Title: Viral exanthems
Authors: Lycia A. Scott, MD,  Mary Seabury Stone, MD
Affiliations: Department of Dermatology, University of Iowa Hospitals and Clinics, Iowa City, Iowa. lycia-scott@uiowa.edu
Citation: Dermatology Online Journal 9 (3): 4

Abstract: 

Viral exanthems are mostly self-limited diseases; however, in some cases diagnosis of an exanthem may be crucial to patients and their contacts. Certain exanthems have fairly characteristic morphology; however in many cases an accurate diagnosis cannot be made based on morphology alone.  Historical factors may be helpful when evaluating these patients, specifically their disease contacts, immunization, season, previous exanthematous illnesses, and associated prodromal symptoms.  This manuscript reviews a number of common childhood exanthems.  We included the most common viral exanthems encountered by primary care physicians and dermatologists.  

Body: 
I: Introduction
Goodyear et al. performed a study of 100 children in 1991 with acute febrile illness and rash. Infectious agents were identified in 65 patients, with 72% of cases caused by viruses and 20% by bacteria.  Their findings suggest that most childhood exanthems, associated with fever, are viral in origin.[1]  Our intention is to help the clinician elucidate the etiology for a given rash using such clues as, prodrome, distribution, and evolution of the lesions.  In particular, a description of the rash morphology, systemic symptoms and appropriate treatment recommendations will be discussed.  For completeness, a synopsis of pertinent related literature is included.  In order to aid in the ease of reading and navigating this manuscript, topics have been organized alphabetically.


I: Eruptive pseudoangiomatosis
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Cherry et al., in 1969, reported a hemangioma-like exanthem in four children aged 8-11 months associated with Echovirus infection.  They described small erythematous papules with central pinpoint vascular supply and surrounding avascular halo.  Direct pressure resulted in complete blanching, and lesions were transient.  They hypothesized these lesions were either a direct effect of viral infection on endothelial cells causing capillary dilatation, or antigen-antibody complexes at the vascular site.[2]

In 1993, Prose et al. described three children with bright red papules occurring in association with upper respiratory symptoms consistent with a systemic viral infection; however no organism was isolated. Two 6 month old children and one 6 year old child were examined. All had 1-4 mm bright red papules that blanched completely. All resolved in 7-10 days. Skin biopsy obtained from the 6 year old showed several dilated capillaries with plump endothelial cells without vascular proliferation or inflammatory infiltrate. They proposed the name eruptive pseudoangiomatosis.[3]

In 1994, two additional cases were reported in siblings with similar skin changes and episodes of fever with diarrhea.  The authors proposed a transmissible vector, such as a virus, as the causative agent; however were unaware of the Cherry article and did not test for echovirus.[4]
Three additional cases were described in the British literature in 2000, with some peculiar features, none revealing evidence of echovirus infection.  The first patient had eruption of lesions when an acute lymphocytic leukemia began.  The second patient had no prodromal symptoms.  In the third patient, there was an increase in lymphocytes when lesions first appeared.  Bacterial cultures were negative.  This same patient had recurrent eruption over three years, always associated with fever; there was no elevation in lymphocytes with subsequent flares.  This pattern had not been previously noted with eruptive pseudoangiomatosis.  Combined, the serologic tests for Epstein-Barr-Virus, cytomegalovirus, Coxsackie virus, parvovirus B19, enterovirus, echovirus and adenovirus were all negative.[5]

In 2000, Guillot and Dandurand reported eruptive pseudoangiomatosis for the first time arising in adulthood.  They performed a retrospective study over ten years, noting eight women and one man with an eruption very similar to those previously reported in children.  Histologic findings in the four patients who were biopsied showed findings identical to the biopsy in the Prose et al. report.  A few differences were noted clinically, including that not all adults had prodromal symptoms and the duration of the disease was longer for the adults.  Onset occurred during hospitalization for treatment of cancer or asthma in four of the nine patients.  In the five remaining patients, two were hospitalized in a retirement home and one was a nurse in a psychiatric hospital.  The authors proposed that association with a health care setting suggested an infectious cause of the eruption despite negative serologic testing.[6] 

Ilona Frieden also discussed this possibility in a review, noting reports of bacillary angiomatosis secondary to Rochalimaea infections and recent reports of epidemic Kaposi's sarcoma caused by HHV-8 emphasize that vascular eruptions can be caused by infectious agents.[7]

Treatment of eruptive pseudoangiomatosis is supportive and the disease is self-limited.


