CHAPTER 6: Dermatology

An acute, rapidly progressive, necrotizing, life-threatening infection of the subcutaneous tissues, often associated with septic shock or Streptococcal toxic shock syndrome.

• Can be rapidly fatal if not recognized and treated promptly and appropriately

EPIDEMIOLOGY

• Rare in children; estimated 500–1500 cases per year in the United States

• Can be seen at any age, including neonates

• Most children with invasive Group A β-hemolytic Streptococcus (GABHS) infection are otherwise healthy; more than 50% of children with non-GABHS necrotizing fasciitis have at least one risk factor

• Risk factors: Antecedent varicella infection (with GABHS-related cases); recent surgery or trauma; intramuscular injection; chronic medical conditions (diabetes mellitus, malnutrition, obesity, immunosuppression). In neonates, circumcision, omphalitis, history of scalp electrode placement, necrotizing enterocolitis

ETIOLOGY

• Inoculation of bacteria into the subcutaneous tissues with resultant proliferation and release of destructive enzymes and exotoxins results in extensive tissue necrosis, thrombosis of blood vessels, and rapid progression along fascial planes

• Common: GABHS. Typically involves the groin or lower extremities

• Less common: Aerobic and non-aerobic organisms, including Staphylococcus aureus, anaerobic streptococci, group B Streptococcus, Proteus vulgaris, Escherichia coli, Pseudomonas aeruginosa, and Bacteroides fragilis. May be polymicrobial. Usually involves the abdominal wall, perianal or genital area, or a postoperative wound

DIFFERENTIAL DIAGNOSIS

• Cellulitis, erysipelas, pyoderma, staphylococcal scalded skin syndrome, toxic shock syndrome, burns

CLINICAL MANIFESTATIONS

• Initial symptoms may be nonspecific and include localized pain, fever, chills, vomiting, pharyngitis, malaise, altered mental status, and myalgias

• Skin manifestations are toxin-mediated, typically seen with GABHS-related necrotizing fasciitis, and present with erythematous ill-defined patch(es) or plaque(s)

• Associated signs and symptoms include severe pain out of proportion to clinical findings, extreme tenderness involving both affected and clinically unaffected areas, numbness, edema, and murky dishwater-like discharge

• Rapid progression to purpuric patch(es) or plaque(s) with or without blistering, followed by the development of ulceration and gangrene. Crepitus may be appreciated in non-GABHS-related necrotizing fasciitis

• Systemic toxicity that may include features of septic shock or, in the case of invasive GABHS, toxic shock syndrome with hypotension and multisystem organ failure

• Fournier’s gangrene: Involvement of the genital and perianal area; typically polymicrobial

DIAGNOSTICS

• Clinical diagnosis requires high level of suspicion

• Cultures of blood, wound, and deep tissue (incisional biopsy)

• Histology of incisional biopsy reveals tissue necrosis

• CBC: Leukocytosis

• CRP, ESR: Elevated

• Metabolic panel: Hyponatremia, elevated blood urea nitrogen, metabolic acidosis, hypocalcemia, elevated serum creatine phosphokinase

• Ultrasound may demonstrate fascial thickening and fluid collections

• MRI is more sensitive than CT but may overestimate involvement; a negative MRI can exclude necrotizing fasciitis

MANAGEMENT

• Prompt surgical consultation and surgical exploration with wide excision of necrotic tissue; delay results in higher mortality. Surgical reexploration and repeat debridement may be required 24–48 hours later

• Wound care: Vacuum-assisted wound closure, flap reconstruction, and split-thickness skin grafting may be required

• Pain management

• Broad spectrum antibiotics should be started empirically and adjusted based on culture results. For GABHS-related cases: penicillin plus clindamycin. For non-GABHS-related cases: clindamycin plus a third generation cephalosporin or ampicillin, gentamycin, and metronidazole are recommended

• Intravenous immunoglobulin (IVIG) may benefit patients with GABHS-related necrotizing fasciitis and toxic shock syndrome.

• Hyperbaric oxygen therapy may be helpful where available

• In children, mortality is about 5% and highest in those with comorbid medical conditions, non-GABHS-related disease, septic shock, multisystem organ failure, and young age

• The risk of secondary invasive GABHS infection is significantly elevated in household contacts and approaches 200 times that of the general population; therefore, chemoprevention should be considered for close contacts

Staphylococcal scalded skin syndrome (SSSS) is a bacterial toxin-mediated exfoliative rash characterized by areas of erythema and superficial desquamation, resembling a superficial burn.

