As a pediatrician on the front line of patient care, you are exposed throughout the day to multiple patients who present with "fever and rash." Differentiating between benign vs. serious cutaneous findings is a challenge that clinicians are confronted with on a daily basis. Prompt detection of early signs and symptoms associated with a life-threatening skin eruption, along with a thorough history, is essential to establishing a correct diagnosis of an evolving serious illness. Given the broad diagnostic differential of fever and rash, it is extremely helpful to recognize and classify the morphology of the primary lesion and its evolving distribution on the body. Developing an organized approach towards analyzing a progressive rash helps to discriminate a minor illness from a critical illness and ultimately influences decisions regarding empiric therapy and overall management. This article reviews the various morphology and distribution patterns of rashes associated with fever in children and focuses on the clinical manifestations, pathophysiology, and treatment of potential life-threatening illnesses with cutaneous eruptions.
HISTORY AND PHYSICAL EXAM
Obtaining a comprehensive history is an integral component in forming a diagnosis. Any predisposing medical conditions that place the patient at increased risk for specific diseases need to be elicited. Travel history, animal exposure, drug use, and contact with those who are sick can provide etiologic clues. A meticulous history of the rash including onset, distribution, morphology, pruritus, progression, and temporal relationship to fever can help narrow the working differential. Upon initial evaluation of a patient with fever and rash, it is imperative to examine vital signs and a patient's overall general appearance. Does the patient appear toxic or lethargic? Is there mucous membrane involvement? What is the hydration status? Does he or she have physical findings consistent with multiorgan involvement, such as lymphadenopathy, organomegaly, new mumurs, or neurologic deficits, including changes in mental status?
Background knowledge of the overall physical exam along with the dermatologie clues provided by analyzing a rash enables a clinician to formulate a diagnostic approach. Categorizing a rash requires a basic knowledge of how to identify the features of primary and secondary lesions including the size, color, morphology, pattern, distribution and arrangement on the body. The Table (see page 33) presents basic descriptions of common primary skin lesions.
Diseases presenting with fever and rash can be organized according to the following dermatologie patterns: generalized erythematous exanthema, predominately maculopapular, vesiculobullous, petechial-purpuric, and nodular. Various illnesses exhibit skin findings that evolve based on the progression of the disease activity.
Understanding the development of a rash in its changing stages is an important diagnostic skill.
GENERALIZED ERYTHEMATOUS EXANTHEMSWITH PREDOMINANCE OF MACULES AND PAPULES
Many cutaneous eruptions at early stages fit this descriptive heading. This section focuses on rashes that predominately present with macules and papules. In addition, all exanthems during the later stages of healing have the potential to shed superficially. The white flaky scale loss of the stratum corneum does not result in denuded skin, as opposed to the vesiculo-bullous conditions that exfoliate.
Viral exanthems are perhaps the most frequent cause of fever and rash. Although viral exanthems can present with multiple patterns, morbilliform eruptions are the most common.1 A morbilliform (measles-like) pattern appears as generalized, discrete, red to pink macules. Some lesions may be slightly raised so that a textural change is appreciated on palpation or tangential lighting. This may be referred to as maculopapular, but the term is nonspecific. Viral eruptions are preceded by fever and prodromal symptoms, which may include malaise, rhinorhhea, cough, or abdominal complaints. These symptoms, along with a history of contact exposure or travel, may be helpful in differentiating a viral illness from other causes of fever and rash. Certain viruses require close follow-up for associated complications. For instance, infectious mononucleosis can be associated with anemia, thrombocytopenia and neurologic involvement. Other viruses pose a danger to public health, and those infected require isolation from vulnerable groups, as exemplified by children with erythema infectiosum (Fifth disease), who should avoid contact with pregnant women and immunocompromised adults. (See "Childhood Viral Exanthems" on page 21 of this issue for a discussion of classic and uncommon viral exanthems.)
Exanthematous Drug Eruptions
Multiple drug-related exanthems have been described, but the most common patterns can be organized under two types of eruptions: morbilliform and scarlatiniform. The morbilliform pattern, most often confused with viral exanthems, initially appears as a macular rash on head, neck, and upper trunk. It is not uncommon for papular lesions to be present within the macules. The rash subsequently extends peripherally to the extremities in a symmetric, confluent fashion.2 Superficial skin desquamation often follows the fading erythema. SuIfonamides and penicillins are the most common offenders.
