Atopic Dermatitis (Eczema)

Atopic dermatitis, also known as eczema, is a chronic, relapsing, pruritic, inflammatory skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin disease that occurs more frequently in children, although adults can also be affected. The condition is often associated with elevated serum levels of IgE and a personal or family history of atopy. Skin dryness, erythema, oozing, crusting, and lichenification are present. Pruritus is a cardinal symptom. Diagnosis is established clinically. The mainstays of management are avoidance of triggers, emollients, and topical corticosteroids.

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Overview

Definition

Atopic dermatitis (also known as eczema) is a disorder of altered skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin barrier integrity and immune dysregulation that presents as a chronic relapsing inflammatory skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin disease.

Epidemiology

  • Prevalence:
    • School-aged children: approximately 17%
    • Adults: 2%–10%
  • Atopic triad (present in 30%–50% of patients):
    • Atopic dermatitis
    • Allergic rhinitis Rhinitis Rhinitis refers to inflammation of the nasal mucosa. The condition is classified into allergic, nonallergic, and infectious rhinitis. Allergic rhinitis is due to a type I hypersensitivity reaction. Non-allergic rhinitis is due to increased blood flow to the nasal mucosa. Infectious rhinitis is caused by an upper respiratory tract infection. Rhinitis
    • Asthma Asthma Asthma is a chronic inflammatory respiratory condition characterized by bronchial hyperresponsiveness and airflow obstruction. The disease is believed to result from the complex interaction of host and environmental factors that increase disease predisposition, with inflammation causing symptoms and structural changes. Patients typically present with wheezing, cough, and dyspnea. Asthma
  • 30% of patients develop asthma.
  • Vast majority of cases in children; linked with family history of atopy
  • Most cases occur prior to age 5.
  • Slight female preponderance
  • Previous history of atopy is an important risk factor.
  • Incidence higher in:
    • Urban areas
    • Developed countries

Etiology

  • Multifactorial and not completely understood
  • Genetics Genetics Genetics is the study of genes and their functions and behaviors. Basic Terms of Genetics:
    • Family history of atopy
    • Filaggrin gene mutations (loss-of-function mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations):
      • Strongest known genetic risk factor
      • Keratinocyte barrier dysfunction
      • Increased susceptibility to potential antigens
  • Immune defects: Th2 disease (T helper cells)
  • Prenatal factors: elevated cord blood IgE
  • Infection:
    • Staphylococcus Staphylococcus Staphylococcus is a medically important genera of Gram-positive, aerobic cocci. These bacteria form clusters resembling grapes on culture plates. Staphylococci are ubiquitous for humans, and many strains compose the normal skin flora. Staphylococcus aureus colonization:
      • Often causes flares
      • Acts as a superantigen
    • HSV HSV Herpes simplex virus (HSV) is a double-stranded DNA virus belonging to the family Herpesviridae. Herpes simplex virus commonly causes recurrent infections involving the skin and mucosal surfaces, including the mouth, lips, eyes, and genitals. Herpes Simplex Virus 1 & 2
  • Hygiene hypothesis: Early childhood exposure to microbes and allergens prevents atopy.

Pathophysiology and Clinical Presentation

Pathophysiology

  • Pathogenesis is poorly defined.
  • Characterized by spongiosis (epidermal edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema)
  • Edema leads to breaking of intercellular attachments → vesicle formation
  • Lymphocytic dermal infiltrates are present.
  • Acanthosis and hyperkeratosis may be present.
  •  2 interrelated pathways have been implicated:
    •  Primary epithelial barrier disruption (outside-in hypothesis):
      • Disruption of tight junctions and increased permeability of stratum corneum
      • Increased transepidermal water loss
      • Can be associated with defects in structural proteins (filaggrin is the major one implicated)
      • Barrier disruption can also be caused by microbial colonization and release of inflammatory cytokines.
    • Immune-response defect (inside-out hypothesis):
      • Secondary immunologic dysregulation
      • Defect in toll-like receptors has been implicated in the loss of epidermal innate immunity (colonization with S. aureus leads to severe inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation).
      • IgE–mediated allergic sensitization → increased susceptibility to irritants/allergens secondary to structural epidermal defects
Histological findings atopic dermatitis