EPIDEMIOLOGY

• Generally occurs in children who lack neutralizing antibodies to staphylococcal toxins, including neonates and children younger than 5 years of age or older children and adults with renal impairment or immunosuppression

• Outbreaks of SSSS may occur in nurseries and neonatal units as a result of asymptomatic carriage by staff

• Occult or apparent infection or colonization with Staphylococcus aureus strains harboring exfoliative exotoxin, typically belonging to phage group II

ETIOLOGY

• Exfoliative toxins ETA and ETB are produced by certain strains of Staphylococcus aureus and act as serine proteases that degrade a specific keratinocyte cell adhesion molecule, desmoglein-1, resulting in the formation of a superficial, substratum corneum blister at the stratum granulosum

• Nidus of infection typically involves head or neck or circumcision site (neonates) but may not be clinically apparent

• Exotoxin dissemination via the bloodstream results in generalized blistering and may result in part from delayed renal clearance of exotoxin and/or lack of anti-exotoxin antibodies

DIFFERENTIAL DIAGNOSIS

• Thermal burn, toxic epidermal necrolysis, Kawasaki disease, toxic shock syndrome, toxin-mediated perineal erythema, erythema multiforme, Stevens–Johnson syndrome, epidermolysis bullosa

CLINICAL MANIFESTATIONS

• Prodrome of fever (low-grade), malaise, irritability, rhinorrhea, pharyngitis and/or conjunctivitis

• Tender, erythematous patches develop initially in intertriginous zones and on face, may become more generalized

• Superficial, flaccid bullae develop in involved areas and often rupture spontaneously, revealing moist, denuded areas resembling burns

• Nikolsky sign: Extension of blister with applied lateral pressure along edge of blister

• Perioral, periocular, and perinasal erythema and crusting are characteristic

• Involved areas eventually desquamate and heal without scarring within 2–3 weeks

DIAGNOSTICS

• Bacterial Gram stain and culture: Nares/nasopharynx, perianal/perineum, conjunctivae, umbilicus (neonates), blood (rarely positive); rarely, source may be osteomyelitis, septic arthritis, pyomyositis, pneumonia, or other non-cutaneous infection. Toxin-induced blisters or areas of exfoliation are generally culture-negative

• Skin biopsy: Rarely necessary but can differentiate SSSS from toxic epidermal necrolysis (TEN), skin biopsy for frozen section can be performed rapidly to differentiate superficial split within granular layer of epidermis (SSSS) from deeper, full-thickness epidermal involvement (TEN)

MANAGEMENT

• Most patients have an excellent prognosis if identified and treated promptly

• Parenteral antibiotics are recommended. Use oxacillin, nafcillin, or cefazolin for empiric therapy. Methicillin resistance is rare in exotoxin-producing strains of Staphylococcus aureus. Clindamycin may be added to decrease exotoxin production

• Localized or limited involvement may respond to oral antibiotics: Clindamycin, penicillinase-resistant penicillin, first- or second-generation cephalosporin

• Topical and/or systemic corticosteroids are contraindicated

• Therapy should be continued for a minimum of 7–10 days

• Wound care: Leave bullae intact. Denuded areas may be covered with petrolatum gauze or other non-adherent contact layer dressing. Minimize friction. Monitor for secondary infection

• Cool compresses applied to areas of facial crusting and application of ophthalmic antibiotic ointment may be helpful

• Patients require supportive therapy with pain management, nutrition, temperature control, and hydration

Stevens– Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare hypersensitivity reactions within the spectrum of severe cutaneous adverse reactions (SCAR). Predominantly drug-related, they share a common pathophysiology. They are dermatologic emergencies with significant morbidity and mortality.

• SJS manifests as atypical targetoid lesions associated with erosions involving two or more mucous membranes. Bullous lesions may be present. Skin involvement is limited to 10% or less of body surface area (BSA)

• SJS/TEN overlap shares features of SJS and TEN with involvement of 10–30% BSA in association with mucous membrane involvement

• TEN manifests as extensive skin erythema, pain, and sloughing involving >30% BSA, usually in association with mucous membrane erosions

EPIDEMIOLOGY

• Estimated incidence of 2 per 1 million in the general population

ETIOLOGY

• Proposed pathogenesis involves activation of cytotoxic T-cells by drug antigens and elaboration of inflammatory cytokines and circulating pro-apoptotic factors, including Fas ligand and granulysin, which leads to keratinocyte apoptosis, skin necrosis, and skin detachment

• Genetic susceptibility has been demonstrated in some populations in association with specific HLA alleles, including HLA-B*1502 and carbamazepine-induced SJS in Han Chinese

• Most common drugs implicated: Antibiotics (aminopenicillins, sulfonamides), allopurinol, NSAIDS of the oxicam type, and aromatic anticonvulsants (phenobarbital, phenytoin, carbamazepine). Other drugs: antibiotics (cephalosporins, tetracyclines, macrolides, quinolones), NSAIDS of the acetic acid type

