key: cord-0981059-8xlp3lea authors: Arnold, Kathryn A.; Gao, Jingyun; Stein, Sarah L. title: A review of cutaneous hypersensitivity reactions in infants: From common to concerning date: 2019-04-25 journal: Pediatr Dermatol DOI: 10.1111/pde.13827 sha: 440686a87880cc0fa264e91a3f65b3330a11c5cd doc_id: 981059 cord_uid: 8xlp3lea Cutaneous hypersensitivity reactions in infants present in a variety of patterns. These skin eruptions can be dramatic, causing alarm in parents and medical personnel. Many of these syndromes have overlapping features, which adds to the confusion and uncertainty regarding diagnosis and management. This review discusses the spectrum of hypersensitivity responses with a focus on their presentation in infants. The clinical findings, pathophysiology, histopathology, management, and complications of these conditions will be reviewed. The patient was diagnosed with acute hemorrhagic edema of infancy (AHEI) given his clinical presentation and history of associated upper respiratory infection and vaccinations. He was treated with prednisolone 2 mg/kg for 6 days due to his severe presentation. Symptoms had resolved by 2 weeks after initial presentation. Physical examination and laboratory abnormalities normalized at the 1-month follow-up evaluation. Acute hemorrhagic edema of infancy is a rare cutaneous leukocytoclastic vasculitis that presents with purpura, edema, and frequently TA B L E 1 Summary of acute hemorrhagic edema of infancy, Henoch-Schönlein purpura, Kawasaki disease, and Sweet syndrome Henoch-Schönlein purpura (HSP), the most common vasculitis of childhood, appears to be closely related to AHEI. 5 HSP is an immune complex-mediated (type III) hypersensitivity reaction associated with a variety of presumed but unconfirmed precipitants, including group A streptococcus infection. 6 It classically presents with the tetrad of palpable purpura, joint pain, abdominal pain, and TA B L E 2 Summary of acute annular urticaria, serum sickness-like reaction, annular erythema of infancy, and eosinophilic cellulitis glomerulonephritis; the presence of fever is variable. The skin rash may be initially urticarial but rapidly becomes purpuric, preferentially affecting the buttocks and lower extremities ( Figure 2 ). HSP primarily affects children between the ages of 2 and 6 years but has been reported as early as 8 months of age. 7 Systemic manifestations are common and include gastrointestinal symptoms, tender swollen joints, and glomerulonephritis. Less commonly, intussusception may occur, as bowel wall vasculitis can result in a pathologic lead point. 8 Routine histology of HSP lesions demonstrates a leukocytoclastic vasculitis. Direct immunofluorescence frequently highlights IgA deposition in vessel walls and/or glomeruli, but this is not a necessary criterion for diagnosis. Serum IgA levels may be elevated in up to one half of patients. 9 The typical course of HSP is self-limited, resolving within 8 weeks. 6 HSP appears to be milder in infants, with less systemic involvement and excellent prognosis; this group more commonly presents with edema and facial purpura. 7 The goals of management are to minimize symptoms, decrease short-term complications, and prevent chronic renal insufficiency. Multidisciplinary care in conjunction with nephrology and rheumatology is indicated to optimally manage end-organ disease. 6 Acute annular urticaria, serum sickness-like reaction, annular erythema of infancy, and eosinophilic cellulitis are reviewed below. Acute annular urticaria (AAU), also referred to as urticaria multiforme, describes a distinct subtype of acute urticaria noted most commonly in infants and preschool-aged children. This entity can be mistaken for EM based on the dramatically annular configuration of the lesions. AAU is thought to result from an allergic hypersensitivity reaction that may be IgE dependent or independent, in association with infection, medication, or immunization. 20 Serum sickness-like reaction (SSLR) falls within the spectrum of urticaria-like eruptions, and unlike classic serum sickness is not a true vasculitis. 22 An immune complex-mediated (type III) hypersensitivity reaction originally described in the setting of exposure to the cephalosporin cefaclor, SSLR has also been linked to other medications, viral infections, and vaccinations. 23, 24 The eruption is composed of erythematous, annular, edematous plaques similar to that of urticaria, though the plaques generally evolve to a lilac or ecchymotic hue which may persist for days to weeks, giving rise to the term "purple urticaria" (Figure 6 ). These patients also frequently present with acral edema, lymphadenopathy, and arthralgias, often refusing to walk; the presence of fever is also variable. 