I: Erythema infectiosum and parvovirus B19
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A Common childhood exanthem first described in 1889, this characteristic exanthem was termed "fifth disease" due to its position in the numerical classification of classic childhood exanthems (following measles, scarlet fever, rubella and Dukes disease, which is no longer considered a distinct disease).[8]  Erythema infectiosum is caused by an acute Parvovirus B19 infection.  Parvovirus is a single stranded DNA unenveloped virus, with a tropism for erythroid progenitor cells.
Erythema infectiosum has a worldwide distribution, with school outbreaks in late winter and early spring.[9]  It affects primarily the 4-10 year age group, with transmission via respiratory droplets.[10]  The incubation period is defined by days prior to appearance of rash, and ranges from 4 to 15 days.[8]   Occasionally, mild prodromal symptoms precede the rash; these include low grade fever, headache, pharyngitis, malaise, myalgias, nausea, diarrhea, and joint pain. The infectious period spans from seven days pre-eruption until the first appearance of rash in normal individuals.[11]   However, in patients with aplastic crises, they are potentially contagious for an extended period of time, including infectivity up to a week or more after the rash appears.[12] 
Erythema infectiosum is characterized by confluent erythematous edematous patches or plaques on the cheeks, sparing nasal bridge and periorbital regions. These "slapped cheeks" fade over 1 to 4 days. The rash spreads to the trunk and extensor extremities , which undergo patchy clearing resulting in a lacy reticular pattern.[8,12]   It may be pruritic. This eruption lasts 5 to 9 days but can recur for weeks to months with triggers such as sunlight, exercise, temperature change, bathing, and emotional stress. [11] 
An enanthem may be present consisting of erythema of the tongue and pharynx, often with red macules on the buccal mucosa and palate. Arthralgia or arthritis are seen in 10% of affected children, and typically involve large joints for a brief duration.[8]
In Adults, primary infection results in more severe constitutional symptoms. Fever, adenopathy, and arthritis, particularly in women, without a rash, is the usual course.[12,13]   If rash is present in adults it is usually a macular lacelike eruption beginning on the extremities and often progressing caudally.[12]
In parvovirus B19 infection severe outcomes may occur in three groups of patients.  These include the immunocompromised, the fetus and patients with hemoglobinopathies.  In the patients with chronic hemolytic anemias, a transient aplastic crisis manifested by anemia, reticulocytopenia, and red blood cell aplasia may result. Aplastic crisis may be seen in hereditary spherocytosis, sickle cell disease, G6PD deficiency, pyruvate kinase deficiency, iron deficiency, and the thalassemias.[8]   Aplasia is self-limited and responds well to transfusions.  Not all individuals have a clinically evident rash and they therefore serve as source for an outbreak.[14]  In normal individuals, parvovirus B19 infections are inconsequential since circulating erythrocytes have a long life span.  
In the immunocompromised patients (HIV, congenital immunodeficiencies, acute leukemia, transplant recipient, lupus erythematosus, and infants in first year of life), parvovirus B19 can cause a serious prolonged chronic anemia due to persistent lysis of RBC precursors. Administration of IVIG, which contains pooled neutralizing anti-B19 antibody, has been used successfully in immunodeficient patients.[12,14]
During pregnancy, parvovirus B19 infection may result in vertical transmission to the fetus, causing infection of erythroid precursors and extensive hemolysis, leading to severe anemia, tissue hypoxia, cardiogenic high-output heart failure, and generalized edema (hydrops fetalis). Most reported fetal losses secondary to parvovirus B19 have occurred in the first trimester of pregnancy.[10]    Immunity is conferred after infection, and 50% of women of child bearing age are seropositive to IgG with absence of IgM, indicating prior infection.[15]  The vertical transmission rate, in infants exposed to infected mothers during gestation (confirmed by IgG positivity in children at 1 year of age) is reported as 16% if exposed during the first 20 weeks and 35% after 20 weeks gestation.  The risk of developing hydrops fetalis from hemolytic anemia is 10%, and the rate decreases as pregnancy progresses.[12]  Levy et al. reviewed the literature and found rates of fetal loss, out of 334 cases, to be  6.5% and additional 0.6% with non-fatal hydrops fetalis.[10]  Newer reports estimate the incidence, up to 20 weeks, to be close to 9% for fetal loss and 3% for hydrops fetalis after the mother is infected.[15]
Other severe sequelae may rarely occur.  In 1997, a  nine month old boy developed encephalopathy associated with the onset of erythema infectiosum, resulting in permanent neurologic sequelae.[16]  More recently, a 2 year old boy developed acute cerebellar ataxia, thought to occur due to transient vascular reaction in the cerebellum during parvovirus B19 infection.[17]
Treatment of Parvovirus B19 infection is symptomatic.  Patients with chronic hemolytic anemias who develop transient aplastic crisis (pallor, weakness and lethargy) need to be treated for symptoms of anemia and may require blood transfusion.[12,14]   Pregnant women, with signs or symptoms suggestive of B19 infection or known recent exposure to infected contacts, should have serum B19 IgM and IgG titers drawn.[11]  If maternal infection is supported, by positive IgM and IgG levels then serial fetal ultrasounds should be performed to evaluate for changes of hydrops fetalis, and interpreted by an experienced physician.[10]  These patients should also be referred to a tertiary care center for cordocentesis and possible fetal blood transfusion, if indicated.[10,12,15] 
Since patients with aplastic crises are contagious for extended periods of time and immunosuppressed patients may have chronic parvoviral infection, droplet precautions are recommended when caring for those patients.[12]   Some patients may only have transient aplasia or erythrocyte crisis and in these individuals droplet precautions should be utilized for seven days.  Pregnant health care workers should be advised of the risks of participating in the care of these patients, and the educated about preventive measures which include non-participation in care of immunosuppressed patients or those with aplasia.[12]   However, routine exclusion of pregnant women from the workplace is unlikely to be effective since the virus is transmitted before the rash appears in routine cases.[11,12]  This philosophy also applies to allowing children attend school who have uncomplicated EI, since these children are not contagious. Transmission of parvovirus, like other infectious agents, is also likely lessened by routine hygiene practices.[12]  