• SJS may also occur with Mycoplasma pneumoniae infection; the clinical presentation often manifests as mucositis without significant cutaneous manifestations (M. pneumoniae-associated mucositis)

• In some cases, no clear etiology can be identified

DIFFERENTIAL DIAGNOSIS

• Exanthematous erythematous macules and papules: Viral exanthems, morbilliform/exanthematous drug eruption, urticarial hypersensitivity, urticarial vasculitis, drug reaction with eosinophilia and systemic symptoms (DRESS)/drug-induced hypersensitivity syndrome (DIHS)

• Targetoid lesions: Annular urticaria, erythema multiforme

• Bullous lesions: Bullous impetigo, linear IgA disease (chronic bullous dermatosis of childhood), childhood bullous pemphigoid, childhood pemphigus vulgaris, generalized bullous fixed drug eruption

• Skin peeling and sloughing: SSSS, toxic shock syndrome, Kawasaki disease, paraneoplastic pemphigus, acute generalized exanthematous pustulosis acute cutaneous graft versus host disease

• Mucositis: Herpetic gingivostomatitis, aphthous stomatitis, pemphigus vulgaris, acute genital ulceration/idiopathic vulvar aphthosis

CLINICAL MANIFESTATIONS

• Generally develops within 2 months of drug initiation, and often within first 1–4 weeks

• Prodrome of fever, malaise, pharyngitis, and eye pain may be noted

• Cutaneous manifestations typically begin on the torso and face and may rapidly generalize

• SJS: Primary lesions are discrete, atypical targetoid lesions, often violaceous and/or blistered. Lesions may coalesce, in particular on face and torso

• TEN: Primary lesions are tender, erythematous patches and plaques that develop large bullae that coalesce and rapidly slough, leaving large denuded areas of skin. Positive Nikolsky sign: extension of blister with applied lateral pressure along edge of blister

• Mucositis (oropharyngeal, conjunctivae, urethral, genital, perirectal) often results in pain, poor oral intake, and dehydration

• Ocular manifestations include conjunctivitis, eyelid edema, blepharitis, corneal erosions, symblepharon, and corneal scarring, which is a major cause of long-term morbidity and may result in blindness

• Rarely, gastrointestinal and respiratory epithelia may become involved

• Severe cutaneous involvement may result in cutaneous dyschromia and scarring. Nail dystrophy and alopecia may occur. Areas of mucous membrane involvement, including the oropharynx, vagina, urethra, and esophagus, are at risk for scarring, adhesions, and strictures. Long-term sequelae are reported in approximately 50% of children

DIAGNOSTICS

• Usually a clinical diagnosis but skin biopsy can be helpful if the diagnosis is uncertain. SJS: intense interface reaction along the dermal–epidermal junction with central necrosis or blister formation. TEN: can be performed as a frozen section and reveals full-thickness epidermal necrosis and a subepidermal split

MANAGEMENT

• Dermatology consultation recommended

• Prompt discontinuation of all possible inciting medications or treatment of etiologic underlying infection (e.g., Mycoplasma)

• Supportive care: Pain management, nutritional support, maintain isothermia, maintain hydration and electrolyte balance (hyponatremia, hypokalemia, and hypophosphatemia are common)

• Close surveillance for infection/sepsis and impending respiratory failure, which increase the risk of death. Hypovolemia and septicemia may result in shock and multisystem organ failure

• Wound care: Bullae should be left intact but may be drained via sterile technique. Application of petrolatum gauze or other non-adherent contact layer. Judicious use of topical antibiotics. Use of specialized mattress to minimize pressure can be helpful. Frequent application of bland emollients/lubricating ointments to involved mucosa. Oral hygiene may be assisted by use of an oral disinfectant rinse such as chlorhexidine

• Appropriate consultation for mucous membrane involvement: Eyes (Ophthalmology); urethral (Urology); gastroesophageal, intestinal, rectal (Gastroenterology); tracheobronchial tree (Pulmonology)

• Systemic corticosteroids are of uncertain benefit. Short-term early use may moderate disease progression, but prolonged use is contraindicated

• Use of IVIG appears to be effective at arresting progression of the disease for both SJS and TEN. For progressive disease, especially if recognized early within first 2–3 days of presentation, IVIG 1 mg/kg/day for 3–4 days may be beneficial. Other therapeutic agents that have been used include cyclosporine and infliximab

A distinct and potentially life-threatening severe adverse drug reaction characterized by a morbilliform cutaneous eruption with fever, lymphadenopathy, hematologic abnormalities, and multiorgan manifestations.

