ABSTRACT: Children who present with rash and fever can be divided into 3 groups: the first group includes those with features of serious illness who require immediate intervention. The second and third groups include those with clearly recognizable viral syndromes and those with early or undifferentiated rash. The morphology of lesions among children with symptoms of serious illness offers clues to the underlying cause. Purpura or ecchymoses in a well-appearing child may not be associated with serious illness; a large percentage of children who present with fever and purpura have Henoch-Schönlein purpura. Kawasaki disease typically manifests with blanching rash and fever. Vesicular or bullous lesions and fever are the hallmark of erythema multiforme, toxic epidermal necrolysis, and staphylococcal scalded skin syndrome. Umbilicated papules and pustules are the sine qua non of molluscum contagiosum and varicella.
Children who present with rash and fever can be divided into 3 groups:
Here, in the second of 4 articles, I will focus on those disorders in group 1 that manifest with fever and blanching rash, with fever and vesicular or bullous lesions, and with fever and umbilicated papules or pustules. In a previous article (see April 2008, page 141), I concentrated on group 1 disorders marked by fever and petechiae/ purpura (ie, meningococcemia, Rocky Mountain spotted fever, and hemolytic uremic syndrome). In future issues, I will address disorders that fall into groups 2 and 3.
Henoch-Schnlein purpura. A significant number of children who present with purpura will not have a serious disease. A large percentage of well-appearing children with fever and rash have Henoch-Schnlein purpura (HSP). This disorder usually affects those between the ages of 2 and 11 years. An upper respiratory tract prodrome occurs in 60% to 70% of patients. Group A streptococcal antigens were found in 30% of patients with HSP in one study.1
HSP usually presents initially with a nonblanching rash. In about half of affected patients, arthritis, nephritis, edema, or abdominal pain precede the rash. Within a few hours to days, the lesions evolve into the "palpable, nonthrombocytopenic purpura" characteristic of HSP. The rash tends to appear on the buttocks and lower extremities, but it can develop elsewhere.
Almost all patients with HSP have splenomegaly.2 Scrotal edema in males and ecchymosis may be early symptoms; in one study, these findings were present in 32% of patients with HSP.3 Overall, 10% to 50% of patients have renal involvement, which varies from microscopic hematuria to gross hematuria, proteinuria, and renal insufficiency. In children younger than 2 years, edema is relatively common and renal involvement relatively uncommon. The location of the edema varies with age, mobility, and sex. Younger infants often have sacral edema, whereas older, mobile children have peripheral edema.
Diagnosis is usually clinical. However, results of a biopsy of skin lesions will demonstrate leukocytoclastic vasculitis. Immunofluorescence studies can show deposition of C3 and IgA in renal glomeruli and within small cutaneous vessels.4
Although children older than 9 years have the worst renal prognosis, chronic renal failure develops in only a small percentage of these youngsters. Hematuria is common but, when combined with proteinuria, the risk of progressive renal insufficiency is 15%. Of all children with HSP, chronic renal disease develops in 1% to 5% and chronic renal failure eventually develops in about 1%.5
Nausea and abdominal pain are common GI manifestations. Microscopic fecal blood loss is also common, but significant lower GI bleeding is rare. HSP is also associated with intussusception, possibly caused by hemorrhage into the wall of the small intestine, which forms a "lead point."
Management of HSP is usually conservative. Nonsteroidal agents are useful for joint pain and appear to be safe. Treatment of children with renal involvement remains controversial. Corticosteroids have been found to decrease inflammation, joint pain, and the intensity of abdominal pain and also to help manage renal involvement by decreasing glomerular damage.6 Many other options have been studied, including corticosteroids, anticoagulation, plasmapheresis, cyclophosphamide, cyclosporine, azathioprine, and IgG. All children with renal involvement should be referred promptly to a pediatric nephrologist.
Kawasaki disease. This major childhood vasculitis manifests with fever and a blanching rash. Most cases occur in children younger than 5 years; children aged 2 years are most commonly affected.
There is no definitive diagnostic test for Kawasaki disease. Diagnosis is based entirely on the clinical manifestations, which include fever of 5 or more days without an identifiable source, and at least 4 of the following 5 features:
Often, extreme irritability-almost universal in children with this disease-and anterior uveitis (in up to 90% of affected patients) are the earliest clues.7 Blood cell counts reveal leukocytosis and elevated levels of acute phase reactants. The platelet count rises during the second week and is often well above 1 million/?L. If a lumbar puncture is performed, it may reveal aseptic meningitis, consisting of a sterile mononuclear pleocytosis usually with fewer than 100 cells/?L and with normal glucose and protein levels.
The most serious complication of Kawasaki disease is coronary artery aneurysm secondary to the acute coronary arteritis. Intravenous immunoglobulin and aspirin therapy that is given within the first 10 days of the illness can decrease the risk. In about 5% of children, this complication develops despite such therapy.8
The presentation of Kawasaki disease is atypical in more than 50% of children younger than 1 year. These patients have a higher incidence of aneurysms. Consequently, early empiric therapy is more of a necessity. The American Heart Association and American Academy of Pediatrics have issued a joint statement on the diagnosis and management of Kawasaki; it includes an algorithm for evaluating atypical or "incomplete" disease.9 A high index of suspicion, early treatment, and pediatric cardiology consultation with echocardiograms are paramount. A pediatric ophthalmologist can best detect anterior uveitis. However, the absence of any single finding does not rule out Kawasaki disease.
