This is a 5 year old male who is referred to your clinic by the school nurse for suspicion of child abuse. The report states that the child's face appears to have been "slapped" repeatedly. From the chart, you note that the patient has no history of trauma or suspicious incidents. He has been seen regularly for well child exams and is up to date on immunizations. The distraught parent states that there have been no recent changes among the family and that the patient has been doing well, other than a moderate tactile fever for two days, alleviated by acetaminophen.
Exam: VS T 38.2, P 95, R 26, BP 110/68, oxygen saturation 99%. Weight and height are at the 50th percentile with normal progress on his growth curve. He is alert, and cooperative in no distress. HEENT exam is significant for slight erythema of his oropharynx. His neck is supple without lymphadenopathy. Heart and lung exams are normal. Examination of his skin is only significant for some slight edema and pinkish red color of his cheeks ("slapped cheek" appearance). There are no bruises or other rashes detected. Exam of his extremities are negative for any signs of injury. Neurologic examination does not reveal any abnormalities.
Following your examination, further questioning reveals an ill cousin with a "rash." Over the next several days, the malar erythema begins to fade and a faint pink rash appear on his trunk and extensor surfaces of his upper extremities. The truncal rash becomes confluent, creating a lacy appearance. Both the fever and rash disappear without any further problems.
An exanthem, originating from the Latin anthos, meaning flower, is a skin eruption occurring as a symptom of an acute infection (1). More than 50 agents (viral, bacterial, or rickettsial) that cause exanthems in children have been identified (2). Therefore, it is not surprising that the febrile child presenting with a "rash" is a diagnostic challenge to many physicians. The goal of this chapter is to provide a systematic framework to approach patients similar to the case outlined above. An accurate diagnosis is possible when close attention is paid to the pattern of patient age, immunization status, prodromal symptoms, character of fever (high-grade, prolonged, chronological relationship to rash, etc), associated manifestations, and the characteristic exanthem. The natural history of each disease is also unique, therefore an attempt has been made to organize the clinical manifestations in chronological order. Several diagnostic lab studies are available, such as specific serologies and rising titers.
Due to the wide differential diagnosis, the scope of this chapter will be limited to common viral exanthems, namely measles, rubella, hand-foot-mouth disease, erythema infectiosum, roseola infantum, and varicella.
Measles (rubeola) is caused by a paramyxovirus which is spread by respiratory droplets produced by sneezing or coughing. Infected persons are contagious for several days before the onset of rash and up to 5 days after the lesions appear. It is highly contagious, resulting in 90-100% transmission among those who are susceptible (2). Prior to the use of the measles vaccine (one component of the MMR), the peak age of incidence was 5-10 years. In underdeveloped countries, up to 45% of cases occur before the age of 9 months. Since widespread immunization began in 1963, measles occurrence is rare. Current small outbreaks in the U.S. occur in unimmunized preschool children and school-aged persons immunized at an early age (who often have not received a second MMR). In Hawaii, most index cases occur in Asian tourists who are not immunized. In the 1980's, there were several outbreaks. The revised recommendation (requirement) for two doses of MMR vaccine prior to school entry has resulted in less than 70 cases of measles in 1998 and 1999 in the U.S. (2). Worldwide, measles is endemic (3).
The measles incubation period is 8-15 days. Measles is rare among immunized patients, especially those who have had two MMR doses. Susceptible individuals exist since some parents have chosen to refuse MMR vaccine for their children. Classically, measles is preceded by the three C's: a hacking cough, coryza (nasal rhinorrhea and congestion), and conjunctivitis, plus photophobia, malaise, and a high fever persisting for several days. The enanthem (mucus membrane eruption) of measles is pathognomonic. Part of the enanthem is called Koplik's spots which appear on or after the second day of fever. The lips, tongue and oral mucosa are hyperemic (red). The Koplik's spots can be described as white spots over the red buccal mucosa (so called, grains of sand in a sea of red) (3). Although pathognomonic, their absence does not exclude measles since this finding is transient, disappearing within 48 hours after onset of the rash (2). The exanthem classically appears on the fourth day of fever. The rash is called "morbilliform" (which means measles-like). This can best be described as non-elevated red spots of varying sizes with a few areas of coalescence. They spread centrifugally and inferiorly to involve the face, trunk, and extremities. Lesions may become confluent, especially on the face, then gradually fade in order of appearance with subsequent residual yellow-tan stain. As the exanthem progresses, systemic symptoms subside (3). There is generalized lymphadenopathy. Otherwise, the exam is unremarkable.