EPIDEMIOLOGY

• Incidence is unknown but some report overall population risk ranging from 1 in 1000 to 1 in 10,000 drug exposures

• Incidence may be as high as 10–50 per 100,000 individuals on anticonvulsants such as phenytoin and carbamazepine and 1 per 100 children on lamotrigine

• Individuals with specific human leukocyte antigen haplotypes (HLA types) are predisposed; HLA alleles are necessary but not sufficient to elicit a drug response

ETIOLOGY

• Considered a severe systemic hypersensitivity reaction to a medication and its reactive drug metabolites; although specific pathophysiology is not known, appears to be mediated by activation of CD4-positive and CD8-positive T-lymphocytes

• Eosinophilia may play a role in visceral complications

• Aromatic anticonvulsants (phenobarbital, carbamazepine, phenytoin, and lamotrigine), minocycline, and sulfonamide antibiotics are most common causes but antibiotics including ampicillin, cefotaxime, streptomycin, and vancomycin have also been implicated

• Antivirals including abacavir and nevirapine, antidepressants including bupropion and fluoxetine, antihypertensives including amlodipine and captopril, nonsteroidal anti-inflammatory drugs (NSAIDs) including celecoxib and ibuprofen, as well as miscellaneous medications including allopurinol, ranitidine, epoetin alfa, and mexiletine have also been implicated

• Most often occurs between 2 and 6 weeks after initiation of a medication but reaction can occur more quickly upon reexposure to a medication

• Individuals with specific human leukocyte antigen haplotypes (HLA types) are predisposed; HLA alleles are necessary but not sufficient to elicit a drug response

• HLA-B*5701 allele has been associated with abacavir-induced DRESS

• HLA-A*3101 is associated with carbamazepine drug reactions including DRESS and SJS/TEN syndrome in Japanese patients

• HLA-DR3 and HLA-DQ2 are associated with carbamazepine-induced DRESS

• HLA-B*5801 is associated with allopurinol-induced DRESS

• Primary or reactivation of herpesviruses, including human herpes virus-6 (HHV-6) infection, cytomegalovirus infection, Epstein–Barr virus, and human herpes virus-7 (HHV-7), have also been implicated

DIFFERENTIAL DIAGNOSIS

• SJS, TEN, toxic-shock syndrome, Kawasaki disease, exfoliative dermatitis, acute generalized exanthematous pustulosis, viral exanthema, acute cutaneous lupus erythematosus

CLINICAL MANIFESTATIONS

• There is no reliable standard for diagnosis. Proposed diagnostic criteria includes acute onset of exanthema with fever, suspicion of drug reaction, hospitalization, lymphadenopathy, involvement of at least one internal organ, and hematologic abnormalities, including lymphopenia, lymphocytosis, atypical lymphocytosis, eosinophilia >10%, or thrombocytopenia

• Often a prodrome of fever, pharyngitis, and malaise 2–3 days before onset of rash

• Characteristic cutaneous features include a morbilliform exanthem with accentuation on the face, upper trunk, and proximal extremities but may progress to erythroderma. Pruritus is common. Other morphologies can occur though are less common and include vesicles, atypical targetoid plaques, purpura, and sterile pustules

• Facial edema is common, especially periorbital

• Diffuse lymphadenopathy occurs in 30–60% of patients

• Associated mucosal involvement includes cheilitis and pharyngeal erythema; erosions are rare

• Desquamation develops several days to weeks after the initial eruption and may last for several weeks

• Multiple organ systems can be involved; hepatic (hepatitis), renal (tubulointerstitial nephritis), and pulmonary complications are the most common

• Shortness of breath, tachypnea, and nonproductive cough may occur; more severe pulmonary manifestations are rare but more common with minocycline-induced DRESS and may include interstitial pneumonitis and pulmonary edema

• Myocarditis and pericarditis may occur but are rare in children. Myocarditis can occur months after withdrawal of the offending medication

• Severe, atypical cases can have neurological (encephalitis, meningitis, polyneuritis) or gastrointestinal (diarrhea, pancreatitis, gastrointestinal mucosal hemorrhage) involvement

• Neurologic manifestations are rare and typically occur weeks after the onset of the rash; they are thought to be related to reactivation of HHV-6

• Autoimmune complications can be seen as a delayed sequelae, especially autoimmune thyroiditis (Graves’ disease). Development of type 1 diabetes mellitus and autoimmune hemolytic anemia have also been reported

• Rash and other abnormalities typically resolve over 1–2 months after discontinuation of the offending medication

• Avoidance of the causative medication as well as any cross-reacting medications is mandatory; family members may also be at risk and should be counseled appropriately

DIAGNOSTICS

• CBC: Lymphocytosis, atypical lymphocytosis, eosinophilia, and/or thrombocytopenia may be seen

• Hepatic function tests: Elevated liver transaminases, in particular alanine aminotransferase (ALT), elevated alkaline phosphatase; markedly elevated ALT and serum bilirubin with jaundice are important predictors of acute liver failure and death

