Strange and Schafermeyer's Pediatric Emergency Medicine, Fourth Edition (Strange, Pediatric Emergency Medicine), 4th Ed.

CHAPTER 94. Skin Signs of Systemic Disease

Ara Festekjian

Vincent J Wang

HIGH-YIELD FACTS

• Erythema nodosum (EN) is an acute panniculitis consisting of deep, painful, bilateral, erythematous nodules, usually on the lower extremities, resulting from an underlying systemic illness

• Erythema multiforme (EM) is an acute, immune-mediated mucocutaneous condition characterized by target lesions with concentric zones of color change, most commonly associated with herpes simplex virus (HSV) infection

• Stevens–Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe immune-mediated hypersensitivity reactions characterized by diffuse bullous lesions and mucocutaneous involvement most commonly precipitated by medications such as anticonvulsants

• Staphylococcal scalded skin syndrome (SSSS) is characterized by an erythematous rash followed by diffuse epidermal exfoliation

• Purpura fulminans is a severe form of rapidly progressive purpura with multiorgan failure, usually associated with meningococcemia

• Nonaccidental trauma should be suspected if bruising occurs on nonbony prominences or in areas not normally subjected to trauma during routine child play

• Toxic shock syndrome (TSS) is an acute, toxin-mediated illness characterized by fever, erythroderma, hypotension, multiorgan involvement, and desquamation. Streptococcal TSS (STSS) is a similar disease caused by invasive group A Streptococcus (GAS). Each of these is a shock state.

• Necrotizing fasciitis (NF) is a rapidly progressive, life and limb threatening infection by virulent bacteria with severe inflammation of the fascia and surrounding subcutaneous tissues

• Kawasaki disease (KD) is an acute, self-limited, vasculitic syndrome in children. The diagnosis is established clinically by the presence of prolonged fever and four of the following five clinical features: conjunctival injection, oropharynx erythema, cervical lymphadenopathy, hand and foot erythema/swelling, and rash.

• Urticaria, often referred to as hives, appears as blanchable, pruritic, raised, well-circumscribed areas of edema and erythema involving the epidermis and dermis

• Angioneurotic edema (AE) is a self-limited localized swelling due to extravasation of fluid into interstitial tissues, most commonly involving the head, neck, hand, and gastrointestinal tract. Laryngeal involvement is life-threatening.

INTRODUCTION

Dermatologic signs of systemic disease will be the primary focus of this chapter. Many diseases have clinical presentations where the dermatologic manifestations play a role in helping the clinician make the underlying diagnosis. Table 94-1 is a list of systemic diseases with their corresponding dermatologic manifestations, and the sections below describe pediatric emergencies in which the dermatologic characteristics play a large role in diagnosis.

TABLE 94-1

Characteristic dermatologic manifestations of systemic diseases

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ERYTHEMA NODOSUM

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EN is a type of acute panniculitis in children.1 It is considered a dermatologic manifestation to a variety of microbial and nonmicrobial stimuli, such as streptococcal pharyngitis, tuberculosis, fungal infections, HSV, inflammatory bowel disease, sarcoidosis, malignancies, and occasionally, drugs such as oral contraceptives and sulfonamides.

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The exact mechanism of EN is unknown. Debate exists as to whether it is an immune complex disorder with deposition of IgM and C3 in the venules of the deep dermis and adipose plexus, or a delayed-type hypersensitivity reaction to a wide variety of antigens.2 In the latter scenario, a noninfective cutaneous eruption represents an inflammatory response to an underlying infection or medication exposure.3

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The classic lesions of EN are deep, painful, erythematous nodules or plaques that may last several weeks. They typically occur on the extensor surfaces of the extremities (Fig. 94-1) bilaterally and symmetrically, and also occur on the calves and buttocks. Ulceration is not a feature. In the context of an underlying illness, the timing of its appearance is variable. EN may be viewed as an id reaction to a large antigen load or from release of antigen after initiation of therapy for fungal infections.4 Constitutional symptoms may be present at the onset, including fever, fatigue, muscle and joint aches.

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FIGURE 94-1. Erythema Nodosum.

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Management focuses on treatment of the underlying cause. Lesions gradually heal as the underlying disease is controlled. In the case of a suspected id reaction to a dermatophytic infection, treatment of the infection should be continued despite development of EN. When its etiology is not clear, symptomatic relief can be obtained with extremity elevation, nonsteroidal anti-inflammatory agents (NSAIDs), and rest.

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A skin biopsy may be necessary when the diagnosis is not clear. Biopsy findings demonstrate panniculitis without vascular inflammation. Laboratory tests and imaging may be considered in the evaluation of underlying disease processes.