22 The no- ring. 26 Histopathology reveals a moderate perivascular lymphocytic and eosinophilic infiltrate. 27 Etiology is poorly understood, though one case of AEI associated with intestinal Candida colonization has been reported. 28 Spontaneous resolution of the episodic flares has been observed over 1 to 2 years. 27 AEI can be distinguished from AAU by the longer duration of individual lesions, variable fever, and lack of edema or pruritus. Eosinophilic cellulitis, or Wells syndrome, is characterized by a prodrome of itching or burning followed by an eruption of erythematous, urticarial or cellulitis-like plaques on the trunk and extremities, and rarely face (Figure 7) . 29 The etiology is unconfirmed but may involve a hypersensitivity reaction to infection, medication exposure, vaccination, or arthropod bite, resulting in eosinophil degranulation. 30 The preponderance of cases occurs in adults, but rare cases have been reported in infants. 31 Congenital Wells syndrome has also been described, presenting as subcutaneous nodules shortly after birth with the more classic lesions appearing after several months. 32 Histopathology is characteristic, demonstrating a diffuse dermal eosinophilic infiltrate with the presence of degranulating eosinophils (flame figures). Peripheral eosinophilia may also be present. 31 The acute lesions of Wells syndrome fade over the course of several weeks, often replaced by atrophy and hyperpigmentation. Recurrence is common, but overall prognosis is favorable. Treatment of the precipitating factor may be sufficient, but oral and/or topical corticosteroids may be additionally necessary. 31 Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are the hypersensitivity syndromes with the most severe cutaneous manifestations, existing on a spectrum characterized by extent of epidermal necrosis. 33 These conditions are extremely rare in infants. 34 In this population, SJS is the more common presentation and most often occurs in the setting of antiepileptic medications. 35 Drug-induced hypersensitivity syndrome (DIHS), also known as drug reaction with eosinophilia and systemic symptoms (DRESS), presents as a rash in the setting of fever, eosinophilia, and internal organ involvement. In the infant population, DIHS/DRESS occurs almost exclusively in the context of antiepileptic therapy. 41 Skin findings are characterized by facial edema and a pruritic, diffuse rash of variable morphology including morbilliform, pustular, scarlatiniform, urticarial, targetoid, or full erythroderma; mucosal involvement is typically mild, in contrast to SJS/TEN. 42 The histopathology of DIHS/DRESS is nonspecific. 43 Visceral manifestations appear 2-6 weeks after onset, with hepatitis being the most common, and thyroid dysfunction presenting as a later sequela. 44 In addition to discontinuation of the inciting medication, systemic corticosteroids historically have comprised the mainstay of treatment, but recent work suggests topical steroids may be effective and sufficient in patients with limited disease. 45 Acute generalized exanthematous pustulosis (AGEP) is the eruption of numerous small sterile pustules on a background of diffuse erythema, typically in the setting of fever, and rarely accompanied by systemic symptoms. The pustules resolve with prominent desquamation. 46 Very few cases have been reported in infants and pustular psoriasis should be strongly considered as an alternative diagnosis. AGEP may be precipitated by medications (most commonly antibiotics), infection, or vaccination. 47 Histopathology is characterized by neutrophil exocytosis, pustules, papillary dermal edema, and a neutrophilic and eosinophilic dermal infiltrate. 46 Management consists of removal of the offending drug and supportive care, with resolution in 4-10 days. Topical steroid therapy has also been reported as beneficial in affected infants. 