• Metabolic panel: Elevated serum creatinine may be seen

• Urinalysis: Proteinuria and eosinophilic sediment may be seen

• Lactate dehydrogenase level may be elevated

• Evaluation of HHV-6, HHV-7, EBV, and/or CMV by serum PCR

• Evaluation of hepatitis A IgM antibody, hepatitis B surface antigen, hepatitis B core IgM antibody, hepatitis C viral RNA may help exclude viral hepatitis

• Consider anti-nuclear antibody (ANA) testing if systemic lupus erythematosus is being considered

• Thyroid function testing should be performed at baseline (TSH, free T4) and then approximately 6 weeks after presentation

MANAGEMENT

• Dermatology consultation is recommended

• Consider consultation of other specialists as appropriate depending on severity of other organ involvement

• Identify and withdraw causative medication

• Fluid replacement and correction of electrolyte abnormalities

• For cases with mild, predominantly cutaneous involvement, initiation of a mid- to high-potency topical corticosteroid is appropriate

• Antihistamines may help with associated pruritus

• For cases with significant systemic involvement initiation of systemic corticosteroids such as prednisone or methylprednisolone at a dose of 1–2 mg/kg per day is recommended. Taper gradually over weeks to months after clinical examination and laboratory abnormalities have improved; rapid taper may precipitate relapse

• IVIG at a dose of 1 g/kg per dose once daily can be considered for severe cases that do not respond to corticosteroids

• Plasmapheresis and immunosuppressive drugs such as cyclophosphamide, cyclosporine, mycophenolate mofetil, and rituximab may also be considered for corticosteroid and/or IVIG-resistant cases

An acute cutaneous reaction characterized by pruritic, transient annular, and polycyclic urticarial plaques that resemble erythema multiforme.

ETIOLOGY

• Acute urticaria results from degranulation of mast cells and basophils and release of vasoactive substances, including histamine, bradykinin, and prostaglandin D2, which cause extravasation of plasma into the dermis

• Acute urticaria may be immune-mediated, either by IgE (most medication- and food-related urticaria), cytotoxic T-cells or immune complex formation; or may be nonimmune-mediated such as occurs with complement-mediated urticaria (radiocontrast agents, bacterial and viral infections, opioids) or physical urticaria

• In children, acute urticaria usually occurs in response to medications (most commonly penicillin and related antibiotics) or infection, most commonly respiratory viruses, gastrointestinal viruses, or Streptococcal infection, although in some cases no clear etiology can be identified

EPIDEMIOLOGY

• Acute urticaria is very common and occurs in up to 10% of children by adolescence

• Acute urticaria occurs more commonly in infants and younger children but may be seen at any age

DIFFERENTIAL DIAGNOSIS

• Serum sickness, serum-sickness-like reaction, erythema multiforme, arthropod bites/papular urticarial, annular/gyrate erythema, viral exanthema, cutaneous mastocytosis, autoimmune disease, urticarial vasculitis (Table 6-1)

CLINICAL MANIFESTATIONS

• Primary lesions: Generalized annular and polycyclic urticarial papules and plaques that typically are evanescent, lasting less than 24 hours. Occasionally, lesions may resolve with a residual ecchymosis or hyperpigmentation

• Angioedema of hands, feet, and face is common and resolves more slowly than urticaria

• Dermatographism: Stroking of the skin results in urtication at the site

• Associated symptoms may include fever and specific symptoms suggestive of associated infection but are often absent

• Progression to anaphylaxis is rare

• By definition, acute urticaria resolves within 6 weeks, but often resolves within several days

DIAGNOSTICS

• No specific diagnostic tests are indicated unless necessary for the identification of a specific associated infection

• Skin biopsy may be performed if the diagnosis is uncertain and manifests dermal edema; dilatation of blood and lymphatic vessels, and a sparse perivascular mononuclear infiltrate with variable numbers of eosinophils and neutrophils

MANAGEMENT

• Discontinue potential causative medications

• H1-antagonist antihistamines may be administered at regularly scheduled intervals. As acute urticaria is self-limiting, therapy is rarely needed for more than 1–2 weeks. Use of non-sedating second-generation antihistamines (loratidine, cetirizine) or third-generation antihistamines(levocetirizine, desloratadine, fexofenadine) typically better tolerated than sedating antihistamines (diphenhydramine, hydroxyzine)

• Consider adjunct H2-antagonist antihistamines: Cimetidine, ranitidine

• The cutaneous urticarial reaction typically responds rapidly to antihistamines; the edema may respond more slowly

• Topical corticosteroids are not indicated

• Rarely, a short course of a systemic corticosteroid may be indicated in the case of a severe, persistent reaction unresponsive to antihistamine therapy

• Treat associated infection as indicated, although will not hasten resolution of urticaria

An acute, self-limited, and sometimes recurrent immunologically mediated mucocutaneous eruption characterized by target lesions with an acral predilection. The oral mucous membranes are commonly affected.