Differential diagnosis includes drug reactions (e.g., Stevens Johnson syndrome), Kawasaki disease, other viral exanthems, secondary syphilis, or scarlet fever (3).
Prevention through prophylactic immunization is the primary approach to measles in the United States. Treatment is otherwise symptomatic (3). In areas of vitamin A deficiency, the World Health Organization (WHO) recommends 200,000 IU of oral vitamin A in three doses over the course of the illness. Immunoglobulin (gamma globulin) is recommended for household contacts, particularly infants less than one year, pregnant patients, and the immunocompromised (2).
Measles is a self-limited infection in most patients. The mortality rate is 0.3% in the United States but ranges from 1-10% in developing countries. Complications are more common in malnourished children, and in those who are immunocompromised. Acute complications include pneumonia (due to measles or a secondary bacterial infection, such as Staph aureus), and measles encephalitis (1 in 800-1000). Subacute sclerosing panencephalitis is a chronic complication (3).
Measles also presents is two other fashions: modified and atypical measles. Modified measles occurs in partially immune individuals. It is characterized by a shorter prodrome and a less severe rash. Atypical measles presents with abrupt onset of high fever, myalgias, and cough. A papular or papulovesicular rash in the extremities begins 2 to 5 days later and spreads centrally. The rash is frequently hemorrhagic and a lobar pneumonia may be present (2).
Rubella, also known as German measles or 3-day measles, is caused by the rubella virus. Transmission is via inhalation of aerosolized respiratory droplets and the period of infectivity is from the end of the incubation period to the disappearance of the rash (3).
Before widespread immunization, this disease was found in children younger than 15 years. Currently it occurs primarily in young adults in hospitals, prisons, colleges, and prenatal clinics. The incidence has decreased by 99% since immunization began in 1969. Rubella is endemic worldwide causing epidemics every 6 to 9 years during the spring.
The incubation period lasts from 14-21 days (2). In 60-90% of adolescents and young adults the exanthem is preceded by anorexia, malaise, conjunctivitis, headache, low-grade fever, mild upper respiratory symptoms, or Forchheimer's sign (petechiae on the soft palate) (3).
The exanthem is characterized by pink macules or papules which appear initially on the forehead, spreading inferiorly to the face, trunk, and extremities in the first day. By the second day, the facial exanthem fades. Truncal lesions may become confluent, creating a scarlatiniform eruption. By the third day the exanthem fades completely (3). On physical examination, lymph nodes are enlarged, particularly postauricular, suboccipital, and posterior cervical, and possibly tender during prodrome. Splenomegaly may also be present (2,3). The differential includes measles, rubella, scarlet fever, erythema subitum, enteroviral infection, and drug reactions.
Rubella is preventable by immunization. If antirubella antibody titers are negative in young women, rubella immunization should be given. In adolescents, pregnancy should be ruled out due to the possible adverse effects of the vaccine on the fetus. Otherwise treatment is symptomatic (2).
In most cases rubella is a mild, self-limiting infection. However, when rubella occurs in the first trimester of pregnancy, infection can be passed transplacentally to the fetus. Of all mothers infected during pregnancy, approximately 50% of fetuses will have manifestations of congenital rubella syndrome, including congenital heart defects, cataracts, microphthalmia, deafness, microcephaly, and hydrocephalus (2,3).