ERYTHEMA MULTIFORME

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EM has been associated with many different drugs and infections, with HSV and Mycoplasma pneumoniae being the most common predisposing infections. Other infectious etiologies include Epstein–Barr virus, cytomegalovirus, adenovirus, Streptococcus pneumoniaeSalmonella species, Mycobacterium tuberculosis, histoplasmosis, and certain parasites. Drugs causing EM include sulfonamides, penicillins, anticonvulsants, and NSAIDs. A large percentage of cases will not have an identifiable cause.5

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The exact pathophysiology of EM is unclear. It is thought to be an acute, immune-mediated mucocutaneous hypersensitivity response triggered by various antigens. Genetic susceptibility can be a predisposing factor in some patients with EM. In patients with HSV-associated EM, a larger percentage of patients will carry specific HLA alleles. Various cytokines have also been identified to play a role, with interferon-gamma found in HSV-associated EM and tumor necrosis factor-alpha in drug-induced EM, further supporting the immune-mediated mechanism.

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The characteristic lesions of EM are described as round, fixed, and erythematous, appearing symmetrically on the skin and demonstrating dusky central clearing known as “target” lesions (Fig. 94-2). The lesions are distributed acrally but can also be found on the trunk, with a predilection for extensor surfaces. They can change and morphologically evolve during the course of the illness. They are sometimes accompanied by oral, genital, or ocular mucosal erosions, or a combination of these. The presence or absence of mucosal involvement separates EM major from EM minor. With EM major, prodromal symptoms of malaise, fever, and myalgias are common. Though EM is usually self-limited, there are recurrent cases, especially when associated with HSV infection.6 Until recently, EM was considered on a spectrum of disorders, including EM major, SJS, and TEN. In a consensus clinical classification, however, EM major and SJS are separate, distinct conditions with similar mucosal erosions.7

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FIGURE 94-2. Erythema Multiforme.

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EM management varies depending on the type of presentation. In acute EM, the key to therapy includes removing the inciting agent and treating an identified illness (HSV and M. pneumoniae). Symptomatic control can be achieved with topical anesthetics and oral antihistamines. Treatment for EM major is dependent on the severity of mucosal involvement, and involves topical or systemic corticosteroids. Ocular involvement may necessitate emergent ophthalmology consultation and treatment with topical eye medications. In HSV-associated recurrent EM or idiopathic recurrent EM, continuous prophylactic antiviral therapy is recommended.68

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Although there are no specific laboratory tests for EM, severe disease can be associated with increased erythrocyte sedimentation rate (ESR), white blood cell count, and liver enzyme levels.9 Other testing or imaging may be completed based on the suspicion of underlying diseases.

STEVENS–JOHNSON SYNDROME/TOXIC EPIDERMAL NECROLYSIS

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SJS and TEN are associated most commonly with medications such as anticonvulsants (especially carbamazepine, lamotrigine, phenytoin, and phenobarbital), antibiotics (especially sulfonamides, penicillins, and cephalosporins), allopurinol, and NSAIDs. HSV and M. pneumoniae are infections associated with SJS and TEN.

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SJS and TEN are considered diseases on a spectrum of the same severe, idiosyncratic, cutaneous hypersensitivity reaction. Cytotoxic T lymphocytes and natural killer cells along with signaling ligands on activated T cells trigger apoptosis of keratinocytes leading to diffuse bullous lesions and mucocutaneous involvement. The role of immune dysregulation is supported by the greater association of SJS and TEN in HIV-positive patients, and more severe reactions when an individual is subjected to the same inciting agent. The presence of HLA-B1502 antigen increases the risk of SJS and TEN induced by carbamazepine, an association specifically found in Asian populations.10 Rapid infusion of the anticonvulsant lamotrigine also triggers the apoptotic process in keratinocytes.11

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SJS/TEN patients present with a 1- to 2-week prodrome of fever, malaise, arthralgia, and anorexia, and occuring more commonly during the spring months. The rash of SJS/TEN starts on the trunk, followed by spread to the face and proximal extremities. The characteristic lesions generally start as macular lesions and may resemble “target lesions” similar to EM. These lesions progress to raised, purpuric lesions, and bullae. Bullae subsequently coalesce, resulting in sloughing of the epidermis (Fig. 94-3). Nikolsky sign, denudation of the skin with gentle tangential pressure, is present in areas of erythema. Ulcers and bullae may develop on any mucous membrane (eyes, nose, mouth, upper airway, gastrointestinal and genitourinary tracts). Severe dermatitis and conjunctivitis can occur in the eyes, leading to ulceration, perforation, and scarring. SJS and TEN are differentiated based on the extent of involvement. Epidermal detachment of <10% body surface area (BSA) is SJS; while 10% to 30% BSA detachment may be either SJS or TEN; and >30% BSA detachment is TEN. SJS is more common than TEN.10 Ocular scarring can be severe and extensive with TEN. Overall symptoms may last for 2 to 6 weeks.

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FIGURE 94-3. Stevens–Johnson syndrome seen with ocular and oral mucosal involvement.

