A wide variety of neonatal and childhood dermatologic conditions can be emergencies. These may arise from genetic disorders, including those causing skin structural protein and keratin dysfunction, vascular birthmarks with systemic associations, autoimmune disorders, and infections. If left untreated, these conditions can lead to systemic effects or may increase risk of developing secondary complications, potentially resulting in death. It is therefore important that these entities be rapidly identified and addressed. The following pages present a limited collection of some of the most important emergency situations.
Neonatal Emergencies
There are broad sets of neonatal dermatologic conditions that are true emergencies. Vesicles, pustules and denuded skin at birth or in the neonatal period may be localized lesions without consequence, such as sucking blisters, or signs of a life-threatening genetic mechanobullous disorder such as epidermolysis bullosa. Herpes simplex virus and opportunistic infections can be dermatologic emergencies, requiring prompt recognition, diagnosis and initiation of therapy. Vascular tumors, including port-wine stains and hemangiomas, may require urgent management including diagnostic work-up, referral for specialty evaluation and/or early introduction of therapy. The conditions discussed below are only a select subset of neonatal dermatologic issues that may be considered emergencies. Other resources more extensively discuss other neonatal dermatologic conditions (e.g. Neonatal Dermatology, 2nd Edition. Eichenfield, Frieden and Esterly, Saunders/Elsevier).
Epidermolysis Bullosa
Epidermolysis Bullosa (EB) is a group of congenital disorders characterized by the profound susceptibility of skin and mucosa to separate from underlying tissues following mechanical trauma. EB generally presents at birth or in the first few weeks of life with denuded skin, vesicles or bullae. Milder forms may present later in life. EB is caused by mutations in structural proteins in the skin, and is generally categorized by the level of blistering and the target proteins: EB simplex (epidermolytic), junctional EB (lysis in the lamina lucida, or “lucidolytic”), dystrophic (dermolytic) and Kindler syndrome (mixed blistering levels).
EB has an incidence of 1 in every 50,000 births, consisting mostly of the milder EB Simplex (EBS) type. Of the three types of EB, EBS and Junctional EB (JEB) generally heal without scarring. In contrast, healing with milia suggests Dystrophic EB (DEB), but has been reported in other types. Some children exhibit a congenital localized absence of skin (Bart syndrome) at birth, which is characterized by large ulcers usually in the lower extremities. Oral erosions are most commonly found in JEB and DEB, and are rarely found in EBS. Extensive blistering can lead to fluid and electrolyte abnormalities, temperature dysregulation as well as sepsis; supportive measures are essential in the treatment plan.
The differential diagnosis of erosions, blisters or denuded skin includes infections (e.g.,herpes simplex virus) and other blistering diseases. To diagnose EB, a biopsy should be taken from unaffected skin. The area to be biopsied may be rubbed for 1 minute, generally with a pencil eraser, to induce cutaneous blistering; after a 5-10 minute wait, a shave or punch biopsy is taken. Evaluation can include light microscopy, immunofluorescence antigen mapping for absent or attenuated antigens diagnostic for the EB subtype, or transmission electron microscopy, which may visualize the ultrastructural level exhibiting the plane of separation. Specific genetic testing may be utilized as well.
Epidermolysis Bullosa Simplex
Epidermolysis Bullosa Simplex (EBS), the mildest and most common type of EB, is characterized by the lysis of basal keratinocytes above the basement membrane zone. Most subtypes of EBS are autosomal dominant mutations in Keratin 5 or 14 (such as Weber-Cockayne, Koebner, and Dowling-Meara); however, autosomal recessive mutations and mutations in other genes have been reported. Keratin 5 and 14 function in the adhesion of cells to the hemidesmosome through plectin, another EBS associated protein. Most EBS children experience an increased tendency to blister as temperature increases; however, their overall prognosis is excellent with normal life expectancy and decreased tendency to blister with time. The Weber-Cockayne (WC) EBS subtype is the mildest, most common subtype of EBS where the bullae, though temperature sensitive, are confined predominantly to the hands and feet. In Koebner (K) EBS, patients experience generalized blistering with little to no mucosal involvement. 20% of patients experience nail involvement; however, all symptoms improve with advancing age. Dowling-Meara (DM) EBS is most severe in the neonate and infant, and can be fatal in the neonatal period. Large generalized blistering predominates; however, blisters do decrease with age. DM children experience profound mucosal involvement, as well as nail involvement and mild acral blistering. Unlike other major EBS disorders, EBS with muscular dystrophy is characterized by an autosomal recessive mutation in the gene coding plectin. These patients experience early onset generalized blistering with laryngeal and mucosal involvement, as well as progressive muscular dystrophy. Finally, EBS with mottled pigmentation is a rare autosomal dominant subtype characterized by mechanically induced blistering, unaffected mucosa, and a mixture of hyper- and hypopigmented macules.
Junctional Epidermolysis Bullosa
Junctional Epidermolysis Bullosa (JEB) (Figure 1.1), characterized by mechanically induced blistering occurring within the basement membrane at the lamina lucida, is the least common form of EB, showing poor outcome in infancy. JEB is caused by autosomal recessive mutations in genes coding components of the hemidesmosome-anchoring complex critical for dermal-epidermal adhesion. The Herlitz and non-Herlitz subtypes of JEB are characterized by mutations in laminin 5, which is essential for the adhesion of keratin intermediate filaments to the basement membrane. In the most common form, the Herlitz subtype, there is significant mortality (approximately 50%) by 2 years of age. This subtype is characterized by exuberant granulation tissue within ulcers especially in the ocular and perioral region with sparing of the lips. Affected individuals experience dental enamel dysplasia, severe blistering of the periungual and finger pad regions, and erosions of the laryngeal and respiratory epithelium, resulting in hoarseness. Blisters heal with atrophy but not milia. The amount of blistering is often not predictive of prognosis. Common complications include anemia of chronic disease and growth retardation. In severe cases, death may be due to severe sepsis and failure to thrive. In contrast, the non-Herlitz subtypes are characterized by less severe but similar manifestations to the Herlitz type including dental, nail, and laryngeal involvement; however, patients experience less mucosal involvement and improved prognosis. Finally, JEB with pyloric atresia is a rare subtype characterized by a mutation in α6β4 integrin and sometimes a mutation in the plectin gene. Patients present at birth with upper gastrointestinal obstruction, most often affecting the pyloric region. There is variable skin involvement; however, the ocular, respiratory, and urogenital epithelium are almost always affected. Prenatal signs include polyhydramnios and abdominal masses. Corrective surgery is necessary. The prognosis is often poor due to failure to thrive, fluid and electrolyte imbalances, and sepsis.