47 This review of cutaneous hypersensitivity reactions as they affect infants illustrates the breadth of conditions and diversity of presentations considered within this category. As there is much overlap in clinical presentation, accurate diagnosis is facilitated by recognizing the similarities and differences between these entities. While many of these conditions are benign and self-limited, others may have serious consequences, and early diagnosis is essential to improving outcomes. Evaluation for an inciting infection should be undertaken when appropriate, given the relatively immunocompromised state of young infants and the likelihood that many of these entities may be triggered by infectious agents. However, the adverse effects of overly aggressive systemic therapy may outweigh more limited potential benefits, and accurate diagnosis will spare unnecessary investigations and treatment. The dermatologist will play a critical role in providing the expertise necessary to recognize these rare syndromes and confirming uncertain diagnoses via skin biopsy when indicated. Further work remains to be done, particularly in the infant population, to better understand pathophysiology and optimize management of these rare conditions. Kathryn A. Arnold https://orcid.org/0000-0003-1276-0130 Cutaneous drug reactions in the pediatric population Acute hemorrhagic edema of infancy: a troubling cutaneous presentation with a self-limiting course Acute hemorrhagic edema of young children (cockade purpura and edema): a case series and systematic review Acute haemorrhagic oedema of infancy, a benign variant of leucocytoclastic vasculitis Acute hemorrhagic edema of infancy (AHEI)-a variant of Henoch-Schönlein purpura or a distinct clinical entity? Clinical practice: diagnosis and management of Henoch-Schönlein purpura The clinical spectrum of Henoch-Schönlein purpura in infants and young children The diagnosis and classification of Henoch-Schönlein purpura: an updated review Henoch-Schonlein purpura Kawasaki disease: part I. Diagnosis, clinical features, and pathogenesis Kawasaki disease at the extremes of the age spectrum Kawasaki disease: part II. Complications and treatment Pediatric sweet syndrome: case report and literature review Are neutrophilic dermatoses autoinflammatory disorders? Sweet's syndrome (acute febrile neutrophilic dermatosis) Paediatric erythema multiforme: epidemiological, clinical and laboratory characteristics Clinical features, diagnosis, and treatment of erythema multiforme: a review for the practicing dermatologist Characteristics of pediatric recurrent erythema multiforme Urticaria multiforme": a case series and review of acute annular urticarial hypersensitivity syndromes in children Urticaria multiforme-a case report Serum sickness-like reaction: histopathology and case report Serum sickness-like reaction in children: a retrospective review -Journal of the American Academy of Dermatology Serum sicknesslike reaction after influenza vaccination Demographic and clinical characteristics of patients with serum sickness-like reaction Annular erythema of infancy Annular erythema of infancy Persistent annular erythema of infancy associated with intestinal Candida colonization Eosinophilic cellulitis in a newborn Eosinophilic cellulitis Bullous "cellulitis" with eosinophilia: case report and review of Wells' syndrome in childhood Congenital Wells syndrome Stevens-Johnson syndrome and toxic epidermal necrolysis: an update Stevens-Johnson syndrome associated with drugs and vaccines in children: a case-control study Recurrence and mortality following severe cutaneous adverse reactions Histopathological and epidemiological characteristics of patients with erythema exudativum multiforme major, Stevens-Johnson syndrome and toxic epidermal necrolysis Toxic epidermal necrolysis: part II. Prognosis, sequelae, diagnosis, differential diagnosis, prevention, and treatment Stevens-Johnson syndrome and toxic epidermal necrolysis in Asian children Morbidity and mortality of mucocutaneous diseases in the pediatric population at a tertiary care center Stevens-Johnson syndrome and toxic epidermal necrolysis: a concise review with a comprehensive summary of therapeutic interventions emphasizing supportive measures Drug-induced hypersensitivity syndrome in pediatric patients Drug reaction with eosinophilia and systemic symptoms (DRESS): an original multisystem adverse drug reaction. Results from the prospective RegiSCAR study Histopathology of the exanthema in DRESS is not specific but may indicate severity of systemic involvement Drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome: clinical features of 27 patients Therapeutic management of DRESS: a retrospective study of 38 cases Acute generalized exanthematous pustulosis: clinical characteristics, etiologic associations, treatments, and outcomes in a series of 28 patients at Mayo Clinic, 1996-2013 Acute generalized exanthematous pustulosis in children A review of cutaneous hypersensitivity reactions in infants: From common to concerning