Juvenile rheumatoid arthritis. Many of the collagen vascular disorders of childhood-including HSP, hemolytic uremic syndrome, systemic lupus erythematosus, polymyositis, and inflammatory bowel diseases- manifest with fever and rash. The most common of these disorders is juvenile rheumatoid arthritis, in which fever and rash often precede the onset of arthritis. The fever is usually intermittent and unresponsive to antibiotic therapy. During flares, the affected child usually has a high white blood cell count and may be relatively thrombocytopenic. The patient appears very ill when febrile but dramatically improves with defervescence.10
Typically, a pink macular rash develops in clusters on the trunk (especially the axilla and waist), face, and proximal extremities. The rash fades significantly with defervescence, only to return with the next fever. The rash may also exhibit Kbner phenomenon, in which lesions may appear or reappear along a site of minor trauma (eg, an area of the skin that has been stroked).11
Juvenile dermatomyositis. This extremely rare disorder manifests with fever, proximal muscle weakness, myalgia, and rash. The most commonly associated rash is an erythematous, often scaly, rash on the dorsal surfaces of the metacarpophalangeal and interphalangeal joints (the so-called Gottron sign). The classic heliotropic "butterfly" rash of the face and the "V"-shaped photosensitive macular erythematous rash of the upper chest and trunk also occur.
This group of lesions is associated with erythema multiforme, toxic epidermal necrolysis, staphylococcal scalded skin syndrome, disseminated gonococcal disease in adolescents, and herpes.
Erythema multiforme. EM consists of a typical rash of symmetrical erythematous macules of the hands (including the palms), face, and extensor surfaces of the extremities; the trunk may also be involved (Figure 1). The lesions can be pruritic. Usually, the patient has a prodrome of fever, headache, sore throat, and cough. The lesions evolve into papules and target lesions that may coalesce to form plaques. The rash may consist of lesions in various stages of development.
Figure 1 - A symmetric, erythematous, macular rash of the hands (including the palms), face (A), and extensor surfaces of the extremities (B) are typical of erythema multiforme.
In erythema multiforme minor, each lesion lasts for at least 7 days. There are no systemic symptoms, and mucosal involvement is limited to a single site. This condition is usually infection related, most often associated with herpes viral antigens.
Stevens-Johnson syndrome and toxic epidermal necrolysis. SJS was formerly considered to be part of the spectrum of EM. It is now accepted that the pathogenesis of SJS and TEN are similar, and that EM is a distinct and unrelated disorder. SJS and TEN differ only in severity and distribution. Most cases of SJS and TEN are related to the use of medications (such as NSAIDs, sulfonamides, and anticonvulsants). The rash typically appears 1 to 3 weeks after the medication is started but can occur much later.12,13
SJS is characterized by high fever and mucosal surface involvement, which includes pustules on 2 or more mucosal surfaces-most commonly, in the mouth (usually with oral and epidermal detachment of less than 10% of total body surface). Removal of the offending agent (if known) and aggressive supportive therapy are required for patients with SJS.14 Even with such therapy, mortality ranges from 5% to 15%.15
Children with TEN have a short 12- to 24-hour prodrome of fever and anorexia before the onset of diffuse erythema of the face and extremities. The mouth, conjunctiva, and anogenital areas also may be involved. The lesions evolve into pustules and bullae and then slough, leaving denuded skin. TEN tends to involve a larger skin surface area-usually about 30%.16 Treatment is the same as that for SJS. Associated mortality is about 5%, despite aggressive therapy.15
Staphylococcal scalded skin syndrome. Children with this disorder usually appear less ill than those with SJS or TEN and improve dramatically with appropriate antibiotic therapy. The disease is caused by an exfoliative toxin produced by phage group II, type 71 staphylococci. It most commonly occurs in childrenaged 6 months to 6 years and is associated with a 3% mortality.
The Nikolsky sign-superficial separation of the skin at the zona granulosa layer caused by mild pressure- is usually positive. The blisters with SJS and TEN are deeper. In difficult cases, a skin biopsy of an affected area can help differentiate the disorders.15
Disseminated gonococcal disease in adolescents. This disease presents with arthralgias or frank arthritis with pustular (or petechial) skin lesions usually on the peripheral extremities. Interestingly, patients tend to have minimal genital findings. Typically, inpatient intravenous antibiotic therapy, given for 1 to 2 days, is followed by an oral regimen.17
Herpes simplex virus infection. Herpes produces painful thin-walled vesicles that have often ruptured by the time the patient is first evaluated. Herpes simplex virus (HSV) type 1 causes most oral lesions, whereas HSV type 2 causes most genital lesions. Like all herpesviruses, HSV cannot be eradicated. It causes recurrent symptoms, and asymptomatic shedding may occur. A full discussion of oral and genital herpes is beyond the scope of this article. However, more information is available through the CDC's regularly published updates on herpes in the Morbidity and Mortality Weekly Report.
Centrally umbilicated lesions occur in molluscum contagiosum and varicella.
Molluscum contagiosum. This benign disorder involves rapidly spreading, small pearly topped papules with central umbilication. There is no history of fever or associated symptoms. The lesions can be treated to hasten resolution, but spontaneous resolution over time is the norm.
Varicella. This disease presents with mild systemic symptoms (lowgrade fever, anorexia, and headache). The rash begins on the trunk and spreads to the extremities. Most of the lesions are clustered on the trunk; they emerge in various asynchronous "crops." Thus, multiple degrees of progression exist simultaneously (Figure 2).
Figure 2 - This rash is the classic clinical picture of chickenpox. The pruritic, erythematous lesions shown here on the trunk of a 6-year-old boy erupted in crops, with the greatest concentration on the trunk; they appeared initially as rose-colored macules, progressed rapidly to papules and vesicles, and finally crusted.