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SJS/TEN patients usually require admission to a burn or intensive care unit in order to closely monitor electrolytes and fluid balance, to perform meticulous skin care, and to provide analgesia and nutritional support. At times, airway support may be necessary when mucosal ulceration is extensive. Loss of the skin barrier predisposes to infections that require treatment, but routine antibiotic prophylaxis is not recommended.12 Intravenous immunoglobulin (IVIG) and systemic corticosteroids have been used for SJS, though this is controversial. Plasmapheresis has been used successfully in TEN. Eye involvement necessitates ophthalmologic consultation. Any known precipitating agents should be discontinued.

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Similar to burn patients, SJS/TEN patients should have their electrolytes checked regularly, along with cultures of skin and blood to address secondary bacterial infections.

STAPHYLOCOCCAL SCALDED SKIN SYNDROME

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SSSS is caused by an exfoliative exotoxin-producing strain of Staphylococcus aureus. The physical exam findings result from the delivery of this toxin through the circulation to the skin. It most commonly presents in infants and children younger than 5 years.10

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The exotoxin is carried through the circulation to the skin, where it targets the epidermal granular cells and activates a serine protease that cleaves the cell adhesion molecule desmoglein. Keratinocyte damage results in epidermal separation. The location of separation in SSSS is midepidermal, as compared to TEN, which is subepidermal at the dermal–epidermal junction. In localized SSSS, S. aureus enters the skin through a disruption, causes local infection, and releases exfoliative toxins. In generalized SSSS, exfoliative toxin circulates throughout the body from a colonization site (e.g., nares, groin, umbilicus) or local infection (e.g., wound infection, septic arthritis, osteomyelitis) and results in large areas of exfoliation.13

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SSSS usually starts with prodromal symptoms including pharyngitis and conjunctivitis, and is soon followed by fever, malaise, and a blistering skin eruption. The area rapidly enlarges and coalesces, appearing similar to sunburn, which usually starts over the face, neck, axillae, and groin. Large, superficial bullae then form over the erythematous areas and rupture. The skin is exquisitely tender and fragile. Gentle rubbing of the skin results in desquamation of the epidermis, exposing a moist red base with the characteristic scalded appearance (Fig. 94-4). In infants and preschool children, the lesions are limited to the upper body, but in newborns, the entire cutaneous surface is involved (Ritter disease).

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FIGURE 94-4. Diffuse erythema and desquamation are the typical features of SSSS.

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Patients with severe SSSS are managed similarly to burn patients because of the increased risk of fluid and electrolyte losses through the exposed skin, and due to the risk of secondary infection. Unlike burn patients, however, the mainstay of treatment for SSSS is the rapid initiation of antibiotics. IV nafcillin is the drug of choice since it adequately treats infections caused by penicillinase-producing Staphylococci. Other options for antibiotic therapy include cefazolin and clindamycin. Skin tenderness can be relieved by local and systemic agents. Due to the fragile nature of the skin, handling should be minimized, and pressure-relieving mattresses can be utilized. Corticosteroids are contraindicated.12,13 SSSS carries an 11% mortality rate in children with severe extensive skin involvement; however, the majority of the cases occur without sequelae or scarring.12

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Blood cultures as well as cultures from the nose, nasopharynx, conjunctivae, and external ear canal may isolate the offending pathogen.

PURPURA FULMINANS

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Purpura fulminans is a life-threatening condition associated with sepsis, and is characterized by hemorrhagic infarction of the skin and multiorgan dysfunction. The most common organisms implicated in pediatric patients are Neisseria meningitidis, followed by S. pneumoniae and group A and B Streptococci.14,15 Most cases of S. aureus sepsis are reported as TSS. Outbreaks occur in semiclosed communities, such as child care centers, college dormitories, and military bases. Transmission occurs by direct contact with secretions or fomites carrying the offending organism.

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The septic lesions are thought to be initiated by local intradermal release of endotoxin leading to an inflammatory reaction and increased vascular permeability. The same endotoxin, 12 to 24 hours later, is responsible for widespread microvascular thrombosis, hemorrhagic infarction of the skin, and necrotizing vasculitis, by causing a disturbance in the anticoagulant and procoagulant pathways leading to disseminated intravascular coagulation (DIC).14

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The sepsis-induced cutaneous lesions are similar regardless of the causative organism. The clinical course of skin necrosis begins with a region of dermal discomfort that quickly progresses to petechiae within minutes to hours. The petechiae, which can be found anywhere on the body, will usually distribute acrally over the hands and feet. They then coalesce to form purpura (Fig. 94-5). Hemorrhagic infarction and subsequent skin necrosis can occur at this point without initiation of aggressive therapy. Frank skin necrosis and gangrene are associated with more than 50% mortality.14 Even though the purpuric rash is the principal feature of purpura fulminans, it is a late sign of the disease. Instead, children may initially develop other signs and symptoms such as fever, malaise, vomiting, poor perfusion, altered mental status, and even hypotension. Most, but not all, patients will be ill appearing.

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FIGURE 94-5. Patient with petechiae and purpura from Gram-negative sepsis.