I: Gianotti-Crosti syndrome (papular acrodermatitis of childhood) 
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This eruption was described in 1955 by Gianotti and again by Crosti & Gianotti in 1957, and  termed papular acrodermatitis of childhood.  Initially, most reported patients, from Italy and Japan, had an associated Hepatitis B infection.  However, Gianotti also described an near identical rash without associated Hepatitis B virus infection, which he termed papulovesicular acrolocated syndrome.[18-20]   Historically, papular acrodermatitis of childhood and papulovesicular acrolocated syndrome were characterized, respectively, by the presence or absence of Hepatitis B infection; however, this distinction has been more recently abandoned.[18]
As stated above, the vast majority of hepatitis-associated cases are in the Mediterranean and Japanese literature where there is a high prevalence of hepatitis B infection. Series of Gianotti-Crosti syndrome (GCS) cases in North America and Western Europe where hepatitis B infection is not as common, have demonstrated the presence other viral etiologies, such as EBV in addition to hepatitis B.[18,19]
In 1992, a retrospective review of 308 cases by Caputo et al. in Italy, found less than 25% of patients to have hepatitis B infection. Furthermore, they were unable to distinguish any difference in the exanthem between patients with and without hepatitis.[20]  Other more commonly reported associations include CMV, Coxsackie A16, Para influenza, MMR, influenza, diphtheria, pertussis, polio, and BCG vaccinations.[21]  A recent report by Andiran et al. reported a combination Measles and Hepatitis B vaccine as a new cause of GCS.[22] 
The majority of patients with GCS are in 1 to 6 year olds; however GCS has been noted to affect 3 month to 15 year olds.  Most patients will have a prodrome consisting of fever and upper respiratory symptoms.  The exanthem consists of discrete non-pruritic erythematous monomorphic papules and occasionally papulovesicles on the face, buttocks and the extensor surfaces of the extremities. The trunk is spared.  Patients may have an associated lymphadenopathy, hepatomegaly, or splenomegaly. The rash usually resolves in 2-3 weeks, although it may last up to 8 weeks.[23]
Treatment is symptomatic.  Appropriate evaluation is recommended if hepatitis suspected by history or physical exam.


I: Hand-foot-mouth disease
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This clinical entity was first reported by Robinson and Rhodes in 1958.  They reported an exanthem with associated fever and oral lesions was noted in over 60 persons in June and July 1957 in Toronto, Canada.  Coxsackie virus A16 was isolated from two-thirds of 27 stool specimens studied.  The next reported epidemic of Coxsackie reported occurred in Birmingham, England in the summertime of a 1960, and was reported by Alsop et al. who described vesicular lesions on the hands and feet with oropharyngeal lesions, terming the eruption, " hand foot and mouth disease".[24]
Hand-Foot-Mouth Disease (HFMD) is highly contagious, spread by oral-oral and fecal-oral routes.  It typically affects children under 10 years of age. Vertical spread from mother to fetus also occurs.  In temperate climates, like U.S., infection is more common during late summer and early fall.[25]
HFMD is caused by enteroviruses, members of the picornavirus group (single stranded RNA, unenveloped), and is most commonly associated with Coxsackie virus A16 or Enterovirus 71.[25]  Sporadic cases associated with coxsackie A 4-7, A9, A 10, B1-B3, and B5 have also been reported.  Infections are usually sporadic but epidemics do regularly occur. Epidemics tend to occur every three years in the U.S.[25]   Initial viral implantation in the buccal mucosa and ileal mucosa followed by spread to regional lymph nodes within 24 hours. Viremia rapidly follows and then spreads to oral mucosa and skin.  By the seventh day after infection, serum antibody levels increase and the virus disappears.[25]
After an incubation period of 3 to 6 days, a brief 12-36 hour prodrome occurs of low-grade fever, malaise, cough, anorexia, abdominal pain and sore mouth.  Patients may present with either enanthem or exanthem but most manifest both.  Painful ulcerative lesions occur anywhere in oral cavity, but  most commonly found on the hard palate, tongue and buccal mucosa. The exanthem begins as 2-8mm erythematous macules and papules, which progress through a short vesicular stage to form a yellow-gray ulcer with an erythematous halo. Lesions may coalesce, the tongue may become red and edematous, and pain may interfere with oral intake. Oral lesions resolve without treatment in 5 to 7 days.  The exanthem, characterized by 2-3 mm erythematous macules or papules with a central gray vesicle, usually appears shortly after oral lesions, with the hands more commonly involved than the feet.  The sides of the fingers and dorsal surfaces more often are involved than palms and soles.  Lesions appear elliptical, with long axis running parallel to skin lines. They range from being asymptomatic to painful.  They crust and gradually disappear over 5 to 10 days without scarring.[25]
Although most cases resolve with no long term complications; first trimester infection may lead to spontaneous abortion or intrauterine growth retardation.[25]  Other complications have been reported including, myocarditis, meningoencephalitis, pulmonary edema, and even death.[25]
Recent epidemics of HFMD with enterovirus 71 have been associated with neurologic complications. 
In September 1999, Huang et al. from Taiwan identified 41 children with confirmed enterovirus 71 infection, 68% diagnosed with HFMD and 15% with Herpangina.  Three neurologic syndromes were identified: acute flaccid paralysis (10%), aseptic meningitis (7%), and brain-stem encephalitis or rhomboencephalitis (90%).  Rhomboencephalitis which had a 14% fatality rate, most commonly presenting with myoclonic jerks, and an MRI showing brain stem involvement.[26]
Another report from Taiwan published in the Journal of Clinical Virology in 2000, noted an outbreak of enterovirus in 1998.  From April through December, 405 children were hospitalized with 78 deaths.  Enterovirus 71 was isolated in 119 cases, with resultant diseases of HFMD in 54, HFMD with CNS involvement in 37, herpangina in 12, aseptic meningitis in three, encephalitis/meningoencephalitis in ten and acute flaccid paralysis in three.  Nine fatal cases were complicated by neurogenic pulmonary edema.  The most critical early sign of Enterovirus 71 infection with CNS involvement was myoclonus with sleep disturbance.[27]
Treatment of HFMD is symptomatic, aimed at providing relief of painful oral lesions with agents such as viscous lidocaine, dyclonine solution, diphenhydramine, magnesium hydroxide and sucralfate. 
An open, uncontrolled study in 1996 by Shelly et al. studied 12 children and one adult with HFMD and treated these patients with oral acyclovir within 1-2 days after onset of the rash.  They observed symptomatic relief and involution of lesions within 24 hours.  The authors proposed efficacy by antiviral effect enhancement of the patients own interferon, since Coxsackie A16 lacks thymidine kinase (the enzyme inactivated by acyclovir).[28]