The use of the terms erythema multiforme minor and erythema multiforme major should be avoided.

EPIDEMIOLOGY

• Overall incidence is reportedly 1–6 per million

• Affects older children and young adults most commonly

ETIOLOGY

• Erythema multiforme is a hypersensitivity reaction seen in response to a plethora of inciting agents including infectious agents, medications, vaccinations, inflammatory conditions, and environmental agents. It is believed to be a cell-mediated delayed-type hypersensitivity reaction (Table 6-2)

• Infectious agents, including numerous bacterial, viral, and fungal microorganisms, appear to be the most common inciting agents, although many cases have no clearly identifiable cause

• Recurrent erythema multiforme is strongly associated with herpes simplex virus (HSV) infection and may occur a few days to a few weeks following HSV infection or recurrence

• Drug-induced EM appears to be related to impaired metabolism of the causative drug, which results in the production of reactive and/or toxic drug metabolites that may serve as haptens

DIFFERENTIAL DIAGNOSIS

• Exanthematous erythematous macules and papules: Viral exanthems, urticaria, urticarial vasculitis, secondary syphilis

• Targetoid lesions: Annular urticaria, fixed drug eruption, annular/figurate erythema

• Mucositis: Herpetic gingivostomatitis, aphthous stomatitis, pemphigus vulgaris

CLINICAL MANIFESTATIONS

• Primary lesions: Classic target lesions present as erythematous papules that rapidly evolve over 1–2 days to manifest a central violaceous macule, which may blister, surrounded by an intermediate ring of pallor and a peripheral erythematous rim. Pruritus or a burning sensation may be reported. Target lesions favor extremities, including hands and feet

• Köebner phenomenon: Lesions may present at sites of recent trauma

• Target lesions typically present over several days, then remain fixed in location and morphology for at least 1 week, after which time they slowly resolve. May resolve with post-inflammatory hyperpigmentation

• Mucositis: Typically mild and limited to one mucous membrane (usually the oral mucosa); rarely involves conjunctival, urogenital mucosa

• Systemic symptoms are uncommon but may include low-grade fever, cough, and rhinorrhea

DIAGNOSTICS

• Usually a clinical diagnosis though skin biopsy may help in atypical cases. Histology demonstrates a vacuolar interface dermatitis with vacuolar changes and dyskeratotic basal keratinocytes; a mild-to-moderate superficial perivascular lymphocytic infiltrate may be seen

• HSV PCR from an oropharyngeal specimen may be performed if there is clinical suspicion for HSV-associated EM

MANAGEMENT

• EM is a self-limited phenomenon, often requiring only supportive care

• Bland emollients or topical antibiotics may be applied to eroded areas

• Patients with mucositis and poor oral intake may require intravenous rehydration or hyperalimentation

• Antihistamines (diphenhydramine, hydroxyzine, cetirizine) may treat associated pruritus

• In patients with HSV-associated EM, treatment with acyclovir may be indicated early in the course of the rash

• Ophthalmologic consultation is recommended for ocular involvement

Hemangiomas of infancy are common vascular tumors that undergo a typical growth pattern of proliferation, stabilization (plateau), and gradual involution. Most hemangiomas require no therapy beyond active nonintervention and appropriate anticipatory guidance. Complications may arise with hemangiomas occurring near vital structures, in certain anatomic locations, or in patients with multiple hemangiomas (Table 6-3).

EPIDEMIOLOGY

• Occur in approximately 10% of infants

• More common in female infants, preterm infants, multiple gestations, and in association with chorionic villus sampling and amniocentesis

• Most complications arise during the proliferative phase, during the first 3–6 months of life

ETIOLOGY

• Most cases are sporadic without clear genetic predisposing factors

• Hemangiomas of infancy share many similar cellular markers with placental tissue and may have a common precursor

DIFFERENTIAL DIAGNOSIS

• Vascular malformations: Venous malformation, arteriovenous malformation, lymphatic malformation, capillary malformation

• Kaposiform hemangioendothelioma

• Rapidly involuting congenital hemangioma (RICH): A congenital hemangioma that involutes rapidly (during the first year) and may result in cutaneous atrophy

• Non-involuting congenital hemangioma (NICH): A congenital hemangioma with overlying telangiectasia that does not involute

• Vascular tumor mimics: Lipoblastoma, fibrosarcoma, or other soft-tissue sarcomas; these are often large, congenital lesions showing rapid growth, ulceration, and fixation to underlying tissue; dermoid cyst; myofibroma

CLINICAL MANIFESTATIONS

• Hemangiomas are often not visible at birth and typically manifest within the first 2–8 weeks of life, often as faint areas of macular erythema that rapidly increase in size