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The majority of affected patients develop septic shock and DIC.14 Early recognition of the disease state and timely treatment is crucial and will decrease mortality. Aggressive systemic organ support is paramount for survival of these patients. Supplemental oxygen and mechanical ventilation help reduce metabolic demands by reducing the work of breathing. Aggressive fluid resuscitation is required to restore intravascular volume. Hypotension may arise despite aggressive fluid resuscitation, and inotropic support may be necessary. Administration of antibiotics should also be initiated soon after diagnosis. Initial antibiotic coverage may be a third-generation cephalosporin, such as ceftriaxone, until an organism has been identified. N. meningitidis is susceptible to most commonly used parenteral antibiotics. Vancomycin should be added if methicillin-resistant S.aureus is suspected. Once a causative organism is identified with antibiotic susceptibilities, the coverage can be modified. Purpura fulminans almost always leads to full-thickness skin loss, necessitating treatment similar to that of burn patients.14 The complications are also similar, including secondary infection and compartment syndrome. Debridement of the necrotic tissue and eventual grafting may be required. When the tissue necrosis is extensive, limb amputation may become necessary.

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A blood culture is valuable and should be obtained even if antibiotics have been given. Other cultures that should be obtained once the patient is stabilized are cerebrospinal fluid and urine cultures. Useful laboratory studies include blood gas measurements, DIC panel, lactate, and complete blood count. However, it is crucial to remember that obtaining supplementary studies is not the priority. Highly sensitive rapid polymerase chain reaction (PCR) tests are available for detection of the most common serotypes of N. meningitidis, which can be performed on blood, urine, and cerebrospinal fluid.

PHYSICAL ABUSE

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Bruising caused by maltreatment is a consequence of blunt trauma inflicted on the patient. This can occur when caretakers attempt to discipline the child or when their anger is displaced on the child as bodily harm. Pediatric victims of nonaccidental trauma are usually too young to protect themselves or retaliate.

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Each year, it is estimated that more than 3 million children will be victims of nonaccidental trauma, and as a result, an estimated 2000 children will die.16 There are multiple risk factors. Children who are younger than 4 years or those who have comorbid conditions such as learning disability, chronic illness, conduct disorder, and mental retardation are at highest risk. Prematurity is another important risk factor. Caretakers who are likely to inflict harm are those who were victims themselves as children. Young, single, nonbiological parents are also more likely to be perpetrators of nonaccidental trauma.

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Appropriate diagnosis of child abuse is achieved by a thorough history and physical as well as laboratory studies and imaging modalities. It is beneficial to separately interview caretakers because inconsistent histories may be given for the same injury. It is also important to be familiar with medical conditions and cultural practices (coining, cupping) that mimic child abuse (Fig. 94-6). The pattern of distribution and location of the traumatic lesions will help differentiate nonaccidental from accidental trauma. Bruising over bony prominences often signify normal trauma in an ambulatory child; however, bruising over the back, earlobes, buttocks, or other protected areas may suggest nonaccidental trauma. Bruising in the shape of teeth marks, belt marks, or hands should also increase your suspicion of maltreatment. The pattern of burns may also suggest nonaccidental trauma. Human bites, compared to animal bites, are more often crush injuries. Animal bites usually produce a puncture wound or cause tearing of the skin. Siblings may be blamed for a bite injury, but a bite width of more than 4 centimeters is indicative of an adult bite.17Another key piece to evaluation is noting the various stages of bruising. Fresh bruises implicate that abuse is ongoing. Aging bruises using standardized aging charts is no longer used. Any unexplained bruising, especially in infants younger than 6 to 12 months, should raise suspicion of nonaccidental trauma.

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FIGURE 94-6. Purpura from “coining,” a cultural practice for fever management.

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In all states, physicians and other professionals (health care providers, teachers, and law enforcement personnel) are mandated by law to report suspected child abuse and neglect to the child protective services or law enforcement.16Consultation with other health professionals and child protective services may be needed in cases in which the physician is uncertain about the likelihood of abuse. The main goal is to safeguard the child from further harm. If the patient’s safety cannot be guaranteed, discharge must be to a safe environment, such as child protective services custody. Other children in the offender’s home may require removal as well.

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It is important to consider any unexplained causes of bruising. A complete blood count will help delineate a platelet abnormality. Coagulation studies may aid in ruling out a bleeding disorder. A skeletal survey helps identify subtle fractures that may be associated with the dermatological findings and is typically obtained in children less than 2 years of age in whom abuse is suspected. When a patient presents with altered level of consciousness or other unexplained neurological findings, a computed tomography (CT) of the head may reveal skull fractures or intracranial bleeding.

DIFFUSE ERYTHRODERMA AND SHOCK

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TSS results from a bacterial toxin, TSS toxin-1 (TSST-1), produced by 20% of S. aureus isolates. STSS is similar clinically to TSS, and is caused by Streptococcus pyogenes.