Dystrophic Epidermolysis Bullosa
Dystrophic Epidermolysis Bullosa (DEB) is characterized by blistering below the lamina densa of the basement membrane zone, causing lysis of the dermis. DEB is caused by autosomal dominant and recessive mutations in type VII collagen, a major component of anchoring fibrils, thus resulting in defective attachment of the basement membrane to the underlying dermis. There exists a profound variation in the prognosis of DEB patients due to the spectrum of presenting symptoms. Dominant DEB is a much milder subtype with an onset from birth to early infancy. Blistering predominates on elbows, knees, lower legs, and the dorsum of hands; 80% of children experience nail dystrophy. Milia are associated with scarring, which was once thought to be pathognomonic for DEB, and some patients develop scar-like lesions on the trunk. In contrast, Recessive DEB is present at birth and characterized by widespread blistering, scarring, and milia. Patients experience deformities due to scarring such as digital fusion and joint contractions. There is severe involvement of the nails and mucous membranes of the gastrointestinal tract, ocular mucosa, and genitourinary system. In severe cases, failure to thrive may result from chronic wound healing, poor nutrition, infection, and blood loss from erosions. Children and adolescents often experience growth retardation and are greatly predisposed later in life to squamous cell carcinoma in heavily scarred areas.
Emergent evaluation of a neonate with possible EB includes skin biopsy and institution of aggressive supportive measures, including excellent skin care. Fluids and electrolytes must be closely monitored, and the temperature must be kept moderate since heat can induce blistering. Care must be taken to minimize new blisters and erosions through gentle handling and the use of non-adhesive bandages especially for the first layer of bandaging. The skin care regimen must promote wound healing through daily bathing and vigilant inspection of blisters. A topical or systemic anti-microbial can be used to prevent infection, though use must be balanced by the potential for selection of resistant microbes. Topical antibiotics may be rotated and the use of such products should be discontinued when the wound is clean. Non-steroidal anti-inflammatory drugs or opiates can be administered to decrease pain during bandaging and other procedures. Intact blisters must be incised on the dependent side using a sterile needle to prevent lesion extension. It is important to properly diagnose the EB type and subtype, as well as counsel and educate parents on prognosis and future therapy. Referral for genetic counseling is appropriate. In-hospital care may be appropriate until the infant is feeding well and gaining weight with stable skin involvement, and the family has adequate training in skin care management.
Disorders of Keratinization (Ichthyosis)
There are several ichthyotic conditions that manifest during the neonatal period as either collodion baby or scaling erythroderma. These disorders encompass a wide range of genetic conditions with molecular defects affecting the epidermis. At birth and up to the first day of life, desquamation of the skin is abnormal and the differential diagnosis includes congenital ichthyosis, intrauterine stress, and postmaturity. For most ichthyotic conditions, early recognition, therapy, and monitoring will be required to prevent infection or fluid and electrolyte imbalance.
Collodion Baby
The collodion infant presents at birth encased in a shiny, thickened, variably erythematous, cellophane-like membrane. This presentation is associated with several disorders, including non-bullous congenital ichthyosiform erythroderma (NCIE), lamellar ichthyosis, and self-healing collodion baby. Less commonly encountered conditions that may present with colloidion membranes include Sjögren-Larsson syndrome, Conradi-Hünermann syndrome, trichothiodystrophy, and neonatal Gaucher’s disease.
Despite the markedly thickened stratum corneum in collodion infants, the membrane acts as a poor barrier due to cracking and fissuring. This results in increased water and electrolyte loss leading to a hypovolemic hypernatremic state, heat loss, and an increased risk of developing cutaneous infections and sepsis. Infants are also at risk for developing pneumonia from aspiration of squamous material in utero, and have difficulty closing their eyes due to the thickened skin and ectropion.
Treatment of an infant with a collodion membrane is primarily supportive. The babies should be placed in a high humidity, neutrally thermal environment with the application of bland emollients such as petrolatum ointment to prevent dehydration. Serum electrolytes and fluids should be monitored. Surgical debridement is contraindicated and the use of keratolytics in the neonatal period through the first 6 months of life is not recommended due to the increased risk of toxicity from excessive absorption through permeable skin.
The management of these infants should include a dermatological consultation to help identify the ichthyotic disorder and tailor the treatment. A skin biopsy evaluating the histologic appearance of lesional skin and the use of electron microscopy and/or specific genetic testing may confirm the etiologic diagnosis. Because involvement of the face may result in ectropion formation, ophthalmologic consultation is appropriate.
Herpes Simplex Virus
Herpes simplex virus (HSV) is a DNA virus that can cause acute skin infections and serious illness in neonates and infants, and ranks as one of the most significant dermatologic emergencies in the first year of life. HSV-2 causes 70% to 85% of neonatal HSV infections, with HSV-1 associated with the remainder of cases. The rate of neonatal HSV disease in the United States is approximately 1 per 10,000 births, roughly 1,500 cases per year.
HSV infection of the neonate can occur during the intrauterine (5%), peripartum (85%), or postpartum (10%) periods. Most neonatal HSV infections are acquired by contact with asymptomatic primary or recurrent genital HSV infection during delivery; the risk of transmission is substantially reduced by caesarean section. Transmission risk is increased by prolonged rupture of the membranes, as well as vacuum or forceps delivery and placement of fetal scalp monitors, which breach the integrity of the mucocutaneous barrier and may serve as an inoculation site for HSV.