I: Herpangina

Herpangina was described as specific entity by Zahorsky in 1920. Reports of outbreaks in nursery schools and summer camps followed in 1939 and 1949. The first viral implication occurred later when Cole et al. isolated group A coxsackie virus from stool samples and throat washing in herpangina patients published in 1951.[29]
Herpangina is typically caused by Coxsackievirus group A1 to 6, 8, 10, and 22.  Other causes include coxsackie group B (strains 1 to 4), echoviruses, other enteroviruses.[30]
Herpangina affects any age group, but is seen primarily in infants and young children below the age of five. In temperate climates, infections occur in late summer or early fall.[29]  A febrile illness without oropharyngeal lesions or a subclinical infection may be seen in the siblings of a patient with herpangina.[29,31]
The incubation period ranges one to ten days, usually lasting four days.  This is followed by the  sudden onset of fever with malaise, headache, neck or back pain.  The enanthem consists of 1 to 2 mm gray white papulovesicular lesions which progress to ulcers surrounded by an erythematous rim with diffuse pharyngeal hyperemia. These are distributed on the anterior tonsillar pillars, soft palate, uvula, and tonsils and last 4 to 6 days. Affected patients often complain of anorexia, dysphagia, and sore throat.[31]  No associated exanthem is typically seen.  Rarely, neurologic complaints may ensue.[26]  The disease is self-limited with high fever rarely lasting more than four days and oral lesions rarely more than seven days.[31]  Treatment is symptomatic.