Differentiating a viral from a drug-related exanthem is challenging and sometimes not feasible, especially in a child with a viral syndrome who has received empiric antibiotics.
A detailed history regarding timing of medication intake in relation to the onset and progression of skin findings can provide valuable clues. Drug eruptions may occur after only a few doses of medication and up to 2 weeks after a medication has been finished. Although both types of exanthems may be accompanied by prodromal symptoms, more focal complaints, lack of pruritus and less intense erythema suggest a viral etiology.3
Figure LEdematous hands, cracked lips, and bulbar conjunctival injection are characteristic of Kawasaki disease, figures courtesy Robert A. Silverman, MD)
Treatment involves immediate discontinuation of the suspect drug and supportive care. Oral antihistamines, emollients, and topical or systemic corticosteroids can be used for comfort and quicker resolution. Although most exanthematous drug eruptions are benign and self-limited, they occasionally may portend the onset of a more serious drug hypersensitivity.
Fever, oral-pharyngeal mucosal symptoms, and the archetypal erythematous rash that desquamates characterize scarlet fever. This illness primarily affects children from ages 2 to 10.
Tonsillopharyngitis, presenting as fever and sore throat, due to Streptococcus pyogenes (Group A Streptococcus') is the most common focal infection associated with scarlet fever. However, scarlet fever can also be associated with skin and soft tissue infection.4 Clinical features of scarlet fever, such as fever, headache, nausea, vomiting, and exanthema, are associated with one or more pyogenic (or erythrogenic) exotoxins (SPE) produced by group A beta-hemolytic Streptococcus. Many children by age 10 appear to have developed lifelong antibodies to some of these exotoxins. Young children are protected presumably by maternal antibodies to erythogenic exotoxin and lack of prior hypersensitization.
Cutaneous changes initially manifest as erythematous macules and pinpoint blanchable papules, imparting a sandpaper-like texture to the rash. Initially occurring centrally on the face, neck, and upper trunk, the exanthem soon becomes more generalized and extends to the extremities, sparing the palms and soles. Accentuated erythema with petechiae in a linear pattern present in antecubital fossae and axillary vaults (Pastia's sign). Subsequent to the rashes fading throughout 5 to 7 days, superficial desquamation occurs on affected areas. Mucocutaneous oral involvement manifests as the classic white and red strawberry tongue, depending on whether a thick white coat overlies hypertrophied papillae. Palatal petechiae and anterior cervical lymphadenitis are additional findings.
Timely treatment of scarlet fever is helpful in reducing infectivity, hastening resolution, andpreventing exotoxin sequelae, as well as preventing subsequent rheumatic fever. Appropriate treatment with oral penicillin or amoxicillin for 10 days or benzathine penicillin G intramuscularly is curative. In the modern era, scarlet fever typically follows a benign course, although rare toxic cases may occur and certainly were more common in past decades.5
Figure 2. Early perineal desquamation is a distinctive presentation of Kawasaki disease.
Rgure S.Typical 3 zone "bulls-eye" lesions of erythema multiforme minorare observed on the knee.
Common Primary Skin Lesions
Kawasaki disease (KD), also known as mucocutaneous lymph node syndrome, is an acute self-limited multisystemic vasculitis of young children (mean age of about 2 years) defined by the clinical criteria in the Sidebar (see page 34).6 The etiology is unknown, although current evidence favors a respiratory viral agent
Clinical presentation usually begins with an abrupt high-spiking fever that if left untreated will last 5 to 30 days (mean 1 1 days) and is unresponsive to antipyretics and antibiotics. During this acute febrile period, irritability is common and prominent erythema develops over the palms and soles. Edema and at times painful induration can also occur on the hands and feet (Figure 1, see page 32).