HSV infections occur with three distinct clinical presentations: 1) disease limited to the skin, eyes, and/or mouth (SEM disease), 2) central nervous system (CNS) disease, with or without skin lesions, and 3) disseminated disease involving multiple visceral organs, including lungs, liver, adrenal glands, skin, eyes, and the brain.
SEM disease accounts for 45% of neonatal HSV cases. Skin is involved in 80% to 85% of cases. Isolated or grouped vesicles on an erythematous base appear 1 to 2 weeks following inoculation. Within 1 to 3 days, vesicles progress to coalescing crusted papules and plaques. The lesions may erode or ulcerate. Systemic therapy is required; otherwise, dissemination of the infection may occur. With treatment, the long-term developmental outcome of SEM disease is good. Neonates with SEM disease often have recurrent cutaneous herpes during early childhood.
CNS disease, which represents 30% of neonatal HSV cases, generally presents in full term infants after 16 to 19 days of life. Skin lesions are only present in 60% of infants. Encephalitis can result from retrograde neuronal spread of mucosal lesions. HSV encephalitis or meningoencephalitis can cause irritability, lethargy, poor feeding, seizures, coma, and death. Prompt initiation of acyclovir therapy substantially improves outcome; prolonged therapy has been associated with better outcomes. A significant number of neonates with HSV-2 CNS infections may have neurologic problems at 1 year, including developmental delay, epilepsy, blindness, and cognitive disabilities.
Disseminated disease occurs in 25% of neonates, and is the most common presentation of HSV in premature infants. Clinical manifestations appear after 1 to 2 weeks of life. Skin or mucosal lesions are present in 60% of cases. Disseminated disease commonly involves the lung, liver, and brain, resulting in shock, disseminated intravascular coagulation, and multiple organ system failure. Mortality is 75% in untreated neonates and can be as high as 30% despite treatment.
The presence of a vesicular rash in a febrile neonate, with or without lethargy, seizures, or systemic findings should raise suspicion for HSV disease. Early consideration and diagnosis of HSV infection allows initiation of therapy thus minimizing significant viral replication and dissemination. HSV infection in neonates may present as eroded or denuded skin. However, since vesicular rashes and erosions may be absent in HSV infection, neonates with CNS infection or sepsis should prompt consideration of HSV. A complete work-up should include cultures of the CSF, blood, mouth, nasopharynx, conjunctivae, rectum, and skin vesicles. Histologic examination of scrapings from the base of a vesicle or mucosal ulceration, for the presence of multinucleated giant cells and eosinophilic intranuclear inclusions typical of HSV (i.e. with Tzanck test), has low sensitivity. Direct fluorescence antibody staining of vesicle scrapings allows for rapid diagnosis. Polymerase chain reaction (PCR) assay of CSF to detect HSV DNA is currently the diagnostic method of choice for CNS disease. A complete blood count and comprehensive metabolic panel, including liver transaminases should be performed to assess systemic involvement.
High-dose parenteral acyclovir is the treatment of choice for neonatal HSV infections. Acyclovir (generally given as 60 mg/kg/day given in three divided doses over 21 days) improves both mortality and morbidity from neonatal disseminated and CNS HSV. Similar dosing for a shorter duration is recommended for SEM disease, and for asymptomatic infants born to women acquiring HSV infection near term. A recent multicenter observational study of neonates with HSV infection determined that delayed initiation of acyclovir therapy is associated with a higher rate of in-hospital death. Thus, it is reasonable to consider empiric acyclovir therapy in ill neonates where HSV is being considered in the differential diagnosis while awaiting diagnostic testing results. Pediatric infectious disease consultation is reasonable in established cases of CNS or disseminated infection. Transient neutropenia may occur in up to 20% of neonates treated with high-dose acyclovir, but may not result in clinically significant adverse outcomes.
Vascular Birthmarks
Hemangiomas
Infantile hemangiomas (IHs) are the most common vascular tumor, affecting 4-10% of all infants born in the United States. IHs are benign tumors that may not be present at birth, but present within the first few weeks of life. Precursor lesions are common but often subtle; early signs include pallor, telangiectases, a bruise-like appearance or, rarely, skin ulceration. IHs typically proliferate, with rapid growth of the tumor in the first several months of life. This phase is followed by an involution stage, with slow, spontaneous diminishment of the lesion over several years. Following involution of the vascular component, there is sometimes a residual fibro-fatty mass.
Occasionally, IHs may require emergent attention and therapy. IHs that are near vital structures may be dangerous and even life-threatening. Of particular concern are IHs in the periorbital, perioral, deep subcutaneous, and perineal regions. Facial and perineal hemangiomas should raise consideration of associated structural anomalies such as the PHACES and PELVIS/SACRAL syndromes, as these may be associated with significant medical risks.
IHs found periocularly may permanently affect vision; unless the lesion is both superficial and small in size, an ophthalmologist should be consulted. For lesions that may partially or fully obstruct vision, systemic therapy is usually indicated. The contralateral eye may be patched for several hours each day to promote opening of the affected eye. Systemic therapy, such as propranolol or prednisolone, should be instituted early by a specialist with expertise in treating IHs. Occasionally, intralesional corticosteroids are utilized for periocular lesions, although there have been rare reports of ipsilateral and even contralateral blindness after such procedures.
Perioral IHs not only risk deformation of the lip cosmetically, but may be associated with pharyngeal or tracheal lesions, potentially causing airway obstruction and stridor. In patients with large mandibular IHs, especially involving multiple areas of the perioral, chin, and bilateral jawline segments, imaging of the airway by direct visualization, CT, or MRI should be considered. Systemic therapy should also be instituted in cases involving airway obstruction. In more severe cases, an otolaryngologist may utilize laser or other surgically destructive techniques.
Deep IHs are more difficult to monitor, as the exact size is less clinically discernible. CT or MRI imaging can aid in determining the extent of involvement as well as elucidate proximity to organs and vascular structures, such as the carotid artery and vein, which are at risk for compression during the proliferative stage. Deep IHs that are in close proximity to vascular structures need to be monitored very closely during the proliferative stage; systemic therapy should also be initiated to minimize the functional impact and potential deformation.