I: Measles (rubeola)
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There are descriptions of measles dating back to the tenth century.   During the seventeenth century measles was delineated from other diseases by clinical and epidemiologic observations by scientists such as Thomas Sydenham.  In 1954 Enders and Peebles isolated the measles virus in tissue culture, and in 1960 successfully attenuated the measles virus.[31]   Measles is caused by paramyxovirus, a ssRNA enveloped virus.   In 1963, the measles vaccine was introduced.  The initial recommendations for a single dose of vaccine at nine months, was changed to 12 months in 1965 and 15 months in 1976.   There was a dramatic reduction in the number of cases to a low in 1983 of 1,497 cases.[32]   
In the mid to late 1980's a resurgence of measles occurred, due to declining immunization rates in poor urban children, and the insufficiency of a single dose of vaccine to provide long term immunity.[32]  The incidence of measles then improved with intensive public health efforts and increased vaccination coverage.  In 2000, a total of 86 confirmed measles cases were reported to the CDC.  This represented a record low and a decrease from 100 cases reported each year for the previous two years.[33]  Currently, the majority of cases in urban centers occur in infants and toddlers; whereas in rural less crowded areas the highest incidence is in the 5 to 10 year old age range.[31]
Measles mainly occurs in the winter and spring, with peak incidence in March and April.[31]  The mechanism of infection is droplet spread of secretions.  The primary site of infection is the respiratory epithelium of the nasopharynx.  
The asymptomatic incubation period is 10-11 days, with a prodromal phase lasting 1-7 days.   Associated fever approaches 40 - 40.3 degrees C at the peak of the rash then falls quickly. Other symptoms, include severe common cold-like symptoms (coryza), and conjunctivitis which extends to the lid margin, resulting in a red-rimmed eye. There is also a brassy barking cough persisting for one week after coryza resolves.[31]
The rash is composed of erythematous macules and papules appearing behind the ears and at the anterior hairline, coalescing and then spreading over the neck and trunk distally then to the  upper and lower extremities including the hands and feet.[31]  Measles spreads more slowly than does Rubella, the entire body involved by the third day.  The rash fades in order of appearance, and as it disappears, it becomes nonblanching and brownish-yellow due to capillary hemorrhage.  Differing amounts of  fine branny desquamation may be seen.
Pinpoint elevations begin on the soft palate which coalesce as the entire pharynx becomes red, lasting 6-7 days.  On the tonsils Herman spots occur, described as bluish-gray areas. However, the pathognomonic lesions are Koplik spot's, which are as punctate blue-white lesions surrounded by an erythematous ring ("grains of sand" on a red background) on the buccal mucosa, opposite the second molars. Koplik's spots appear 1-2 days prior to the onset of the exanthem and remain for 2-3 days. Similar lesions are occasionally seen on the conjunctivae at the medial canthus and in the large intestines.[31]
Atypical measles occurs in patients who received killed viral vaccine (used in U.S. from 1963-67) and are subsequently infected with natural measles. High fever, myalgias, cough, headache, abdominal pain, edema of extremities, pleural effusion, pneumonia and hilar adenopathy occur. Lesions are erythematous maculopapules, which progress to petechiae, vesicles and palpable purpura, beginning on hands and feet and spreading centripetally. The major differential diagnosis is Rocky Mountain spotted fever.[31]
Modified measles occurs in partially immune host secondary to a prior infection, persistent maternal antibodies, or immunization. Clinically, the illness is much milder than ordinary measles. The course is shorter, the exanthem is less confluent, and Koplik spots may be absent.
Complications are more likely to occur in the very young and in the malnourished.  Encephalitis occurs in 1/800 cases, is unpredictable, and most recover fully.  Death and brain damage occur only in a small minority. Thrombocytopenia and resultant purpura or lymphopenia may occur.  Bacterial superinfections, including otitis media or pneumonia, are heralded by a second fever spike.  Subacute sclerosing panencephalitis (SSPE) may be a late developing complication and occurs in 1 in 100,000 cases. It is a delayed degenerative disorder of the nervous system resulting in mental and motor deterioration months or years after uneventful acute measles. Personality changes, myoclonic seizures, coma, and death characterize SSPE.  Measles viral antigen has been demonstrated in brain tissue, with elevated serum and CSF antibody titers and elevated total CSF IgG.  Infection in pregnant patients is associated with fetal death.[31]
Therapy for measles is supportive including rest, hydration, nutrition, vaporizer, antitussives and respiratory isolation.  Ribavarin intravenously or via aerosol has been used for severely affected patients or those who are immunocompromised; however, there are no current recommendations regarding antiviral therapy.[34]
In 1987, the WHO and UNICEF issued a joint statement recommending administration of vitamin A to all children diagnosed with measles in communities where vitamin A deficiency is a recognized problem.[35]  This was because it had been shown to decrease morbidity in hospitalized patients.  However, Hussey and Klein documented low serum retinol levels during the acute phase of measles, in a population without endemic vitamin A deficiency.  They found low retinal levels to be associated with more severe measles, assessed by higher fever, longer febrile episodes, increased rates of hospitalizations, and lower antibody titers.  Treatment with vitamin A, in the study by Hussy and Klein, decreased morbidity and mortality.  Their recommendation is that all children with severe measles should be given vitamin A supplements, regardless of nutritional state.[34]  Immune serum globulin (ISG) may prevent or possibly modify disease if given within 6 days of exposure, and is recommended in exposed infants who are too young for vaccination or immunocompromised children and adults.[31]
People are considered susceptible to measles unless they have history of physician-diagnosed measles, serologic evidence of immunity, or documented vaccination.  The current recommendation is for administration of live attenuated vaccine, in a two-dose schedule. The first MMR dose is recommended at 12 to 15 months followed by second dose at 4 to 6 years. HIV infection is not a contraindication to measles vaccine.[31]


I: Papular-purpuric gloves and socks syndrome
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In 1990 Harms et al. described five patients with this acute self-limited eruption.[36]   
More than half of the reported cases of Papular-purpuric gloves and socks syndrome (PPGSS) are linked to Parvovirus B19, first noted in serology reported by Bagot and Revuz published in 1991.[37]  This finding was confirmed by Halasz et al. with antibody titers, in 1992,  and in 1997 by Smith et al.[38,39]  Other reported etiologies include Measles virus, EBV, CMV, HHV6, Coxsackie B6, and Hepatitis B.[40-46]  Parvovirus B19 however, is the only etiologic agent which has been found to be present in peripheral blood and skin biopsy specimens by PCR.[47]
Recently, Van Rooijen et al. from Germany reported a classic case of PPGSS developing after taking trimethoprim-sulfamethoxazole. The patient re-developed identical symptoms after re-challenge of the drug. This suggests that PPGSS is a manifestation of an underlying immunologic mechanism that may be induced by viral or drug related antigens.[48]
PPGSS occurs most commonly in young adults, primarily during the spring and summer.  
The incubation period is about 10 days. The rash may be followed in 2-4 days by myalgias, arthralgias, lymphoadenopathy, anorexia and fatigue.  Leukopenia or thrombocytopenia may be seen.  The patient is overall non-toxic appearing.  Symmetric erythema and edema of the hands and feet progress to petechial and purpuric macules, papules and patches, is followed by fine desquamation. There is a characteristic sharp demarcation at the wrists and ankles. Rarely, the eruption may extend to non-acral sites such as face, buttocks, trunk, groin, and extremities. The eruption may occasionally be painful or pruritic.[39]  The majority of patients have an associated polymorphous enanthem, including diffuse hyperemia, aphthae, petechiae, and erosions on palate, pharynx, tongue, and possibly inner lips.
Grilli et al. described one case with accompanying vulvar edema, erythema, dysuria, and unilateral petechial rash on the breast with confirmed acute parvovirus B19 infection.[47] 
PPGSS spontaneously resolves in 1 to 2 weeks without any known late sequela.[39] 
Histopathologic examination has not been done on the majority of reported patients; however, reported biopsies have shown a lymphocytic, perivascular infiltrate in papillary dermis with extravasated RBC's.  No vasculitis is seen.  By immunofluorescence, using antibody to  parvovirus B19, virus is detected in the endothelial cells of dermal vessel walls, in the sweat glands, and epidermal ductal structures, suggesting a vascular reaction to a viral antigenic stimulus.[39] 
Treatment is symptomatic with moisturizers and antihistamines as needed. 
PPGSS is unlike Erythema Infectiosum where skin signs develop after clearance of viremia and in the presence of rising Antibody titers.  Patients with "slapped cheeks" are therefore considered non-infectious. In PPGSS, the immune response against parvovirus B19 occurs later, after the onset of the skin eruption. So, patients with clinical signs of "purpuric gloves and socks" secondary to parvovirus B19 are potentially infectious. This has important implications regarding contact with seronegative pregnant patients and immunocompromised individuals and those with chronic hemolytic anemias.  This is because of the same concerns as in Fifth's disease for aplastic anemias, hydrops fetalis or fetal loss, and a prolonged severe infection.[49,50]


