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Potentially life-threatening emergency
Toxic epidermal necrolysis in Infant/Neonate
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Potentially life-threatening emergency

Toxic epidermal necrolysis in Infant/Neonate

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Contributors: Andrew R. Blundell MSc, Andrew Walls MD, Elena B. Hawryluk MD, PhD, Susan Burgin MD
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Synopsis

Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) are acute, severe eruptions manifesting desquamative skin lesions, multifocal mucositis, and systemic symptoms. SJS is characterized by involvement of detached and detachable skin that is less than 10% of body surface area (BSA), while TEN involves greater than 30% BSA. SJS-TEN overlap occurs when 10%-30% BSA is involved. Note that SJS can rapidly evolve into TEN, and both can have an unpredictable clinical course. Historically, terminology surrounding this entity has been imprecise, and terms such as erythema multiforme major and Mycoplasma pneumoniae-associated SJS/TEN have been used to embody a heterogenous group of mucositides resulting from a variety of drug and infectious exposures. Recently, there has been a movement toward reclassification of this entity into 3 separate entities:

SJS/TEN spectrum drug hypersensitivity:
  • Induced strictly by medication exposure (sulfamethoxazole / trimethoprim, NSAIDs, allopurinol, antiepileptics, etc)
  • SJS when < 10% BSA is involved, SJS/TEN overlap when 10%-30% BSA is involved, TEN when > 30% BSA is involved
  • Dusky macules (so-called "targetoid" with 2 zones of color) evolving into flaccid bullae and skin desquamation
  • Skin lesions favor truncal sites
  • Oral, ocular, and genitourinary mucositis
  • Nikolsky sign and Asboe-Hansen sign are positive
  • Skin pain as a sign alerting to this diagnosis
Erythema multiforme (EM):
  • Secondary to infection, typically herpes simplex virus (HSV), or medication
  • Presents with typical, true target lesions (3 zones of color as opposed to 2 zones of color in SJS/TEN)
  • Lesions predominate on acral locations, particularly palms and soles
  • Lesions may or may not be vesiculated but do not desquamate or result in widespread erosions as seen in SJS/TEN
  • Mucositis may be entirely absent or limited to a single mucosal site and skin findings are more prominent than mucositis
  • Nikolsky sign is negative
Mycoplasma pneumoniae-induced rash and mucositis (MIRM):
  • Secondary to Mycoplasma infection as evidenced by clinical pneumonia, imaging studies, and/or Mycoplasma titers
  • Pronounced oral and ocular mucositis with absent, spare, or mild cutaneous involvement
  • Cutaneous lesions are most often tense and vesiculobullous, with or without target or targetoid lesions
  • Cutaneous lesions do not erode or desquamate as seen in SJS/TEN (Note: erosion is seen in the genital and perianal skin, which are considered akin to mucosal surfaces)
  • Nikolsky sign is negative
These entities all represent a hypersensitivity response presenting with varying degrees of mucositis and skin lesions as a result of infectious or pharmacologic exposure. Given the degree of overlap between these entities, each patient presenting with these findings should be evaluated for each possible diagnosis.

In SJS/TEN, common drug precipitants include sulfonamides, phenytoin, lamotrigine and other anticonvulsants, allopurinol, penicillins, and NSAIDs. Studies have linked certain HLA haplotypes and genetic p450 polymorphisms to increased risk of SJS/TEN when exposed to specific medications. AIDS is associated with a thousandfold increased risk of SJS/TEN.

More commonly in children, infections rather than drugs are pointed out as the main precipitant of SJS/TEN. This contributes in part to the higher rate of SJS/TEN recurrence in children, given that many infections can recur and cannot be as easily avoided as foregoing a particular drug.

All reported cases in infants younger than 6 months have been due to either bacterial sepsis combined with multiple antibiotic regimens or acute graft-versus-host disease (GVHD). In infants and neonates, SJS/TEN is exceedingly rare. Cases were often associated with gram-negative bacteremia and lack confirmatory histopathology. Consideration of more common diagnoses should be carefully evaluated.