IHs in the perineal region need special consideration, since these lesions can affect genitourinary and gastrointestinal functions. CT or MRI imaging may be helpful in delineating the extent of involvement, and systemic therapy may be required.
PHACE syndrome (Figure 1.2), a constellation of clinical findings associated with IHs, refers to Posterior fossa brain abnormalities, Hemangiomas, Arterial malformations, Coarctation of the aorta and other cardiac defects, and Eye abnormalities. Diagnostic criteria for PHACE syndrome and possible PHACE syndrome include major and minor findings such as cerebrovascular, cardiovascular, ocular, brain and ventral or midline defects. An IH of at least 5 centimeters in size found on the head and neck region should undergo a work-up to rule out underlying abnormalities that may be life-threatening. An MRI and MRA of the soft tissues of the head and neck, as well as of the brain, should be performed. An ECHO and EKG may identify cardiac anomalies, and an eye exam should be performed. Despite their a benign appearance, facial IHs may portend serious underlying malformations.
Large, segmental hemangiomas in the anogenital region have also been found to be associated with underlying anomalies. The acronyms PELVIS syndrome (Perineal hemangioma, External genitalia malformations, Lipomyelomeningocele, Vesicorenal abnormalities, Imperforate anus, and Skin tag), LUMBAR syndrome (Lower body hemangioma and other cutaneous defects, Urogenital anomalies, ulceration, Myelopathy, Bony deformities, Anorectal malformations, arterial anomalies, and Renal anomalies), and SACRAL syndrome are all used to refer to the similar findings associated with larger IHs in the anogenital region. There are no published guidelines regarding the appropriate threshold for performing imaging and work-up to look for associated anomalies. Further studies are needed to establish both the size and location of perineal IHs of concern. Functionally significant or potentially deforming hemangiomas warrant early referral to specialists with expertise in work-up and management.
Port-Wine Stains
Port wine stains (PWS) (Figure 1.3) are non-palpable vascular malformations composed of capillary venules present at birth, which may be isolated cutaneous findings or associated with syndromic features. Port wine stains on the face, primarily involving the ophthalmic branch of the trigeminal nerve (V1), may be associated with Sturge-Weber Syndrome (SWS). SWS may manifest with seizures and developmental delay, and/or glaucoma. Port wine stains may also be associated with more complex vascular malformations.
Management in the neonatal period should include consideration of the differential diagnosis (port-wine stain, hemangioma, complex malformation) and evaluation for possible syndromic features that may require emergent measures. Facial port wine stains overlying the V1 distribution require urgent evaluation for possible glaucoma. Evaluations for CNS manifestations may be considered, but need not be performed as a part of emergency management.
Opportunistic Fungal Infections
Due to their immature skin barrier, premature neonates are at risk for cutaneous fungal infections. These infections can manifest as pustules, vesicles, plaques, indurations, ecchymoses, crusts, erosions and necrotic lesions often initially appearing at sites of skin trauma. Opportunistic fungi can easily disseminate, and even with treatment are associated with high mortality rates.
An aggressive workup is necessary given the very broad differential diagnosis (intrauterine epidermal necrosis, HSV, Behçet’s disease, lupus, etc.) The infant’s maternal, family, perinatal, and neonatal histories should be evaluated. A CBC with differential, coagulation studies, and antibody studies if cutaneous lupus is being considered (anti-SSA/Ro, SSB/La, U1RNP, ANA) are recommended. Tissue cultures, blood cultures, biopsies, and appropriate rapid diagnostic testing (e.g. HSV direct fluorescent antibodies, PCR) should be performed and are critical for identifying causative organisms.
Treatment consists of excision or debridement along with systemic antifungals. The antifungal therapy of choice is dependent on the identity of the organism, and infectious disease specialists should advise its selection.
Childhood Emergencies
Emergency dermatologic conditions in children are extensive in number and scope. While many conditions are discussed elsewhere in this book, this section emphasizes several conditions that may commonly be considered in the differential diagnosis of emergent conditions in childhood, including urticarial eruptions, drug eruptions, Stevens-Johnson Syndrome and toxic epidermolysis, acute infectious complications of atopic dermatitis, and some primary infections due to bacteria, viruses and fungi.
Drug Eruptions and Drug Hypersensitivity
Urticaria
Urticaria is characterized by pruritic, well-circumscribed, pink, edematous papules or plaques (wheals) usually associated with allergic responses or infections. The lesions may be localized or generalized, and usually last less than 24 hours; however, associated angioedema can last hours to days. Systemic symptoms may include diarrhea, breathing difficulties, fever, fatigue, or arthralgias.
Acute urticaria is caused by viral infection in 80% of children as well as by foods and drugs in most teenagers. Penicillins, sulfonamides, cephalosporins, aspirin, NSAIDs, anticonvulsants, tetracyclines, opiates, and radiocontrast are common causes of urticaria. Milk, eggs, nuts, shellfish, and wheat are examples of food triggers. Contact, pressure, aquagenic, cholinergic, and cold urticaria are further considerations. The differential diagnosis includes arthropod bites, contact dermatitis, erythema multiforme, mastocytosis, dermatographism, serum sickness-like reaction, and urticarial vasculitis.
The diagnosis is made clinically. In contrast to erythema multiforme, lesions of annular urticaria usually lack a dusky center. However, in younger children, bruising may occur secondary to urticaria that can be confused with erythema multiforme. For atypical lesions with purpura or those lasting longer than 24 hours, a biopsy should be performed to rule out urticarial vasculitis.