Typically, within 5 days of the fever, a polymorphous exanthem appears and spreads within two days. A diffuse erythematous maculopapular eruption, a scarlatiniform pattern or an urticaria-like rash are most common. A generalized erythroderma or an erythema multiforme-like rash can occur but are less likely.7 Perhaps the most underappreciated presentation of KS is a prominent, bright red, desquamative eruption in the perineum in young children that develops in the first few days of the illness (Figure 2). Weeks later in the convalescent phase, desquamation occurs on the fingers and toes, beginning in the periungual region. Epidermal sheets of the palmar/plantar area are progressively shed.8
Additional mucocutaneous changes include bilateral non-exudative conjunctival injection and anterior uveitis with limbic sparing. Lips usually appear red, dry, fissured, peeled, or cracked. There is diffuse erythema of the oropharynx with a "strawberry tongue," but erosions and ulcers are absent. Unilateral cervical lymphadenopathy is the least common diagnostic feature.
The major determinants of short and long-term morbidity and mortality in KD are related to cardiovascular complications. Untreated patients carry a 15% to 25% risk of development of coronary artery abnormalities.9 Coronary arteritis may result in coronary artery dilation, aneurysm formation, and, rarely, myocardial ischemia. Additional complications consistent with multisystemic vasculitis include respiratory symptoms, arthritis, arthralgia, gastroententeritis, myocarditis, and aseptic meningitis. Elevated ESR and CRP levels reflect acute inflammation. An elevated white blood cell count is often present, and the platelet count reaches a peak between the 10th and 20th day of the illness.10 Sterile pyuria, mild hematuria, or proteinuria may also be seen.11
Timely diagnosis and treatment is critical to the prevention of cardiovascular sequelae. An initial echocardiogram with 2D imaging should be performed as soon as the diagnosis is suspected in order to establish a baseline. A single dose of intravenous immune globulin (IVIG), 2 g/ kg administered before day IO,12 together with high-dose aspirin (80 to 100 mg/kg/ day), is effective in reducing inflammation and fever in most patients. Controversy persists regarding the role (if any) of corticosteroids. Infancy and cardiovascular abnormalities portend a worse prognosis.
Figure 4. Stevens-Johnson syndrome is characterized by mucosal ulcérations.
Erythema Multiforme (EM Minor)
EM is a peripherally distributed rash characterized by an acute onset of symmetrical red macules that progress to the classic fixed target lesions of three concentric zones of color during a 1- to 2-day period (Figure 3, see page 33). When completely formed, the central zone of the target lesion may become papulovesicular or crusted. The aerai distribution favors the backs of the hands and feet, elbows, knees, and the extensor aspect of the forearms and legs.13 Mucosal involvement is minimal or absent Skin lesions may be preceded by a fever, malaise, and upper respiratory symptoms. Annular urticaria and serum sickness-like drug reactions are frequently confused with EM minor. In these diseases, lesions migrate and are not fixed.
Herpes simplex virus infection or reactivation is the most commonly identified inciting agent of EM. EM is usually a self limited, benign condition that typically resolves within 2 to 3 weeks. Recurrent EM associated with HSV infection may benefit from acyclovir therapy.14 Mycoplasma pneumoniae infection also may be associated with EM. Emollients, topical steroids, and antihistamines provide symptomatic relief. The use of oral corticosteroids at a dose of 1 mg/kg/day for 5 days may also provide symptomatic relief, but their use is still controversial.
VESICULO-BULLOUS RASHESWITH EXFOLIATION
Exfoliation in these conditions results in loss of the epidermal layer leaving denuded skin exposed.
figure 5. Large areas of scartetinaform erythema or confluent targetoid papules coalesce to form bullae in toxic epidermal necrolysis (TEN).
Hyper sensitivity Reactions
Stevens-Johnson syndrome (SJS), also known as erythema multiforme major (EM major), and toxic epidermal necrolysis (TEN) are mucocutaneous disorders that encompass a clinical spectrum of the same disease process of epithelial necrosis and subsequent denudatioa TEN involves at least 30% of the body surface area.
Stevens-Johnson Syndrome (Erythema Multiforme Major)
SJS is characterized by extensive mucosal involvement (eyes, nose, mouth, upper airway, gastrointestinal, and genitourinary tracts) with widespread blistering, erosions and ulcérations. Stomatitis and conjunctivitis are extremely common findings. Hemorrhagic crusting of the nose, lips and oral mucosa are typical (Figure 4). Mucosal involvement often heralds the rash by 1 to 2 days. Prominent constitutional symptoms with high fever may precede cutaneous lesions by 1 to 3 weeks. Most affected individuals are children in the second decade of life.