I: Pityriasis rosea 
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Pityriasis rosea (PR) is an acute self-limited disorder affecting primarily children and young adults.  PR exhibits seasonal clustering, and a viral trigger has long been suspected.
There are many factors that are suggestive of a viral etiology, the case clustering, prodromal features, increased erythrocyte sedimentation rate, biopsy findings of dyskeratotic cells and multinucleated giant cells in the epidermis, and the induction of a PR-like eruption by subcutaneous injection of tissue fluid from PR lesions.  However, based on the current literature, no conclusive association of a known virus has been established.[51] 
In 1997, Drago et al. evaluated human herpesvirus (HHV) -6 and HHV-7 as candidates for the etiology of PR.  They studied skin tissue and blood from 12 patients with acute PR, 12 with other dermatoses (dermatologic controls)  and 25 healthy controls. They found HHV-7 in the peripheral blood mononuclear cells of all patients with active or relapsing PR, and 11 out of 25 healthy controls.  HHV-7 was also found in all skin specimens and plasma evaluations in the patients with PR.  None of the dermatologic controls had HHV-7 in skin specimens and no healthy controls had plasma HHV-7.  Detection in the PBMC indicates infection but not causality or activity.  Viral DNA in body fluids indicates active viral replication in vivo, the plasma therefore represents a biologic marker of active infection and supports a causal relationship.  Additional supporting evidence for a viral infection are numerous cytopathic changes, including viral 'footprints' such as Interferon alpha in plasma and a cytopathic effect in co-cultured mononuclear cells that were observed.[52]   
Conversely in 1999, Kempf et al. performed a retrospective cross-sectional survey of 13 patients with PR and 14 control subjects.  They found by PCR HHV-7 DNA prevalence to be slightly lower in lesional skin of PR patients than controls.  They argued that the low detection rate of HHV-7 DNA spoke against a causal role for HHV-7 in PR.[53]  
A letter to the editor in 2000, proposed that the results found by Drago et al. may have seen false positive results because of PCR contamination.[54]
In the 2000 British Journal of Dermatology, Kosuge et al. found no difference in the prevalence of HHV-6 or HHV-7 in peripheral blood mononuclear cells between 44 patients with PR versus 25 patients with other skin disorders.  However, serologically increased HHV-6 and HHV-7 titers were noted in four and seven PR patients, respectively, consistent with active infection.  They concluded that HHV-6 and HHV-7 may play a part in some patients with PR, but other causative agents may exist.  They noted that differences in the time of collection of tissue samples may explain the different results reported and that many causative agents may cause the same exanthem.[55]
A correspondence by Drago et al. in 2001 to the British Journal of Dermatology argued that the difficulty with implicating HHV's is due to their ability to establish a state of latent infection and therefore negative test results are of limited utility.  They note HHV may be implicated but difficult to prove without evidence of viral replication, which Drago et al. did in 100% of PR cases in 1997.[56]
PR occurs primarily in 15 to 40 year olds, especially women, typically in the spring and autumn.  The exanthem in PR consists of discrete oval salmon-colored papules and macules that may become confluent.  This often begins with a single "herald" patch, a week or more before the other smaller lesions.  Mild constitutional symptoms may precede the herald patch.  The oval patches are covered by a finely crinkled, dry epidermis which desquamates with a resultant collarette of scale.  Lesions spread rapidly and usually disappear spontaneously after two to six weeks.[51]  The  lesions follow Langer's cleavage lines, arranged along their long axis.  Chuh has recently argued that rash orientation is inappropriately described when terms such as, Christmas-tree pattern, fir tree pattern, parallel to the ribs, or along skin cleavage lines are used.[57]  Pruritis may be present.  An unusual variant, common in children under the age of five,  especially black children, is papular PR.  This has the same distribution and the course is similar.  An inverse variant, involving the axillae and groin of PR also occurs.
In 2000, Sharma et al. reported a double-blind placebo controlled clinical study with ninety PR patients over two years placed in either an erythromycin treatment group or placebo group.  Patients received erythromycin for 14 days.  Complete response was observed in 73% of treatment group in two weeks versus none in the placebo group.[58]
A follow-up study by Chuh et al. published in the European Journal of Dermatology in 2002 used the success of erythromycin as the background basis for a prospective case control study of 13 patients with PR for an infectious etiology.  Serology profiles were not diagnostic of an active infection by Chlamydia pneumoniae, C. Trachomatis, Legionella longbeachae, L. micdadei, L. pneumophila or Mycoplasma pneumonia infections.  They concluded that anti-inflammatory and immunomodulatory effects might explain the action of erythromycin in PR.[59]
Treatment is generally symptomatic.  After the acute inflammatory stage has passed, Ultraviolet B may be used to expedite involution of the lesions.  Topical steroids, emollients and antihistamines may be used for the pruritus, which  may be intense.[31]  