Hand-foot-mouth disease (HFMD) is caused by coxsackie virus. The primary strain is A16 but sporadic cases have been reported with coxsackie viruses A4-7, A9, A10, B2, B5 and enterovirus 71. Highly contagious, it is transmitted from person to person by oral-oral or fecal-oral routes (3). Incubation is 3 to 6 days
The age of onset is usually in children younger than 10 years old, but may occur in young and middle-aged adults. Epidemic outbreaks occur every 3 years. In temperate climates, outbreaks occur during the summer. The prodrome is 12-24 hours of low-grade fever, malaise, and abdominal or respiratory symptoms. Oral mucosal lesions are macules or grayish vesicles (small, less than 0.5 cm circumscribed elevation containing fluid) that evolve to punched-out, painful ulcers that may result in refusal to eat in children. The cutaneous lesions appear on the palms or soles together or shortly after the oral lesions. The sides of the fingers, toes, and buttocks may also be involved. Pink to red macules or papules appear, 2-8 mm in diameter, in a characteristic linear arrangement. They quickly evolve to form vesicles with a clear, watery appearance or yellowish hue. Lesions on the palms and soles usually do not rupture, but other sites may with formation of erosions and crusts (3). The sudden onset of oral and distal extremity lesions is pathognomonic for HFMD. In the absence of an exanthem, the differential diagnosis includes herpes simplex virus, aphthous stomatitis, and herpangina.
Management is symptomatic treatment, including optional topical applications of various local anesthetics to reduce oral discomfort. A diet of vanilla ice cream is the easiest to tolerate. Most commonly, HFMD is a self-limited disease with resultant acquired immunity. A few cases have been prolonged or recurrent. Serious complications are rare, but coxsackie virus has been implicated in myocarditis, meningoencephalitis, aseptic meningitis, paralytic disease, and a systemic illness resembling rubeola. Infection acquired in the first trimester or pregnancy may result in spontaneous abortion. Cutaneous lesions heal without scarring (3).
Erythema infectiosum (EI), also known as Fifth disease, is caused by parvovirus B19. Transmission is via respiratory droplets, with attack rates among close contacts up to 50%. Incubation is 4-14 days. This disease typically affects children 3 to 12 years old but may also appear in non-immune adults. In 20-60% of children, a prodrome of fever, malaise, headache, and coryza appears two days before the rash. Headache, sore throat, fever, myalgias, nausea, diarrhea, conjunctivitis, and cough may coincide with the rash. Pruritus is variably present. Arthralgias may occur but are uncommon. Presentation may differ considerably in adults.
The exanthem has a characteristic "slapped cheeks" appearance. An erythematous, edematous, confluent plaque on the malar face appears first which fades over 1 to 4 days. Erythematous macules and papules then appear on the extensor surfaces of extremities, trunk, and neck. These become confluent causing a lacy or reticulated appearance. Less commonly, lesions may be morbilliform (measles-like), circinate, annular, or rarely form pustules, vesicles, or palmoplantar desquamation. The eruption lasts 5 to 9 days but can characteristically recur for weeks to months, triggered by sunlight, exercise, temperature change, bathing, or emotional stress. Uncommonly, an enanthem with glossal and pharyngeal erythema and red macules on buccal and palatal mucosa may be present. The differential diagnosis includes measles, rubella, scarlet fever, roseola, enteroviral infection, Hemophilus influenza cellulitis, or drug reactions.
Management of EI is symptomatic and is usually a self-limited disease. In patients with hemoglobinopathies or RBC defects, human parvovirus may cause a transient RBC aplastic crisis, manifested by fatigue, pallor, and worsening anemia. Fetal infection may be complicated by fetal hydrops secondary to infection of erythroid precursors, hemolysis, severe anemia, tissue anoxia, and high-output failure. This is a serious concern in schools since children may commonly expose young women who are potentially pregnant (e.g., teachers) to this.