Skin lesions are variable, with vesicles and bullae occurring on large concentrically colored, two-zoned, round or irregularly shaped, nonpruritic plaques.15 Discrete target-like lesions may form with central blistering. Cutaneous findings mainly affect the extremities but can be more generalized and include the trunk and face affecting up to 30% body surface area. Palms and soles are often affected. The average time course of this illness ranges from 2 to 6 weeks depending on the continued eruption of new lesions and re-epithelization.
Toxic Epidermal Necrolysis (TEN)
TEN initially presents as either diffuse, pronounced erythema, a morbilliform rash, or target lesions that rapidly become confluent to involve more than 30% of the body surface area (Figure 5). Overlying these rashes, superficial blisters rapidly develop, progress into large bullae and rupture, leaving inflamed denuded tender skin.16 Similar to SJS, constitutional symptoms and mucosal involvement often precede the skin lesions by 24 hours. Ocular involvement and scarring can be severe and extensive. TEN can occur in all age groups including newborns. Although TEN and the staphylococcal scalded skin syndrome have skin tenderness in common, the denuded blister base of TEN is bloody, similar to that of a second-degree burn. A biopsy and frozen section is sometimes necessary to distinguish the two disorders in neonates or atypical cases.
Figure 6. The painful, sun-bum-like erythema of staphylococcal scalded skin syndrome shears and blisters easily (positive Nikolsky's sign).
Etiologic factors of SJS and TEN include drugs and infections, although over 50% of those affected have no known cause. SJS is strongly associated with Mycoplasma pneumoniae in the pediatrie population.17 Antibiotics (penicillins, sulfonamides), and anticonvulsants and, less often, analgesics are most commonly implicated in SJS and TEN.
Management and Prognosis
Possible precipitating medications should be immediately discontinued. Treatment of underlying infection such as Mycoplasma pneumoniae, especially in a patient with SJS, is recommended. Patients with SJS and TEN require close monitoring in an intensive care setting or burn unit Supportive care, including vigilant fluid and electrolyte balance, nutritional support, fever control, and meticulous wound care are the mainstays of therapy. Prevention of secondary bacterial infections and close attention to ophthalmologic involvement are important components of care. Use of systemic steroids is highly controversial due to increased susceptibility to infection and possible aggravation of complications. A recent comprehensive review of the use of intravenous immunoglobulin (IVIG) in children with SJS and TEN indicated IVIG to be safe and effective in most cases;18 however, the basis for non-response needs to be elucidated.
Staphylococcal Scalded Skin Syndrome
Staphylococcal scalded skin syndrome (SSSS) is an acute infection characterized by an erythrodermic blistering eruption followed by desquamation (Figure 6). Most commonly presenting in infants and children less than 5 years of age, SSSS is caused by an exfoliative exotoxin-producing strain of Staphylococcus aureus (phage group II). Prodromal symptoms of pharyngitis and conjunctivitis are followed within 24 hours by fever, malaise, and an exquisitely tender, sunburn-like erythematous eruption with crusting on the face, neck, and to a lesser extent, the axilla and perineum (flexure areas). Gentle friction applied to the skin causes separation of the superficial epidermis (positive Nikolsky's sign). Flaccid bullae may develop over these areas and progressively enlarge and rupture, thereby exposing a moist red base with the characteristic scalded appearance.19 In the newborn, the entire body surface may be affected with desquamation of large sheets of skin (Ritter's disease).
Figure 7. Toxic shock syndrome produces prominent desquamation without the formation of blisters.
SSSS is caused by the systemic (hematogenous) circulation of staphylococcal exfoliative exotoxins A or B (ETA, ETB). The heat-stable protein ETA is the more common toxin produced in the US and Europe (89% of isolates).20 These exotoxins target the desmosome cell adhesion protein (desmoglein 1 complex) within the superficial epidermis, results in blistering of the upper skin layer. Diagnosis is based on clinical, histological and microbiological findings. Culturing for S aureus from the nose, nasopharynx, conjunctivae, and external ear canal increases the likelihood of isolating this offending pathogen.