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Greater than 60% of cases occur in women, with an incidence of 3.4/100,000 in women aged 15 to 44 years. TSS is associated with menstrual (superabsorbent tampons) and nonmenstrual causes. Nonmenstrual causes include surgical wounds, postpartum wounds, sinusitis, and osteomyelitis. Associated conditions include influenza, pneumonia, varicella, and NF.18 STSS predisposing factors are deep-seated GAS infections, NSAIDs use (in younger children), and preceding varicella infection. STSS incidence corresponds to the incidence of invasive GAS disease.18

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TSST-1 is a superantigen, which can activate up to 20% of T cells at a single time leading to overwhelming cytokine release. This immune cascade results in massive vasodilation and rapid movement of serum proteins and fluid from the intravascular to the extravascular space, resulting in oliguria, hypotension, edema, and low central venous pressure. STSS is caused by invasive GAS, which is thought to produce the streptococcal enterotoxin. Sites of infection in STSS are much deeper than in TSS. In TSS, the bacteria are colonizers with the disease resulting only from the toxin. In STSS, the toxigenic organism produces infection with clinical manifestations attributed to the infectious process and the presence of toxin.18

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TSS is characterized by an acute illness with fever, hypotension, and multisystem organ involvement. The dermatologic hallmark of TSS is nonpruritic, blanching macular erythroderma. The erythroderma is usually diffuse, resembling sunburn, and at times it may be confined to the extremities or trunk. The rash may be subtle and missed in heavily pigmented patients. Erythroderma usually resolves in 3 to 5 days, followed by a fine desquamation of the hands and feet in 5 to 14 days. Other dermatologic manifestations include conjunctiva and mucosal hyperemia, petechiae, alopecia, and fingernail loss. STSS presents as sudden onset of shock and organ failure in the presence of any streptococcal infection. The clinical presentation includes fever, hypotension, skin edema, and erythema, or bullae. Tender erythroderma is the most suggestive symptom of STSS. It appears abruptly, and the hyperesthesia may seem out of proportion to the degree of skin involvement. These patients need to be evaluated for GAS NF. Subsequent desquamation occurs less commonly than TSS.19

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The cornerstone of therapy for erythroderma and shock is prompt recognition, aggressive volume and inotropic support of shock, and removal of any inciting agent such as tampons in TSS.18,20 Clindamycin can be used for both TSS and STSS given its ability to inhibit toxin production. Penicillin G can be used for GAS infections. Vancomycin is recommended given the increasing prevalence of community acquired methicillin-resistant S. aureus. Adjunctive therapy to neutralize toxins includes IVIG or fresh frozen plasma.21

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Laboratory studies include complete blood count, blood culture, culture of offending site (e.g., surgical site, wound culture, vaginal culture), complete metabolic panel, creatine phosphokinase, and coagulation studies. Early surgical consultation is needed for debridement evaluation.

NECROTIZING FASCIITIS

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NF is a rapidly progressive, wide spread necrosis involving the subcutaneous tissue and fascia. NF can be polymicrobial, which is the most common, composed of aerobic and anaerobic bacteria. NF can also be due to a single pathogen, invasive GAS (S. pyogenes), discussed in the previous section.

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NF is not common in children: 0.08 to 0.3 cases per 100,000 children per year.22 An increase of group A beta-hemolytic streptococcus (GAS)-related NF, also termed “flesh-eating bacteria” occurred in the 1990s. Diabetes and underlying malignancy predispose patients to the polymicrobial form of the infection, whereas varicella infection (active or recent), immune-compromise, and NSAIDs use are considered predisposing factors in the single pathogen form seen in children.

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The mechanism for widespread fascial plane necrosis appears to be secondary to a vasculitis and thrombosis of regional blood vessels. There seems to be a symbiotic relationship between the different bacteria. The facultative Gram-negative organisms lower the oxygen-reducing potential of the tissue, which promotes anaerobic organism growth. The anaerobic organisms impede phagocyte function favoring aerobic bacterial growth. Common pathogens include Escherichia coliKlebsiellaPseudomonas species, and S. aureus. The combination of bacterial toxins and vessel thrombosis leads to ischemia of the skin, subcutaneous fat, and fascia, increasing the spread of bacteria and resulting in alarming spread of the infection. Bacteremia is present in ~30% of cases consistent with this mechanism and contributing to a high mortality.23

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The main presenting complaint in patients with NF is pain well out of proportion to the physical exam findings, which is true for both polymicrobial and single pathogen types of the disease. The skin is erythematous and possibly edematous. Purple/bluish discoloration and crepitus are typically later findings, but are highly suggestive.23 In adults, a majority of cases involve the lower extremities, with the upper extremities, perineum, trunk, head and neck, and buttocks following in decreasing order. The trunk is more common in children.24 Fever and tachycardia are common. Patients usually have a normal sensorium at the time of presentation. Patients with the single pathogen form of NF, invasive GAS, may have a more rapid progression of illness and are more prone to bacteremia and subsequent development of STSS.25