Atopic dermatitis:
Histological image of the epidermal layer with a mild lymphohistiocytic and granulocytic infiltrate, predominantly eosinophilic

Image: “Atopic dermatitis, short stature, skeletal malformations, hyperimmunoglobulin E syndrome, hypereosinophilia and recurrent infections” by Leonardi S, Filippelli M, Costanzo V, Rotolo N, La Rosa M. License: CC BY 2.0

Clinical presentation

  • Chronic course with periods of remission and exacerbation
  • Intense pruritus: cardinal symptom
  • Cutaneous hyperreactivity to environmental stimuli
  • Age:
    • Infants and younger children:
      • Papulovesicular lesions
      • Intense pruritis
      • Erythema
      • Edema
      • Excoriations: result of itching
      • Location: face, scalp, extensor surfaces, with sparing of the diaper area
    • Older children and young adults:
      • Chronic lesions with lichenification
      • Flexor surfaces of elbows, knees and sides of the neck, wrists, and ankles
      • Improves with age with remission seen by 13 years of age in approximately 50% of cases
  • Severity:
    • Mild:
      • Areas of dry skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin
      • Pruritus: infrequent
      • Minimal impact on activities, sleep Sleep Sleep is a reversible phase of diminished responsiveness, motor activity, and metabolism. This process is a complex and dynamic phenomenon, occurring in 4-5 cycles a night, and generally divided into non-rapid eye movement (NREM) sleep and REM sleep stages. Physiology of Sleep, and psychosocial well-being
    • Moderate:
      • Areas of dry skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin
      • Pruritus: frequent
      • Redness
      • Localized skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin thickening with or without excoriation
      • Moderate impact on activities and psychosocial well-being
      • Sleep frequently disturbed
    • Severe:
      • Widespread dry skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin
      • Pruritus: incessant
      • Redness
      • Extensive skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin thickening, bleeding, oozing, cracking, and pigmentation alteration
      • Severe impact on activities, psychosocial functioning, and sleep Sleep Sleep is a reversible phase of diminished responsiveness, motor activity, and metabolism. This process is a complex and dynamic phenomenon, occurring in 4-5 cycles a night, and generally divided into non-rapid eye movement (NREM) sleep and REM sleep stages. Physiology of Sleep

Diagnosis

History

  • Pruritus
  • 3 or more of the following (in addition to pruritus):
    • Skin creases involved:
      • Antecubital fossae
      • Popliteal fossae
      • Neck
      • Periorbital areas
      • Ankles anteriorly
    • Asthma Asthma Asthma is a chronic inflammatory respiratory condition characterized by bronchial hyperresponsiveness and airflow obstruction. The disease is believed to result from the complex interaction of host and environmental factors that increase disease predisposition, with inflammation causing symptoms and structural changes. Patients typically present with wheezing, cough, and dyspnea. Asthma or hay fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever history (or 1st-degree relative if child < 4 years of age)
    • Dry skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin in the past year
    • Symptoms beginning prior to age 2 (not used if child is < 4 years old)
    • Dermatitis of flexural surfaces (if child < 4 years old, cheeks, forehead, or outer aspects of extremities)
  • Chronic or relapsing history
  • Environmental stimuli (certain foods, allergens, medications)

Physical exam ( skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin)

  • Young children/infants:
    • Face
    • Scalp
    • Neck
    • Extensor surfaces
    • Papulovesicular lesions
    • Erythema
    • Edema
    • Excoriations
  • Older children and adults:
    • Lichenification
    • Flexor surfaces:
      • Elbows
      • Knees
      • Sides of neck, wrists, ankles
  • Dry skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin

Laboratory studies

  • Only to rule out other skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin conditions
  • Serum IgE: elevated in 80% of patients
  • Skin biopsy
  • Potassium hydroxide preparation of skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin scrapings to rule out Tinea corporis
  • Patch testing to rule out contact dermatitis
  • Genetic testing

Management

Supportive/prophylactic measures

Patient education:

  • Children
  • Parents

Elimination of exacerbating factors:

  • Avoid triggers:
    • Heat
    • Low humidity
    • Excessive bathing (without moisturization)
    • Stress and anxiety
    • Exposure to solvents and detergents
    • Xerosis (dry skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin)
    • Overheating of skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin
    • Harsh detergents
  • Treat associated skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin infections:
    • S. aureus
    • Herpes simplex