Management and Prognosis
Prompt systemic treatment with a semisynthetic penicillinase-resistant penicillin or clindamycin is indicated. Although this illness tends to carry good prognosis with no sequelae or scarring, the 4% mortality rate of childhood SSSS is usually associated with extensive and severe skin involvement Because of the skin tenderness, appropriate analgesic medications, gentle handling, pressure relieving mattresses with sterile sheets, and emollient lubrication with white-petrolatum can minimize discomfort during the resolution phase. Corticosteroids are contraindicated in the treatment of SSSS.
Toxic Shock Syndrome
Toxic shock syndrome (TSS) is an acute illness characterized by high fever, erythroderma with flexural accentuation, and followed by desquamation, particularly of hands and feet Additional features include hypotension, conjunctival hyperemia and multi-organ dysfunction.21
Figure 8. Palpable purpura of meningococcemia (A) are a reflection of septic emboli and differ from purpura fulminans of (B) disseminated intravascular coagulation.
TSS is especially common in young menstruating women who use hyperabsorbable tampons or vaginal barrier contraceptives. Non-menstrual TSS (NMTSS) accounts for over 55% of cases22 and has been associated with soft tissue infections, surgical wounds, burns, visceral abscesses, and sino-pulmonary infections.23
In adolescents or women who are menstruating, the onset of symptoms is typically within 4 days of menses.
Clinical symptoms typically involve the sudden onset of fever, chills, headaches, severe myalgias, vomiting, diarrhea, and weakness. Within the subsequent 24 to 48 hours, diffuse erythroderma appears on the body, along with pronounced hypotension resulting in hypoperfusion, capillary leak, and multiorgan system dysfunction. This manifests as peripheral cyanosis, edema, pulmonary edema, myocarditis, and mental status changes.
Hyperemic conjunctivae with ulcerated red mucous membranes can be additional features of this illness. Desquamation beginning on the trunk and extremities occurs around day 5 to 7 of the illness and intensifies to full thickness shedding of the palms, soles, fingertips and toes by day 10 to 12 (Figure 7).24
Classic TSS is caused by the toxin producing strains of S. aureus. The most important toxin is TSST-I. A toxin-producing S, pyogenes strain also produces a similar clinical picture termed streptococcal toxic shock syndrome (STSS), which is less associated with erythroderma. Most cases of STSS tend to originate from a skin or soft tissue or mucosal infection.25
Management and Prognosis
Treatment of Staphylococcus with a beta-lactamase-resistant antibiotic like clindamycin, vancomycin, or cephalosporin should be administered intravenously immediately. Removal of foreign bodies (tampons) and drainage of any abscesses or sources of infection are crucial. Supportive care with fluid replacement in an intensive care setting is paramount. The extent of organ dysfunction is related to the duration of hyp operfusion. A high recurrence rate of menstrual TSS is postulated to be due to persistent colonization with a toxigenic strain and the absence of neutralizing antibody production.26 Reduction of recurrences can be attained by treatment with an anti-staphylococcal antibiotic and refraining from tampon use.
PETECHIAL - PURPURIC RASHES
Meningococcemia and Purpura Fulminans
Meningococcal infections caused by Neisseria meningitidis are a major worldwide concern due to their potentially rapid, fulminant course and high mortality rate. This explains the challenge and anxiety distinguishing this infection from other less serious illnesses.
This disease typically afflicts patients younger than 20, although children less than 5 years are most at risk, and it accounts for more than 50% of reported cases of meningitis.27 Outbreaks also occur in semi-closed communities, such as child-care centers, schools, college dormitories, and military bases. Risk factors for carriage of JV. meningitides and invasive disease include infancy, functional absence of the spleen and complement deficiencies (C5-9).28
Transmission occurs by direct contact or droplets spread carrying JV. meningitidis from the upper respiratory tract, and there is a 2- to 10-day incubation period. Invasive disease can present as either meningococcemia or meningitis (with or without meningococcemia).