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The cornerstone of therapy for NF is prompt recognition, aggressive volume support of shock, and early surgical consultation for exploration and debridement. Empiric antibiotics are needed for broad-spectrum treatment of Gram-negative anaerobes and Streptococci with consideration of coverage for methicillin-resistant S.aureus. If GAS is identified as the sole organism, penicillin and clindamycin are appropriate for therapy. Imaging should not take priority ahead of surgical consultation. If radiographs of the affected extremity are obtained, GAS may be seen in soft tissue, which is pathognomonic for NF. Most NF patients need to be managed in an intensive care unit setting. Adjunctive therapies with limited evidence include hyperbaric oxygen and IVIG.26,27

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Laboratory studies include complete blood count, blood culture, wound culture, complete metabolic panel, creatine phosphokinase, coagulation studies, and lactate. Imaging studies in the setting of low NF suspicion may aid in the subsequent management. CT and magnetic resonance imaging will demonstrate subcutaneous/fascial inflammation or tissue gas. Ultrasound will demonstrate a thickened fascial layer with fluid accumulation. Early surgical consultation is paramount for the treatment of NF.

KAWASAKI DISEASE

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KD is an acute, self-limited, multisystem vasculitis with unknown etiology diagnosed clinically in children with fever. Although multiple theories have been suggested, no one single microbial agent or environmental toxin has been proven as having a role.28 Hypotheses include an infectious agent, an immune response to an infectious agent, or a unique response to an unidentified agent in a genetically predisposed individual.

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KD has surpassed rheumatic fever as the leading cause of acquired heart disease in children in the United States and Japan.29 KD affects 10 to 15 per 100,000 children younger than 5 years of age, with a male to female ratio of 1.5 to 1.7:1, and greater incidence in children of Japanese ancestry.30 Mortality ranges from 0.1% to 0.2%, with infants younger than 1 year at greatest risk.28

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KD is an immune-mediated disorder with cytokine cascade and endothelial cell activation resulting in an acute vasculitis affecting small- and medium-sized blood vessels.28 Nearly every organ system is involved. In the heart, the vasculitis will result in aneurysm formation in 15% to 25% of untreated patients, with long-term sequelae including ischemic heart disease, sudden death, and myocardial infarction.31

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Classic KD diagnosis is established using clinical criteria, which includes fever for at least 5 days and four out of the five major clinical features: bilateral bulbar nonexudative conjunctivitis (Fig. 94-7), lip and pharyngeal erythema without exudate (Fig. 94-8), nonpurulent cervical lymphadenopathy, hand and foot swelling and erythema/skin peeling, and polymorphous exanthem. The rash is morbilliform, usually not vesicular, and commonly in the perineal area. With ≥4 clinical criteria, KD diagnosis can be made on day 4 of fever. Alternatively, patients with fever for at least 5 days and fewer than 4 criteria can be diagnosed with KD when coronary artery aneurysms are detected. Incomplete KD, where patients do not fulfill the classic criteria, is an important entity to recognize given it is more common in children younger than 1 year of age and more likely to result in cardiac manifestations. Incomplete KD and echocardiography should be considered in younger children with fever >7 days with elevated C-reactive protein (CRP) and ESR levels in the absence of any explanation for a febrile illness. KD can be divided into three phases: acute febrile, subacute, and convalescent. The acute phase is the initial 1 to 2 weeks, where most of the clinical findings are present: high, unrelenting fevers >39°C, excessive fussiness/irritability, painless and nonexudative, limbus sparing bulbar conjunctivitis (anterior uveitis present in 80% of patients),32 mouth erythema, fissures, crusting of the lips and/or strawberry tongue, adenopathy usually in the anterior cervical triangle that is nonpurulent, nontender, and nonerythematous, carditis consisting of tachycardia out of proportion to fever, gallop, hyperdynamic precordium, and rarely cardiogenic shock. Presence of right upper quadrant tenderness with a mass is consistent with hydrops of the gallbladder, hepatomegaly, and jaundice. Findings limited to the skin are the following: acute phase—erythroderma of palms and soles and/or induration of the hands and/or feet, with accentuation in the perineal area. Erythema and induration may also exist at the site of previous bacillus Calmette–Guérin (BCG) vaccination.33 In the subacute phase, there is periungual desquamation. In the convalescent phase, there are Beau lines, which are transverse grooves across the fingernails.

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FIGURE 94-7. Conjunctival injection of Kawasaki disease.

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FIGURE 94-8. Lip findings in Kawasaki disease.

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Management of KD consists of administration of IVIG at a dose of 2 g/kg, which reduces the aneurysm rate from 25% to 3% to 5% if administered within the first 10 days after the onset of fever.28 Aspirin (80–100 mg/kg/day orally for the first week, then 3–5 mg/kg/day when fever is controlled) is also crucial to KD management. Cardiac anatomy evaluation should be completed promptly; however, IVIG administration should not be delayed. Aspirin is continued at the low dose for at least 6 to 8 weeks or until resolution of cardiac abnormalities diagnosed on initial cardiac evaluation. There is new evidence to suggest a possible role of corticosteroids in combination with IVIG to further reduce the risk of cardiac abnormalities, though a large multicenter trial is still needed to support this role.34