Roseola infantum (exanthem subitum, sixth disease) is caused by human herpes virus 6. This disease usually affects patients under the age of 3 years (2). The incubation period is 5-15 days. The prodrome consists of constant or intermittent high fever with malaise and irritability lasting 3 to 5 days. Occasionally, periorbital edema and febrile seizures are also associated. The exanthem appears after an abrupt defervescence (2). Erythematous to pink macules and papules appear, often arranged in rosettes, mainly involving the trunk with extension to the neck and proximal extremities lasting for 1 to 2 days (2). Treatment is symptomatic (4). Most infants are affected subclinically with two studies showing only 9-17% developing clinical roseola infantum (4). The course is generally benign, but febrile seizures, meningitis, and encephalitis are well-recognized complications. Several case reports have described fulminant hepatitis in primary HHV-6 infection (4).
Varicella (chicken pox) is caused by the varicella-zoster virus (VZV). The period of infectivity extends from the beginning of the prodromal illness through the time that the uncrusted lesions are present (2). Transmission is via respiratory secretions and the fluid produced by skin lesions, either airborne or through direct contact. In the United States pre-vaccine era, 90-95% of individuals acquired VZV infection in childhood with epidemics occurring in the winter and spring. Transmission to susceptible individuals occurred at a rate of 80-90% for household members. Casual contact (e.g. the classroom setting) is associated with attack rates of less than 30% (5).
The incubation period is 14 to 16 days and initial symptoms typically consist of fever, malaise, headache, anorexia, or abdominal pain (2). Temperature elevation is usually moderate but may be as high as 41 degrees C (106 degrees F) (5). The skin lesions appear 24 to 48 hours after the prodromal illness has begun. They begin as intensely pruritic, erythematous macules which rapidly evolve into vesicles containing serous fluid. The exanthem first appears on the face, scalp, or trunk and spreads peripherally. Over a 24 to 48 hour period, the vesicles umbilicate, the fluid clouds, then transforms into crusts before finally resolving. Healed lesions may leave residual hypopigmentation lasting weeks, but scarring is uncommon. The number can vary from as few as 10 to as numerous as 1500 (5). Ulcerative lesions of the oropharynx and vagina commonly develop concurrently with the exanthem.
Prevention is currently available with the varicella vaccine. The vaccine has reduced the historical transmission rate from 87% to 7% (6). Acyclovir and varicella-zoster immune globulin have been effective in the prophylaxis and treatment of progressive disease, as described below. The course is generally benign, although in certain populations it may be associated with several complications. Perinatal transmission can cause life-threatening infection in the fetus. Progressive varicella is characterized by visceral organ involvement, coagulopathy, severe hemorrhage, and continued lesion development. Severe abdominal pain and the appearance of hemorrhagic vesicles in otherwise healthy adolescents, immunocompromised children, pregnant women, and the newborn may be a red flag for this serious complication (5).
Delivery within one week before or after the onset of maternal varicella frequently results in the newborn developing varicella, which may be severe and requires the administration of varicella-zoster immune globulin and acyclovir. Those who receive prompt treatment have an excellent prognosis. Mothers who had varicella between 8-20 weeks of pregnancy may demonstrate congenital varicella syndrome, characterized by interruption of organogenesis, in particular, the CNS, limbs, and eyes. A characteristic zig-zag scarring, often in a dermatomal distribution, can sometimes be seen (5).
Herpes zoster (also called shingles), due to reactivation of latent VZV, is uncommon in childhood, but more common in teens and adults. When it occurs, it originates in a single dermatomal pattern (e.g., T10), preceded by pain within the dermatome, followed by a dense collection of vesicles within the dermatome. Immunosuppressed children (those receiving immunosuppressive therapy for diseases like malignancy or with HIV) are at higher risk for developing herpes zoster in childhood. The lifetime risk for those with a history of varicella is 10%, with 75% of cases occurring after 45 years of age (5).