Meningococcemia is often preceded by a prodrome of upper respiratory symptoms. These are followed within a week by an abrupt spiking fever, chills, headache, vomiting, malaise, and the cardinal petechial rash of the skin and mucous membranes. Within 12 to 36 hours the petechiae take on the appearance of palpable purpura (Figure 8a, page 36). Sites of predilection include the trunk and extremities, especially areas of friction such as the waistband of clothing. There is not an early predelection for the wrists, ankles, palms, or soles. Petechiae signify dermal microvascular thrombosis and perivascular hemorrhage. By the time a child displays the gun-metal grey or blue-black well-demarcated plaques, shock and disseminated intravascular coagulation (DIC) may be well established (Figure 8b, see page 36).
Various studies have shown up to a 15% likelihood of a meningococcal infection in children with an acute nonblanching rash.29'30 Differential diagnosis of a child with the constellation of high fever, a rapidly progressive petechial eruption and hypotension include bacteremias from Haemophilus influenzae, S pneumoniae, Pseudomonas spp, and overwhelming viral and fungal infections. Early in the course of the illness, the appearance may be maculopapular, rendering it difficult to differentiate from a viral exanthem.31
The diagnosis of fulminant meningococcemia is made by cultures of blood, cerebrospinal fluid, and skin. All household contacts need to be treated prophylactically to prevent secondary cases. Highly sensitive rapid polymerase chain reaction (PCR) tests are currently available for detection of the most common serotypes of JV. meningitidis and can be performed on blood, urine or cerebrospinal fluid.
Management and Prognosis
Fjnpiric treatment with broad-spectrum intravenous antibiotics that cover the multiple pathogens that may cause sepsis and meningitis should be administered as soon as the diagnosis is suspected. Once JV. meningiditis is isolated, IV penicillin G, cefotaxime, ceftriaxone, or ampicillin are administered. Supportive intensive therapy with volume support is crucial. Monitoring and aggressive treatment of mutisystemic signs of shock and DIC in an intensive care setting are paramount for survival.32
Rocky Mountain Spotted Fever (RMSF)
RMSF, a tick-borne disease caused by the gram-negative intracellular bacterium Rickettsia rickettsii, is transmitted to humans through a tick bite/feeding or via contact with crushed tick tissues, fluids, or feces. Initially recognized in the northern Rocky Mountains, it is now most prevalent in the South Central region of the United States (North Carolina, Tennessee, Oklahoma, South Carolina, and Arkansas).33 Common tick vectors of RMSF include Dermacentor andersoni (wood tick), Dermacentor variabilis (dog tick), and Amblyomma americanum (Lone Star tick) that can be found in urban and rural settings and can be carried by household pets. Most cases are reported during the months of April through October in children younger than 15 years of age (peak age of 5 to 9 years).
A history of tick bite is obtained in only 60% of cases. Typically after 12 to 24 hours of tick attachment, the rickettsiae multiplies within endothelial cells lining small blood vessels and disseminate into the bloodstream.34 This endothelial cell injury and lymphocytic vasculitis lead to thrombosis and capillary leak into surrounding tissues, manifesting as petechiae and edema.
Following tick exposure (2 to 14 days), prodromal symptoms develop, such as fever, nausea, vomiting, severe headache, malaise, photophobia, and abdominal pain. The classic rash appears between the second and fifth day of illness as red blanching macules and papules 2 to 3 mm in diameter beginning on the wrists and ankles and somewhat later on the palms and soles. Within 6 to 18 hours, the rash spreads centripetally to the arms, thighs and trunk. The classic petechial rash is typically seen on day 6 in only 35% to 60% of patients. Also, 10% to 15% of those affected never develop a rash.
Widespread necrosis and purpura may occur in severe cases resulting in gangrene, scarring, loss of parts of extremities, and multi-organ failure. A high index of suspicion and rapid/early treatment is recommended to prevent deterioration of condition.
Management and Prognosis
The drug of choice for treatment of RMSF is doxycycline, regardless of the patient's age, because it is more effective than chloramphenicol. Avoiding tick exposure by wearing protective clothing and using tick repellents is the most effective means of prevention. In addition, full-body exams should be done after returning from tick-infested areas.
The differential diagnosis of a fever and rash presenting in a pediatrie patient is quite extensive. This article is not all-inclusive but is meant to aid in the diagnosis to differentiate serious, life-threatening eruptions from more benign common rashes.
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Common Primary Skin Lesions