Urticaria is usually self-limited once the inciting agent is removed, and lesions usually disappear in a few days. If urticarial lesions persist for more than 6 weeks, an infectious work-up may be warranted; although without specific signs or symptoms it may be difficult to make a causative diagnosis. Approximately 80% of patients respond to oral therapy with twice daily dosing of second generation antihistamines such as cetirizine, loratadine, levocetirizine, or fexofenadine. These agents should be tapered over several weeks after the urticaria resolves. Severe outbreaks or pruritus can be treated with first generation antihistamines such as hydroxyzine or diphenhydramine, doxepin, or even H2 blockers such as ranitidine or cimetidine. Oral corticosteroids should be reserved for non-responsive cases in order to avoid potential side effects and rebound. Epinephrine can be used for anaphylaxis and an epinephrine pen should be considered in patients at risk for severe allergic responses.
Exanthematous Reaction
Exanthematous or morbilliform drug reactions are the most common type of drug eruptions. Classic findings are pruritic, pink macules or papules coalescing into patches or plaques beginning 1 to 2 weeks after starting a medication. The eruption is symmetric and usually appears on the trunk before generalized dissemination. A coexisting viral infection can increase the incidence and severity of a morbilliform reaction as seen when amoxicillin is prescribed during an Ebstein-Barr Virus infection.
Penicillins, sulfonamides, cephalosporins, and anticonvulsants are common causes of exanthematous reactions. The differential diagnosis includes viral exanthems, pityriasis rosea, acute graft versus host disease, allergic contact dermatitis, scarlet fever, and eczema. In contrast to viral exanthems, a drug exanthem is more likely to be pruritic.
Usually, the diagnosis is made on clinical grounds. Occasionally, a skin biopsy may be helpful, especially in differentiating from other conditions, such as graft versus host disease. It is important to assess if drug reactions are isolated to the skin, or affect other organ systems, as occurs with DRESS syndrome (Drug Reaction with Eosinophilia and Systemic Symptoms), which affects hematologic, lymphatic, hepatic, renal and pulmonary systems. The offending drug should be discontinued if not completely necessary. Oral antihistamines such as diphenhydramine, cetirizine, or hydroxyzine, bland emollients, or topical corticosteroids may be administered for pruritus. After 1 to 2 weeks, the eruption usually desquamates leaving a temporary hyperpigmentation.
Serum Sickness-like Reaction
Serum sickness-like reaction (SSLR) is characterized by fever, an urticarial-like eruption, and arthralgias that occur 1 to 3 weeks after a drug exposure. The eruption can be fixed and may become purpuric. Unlike true serum sickness, this type of eruption is not associated with immune complexes, vasculitis, hypocomplementemia, or renal involvement.
Cephalosporins, penicillins, minocycline, sulfonamides, and bupropion are the main causes, with cefaclor being the most common. The differential diagnosis includes viral or drug exanthems, rheumatoid arthritis, urticarial vasculitis, urticaria, drug vasculitis, and post-viral synovitis.
Management includes discontinuing the offending medication; antihistamines and topical corticosteroids can be administered for pruritus. If fever or arthralgias are severe, a short course of oral corticosteroids (1-2 mg/kg/day) may be prescribed. Since cefaclor rarely cross reacts with other beta-lactam antibiotics, other cephalosporins are usually tolerated.
Fixed Drug Eruption
A fixed drug eruption is characterized by a few well-circumscribed, oval, erythematous or hyperpigmented plaques that recur at the same sites with repeat drug administration. Lesions favor the lips, extremities, upper trunk, and genitalia. The eruption occurs 1 to 2 weeks after drug exposure and tends to be asymptomatic. Barbiturates, sulfonamides, acetaminophen, ibuprofen, aspirin, tetracyclines, pseudoephedrine, lamotrigine, and phenolphthalein are the typical triggers. The differential diagnosis includes arthropod bites, contact dermatitis, eczema, cellulitis, urticaria, and erythema multiforme.
To confirm the diagnosis, a skin biopsy or drug rechallenge may be performed. Histologically, a fixed drug eruption resembles erythema multiforme with additional evidence of chronicity. Identifying and removing the offending drug is essential. Other treatments are usually not necessary, but topical corticosteroids may be used for pruritus.
Erythema Multiforme
Erythema multiforme (EM) is a type of hypersensitivity that occurs in response to infections, medications, or other illnesses. The eruption consists of symmetric, targetoid, erythematous plaques on the skin and sometimes the oral cavity (Figure 1.4). Epidermal detachment is not a hallmark finding. Lesions may appear anywhere, with a preference for the palms and soles, extensor extremities, and the backs of hands and feet. Local symptoms include pruritus or burning. Fever, fatigue, arthralgias, or other viral-like symptoms may be present. The majority of EM cases in children are caused by infections, mostly from a herpes simplex virus, followed by mycoplasma. Less commonly NSAIDs, sulfonamides, penicillins, allopurinol or anticonvulsants may cause this eruption. The differential diagnosis includes bullous diseases, fixed drug eruption, subacute lupus erythematosus, polymorphous light eruption, vasculitis, urticaria, and tinea corporis.
The diagnosis of EM is mainly clinical, but a biopsy should be considered if lupus erythematosus, vasculitis or another condition is suspected. Herpes or mycoplasma cultures and antibody titers may be performed if appropriate. Most cases of EM resolve within 2 to 3 weeks. Symptomatic treatment with oral antihistamines, emollients, and topical corticosteroids may be administered for pruritus. For recurrent episodes associated with herpes simplex virus, prophylactic acyclovir should be considered; however, treatment with acyclovir during each EM episode is usually not effective. In most cases, oral corticosteroids can result in longer and more frequent recurrences, but are sometimes prescribed for severe symptoms.
Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening skin conditions defined by the percentage of epidermal detachment. Epidermal detachment of less than 10% of the total body surface is considered to be SJS, while 10-30% is SJS/TEN overlap, and >30% is TEN. These eruptions are immune-mediated hypersensitivity reactions involving the skin and membranes, which may include eyes, nose, mouth, respiratory tract, gastrointestinal, genital and urethral mucosa. Prior to the rash, patients have prodromal symptoms such as malaise, fever, cough, headache, and anorexia. SJS and TEN are characterized by confluent targetoid lesions, erythroderma, or bullae, requiring involvement of at least 2 mucous membranes, with patients demonstrating the Nikolsky sign. Lesions usually start on the face and upper trunk, but can spread to other areas, often involving the palms and soles.