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Laboratory studies include complete blood count, complete metabolic panel (including serum bilirubin, transaminase, and gamma-glutamyl-transferase [GGT] levels), CRP and ESR levels, and urinalysis. These findings, though nonspecific, may be helpful in the diagnosis of incomplete KD and in delineating extent of disease, as exemplified by elevated serum bilirubin, transaminase, and GGT levels aiding in the diagnosis of gallbladder hydrops.35Electrocardiograms may show dysrhythmias such as prolonged PR or QTc intervals and ST-T wave changes. Chest radiography may demonstrate pulmonary infiltrates or cardiomegaly suggestive of underlying cardiac dysfunction. Sterile pyuria may be present with urethritis. Abdominal ultrasound may reveal gallbladder hydrops. Ancillary findings associated with a greater risk of cardiac manifestations include peripheral white blood cell bandemia, hemoglobin <10 g/dL, platelets <350,000/uL, ESR > 101, and electrocardiographic abnormalities.

URTICARIA

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Multiple types of urticaria exist: acute IgE-mediated, chemical induced (non–IgE-mediated), vasculitic, autoimmune, cholinergic, and cold urticaria. Urticaria is further divided clinically into acute (lasting 6 weeks), chronic (lasting 6 weeks), or episodic/recurrent. In acute urticaria, the etiology remains undetermined in >60% of cases. Known causes include the following: infections, foods, medications, latex, pressure, cold, heat, emotional stress, exercise, and pregnancy. In chronic urticaria, the etiology is not known in 80% to 90% of cases. A large number of these cases have an autoimmune component (i.e., systemic lupus erythematosus (SLE) or rheumatoid arthritis). Other causes include hyperthyroidism, amyloidosis, polycythemia vera, malignant neoplasms, lymphoma, cryoglobulinemia, syphilis, mastocytosis, and cryofibrinogenemia.

image EPIDEMIOLOGY

Urticaria is common, affecting 15% to 25% of the general population at some time during their lifetime. Acute urticaria is more common in children and young adults, occurring in 6% to 7% of preschool children and in 17% of children with atopic dermatitis.36,37 Chronic urticaria is more common in adults, affecting women (60%) more than men.36

image PATHOPHYSIOLOGY

Urticaria results from the release of histamine, bradykinin, and other vasoactive substances from mast cells and basophils in the dermal layer of skin, leading to the pruritic urticarial lesion caused by extravasation of fluid into the dermis. H1 histamine receptor activation on endothelial and smooth muscle cells leads to increased capillary permeability, while H2 histamine receptor activation results in arteriolar and venule vasodilation. The different types of urticaria also have different mechanisms. In acute IgE-mediated urticaria, antigen-mediated IgE immune complexes bind and cross-link receptors found on the surface of mast cells and basophils causing degranulation and histamine release. In non–IgE-mediated urticaria, certain chemicals such as radio contrast dye, directly cause degranulation of mast cells. In vasculitic urticaria, a type II allergic response by cytotoxic T cells results in deposits of immunoglobulin, complement, and fibrin around blood vessels. A type III immune complex is implicated in autoimmune-mediated urticaria in diseases such as SLE.

image RECOGNITION

The urticarial rash presents as blanching, edematous papules or wheals that vary in size from 1 mm to many centimeters. They may have minimal to intense pruritus and may be localized or generalized. In the localized variant, patients may display dermatographism, physical pressure (such as a scratching, rubbing, or stroking) induced urticaria. The discovery of possible precipitants in the patient’s history is an important tool in the diagnosis, though most often the cause is not determined. A pregnant patient can present in the last trimester with urticaria, which typically resolves soon after delivery. The most important aspect to recognize is the presence of a systemic reaction including anaphylaxis.

image MANAGEMENT

The primary management of urticaria is removal of the precipitating agent, if identified, and symptomatic relief. Anaphylaxis in the setting of urticaria requires prompt recognition and airway assessment. Symptomatic relief can be achieved by first and second generation H1 antihistamine agents. First generation drugs such as diphenhydramine (5 mg/kg/d divided q6-8h) or hydroxyzine (2–4 mg/kg/d divided q6-8h) can be given alone, especially at night given their sedating affects, or in combination with second generation H1 antihistamine agents such as cetirizine or desloratadine.38 Addition of an H2 antihistamine such as ranitidine may achieve better control.39 Epinephrine (0.01ml/kg intramuscular of a 1:1000 solution) may be given for anaphylaxis and laryngeal edema, and considered for severe pruritis or rapidly progressive urticaria. A short course of corticosteroids such as prednisone (1 mg/kg/d) may be of benefit in severe, acute urticaria. Prolonged corticosteroid courses should be avoided whenever possible, though this may be difficult in urticarial vasculitis. Immunomodulating agents are reserved for patients with chronic autoimmune urticaria with disabling disease.40

image ANCILLARY STUDIES

Given its clinical diagnosis, laboratory studies are typically not indicated for most patients with acute urticaria. If a precipitating agent is identified, skin prick testing can confirm IgE-mediated reactions. Laboratory testing in chronic urticaria is guided by the suspected underlying diagnosis (i.e., C3 and C4 complement levels in SLE).

