis B infection.33 In North America, Epstein-Barr virus is the most common etiologic agent, although cytomegalovirus and Coxsackievirus have also been reported. Immunizations with the MMR, DPT, influenza, and BCG vaccines apparently have also triggered GCS.34 Patients often exhibit a prodrome of upper respiratory infection, cough, and fever. Occasionally, systemic findings are noted including lymphadenopathy, hepatomegaly, and splenomegaly. The exanthem is composed of symmetric, homogenous, flat-topped pink-brown papules distributed classically on cheeks, extensor extremities, and buttocks (see Figure 7). Occasionally, hemorrhagic or moist eczematous papules are noted. Lesions typically last for 15 to 20 days, but some have lasted 8 weeks or more.
Figure 7. Gianotti-Crosti syndrome - Typical symmetric erythematous papular lesions on aerai surfaces.
This hemangioma-like exanthem was first reported in association with echovirus infections (echovirus 25 and 32). The exanthem is composed of small 2 to 4-mm erythematous papules with a central pinpoint vascular supply and surrounding avascular halo. The lesions resemble cherry angiomas and are few in number (often <10). They are typically located on the face, trunk, and extremities and direct pressure on the lesions causes complete blanching. The lesions are transient, resolving in 10 days. Treatment is supportive. Recently, outbreaks in adults and secondary to insect bites have been reported.35'38
Figure 8. Hand-Foot-and Mouth disease - Typical asymptomatic gray vesicles on erythematous bases oriented along skin lines.
Numerous exanthems have been described in association with enteroviral infections. Hand-foot-and-mouth disease (HFM) is the most recognized. Epidemics of HFM occur about every third year in the United States and are typically caused by infection with Coxsackievirus Al 6 or enterovirus 71. Sporadic HFM is caused by Coxsackievirus A4 through A7, A9, Al O, B 1 through B3, and B5. Enteroviruses are highly contagious and spread via contact with nasal/oral secretions, fecal material, or aerosolized droplets in a fecal-oral or oral-oral fashion. In HFM, the incubation period is approximately 3 to 6 days. After virus implantation in the buccal or ileal mucosa, rapid spread to the lymph nodes occurs within 24 hours. A rapid viremia then occurs with neutralizing antibodies developing by day 7, and there is subsequent elimination of the virus. Infection is often more severe in infants and children. Enterovirus 71 may also lead to more severe infections. A 12to 36-hour long prodrome with low-grade fever, anorexia, malaise, abdominal pain, sore mouth, and cough is often noted. The classic enanthem precedes the exanthem and exhibits red macules becoming small vesicles on an erythematous base. The vesicles are evanescent and rapidly break down into painful ulcers. Often only 5 to 10 lesions are present The exanthem of HFM is distributed on the hands, feet, and buttocks. Individual lesions are erythematous macules, which develop a central, often elliptical, gray vesicle with the long axis parallel to skin lines (see Figure 8). These lesions are asymptomatic and resolve in 3 to 7 days.39'40 Nail matrix arrest with resultant nail shedding following HFM is temporary.41 Complications of Coxsackievirus infection include myocarditis, pneumonia, meningoencephalitis, and rarely death (except in neonates). Treatment is typically supportive. Other exanthems caused by enteroviral infections are summarized in the Table (see page 23). Pleconaril has shown efficacy in enteroviral infections but is not FDA approved.
Many viral infections exhibit cutaneous lesions. Recognition of the exanthems associated with these infections and the broader clinical scenarios in which they occur can lead to more rapid diagnosis and appropriate treatment for affected patients.
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Enteroviruses and Associated Exanthems