Skin hydration (mainstay of treatment to reduce itching and episodes of inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation):

  • Emollients:
    • Apply at least twice a day
    • Immediately after bathing or handwashing
  • Moisturizers containing:
    • Glycyrrhetinic acid
    • Urea
    • Glycerol

Medications/interventions

Topical treatments:

  • Corticosteroids: Prolonged use may cause skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin atrophy or other adverse effects.
  • Calcineurin inhibitors: 2nd-line treatment
  • Phosphodiesterase 4 (PDE4) inhibitors (crisaborole)

Oral antihistamines Antihistamines Antihistamines are drugs that target histamine receptors, particularly H1 and H2 receptors. H1 antagonists are competitive and reversible inhibitors of H1 receptors. First-generation antihistamines cross the blood-brain barrier and can cause sedation. Antihistamines:

  • H1 agents
  • Beneficial when sleep Sleep Sleep is a reversible phase of diminished responsiveness, motor activity, and metabolism. This process is a complex and dynamic phenomenon, occurring in 4-5 cycles a night, and generally divided into non-rapid eye movement (NREM) sleep and REM sleep stages. Physiology of Sleep disturbed by pruritus
  • Diphenhydramine
  • Hydroxyzine
  • Cyproheptadine

Oral immunosuppressants Immunosuppressants Immunosuppressants are a class of drugs widely used in the management of autoimmune conditions and organ transplant rejection. The general effect is dampening of the immune response. Immunosuppressants:

  • Cyclosporin
  • Recurrence common upon discontinuation of treatment

Human monoclonal antibody:

  • Dupilumab
  • Inhibits IL-4 and IL-13

Phototherapy:

  • Used in patients with diffuse pruritus not controlled with topical therapy alone
  • Reduced production of histamine from mast cells and basophils
  • Narrowband ultraviolet B (NBUVB)
  • Ultraviolet A1 (UVA1)