Other viruses which commonly cause exanthems include adenovirus (rash, conjunctivitis), echovirus ("Boston exanthem" similar to roseola), and Epstein-Barr virus (see chapter on Epstein-Bar virus). A common rash associated with amoxicillin use is probably related to a viral etiology. Commonly called an "amoxicillin rash", this is a non-allergic rash which occurs when amoxicillin is used in conjunction with some viruses (which are poorly defined). Later, when the viral infection is resolved, amoxicillin use does not result in a rash. This is similar to infectious mononucleosis which results in an impressive rash with amoxicillin/ampicillin use, but no recurrence of a rash with the same antibiotic use, once the viral infection has resolved. Patients are commonly labeled as amoxicillin allergic because of this phenomenon. Most amoxicillin rashes are non-urticarial which is the best (though not perfect) clue that this is probably not due to an allergic mechanism.
1. Name the type of exanthem depicted in the case described at the beginning of this chapter.
. . . . . a. Exanthem infectiosum
. . . . . b. Exanthem subitum
. . . . . c. Hand-foot-mouth disease
. . . . . d. Varicella
. . . . . e. Measles
2. Symptoms of congenital rubella include all of the following EXCEPT
. . . . . a. congenital heart defects
. . . . . b. hydrocephalus
. . . . . c. deafness
. . . . . d. microphthalmia
. . . . . e. zig-zag scarring
3. The mother of a patient comes in to your office stating that she has read terrible things about the vaccinations and doesn't want to give her child any. Which of the following statements is FALSE regarding vaccinations.
. . . . . a. The risk of acquiring chicken pox after exposure in the healthy, varicella immunized child is less than 10%.
. . . . . b. Vaccines have no adverse affects.
. . . . . c. Many vaccines need to be administered more than once.
. . . . . d. Rubella incidence has decreased 99% since 1969.
. . . . . e. Adverse effects of illnesses prevented by vaccines include death and damage to the central nervous system.
4. A 3 year old patient is seen for several days of fever and refusal to eat. Physical examination reveals a slightly dehydrated child with punched out, painful oral ulcers with associated small red macules on the palms and soles. What type of treatment would you recommend?
. . . . . a. Rest and fluids
. . . . . b. Rest, fluids, and amoxicillin
. . . . . c. Rest, fluids, acetaminophen, and vanilla ice cream
. . . . . d. Rest, fluids, acetaminophen, and acyclovir
. . . . . e. Rest, fluids, acetaminophen, and ciprofloxacin
5. Your patient has been diagnosed with varicella. Her aunt is pregnant and is not immune to chicken pox. When is the soonest that the aunt can visit the patient?
. . . . . a. Immediately, if she is his favorite aunt.
. . . . . b. When the lesions crust over.
. . . . . c. When the lesions are completely healed.
. . . . . d. Two months after the lesions heal.
. . . . . e. After the delivery of the fetus.
1. Spraycar M (ed). Stedman's Medical Dictionary, 26th edition. 1995, Baltimore: Williams and Wilkins.
2. Gable EK, Liu G, Morrell DS. Pediatric Exanthems. Prim Care 2000;27(2):353-369.
3. Fitzpatrick TB. Section 23 - Viral infections in skin and mucosa. In: Fitzpatrick TB (ed). Color Atlas and Synopsis of Clinical Dermatology: Common and Serious Diseases, 4th edition. 2001, New York: McGraw-Hill, Medical Pub. Div, pp. 754-818.
4. Straus SE. Ch 129 - Human Herpesvirus 6 and 7. In: Mandell GL, Douglas RG, Bennett JE, Dolin R (eds). Principles and Practice of Infectious Diseases, 5th edition. 2000, Philadelphia: Churchill Livingstone, Inc., pp. 1614-1615.
5. Meyers MG, Stanberry LR. Chapter 246 - Varicella-Zoster Virus. In: Behrman RE, Kliegman RM, Jensoe HB (eds). Nelson Textbook of Pediatrics, 16th edition. 2000, Philadelphia: WB Saunder's Company, pp. 946-951.
6. Vessey SJ. Childhood vaccination against varicella: persistence of antibody, duration of protections, and vaccine efficacy. J Pediatr 2001;13(2):297-304.
Answers to questions
1.a, 2.e, 3.b, 4.c, 5.b