In contrast to EM, SJS or TEN is most commonly caused by drugs, mainly sulfonamides, NSAIDs, allopurinol, penicillins, and anticonvulsants. Infections have also been associated with SJS and TEN. The differential diagnosis includes erythema multiforme, Kawasaki disease, Staphylococcal scalded skin syndrome, pemphigus, and bullous lupus erythematosus. Staphylococcal scalded skin syndrome presents with a more superficial exfoliation pattern with crusting, and primarily affects periorificial and flexural areas.
Mortality estimates for SJS and TEN are as high as 1-5% and 25-35%, respectively. Withdrawing the offending drug is essential. If epidermal detachment is extensive, patients should be transferred to an ICU or burn unit to optimize wound care, prevent infections, and attend to hydration and nutrition. Ophthalmology should be consulted for ocular involvement. The administration of systemic corticosteroids is controversial and is advocated by some for treatment during the first few days of the eruption. A longer course may increase morbidity due to increased risk of infections. Furthermore, IVIG (2.5-3mg/kg/day) over 3 to 5 days has been advocated as another treatment option. Additionally, there have been reports of improvement with cyclosporine, plasmapheresis, and cyclophosphamide. Of importance, aromatic anticonvulsants (phenobarbital, phenytoin, and carbamazepine) may cross-react and should not be substituted for one another.
Drug Rash with Eosinophilia and Systemic Symptoms
Drug rash with eosinophilia and systemic symptoms (DRESS) is a life-threatening condition that develops 1 to 8 weeks after drug exposure. Patients usually present with a morbilliform eruption, as well as edema, cervical lymphadenopathy, fever, and internal organ involvement (hepatitis, pneumonitis, interstitial nephritis, encephalitis, myocarditis, and thyroiditis). Drugs implicated in DRESS include aromatic anticonvulsants, dapsone, allopurinol, minocycline, sulfonamides, lamotrigine, and terbinafine. Furthermore, the differential diagnosis consists of bacterial or viral infections, lymphoma, and idiopathic hypereosinophilic syndrome. A new rash associated with unexplained eosinophilia, atypical lymphocytosis, and elevated transaminases may be indicative of DRESS. Hepatic transaminases, a CBC, urinalysis, serum creatinine, and thyroid testing should be ordered at baseline and followed. A skin biopsy is usually nonspecific.
Management includes immediate removal of the offending drug. In cases of visceral involvement, systemic corticosteroids (1-2 mg/kg/day) may be useful. Topical corticosteroids and antihistamines can be prescribed for pruritus. Symptoms and labs may initially improve and then flare after a few weeks. Thyroid testing should be repeated 2 to 3 months after treatment to test for autoimmune thyroiditis, even if the results are normal at baseline.
Selected Pediatric Systemic Diseases
Juvenile Dermatomyositis
Juvenile Dermatomyositis (JD), a humoral and cellular immune-mediated chronic inflammatory condition characterized by generalized capillary vasculopathy, results in a pronounced erythematous rash of the face or extremities and symmetrical muscle weakness. JD has an incidence of 3 per million children per year. Specific HLA and cytokine polymorphisms, as well as environmental triggers such as group A hemolytic streptococci and other microbial infections have been implicated in disease pathogenesis. JD should be considered when a child presents with characteristic rashes (a violaceous rash of the periocular area; pink-red papules of the dorsal fingers, photosensitive dermatitis) and two or more of the following: progressive symmetrical proximal muscle weakness, inflammatory and atrophic muscle histopathology, elevated muscle-derived enzymes, and EMG changes or MRI appearance of inflammatory myopathy. Fifty percent of patients report a progressive onset characterized by weakness, anorexia, malaise, abdominal pain, and a violaceous rash that precedes or follows muscle weakness. Thirty percent have fulminant onset of fever, weakness, and multi-system involvement.
Cutaneous signs include photosensitive skin changes of the hands and knuckles, “Gottron’s sign”, cutaneous ulceration at pressure points, heliotrope rash of the face, periungal changes (telangiectasia, cuticular overgrowth), and less commonly calcinosis. Non-destructive, non-deforming arthritis of the knee can occur in parallel with proximal muscle weakness, resulting in an inability to rise from the floor. Currently, there has been no association with malignancy in children; however, myositis and muscle weakness can result in decreased esophageal motility, reflux with ulceration or aspiration pneumonia, and decreased respiratory capacity. Vasculitis of mesenteric vessels, the retina and eyelid, and renal ischemia leading to renal failure are further complications that must be considered.
Prompt evaluation by a specialist is warranted, as earlier diagnosis and initiation of therapy may improve overall prognosis. Work-up may include CBC, CPK, LDH, Aldolase, antibody screens, and MRI.
First-line treatment includes high-dose oral corticosteroid therapy (1-2 mg/kg/day) or intravenous methylprednisone (3-day pulses of 30 mg/kg) when there is multisystem involvement. Methotrexate can be administered as second-line therapy, and has been shown to improve muscular strength as well as other signs of disease activity; evolving use of biologics should be considered. Patients should be counseled in sun protection and referred to physiotherapy following resolution of the acute phase of the disease.
Henoch Schönlein Purpura
Henoch Schönlein Purpura (HSP), an acute non-granulomatous vasculitis of small blood vessels, is the most common childhood vasculitis. HSP affects predominantly male children age two and older, and is characterized by the differential regulation of pro- and anti-inflammatory cytokines in response to IgA immune complex deposition. Although several HLA alleles have been linked to this disease, in more than half the cases, HSP is preceded by upper respiratory tract infections of viral or bacterial nature. Noninfectious triggers include antibiotics, non-steroidal anti-inflammatory drugs, vaccinations, immune response modifiers, and insect bites.