• Superficial hemangiomas have a “strawberry” appearance. Deep hemangiomas may appear soft and bluish without much superficial change. Mixed hemangiomas may have features of both superficial and deep morphology

• Hemangiomas undergo proliferation and may grow rapidly during the first 6–9 months of life; they then plateau or stabilize until approximately 1 year of age. After 1 year of age, hemangiomas undergo slow, gradual involution over 5–8 years

• Most involute significantly, but residual telangiectasia or fibrofatty tissue may remain

• Complications prompting treatment may include rapidly growing periocular hemangiomas threatening vision, symptomatic airway hemangiomas, extensive ulcerated hemangiomas with secondary infection or sepsis, symptomatic visceral hemangiomatosis resulting in congestive heart failure, PHACES syndrome, and SACRAL/PELVIS syndrome

• PHACES syndrome: Posterior fossa abnormalities, large segmental facial Hemangioma, cerebrovascular Arterial anomalies, Coarctation of the aorta, Eye abnormalities, and midline Sternal anomalies

• PELVIS/SACRAL syndrome: Perineal/buttock segmental hemangioma, External genitalia anomalies, Lipomeningocele, Vesicorenal anomalies, Imperforate anus, and Skin tags (perianal)

DIAGNOSTICS

• MRI of the orbits or neck, respectively, may help delineate anatomic extent of orbital or airway hemangiomas

• MRI of the brain is recommended to evaluate for associated anomalies as seen in PHACES syndrome. MRA of head and neck is also important for delineating the cerebrovascular arterial anomalies of PHACES syndrome

• MRI of the lumbosacral spine and renal ultrasound are recommended to evaluate suspected cases of PELVIS/SACRAL syndrome

• Electrocardiogram (ECG) and echocardiography are recommended when PHACES is suspected

• Skin biopsy for atypical lesions may help confirm the diagnosis of a hemangioma and exclude a diagnosis of fibrosarcoma, other vascular tumor, or vascular malformation

MANAGEMENT

• Consultation with Dermatology is recommended for complicated hemangiomas

• Consultation with other subspecialists, including Ophthalmology, Otolaryngology, Plastic Surgery, and Cardiology, as appropriate, should be considered when complications are present or suspected

• The following are indications for systemic treatment: Periocular hemangiomas threatening vision; symptomatic airway involvement; ulcerated hemangiomas unresponsive to conservative management; congestive heart failure due to coarctation of the aorta or hepatic hemangiomatosis; large segmental hemangiomas such as seen in PHACES syndrome and PELVIS/SACRAL syndrome; proliferating hemangiomas with risk for significant cosmetic disfigurement

• Consider propranolol therapy 2–3 mg/kg/day divided every 8–12 hours. Propranolol is now considered as first-line therapy. Monitor for propranolol-related side effects including bradycardia, hypotension, and hypoglycemia

• Consider systemic steroid therapy (2–3 mg/kg/day of prednisone or prednisolone) if propranolol is contraindicated or as adjunctive therapy if suboptimal response to propranolol. If initiating corticosteroids consider gastrointestinal prophylaxis with ranitidine or cimetidine

• Management of ulcerated hemangiomas should include evaluation for infection; soaks with tap water, saline, or acetic acid twice daily; topical antibiotic therapy (topical mupirocin or topical metronidazole); and daily to twice-daily dressing changes with non-adherent dressing (Telfa, petrolatum gauze, or Mepilex). Consider timolol 0.5% solution applied topically twice daily or pulsed dye laser therapy

• If response to propranolol and/or corticosteroids is suboptimal, consider surgical intervention or interventional radiologic embolization of selected hemangiomas

• Patients with six or more hemangiomas are at increased risk for visceral hemangiomatosis (although visceral hemangiomas may be seen in the absence of cutaneous hemangiomas); the liver is the most common extracutaneous site although almost any organ may be involved. Hepatomegaly, splenomegaly, congestive heart failure, and hypothyroidism are potential complications. Abdominal ultrasound or MRI, MRI of the brain, MRI of the chest, and/or MRI of the spine may help delineate extent of involvement where appropriate

• Uncomplicated hemangiomas with little to no risk for complications may be managed with active nonintervention or initiation of topical timolol 0.5% solution, as appropriate

A chronic, relapsing inflammatory skin disease characterized by pruritus, erythema, scaling, oozing, and crusting. Impaired skin barrier function and abnormalities in the immune response lead to a predilection for recurrent bacterial and/or viral skin infections. Associated with other atopic diseases: asthma, allergic rhinosinoconjunctivitis, food allergy, eosinophilic gastrointestinal disorders.