I: Roseola infantum (exanthem subitum) 

Roseola infantum (RI) was described by Zahorsky in 1910 as a febrile exanthem occurring in infants and young adults.[60]  This description was followed in 1913 by the definitive description of roseola in JAMA.[61]   The earliest published description was likely in 1809 by British dermatologist Robert Willan in the textbook On Cutaneous Diseases in which he describes a nearly identical eruption.  In 1988, Yamanishi et al. demonstrated, by isolating from peripheral blood lymphocytes and culturing in cord blood, that Human Herpesvirus 6, a dsDNA B cell lymphotrophic virus is the major agent responsible for roseola infantum.[62] 
HHV-6 primarily affects children between 6 months and 2 years.  Maternal antibodies play a role in preventing infection prior to 6 months of age.  By 12 months, 2/3 of children have been infected with HHV6 with peak antibody levels being reached at 2 to 3 years.  HHV6 is shed in the saliva.  In adults, primary infection with HHV6 can produce a mononucleosis-like illness, and more rarely cause severe disease, including encephalitis. This same illness can be caused by HHV6 during reactivation, particularly in immunocompromised persons.[63]
The incubation period of HHV-6 is estimated at 5 to 15 days followed by abrupt onset of high fever (39 to 40 degrees C), cervical lymphadenopathy and mild upper respiratory symptoms.   The fever lasts 3 to 5 days, after which there is an abrupt defervescence, coinciding with rapid onset (subitum is latin for suddenly) of a rash within 24-48 hours.  The exanthem consists of a non-pruritic rose-pink 2 to 3 mm discrete macules and papules, which blanch on pressure and are surrounded by white halo. First seen on the trunk, the eruption then spreads to neck and extremities. The rash fully evolves in 12 hours and lasts 1 to 2 days.  Palpebral and periorbital edema (Berliner's sign "heavy eyelids") is quite common.[63]
In addition to RI, HHV-6 has been associated with seizures and in some cases is unclear whether seizures are secondary to fever or to the HHV-6 infection itself.[64]   There are also rare reports of hepatitis, pneumonitis, neuropathy, meningoencephalitis, thrombocytopenia, intussusception, and encephalopathy having been observed after classic exanthem subitum.[63]
A study in 2002 by Hashimoto et al. suggests that thrombocytopenia observed with roseola infantum results from bone marrow suppression rather than from immune-mediated peripheral consumption.[65]  Even though many patients with central nervous system involvement have a normal recovery, chronic neurologic sequelae such as hemiparesis have been reported.[66]  It is postulated that active viral replication occurs in the central nervous system, since the virus has been cultured from the cerebral spinal fluid.[67]
Since most cases are benign and self-limited.  Treatment is supportive.[63]