HSP usually presents with characteristic non-blanching palpable purpura or petechiae due to edema and extravasation of erythrocytes, with lower leg predominance. Organ involvement other than skin usually involves joints, gastrointestinal tract, and or kidneys. Skin lesions can begin as urticarial macules or papules that may become purpuric, bullous or necrotic. Although 80% of cases have joint and skin involvement, in 25% of cases, non-migratory oligoarthritis may be the only presenting sign. Gastrointestinal symptoms range from colicky abdominal pain and positive fecal occult blood to serious complications such as intussusception, acute pancreatitis, bowel perforation, and protein-losing enteropathy. Renal complications include transient microscopic hematuria, proteinuria, gross hematuria, nephrotic syndrome, acute nephritis, and in the long-term, end-stage renal disease, however, most renal cases have excellent prognosis with complete resolution. In rare cases, neurological symptoms such as headache, intracerebral bleeds, and seizures have been reported.
Often the diagnosis is straightforward in children presenting with purpura of the buttocks and lower extremities with other associated system findings. A differential diagnosis of hypersensitivity vasculitis can be excluded by a careful diagnostic workup including patient history detailing recent infections and medications, and relevant laboratory investigations, including metabolic panels, blood cell counts, coagulation studies, radiographic studies, stool guaiac testing, urinalysis, abdominal ultrasonography for GI symptoms, and kidney biopsy with IgA immunofluorescence. A skin biopsy with IgA immunofluorescence is unnecessary unless the child presents with atypical symptoms such as hemorrhagic bullous purpura. Treatment includes supportive hydration, bed rest, and symptomatic pain relief such as non-steroidal anti-inflammatory drugs for joint pain. Systematic corticosteroids may be administered for severe GI, joint, and renal complications, as well as hemorrhagic bullous purpura, but may not prevent long-term renal impairment. Most cases of HSP resolve spontaneously within four weeks; however, patients must be educated regarding recurrent attacks. Furthermore, patients with renal abnormalities require laboratory monitoring and subsequent follow-up.
Kawasaki Disease
Kawasaki disease (KD, mucocutaneous lymph node syndrome) is an acute febrile systemic inflammatory illness with vasculitis primarily occurring in young children. It has a proclivity to involve the coronary arteries, and is therefore a leading cause of acquired heart disease in the pediatric population.
The disease typically manifests as a fever lasting at least 5 days that is unresponsive to antipyretics, with at least four of the five following findings: 1) non-exudative bilateral conjunctival injection (Figure 1.5); 2) peripheral extremity changes including erythema, edema, and periungual desquamation; 3) oropharyngeal changes including erythematous or fissured lips, strawberry tongue, and pharyngeal injection; 4) polymorphous rash; 5) acute non-purulent cervical adenopathy. Other findings can include cardiac manifestations (arrhythmia, myocarditis, pericardial effusion), CNS manifestations (aseptic meningitis, mononuclear CSF pleocytosis, facial palsy, hearing loss), gastrointestinal manifestations (diarrhea, abdominal pain, jaundice, enlarged gallbladder, enlarged liver), musculoskeletal manifestations (arthritis, arthralgia), irritability or lethargy, urethritis and sterile pyuria, and anterior uveitis.
KD should be considered in the differential diagnosis of children with prolonged fever and rash. Management of KD is focused on the reduction of systemic and coronary artery inflammation. Treatment during the early, acute stage is usually IVIG plus high doses of aspirin until the fever is controlled or until day 14 of the disease, followed by low doses of aspirin until blood counts and echocardiograms normalize (usually 2-3 months after onset). If symptoms persist (often signaled by a rising or elevated CRP), a second course of IVIG is often effective. Other therapies for refractory KD include corticosteroids, pentoxifylline, methotrexate, TNF inhibitors, cyclophosphamide, ulinastatin, plasmapheresis, and cyclosporine.
Atopic Dermatitis
Atopic Dermatitis is the most common eczematous eruption. It presents as a chronic pruritic eruption, commonly in the first few years of life. Severe atopic dermatitis may be considered a medical emergency if associated with significant infection and/or erythroderma.
Eczema Herpeticum
Eczema Herpeticum (EH, Kaposi’s varicelliform eruption) is a cutaneous herpes simplex virus infection in patients with atopic dermatitis. The herpes virus can disseminate, leading to further complications. Patients usually present with clustered vesicles, pustules, crusts, and punched-out lesions often in areas of active dermatitis. Direct fluorescent assay, viral culture, Tzanck tests, or HSV genomic probes can verify the diagnosis, although these techniques are not standardized for skin use. Antiviral treatment should be initiated with acyclovir or similar anti-virals intravenously or orally depending on disease severity. Additional supportive treatments include antipyretics, analgesics, topical corticosteroids, skin care, and antibiotics. The consideration of concurrent bacterial infection with staphylococcus or streptococcus species is appropriate.
Bacterial Superinfection
Staphylococcus aureus superinfections are very common in patients with atopic dermatitis. They can manifest as honey-colored crusted lesions, impetigo, pustules, abscesses, and cellulitis. Active superinfected atopic dermatitis may be associated with systemic findings and can therefore be considered a dermatologic emergency. Management should include antibiotic therapy with coverage for methicillin-sensitive S. aureus. In the case of a more significant or life-threatening infection, broader antibiotic coverage including methicillin-resistant S. aureus antibiotics is appropriate.
Erythroderma
Erythroderma is a generalized erythema of essentially all skin surfaces (Figure 1.7) with inflammation and scaling, most commonly secondary to atopic dermatitis and psoriasis. The differential diagnosis includes other conditions such as cutaneous lymphoma, malignancy, drug hypersensitivity and metabolic diseases. Erythroderma in children is generally an emergency that warrants evaluation for underlying diagnosis as well as acute skin management, and may be complicated by sepsis. Treatment for systemic infection and intensive skin care are appropriate.
Primary Infections
Staphylococcal Scalded Skin Syndrome
Staphylococcal scalded-skin syndrome (SSSS) is a superficial desquamative condition that usually presents with fever and tender skin. The exfoliative toxin-producing Staphylococcus aureus phage group II, with hematogenous transport of the exotoxin to the skin, causes characteristic erythema and widespread sloughing of the superficial epidermis. SSSS predominately affects children less than 5 years old, who have not yet developed protective antibodies against the staphylococcal toxins and have reduced renal clearance of exfoliatins, leading to their accumulation in the body. Transmission occurs by asymptomatic carriers, such as nursery attendants and parents.