SJS/TEN runs an unpredictable clinical course. It is typically preceded by nonspecific prodromal symptoms followed by characteristic skin and mucosal lesions.

Prodromal symptoms include fevers, malaise, arthralgias / myalgias, ocular irritation, upper respiratory tract symptoms, and oropharyngeal pain and may precede skin / mucosal findings by 1-3 days. Importantly, cutaneous pain is a prominent early feature of SJS/TEN, and its presence could signify an ominous sign of impending necrolysis.

Cutaneous lesions may begin as a more typical exanthematous eruption that evolves to dusky, irregular, ill-defined coalescing macules with purpuric or detached centers. Lesions typically appear first on the central trunk, palms, and soles and then spread to involve the face and proximal extremities. As the disease progresses, large areas of serous blistering and sloughing may occur. Skin is typically painful and tender.

Mucosal lesions: Oral mucosal sloughing and crusting are present in more than 90% of cases, and ocular involvement is present in more than 80%. Urogenital and, more rarely, respiratory and gastrointestinal (GI) mucosa may also be involved.

With severe involvement of the eyes, ulceration, scarring, visual impairment, and ultimately blindness may result. An estimated 50%-90% of patients will experience chronic ocular sequelae that may develop as long as 8 years following acute SJS/TEN.

Esophageal, anal, vaginal, and urethral meatal stenosis may be seen. GI bleeding, hepatitis, urinary retention, nephritis, anuria from dehydration and genitourinary injury, myocarditis, pneumothorax, obtundation, and seizures are rare complications. Other involvement includes GI lesions with diarrhea, cystitis, splenic inflammation, arthritis, pneumonitis, otitis media, paronychia, and nail shedding.

Prognosis:
SJS carries a 1%-5% mortality risk, may or may not have systemic symptoms, and involves the trunk and face with many isolated lesions. TEN carries a 25%-35% mortality risk and invariably has systemic symptoms, and the lesions on the trunk and face are largely coalesced. Secondary infection of denuded skin plays a significant role in mortality, as does respiratory compromise from mucositis.

Risk factors that confer a worse prognosis include extent of BSA involved, underlying malignancy, number of medications, leukopenias, and elevated serum urea, glucose, and creatinine levels. SCORTEN is a prognostic scoring system for patients with epidermal necrolysis that contemplates many of the above-mentioned risk factors and several others. While SCORTEN was validated in adults, studies have demonstrated that other pediatric-tailored assessment tools are not superior to SCORTEN in children, which has accurately predicted clinical outcomes.

Rapid identification and withdrawal of the offending drug and transfer to a burn unit with aggressive supportive care are the most critical steps in management. Fortunately, SJS/TEN mortality seems to be lower in children when compared to adults. It is of utmost importance to closely follow, manage, and strive to mitigate the potential long-term ocular and genitourinary complications.

Codes

ICD10CM:
L51.2 – Toxic epidermal necrolysis [Lyell]

SNOMEDCT:
768962006 – Lyell syndrome

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Differential Diagnosis & Pitfalls