• Infectious complications, namely bacterial superinfection with Staphylococcus aureus and eczema herpeticum, are associated with acute flares

EPIDEMIOLOGY

• Atopic dermatitis affects approximately 20% of the pediatric population

• Age of onset is typically within the first 2 years of life, and while many children will “outgrow” their atopic dermatitis, a small but significant minority will develop persistent and/or progressively worsening disease

• Eczema herpeticum is seen in 10–20% of patients with atopic dermatitis and is associated with early onset atopic dermatitis and more severe disease

• Bacterial colonization and superinfection with Staphylococcus aureus is very common, and systemic infection such as osteomyelitis and septicemia may also occur. Staphylococcal superantigens promote inflammation

• Secondary bacterial infection with Streptococcus pyogenes may also be seen, either alone or in combination with Staphylococcus aureus infection

• In addition, patients with atopic dermatitis may develop other cutaneous infections, including widespread viral infection with molluscum contagiosum, coxsackievirus, vaccinia or papilloma virus, and fungal infections with dermatophyte molds or Pityrosporum

ETIOLOGY

• Atopic dermatitis is a complex disease in which genetic and environmental factors contribute to chronic skin inflammation; allergic sensitization to food and environmental allergens and the production of specific IgE antibodies predicts more severe, persistent disease

• Impaired skin barrier function as a result of decreased expression of proteins involved in the formation of the cornified cell envelope, including filaggrin, and dysfunction of both innate and adaptive immunity lead to increased susceptibility to microbial colonization of the skin and cutaneous infections

• Bacterial superantigens and toxins contribute to inflammation and disease flares

DIFFERENTIAL DIAGNOSIS

• Seborrheic dermatitis, scabies, contact dermatitis, nummular dermatitis, immunodeficiency

CLINICAL MANIFESTATIONS

• Colonization of the skin in patients with atopic dermatitis is common and must be distinguished from infection

• Acute flares of atopic dermatitis manifest as erythematous, scaling patches and plaques, often with excoriations and crusting when secondary bacterial infection is present

• Systemic symptoms such as fever or malaise may be present but are often absent unless Streptococcus pyogenes infection or eczema herpeticum is present or a systemic infection has developed

• Complications of secondary bacterial infection include acute post-streptococcal glomerulonephritis

• Eczema herpeticum presents acutely with the development of grouped, monomorphous round “punched out” erosions; crusting may be present. If herpes keratoconjunctivitis is present there may be associated ocular pain, tearing, erythema, blurry vision, and/or photophobia. Secondary bacterial infection is common

• Other complications of eczema herpeticum include meningitis, encephalitis, and bacterial sepsis, which have the potential for significant morbidity and mortality

DIAGNOSTICS

• Wound culture for bacterial Gram stain and culture may be performed from any crusted area

• HSV PCR should be performed if eczema herpeticum is suspected

• Enterovirus PCR can also be performed from vesicles or from stool if suspected coxsackievirus superinfection

MANAGEMENT

• Initiate use of topical corticosteroids of appropriate potency based on the age of the patient, the site(s) involved, and the severity. In general, topical corticosteroids should not be withheld during the treatment of bacterial superinfection and eczema herpeticum

• In cases of suspected bacterial superinfection, parenteral antibiotics should be started empirically and adjusted based on culture results. Use of recent prior skin culture results may help guide antibiotic choice. In the absence of a history of methicillin-resistant Staphylococcus aureus infection, use of a first- or second-generation cephalosporin for 7–10 days is recommended. For the treatment of Streptococcus pyogenes use of either a first- or second-generation cephalosporin or amoxicillin/clavulanate for 10 days is recommended

• In the absence of clinical features suggestive of infection, mupirocin ointment or retapamulin ointment should be applied to eroded or crusted areas to minimize bacterial colonization

• In cases of suspected eczema herpeticum, acyclovir should be started empirically. In patients with periocular involvement, Ophthalmology consultation is recommended and use of antiviral ophthalmic medications such as 1% trifluridine or 3% vidarabine considered

• Wet wraps performed 1–2 times daily as helpful for acute flares. Apply topical corticosteroids to affected areas, followed by damp gauze or pajamas; should be left in place for at least 1–2 hours. Apply bland emollients after wet wraps are removed. Use of tubular gauze such as Tubifast^® (Molnlycke) simplifies the regimen

• Atopic skin care consisting of frequent application of bland emollients, limiting bathing to less than 10 minutes, and use of a gentle non-soap cleanser is recommended

• Use of a sedating antihistamine such as diphenhydramine or hydroxyzine may be helpful in reducing pruritus and facilitating sleep at bedtime and naptime

• For patients with recurrent bacterial superinfection, initiation of bleach baths or use of an antibacterial skin cleanser such as chlorhexidine 2–3 times weekly in addition to use of mupirocin ointment to any eroded or crusted skin areas may be helpful

• For patients with recurrent eczema herpeticum, initiation of oral acyclovir at prophylactic dosing may be considered