SSSS begins as fever, malaise, and generalized, tender, macular erythema that rapidly evolves into a scarlatiniform eruption. Over 2 to 5 days, flaky desquamation of the entire skin occurs [3]. In severe cases, after the erythrodermic phase, diffuse, sterile, flaccid blisters develop with bullous desquamation of large sheets of skin. At this stage, the epidermis may separate upon gentle shear force (Nikolsky’s sign) resulting in a scalded appearance. Mucous membranes are spared, distinguishing SSSS from toxic epidermal necrolysis.
Cultures of blood, cerebrospinal fluid, urine, nasopharynx, umbilicus, etc. should be obtained to identify the primary infection site. However, skin cultures are classically negative, since cutaneous findings are due to a systemic toxin, not local infection. Histopathological examination of a biopsy of the roof of a blister demonstrating intraepidermal acantholysis within the stratum granulosum confirms the diagnosis.
In older literature, childhood mortality was cited as approximately 11% and usually occurred in conjunction with extensive exfoliation, overwhelming sepsis and the resulting electrolyte imbalance [20]. Improved recognition and diagnosis has markedly decreased mortality. Treatment with intravenous antibiotics, such as a beta-lactamase resistant anti-staphylococcal antibiotics or, if methicillin-resistant Staphylococcal aureus is suspected, vancomycin is appropriate. Alternatively, clindamycin may be prescribed if the Staphylococcus aureus strain is found to be susceptible to this agent. Management also consists of analgesia, sterile dressings, temperature regulation, and fluid replacement. The skin usually heals without scarring.
Necrotizing Fasciitis
Necrotizing fasciitis is a bacterial infection of the superficial fascia and subcutaneous cellular tissue, and is considered an acute emergency with high morbidity and mortality. Type 1 infection is polymicrobial, commonly with streptococcus, staphylococcus, bacteroides, and gram-negative enterobacteriaceae. Type 2 is a monomicrobial infection, classically caused by group A Streptococcus (GAS) either alone or in association with Staphylococcus aureus. Recently, community-acquired methicillin-resistant Staphylococcus aureus (MRSA) has been identified as a cause of necrotizing fasciitis in up to 39% of cases, with 93% of these cases monomicrobial in nature. GAS is reportedly the most commonly isolated organism in children with necrotizing fasciitis. Pediatric risk factors include chronic illness, trauma, surgery, and recent infection with varicella.
Necrotizing fasciitis commonly presents with localized pain and erythema. Within hours to days the infection can progress to a large area of necrosis, ulceration, and bullae, as well as septic shock. Imaging studies may aid in the diagnosis of necrotizing fasciitis. However, imaging should not delay surgical inspection to identify and debride deep soft tissue infection, as well as to obtain surgical specimens for Gram culture and stain. Delay in surgical debridement is a significant modifiable contributor to increased mortality. Currently, pediatric mortality rates are as high as 5.4%.
If necrotizing fasciitis is suspected, immediate management should be in an intensive care setting involving surgical consultation, antibiotic coverage, and fluid resuscitation. The priority is early surgical debridement to remove all affected, necrotic tissue. GAS infections should be treated with intravenous penicillin and clindamycin while treatment for non-GAS infections should include intravenous broad spectrum antibiotics with aerobic, anaerobic and MRSA coverage.
Herpes Simplex Virus
Gingivostomatitis is the most common clinical manifestation of primary herpes simplex virus (HSV) infection in childhood. HSV-1 causes 90% of cases. Gingivostomatitis is characterized by multiple crops of vesicles on any oral mucosal surface. An intensely erythematous, edematous and ulcerated gingiva may be accompanied by fever, malaise, headache, dysphagia, salivation, regional lymphadenitis and even life-threatening encephalitis. Treatment includes adequate hydration, nutrition, analgesia and antipyretics. While there is insufficient evidence that oral acyclovir is effective in decreasing symptoms, many experts treat severe cases.
A less common presentation of HSV is herpetic whitlow (herpetic paronychia). In children, this may be the result of digital/oral contact; in adolescents, digital/genital contact is more common, making HSV-2 the principal infectious agent. Herpetic whitlow usually manifests with local swelling, erythema, and one or more small, tender, ulcerated vesicles on the pulp of the distal phalanx of the hand. Fever and malaise may be present, especially in infants. Oral antiviral medications may be used in extensive disease.
Fungal Infections
Cutaneous fungal infections, which include dermatophyte infections of hair, skin, and nails, are not generally pediatric emergencies. However, there are some fungal infections that are associated with a more severe clinical picture, and these may be life-threatening in immune-compromised patients. Risk factors for cutaneous fungal infections include immunosuppression, long-term hospital stays, prolonged broad-spectrum antibiotic use, parenteral feeding, and long-term intravascular catheters. Some of the most important and/or dangerous of these life-threatening cutaneous fungal infections are systemic candidiasis, paracoccidiodomycosis, sporotrichosis, zygomycosis, and histoplasmosis and should be included in the differential diagnosis of atypical cutaneous rashes and viral drug reactions.
Candida and Aspergillus species are the leading causes of invasive fungal infections in pediatric patients. Dermatologic manifestations of systemic candidiasis affect 13% to 35.8% of patients. Cutaneous findings in systemic candidiasis are typically erythematous or purpuric plaques, macules, or nodules, sometimes with central pale vesicular or pustular centers. The rash may be generalized or localized to the extremities. Pediatric invasive Aspergillus (Figure 1.8) cases have cutaneous involvement in 13.7% to 41%. In a large multicenter pediatric study, 52.6% of children with cutaneous manifestations presented with disease strictly localized to the skin. Cutaneous findings are typically tender, erythematous macules or vesicles, which frequently progress to necrotic eschars.