I: Rubella (German or 3-day measles) 
figures 19 and 20: 19.jpg, 20.jpg

A Togavirus causes rubella, also known as German measles,, which is a ssRNA enveloped virus.  The distribution of disease is worldwide, and in North America outbreaks tend to occur more frequently in spring.[68] 
In the U.S. today, rubella outbreaks usually involve individuals from foreign countries where rubella vaccinations are not routine. Outbreaks mainly occur in Latin American communities in recent immigrants.[69] 
Rubella is thought to be spread by respiratory secretions with an incubation period of 12-23 days. A prodrome occurs 1-5 days prior to the rash with low grade fever, headache, conjunctivitis, sore throat, rhinitis, cough, and adenopathy.  The eruption presents with pink-red macules and papules on the face and then over 24 hours spreads caudad.  The eruption begins to fade after 1-2 days in order of appearance, and completely disappears in 2-3 days.  There is often an enanthem with punctate erythematous spots scattered over the soft palate and uvula, called Forcheimmer's sign.[68]   Lymphadenopathy is prominent in Rubella, affecting all nodes but most prominent in suboccipital, postauricular, and posterior cervical nodes. Splenomegaly is noted on occasion. Arthritis, may occur and is more common in adults, especially women.  Arthritis usually first noted as the rash fades and involves both small and large joints with or without swelling.[68]
Encephalitis occurs in 1 in 6000 cases, is usually mild, and followed by complete recovery. Thrombocytopenia with resultant purpura, epistaxis, GI hemorrhage, and hematuria may occur and usually resolves within in one month. Peripheral neuritis is a rare complication.[31]
In the U.S. population about 10% of women of childbearing age may be susceptible to rubella.[70]  The reported rubella and congenital rubella syndrome (CRS) cases are at record low levels.  Most rubella cases in the US occur among young Hispanic adults born outside the U.S., and most infants with CRS are born to foreign born mothers.[71]  In the U.S. from 1997 through  1999, 83% of CRS infants were born to Hispanic mothers and 91% born to foreign born mothers.[69]  
Rubella exposure during pregnancy may result in intrauterine infection and subsequent fetal damage.  The fetus is most susceptible during the first and second trimesters.[70]  Approximately 90% of exposed fetuses during the first trimester develop clinical infection but not all develop CRS.
Infection early on in pregnancy may result in low birth weight, microcephaly, mental retardation, cataracts, nerve deafness, and congenital heart disease (usually patent ductus arteriosus or ventricular septal defect), neonatal purpura and neurologic defects.
Infection occurring later in pregnancy, after organogenesis provides a variable clinical picture; this may include hepatitis, splenomegaly, pneumonitis, myocarditis, encephalitis, osteomyelitis, retinopathy, and bone marrow involvement leading to "blueberry muffin" baby with petechiae and ecchymoses. The "blueberry muffin" lesions represent sites of dermal erythropoiesis and are also seen in other congenital TORCH infections, such as, Cytomegalovirus and toxoplasmosis infections.[70]
The virus may be cultured from nasopharynx, urine, CSF and cataract lens. Eighty-one percent of CRS patients shed virus in first month of life and some become chronic carriers of the virus. Therefore, these patients should not be handled by those caregivers at risk for infection.[70] 
Treatment of rubella is supportive.[70]  Lifelong immunity usually follows an acute infection. Subclinical reinfection is rare.  The live attenuated vaccine is given as part of measles, mumps and rubella (MMR) vaccine in two doses, one at 12 to 15 months followed by a second dose at four to six years. Seroconversion is 95% or higher after a single dose. Prenatal screening of susceptibility in mothers is now routine. Immunization was previously not recommended less than three months prior to pregnancy. However, recent MMWR indicates that no cases of CRS have been identified among infants born to women who were vaccinated inadvertently within three months of pregnancy or early in pregnancy.[72]  Therefore, the Advisory Committee on Immunization (ACIP) shortened its recommended period to avoid pregnancy after receipt of rubella-containing vaccine from three months to 28 days prior to pregnancy.
A child or adult who is immunized does not shed sufficient virus to infect susceptible individuals in close contact. Immunization of children in family in which the mother is pregnant is considered safe.[70,72]


I: Unilateral laterothoracic exanthem (asymmetric periflexural exanthem of childhood) 
figure 21: 21.jpg

Brunner et al. described an eruption as "lichen miliaris" in 1962 which had unilateral periflexural involvement.[73]  The term Unilateral Laterothoracic Exanthem (ULE) was proposed by Bodemer and de Prost in 1992 who reported 18 children with a mean age of 23.3 months with a unilateral eruption, either eczematous or scarlatiniform, localized to an axilla.  The majority of patients (10/18) had fever, sore throat, conjunctivitis, rhinopharyngitis or diarrhea.  Serologic testing for virus was negative.  An etiology was not established but a viral cause was suggested.[74]  In a recent prospective case series of 67 children, Coustou et al. also found no evidence to support interhuman transmission, nor was a link with Pityriasis Rosea evident.[75]   In 1993, Taieb et al. reported 21 cases with a similar eruption and since the eruption did not always remain unilateral and could involve the lower extremities, they suggested the acronym Asymmetric Periflexural Exanthem of Childhood (APEC).[76] 
A large prospective study reported the mean age of those affected with ULE was 24.3 months, with a 2:1 female predominance.  The majority of cases (85.4%) occur in winter and spring.[77]
The rash has erythematous macules or papules that form morbilliform, scarlatiniform, or eczematous patterns. The primary lesion is a micropapule with a surrounding pale halo that progresses through an eczematous phase.[50]  This begins unilaterally in the axilla or groin, spreading centrifugally, and usually resolves spontaneously by four weeks.   Both sides of the body are usually ultimately involved, however there is continued unilateral predominance. Sparing of the palms, soles, and mucous membranes is typical.  Adenopathy and low grade fever are present.[50,75,77]
In 1999, Coustou et al. reported new clinical variants including association with fever, up to 40 degrees Celsius, and confirmed their previous findings, reported in 1993 (Taieb), of an extended course, up to 60 days, of the eruption.  They also confirmed previous clinical observations of atypical features, such as facial involvement and peripheral extension of the rash.  Skin biopsy specimens obtained had a dermal lymphocytic infiltrate predominantly around sweat glands, with less involvement around blood vessels and hair follicles.[75]
A prospective study in 1996 by McCuaig et al. in Quebec studied 48 children to determine the clinical evolution of ULE, its response to therapy, and histologic features.  Thirty children had pruritis, late desquamation was present in all patients, and mild lymphadenopathy was noted in eight patients.  They also found patients with involvement of the face, genitals and the hands and feet.  Histologic findings also revealed a prominent lymphocytic infiltrate of eccrine glands and ducts.[77]
The origin of this eruption remains unknown, in spite of continued active research for an infectious etiology.[77]  However, an infectious etiology is suspected due to seasonal pattern and prodromal symptoms.  The study by Bodemer and de Prost had negative serologic testing for hepatitis B, EBV, CMV, HIV, coxsackie, parvovirus, Mycoplasma, borreliosis, rickettsiae, toxoplasmosis and spiroplasma (which was implicated in earlier reports).[74]
The treatment of ULE is symptomatic, utilizing moisturizers or antihistamines if needed.  Topical steroids have been found to be ineffective.[75]

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