  • Stevens-Johnson syndrome (SJS) – Same disease but less severe clinical phenotype.
  • Staphylococcal scalded skin syndrome – Usually occurs in newborns, infants, and young children; mucous membranes are spared. The exfoliated skin is more superficial (subcorneal versus epidermal-dermal). Also look for purulent discharge from the nose. Histologically very different from SJS/TEN. Nikolsky sign can be positive.
  • Erythema multiforme (EM) – Histologic features may not differentiate EM from SJS/TEN. Clinically, however, EM has characteristic target lesions (3 concentric colors that are round and well demarcated) that occur on the extremities more often than the trunk. Precipitating factors are usually infectious (typically HSV) but may include medications. Lesions may be papular or vesicular but do not result in widespread desquamation. Note that EM is not considered within the same disease spectrum as SJS/TEN and confers no risk in progressing to TEN. Nikolsky sign is negative. Other implicated infections include influenza, hepatitis, Epstein-Barr viruses, Yersinia, tuberculosis, histoplasmosis, and coccidioidomycosis.
  • Mycoplasmae pneumoniae-induced rash and mucositis (MIRM) – Mucositis accompanied by no or mild cutaneous involvement, usually of vesicles or tense bullae secondary to Mycoplasma infection. Oral and usually ocular mucositis is pronounced relative to skin findings.
  • Purpura fulminans / disseminated intravascular coagulation (DIC) – Can present with sudden superficial desquamation that may be easily misdiagnosed as SJS/TEN. Look for dusky macules or retiform purpura underlying denuded skin. Areas of retiform purpura and necrosis of the digits or face suggest this diagnosis.
  • Toxic shock syndrome and toxic-shock-like syndrome – Fever > 38.9°C (102ºF), hypotension, diffuse sunburn-like erythroderma (commonly affects palms and soles), and involvement of at least 3 organ systems. Ocular hyperemia and oral mucosal redness may be features. Delayed desquamation of the hands occurs (development of desquamation may be delayed). Severe cases have noted bullae.
  • Acute graft-versus-host disease – Clinically and histopathologically indistinguishable from TEN.
  • Usually secondary to engraftment of maternally transmitted or transfusion-derived T lymphocytes in infants with SCID. Drugs are a more important etiology in infants older than 6 months. Infants may have associated alopecia, diarrhea, splenomegaly, or eosinophilia.
  • Acute generalized exanthematous pustulosis (AGEP) – Look for neutrophilia, eosinophilia, almost confluent erythema with overlying nonfollicular pustules. Nikolsky sign can be positive. Histology will clearly differentiate AGEP from SJS/TEN.
  • Generalized fixed drug eruption – Look for erythematous plaques that develop on the lips, face, distal extremities, and genitalia 1-2 weeks after drug ingestions. Oral mucosa can be involved. Histology will differentiate fixed drug eruptions from SJS/TEN.
  • Chronic bullous dermatosis of childhood (linear IgA bullous dermatosis of childhood) – Look for tense blisters; histology will help differentiate linear IgA from SJS/TEN. Direct immunofluorescence (DIF) will demonstrate linear IgA deposition. DIF is negative in SJS/TEN.
  • Drug hypersensitivity syndrome (DRESS) – Look for facial edema (hallmark of DRESS), eosinophilia, hepatitis, and other viscera.
  • Bullous pemphigoid – Rare in children and presents with tense bullae arising within urticarial plaques. If necessary, immunofluorescence studies help confirm this diagnosis.
  • Pemphigus vulgaris is extremely rare in children and presents with flaccid blisters and erosions. If necessary, immunofluorescence studies help confirm this diagnosis.
  • Paraneoplastic pemphigus is extremely rare in children and presents with extensive, severe mucosal lesions. As in other autoimmune blistering diseases, characteristic immunofluorescence findings help confirm the diagnosis.
  • SJS/TEN-like variant of chikungunya
  • Neonatal candidiasis
  • Keratitis-ichthyosis-deafness (KID) syndrome
  • Exanthematous drug eruption
  • Drug-induced erythroderma
  • Erythrodermic psoriasis
  • Atopic dermatitis with erythroderma
  • Contact dermatitis
  • Erysipelas
  • Necrotizing fasciitis – Rapidly progressing necrosis of fascia and subcutaneous fat.
  • Intrauterine epidermal necrosis
  • Aplasia cutis congenita
  • Dystrophic epidermolysis bullosa
  • Epidermolytic ichthyosis
  • Congenital erosive and vesicular dermatoses

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Therapy

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Drug Reaction Data

Below is a list of drugs with literature evidence indicating an adverse association with this diagnosis. The list is continually updated through ongoing research and new medication approvals. Click on Citations to sort by number of citations or click on Medication to sort the medications alphabetically.

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References

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Last Reviewed: 10/28/2019
Last Updated: 11/26/2019
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Potentially life-threatening emergency
Toxic epidermal necrolysis in Infant/Neonate
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Toxic epidermal necrolysis (Prodrome) : Fever, Eye irritation, Malaise, Sore throat
Clinical image of Toxic epidermal necrolysis
A close-up of denuded erosions, with adjacent peeling and detached necrotic epidermis, secondary to an anticonvulsant.
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