Differential Diagnosis

  • Contact dermatitis: an erythematous, papular dermatitis, often with areas of vesiculation. Occurs due to direct skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin exposure to an offending irritant with a direct cytotoxic effect. Diagnosis is made by history and physical exam findings. Treatment is with avoidance of offending irritants and adoption of protective measures as well as emollients and moisturizers. Topical steroids are the 1st-line intervention.
  • Seborrheic dermatitis Seborrheic dermatitis Seborrheic dermatitis is a common chronic, relapsing skin disorder that presents as erythematous plaques with greasy, yellow scales in susceptible areas (scalp, face, and trunk). Seborrheic dermatitis has a biphasic incidence, occurring in two peaks: first in infants, then in adolescence and early adulthood. Seborrheic Dermatitis: a chronic, relapsing, and usually mild form of dermatitis with a biphasic incidence in infants and adults. The condition is characterized by well-demarcated, erythematous plaques with greasy-appearing, yellow-like scales in sebaceous gland rich areas. The cause is unknown, but sebaceous glands appear to be necessary for the development of the disorder. The diagnosis is made clinically. Treatment is with topical antifungal, anti-inflammatory, and over-the-counter agents.
  • Diaper dermatitis: a form of irritant dermatitis most common in infants and children. Excessive moisture, friction, increased pH, and high enzymatic activity contribute to local disruption of the skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin barrier. The condition is limited to the groin area and often spares folds where urine/feces do not contact the skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin. The diagnosis is made clinically. Treatment involves general skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin care measures (frequent diaper changes, exposure to air, and cleaning), topical steroids, and antifungals (in severe cases of superinfection by Candida Candida Candida is a genus of dimorphic, opportunistic fungi. Candida albicans is part of the normal human flora and is the most common cause of candidiasis. The clinical presentation varies and can include localized mucocutaneous infections (e.g., oropharyngeal, esophageal, intertriginous, and vulvovaginal candidiasis) and invasive disease (e.g., candidemia, intraabdominal abscess, pericarditis, and meningitis). Candida/Candidiasis).
  • Mycosis Mycosis Fungi belong to the eukaryote domain and, like plants, have cell walls and vacuoles, exhibit cytoplasmic streaming, and are immobile. Mycosis is an infection caused by fungi. Mycology: Overview fungoides: a type of cutaneous T cell lymphoma. The disease presents in the skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin but also can involve the lymph nodes, blook, and viscera. Mycosis Mycosis Fungi belong to the eukaryote domain and, like plants, have cell walls and vacuoles, exhibit cytoplasmic streaming, and are immobile. Mycosis is an infection caused by fungi. Mycology: Overview fungoides often involves sites beneath undergarments and is uncommon in children. The disease presents with persistent progressive skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin lesions of varying shapes and sizes and can be localized or widespread plaques or tumors, or generalized erythroderma. Pruritus is common. Diagnosis is clinical along with skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin biopsy with routine histology. Treatment involves topical agents, including steroids, chemotherapy, retinoids, imiquimod, local radiation, and phototherapy. 
  • Psoriasis Psoriasis Psoriasis is a common T-cell-mediated inflammatory skin condition. The etiology is unknown, but is thought to be due to genetic inheritance and environmental triggers. There are 4 major subtypes, with the most common form being chronic plaque psoriasis. Psoriasis: a common chronic inflammatory skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin disorder characterized by erythematous papules and plaques with a silver scale. Psoriasis Psoriasis Psoriasis is a common T-cell-mediated inflammatory skin condition. The etiology is unknown, but is thought to be due to genetic inheritance and environmental triggers. There are 4 major subtypes, with the most common form being chronic plaque psoriasis. Psoriasis is a complex immune-mediated disease whereby T lymphocytes T lymphocytes T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells, cytokines, dendritic cells, and tumor necrosis factor Tumor necrosis factor Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF) play a predominant role. Previously, it was viewed as a disease of hyperproliferation. Diagnosis is made by physical exam. Management is with topical corticosteroids, phototherapy, retinoids, methotrexate, cyclosporin, or biologic immune modifying agents.
  • Scabies Scabies Scabies is an infestation of the skin by the Sarcoptes scabiei mite, which presents most commonly with intense pruritus, characteristic linear burrows, and erythematous papules, particularly in the interdigital folds and the flexor aspects of the wrists. Scabies: a cutaneous infestation caused by the mite Sarcoptes scabiei. Scabies Scabies Scabies is an infestation of the skin by the Sarcoptes scabiei mite, which presents most commonly with intense pruritus, characteristic linear burrows, and erythematous papules, particularly in the interdigital folds and the flexor aspects of the wrists. Scabies is an intensely pruritic eruption with small erythematous papules on the fingers, wrists, axillae, areolae, waist, genitalia, and buttocks areas. Diagnosis is by history and physical exam along with detection of mites, eggs, or fecal pellets under microscopic evaluation. Treatment is aimed at both the patient and close contacts. Topical permethrin and oral ivermectin are the mainstays of therapy.

References

  1. Weston, W., Howe, W. (2021). Atopic dermatitis (eczema): Pathogenesis, clinical manifestations, and diagnosis. In Corona, R. (Ed.). UpToDate. Retrieved March 15, 2021, from https://www.uptodate.com/contents/atopic-dermatitis-eczema-pathogenesis-clinical-manifestations-and-diagnosis
  2. Weston, W., Howe, W. (2021). Treatment of atopic dermatitis (eczema). In Corona, R. (Ed.). UpToDate. Retrieved March 15, 2021, from https://www.uptodate.com/contents/treatment-of-atopic-dermatitis-eczema
  3. Spergel, J., Lio, P. (2021). Management of severe atopic dermatitis (eczema) in children. In Corona, R. (Ed.). UpToDate. Retrieved March 15, 2021, from https://www.uptodate.com/contents/management-of-severe-atopic-dermatitis-eczema-in-children
  4. Kim, B. (2020). Atopic Dermatitis. In James, W. (Ed). Medscape. Retrieved March 15, 2021, from https://reference.medscape.com/article/1049085-overview
  5. Eichenfield, L.F., et al. (2014). Guidelines of care for the management of atopic dermatitis: section 2. Management and treatment of atopic dermatitis with topical therapies. J Am Acad Dermatol. 71(1), 116–132. https://pubmed.ncbi.nlm.nih.gov/24813302/
  6. Weidinger, S., Novak, N. (2016). Atopic dermatitis. Lancet. 387(10023), 1109–1122. https://pubmed.ncbi.nlm.nih.gov/26377142/

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