ANGIONEUROTIC EDEMA

image ETIOLOGY

Though there are multiple inducing agents, AE most commonly is idiopathic. Etiologic agents include the following: foods (eggs, peanuts, shellfish, and cow’s milk), medications (trimethoprim/sulfamethoxazole, other sulfa derivatives, penicillins, NSAIDs, and cephalosporins), certain insects such as fire ants, latex in children with myelomeningocele, and physical factors (i.e., heat, cold, pressure). Viral infections (i.e., HSV, Epstein–Barr virus, and coxsackievirus) can trigger AE and urticaria. Bacterial infections such as otitis media, sinusitis, and urinary tract infections are associated with AE. In hereditary angioneurotic edema (HAE), which is transmitted as an autosomal dominant condition, there is a mutation in the C1 esterase inhibitor (C1-INH) gene. In acquired AE, there is increased destruction or metabolism of C1-INH, which becomes clinically apparent after 40 to 50 years of age and is associated with lymphomas and rheumatologic conditions.

image EPIDEMIOLOGY

AE is a common allergic disease that leads to hospitalization, though its exact incidence is not known. It has a higher prevalence in children with atopic dermatitis, asthma, allergic rhinitis, and food allergies. The prevalence of HAE is estimated between 1 in 10,000 and 1 in 150,000 worldwide, with an estimated 6000 to 10,000 people with HAE in the United States.41

image PATHOPHYSIOLOGY

AE, similar to urticaria, may occur through IgE-mediated or non–IgE-mediated pathways. In the former, IgE-antigen complexes cross-link mast cells leading to histamine release, which increases vascular permeability and leakage of fluid into the skin. In the latter, nonIgE mediated release of kinin, a potent vasodilator, leads to vascular permeability and edema. AE caused by angiotensin-converting enzyme inhibitors exemplifies the kinin mediated pathway.42Also similar to urticaria, certain agents such as radio contrast dye, physical stimuli, medications (i.e., vancomycin), and foods such as strawberries directly cause AE. In HAE, a mutation in the C1-INH gene triggers kinin pathway activation.43 In type I HAE (85%), there is a quantitative deficiency in C1-INH.43 In type II HAE (15%), dysfunctional C1-INH is released.43

image RECOGNITION

AE presents as nonpitting edema involving the deeper layers of the dermis and subcutaneous tissues. Compared to other forms of edema, AE is asymmetric, has a rapid onset, and occurs in nondependent areas of the body. It can present in the face, lips, hands, feet, and gastrointestinal tract with edema that has ill-defined margins. Gastrointestinal tract edema can present with acute vomiting, abdominal pain, and nausea with or without cutaneous features. Throat AE can cause rapid airway obstruction. There are three clinical forms of HAE: subcutaneous, abdominal, and laryngeal edema. In the subcutaneous form, edema is circumscribed, nonerythematous, nonpruritic, and not associated with urticaria. In the abdominal form, edema may manifest itself as vomiting, diarrhea, ileus, and diffuse abdominal pain, at times mimicking a surgical abdomen. In the laryngeal form, edema is life threatening and presents as stridor, dyspnea, hoarseness, and dysphagia.

image MANAGEMENT

Immediate airway assessment and intervention (as needed) along with administration of epinephrine (0.01 ml/kg intramuscular of 1:1000 solution) is of paramount importance in laryngeal angioedema. Epinephrine can be repeated at 5- to 15-minute intervals. Antihistamines, both H1 (diphenhydramine 1 mg/kg divided q6h) and H2 (famotidine 0.5 mg/kg IV with maximum dose of 40 mg), are also used in the treatment of AE. Steroids are indicated for airway involvement or extensive cutaneous involvement (dexamethasone 0.2 mg/kg). Any identified triggers should be removed and not used in any confirmatory allergy testing. For HAE, epinephrine, antihistamines, and steroids are ineffective and not recommended.44 In laryngeal HAE, the most important aspect is early, aggressive support of the airway. Pharmacologic interventions for acute attacks of HAE include plasma derived C1-INH concentrate or kallikrein inhibitor. Recombinant C1-INH is used in Europe, and recently, a bradykinin-receptor antagonist was approved for use in the United States for patients 18 years of age and older.44 Pharmacologic options are available for HAE prophylaxis, though there is no indication for their use by the emergency physician.

image ANCILLARY STUDIES

There is no routinely recommended laboratory test for AE. An elevated tryptase level may reflect mast cell degranulation, but normal levels do not exclude AE. In patients with recurrent AE, one may have to pursue an underlying autoimmune etiology. In HAE, complement C4 levels are usually low during acute attacks as well as between episodes. C1-INH levels help distinguish between type I and II HAE. Routine imaging is also not indicated, though abdominal ultrasound may help differentiate abdominal AE that mimics a surgical abdomen. In abdominal AE, 80% have ascites and edema of the intestinal wall.45

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