DynaMed Plus: Atopic dermatitis

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Atopic dermatitis
Overview and Recommendations
Background
Atopic dermatitis is a chronic, relapsing, inflammatory skin disease affecting primarily children.
Genetic, dietary, environmental, and infectious factors promote the condition and may trigger
relapses and exacerbations.
It is associated with asthma, allergic rhinitis, food allergy, and Wiskott-Aldrich syndrome.
Evaluation
Diagnosis is based on history and physical findings. Atopic dermatitis often presents as an itchy,
erythematous rash but with characteristic locations and patterns found in particular age groups:
in infants, atopic dermatitis most often affects the cheeks, chin, scalp, and extensor surfaces
of extremities
in older children and adults, the flexor surfaces, neck, wrists, and ankles may be affected
Testing is not necessary unless the patient is not responding to therapy or there is significant
diagnostic uncertainty.
Management
Avoid food or environmental triggers or irritants if clear clinical reaction after exposure to the
suspected trigger, and positive allergy testing, if available.
Use emollients (moisturizers), including application soon after bathing (Strong recommendation).
Use topical steroids on flaring areas (Strong recommendation).
Use low potency for mild symptoms, and for eczema on face and neck, Consider desonide
(Desonate) 0.05% gel, cream or ointment, or foam; or fluocinolone (generic) 0.01% cream
twice daily.
Use medium potency, such as for moderate to severe symptoms. Consider betamethasone
valerate (Beta-Val) 0.1% cream or lotion; or fluticasone propionate (Cutivate) 0.05% cream
twice daily for moderate atopic dermatitis
In patients with recurrent flares, use topical steroids once or twice weekly at sites of prior
dermatitis, for proactive, maintenance therapy (Strong recommendation).
Use topical calcineurin inhibitors (such as tacrolimus 0.1% or pimecrolimus 1% twice daily) for
(Strong recommendation)
recalcitrance to steroids
sensitive areas (face, anogenital, skin folds)
steroid-induced atrophy
long-term uninterrupted topical steroid use
Consider ultraviolet light therapy or 5-methoxypsoralen plus ultraviolet A (PUVA) after failure of
treatment with emollients, topical steroids, and topical calcineurin inhibitors (Weak
recommendation).
Consider cyclosporine or azathioprine in severe, refractory atopic dermatitis (Weak
recommendation).
Consider dupilumab in severe, refractory atopic dermatitis.
Consider bleach baths and intranasal mupirocin if there are signs of secondary bacterial infection
(Weak recommendation).
Do not recommend dietary exclusions unless confirmed IgE-mediated food allergy (Strong
recommendation).
Related Summaries
Contact dermatitis
General Information
Description
chronic, relapsing, pruritic inflammatory skin disease associated with epidermal barrier defects(1,
2,3, 7)
occurs most commonly in children, but is also seen in about 10% of adults
associated with elevated serum immunoglobulin E levels, allergic rhinitis, and asthma
Also called
atopic eczema
eczema
Epidemiology
Who is most affected
in about 60% of cases, onset occurs in first year of life, commonly at ages 3-6 months(1, 7)
 66% of patients with eczema had onset by age 7 years
based on 870 patients in British community-based study with eczema by age 16 years
Reference - Br J Dermatol 1998 Nov;139(5):834
late-onset atopic dermatitis presents in patients aged ≥ 16 years (G Ital Dermatol Venereol 2016
Aug;151(4):403)
Incidence/Prevalence
10%-20% reported prevalence in developed countries(7)
 1%-22% prevalence of eczema symptoms in children and adolescents worldwide
based on cross-sectional questionnaire survey 2002-2003 of
193,404 children aged 6-7 years from 66 centers in 37 countries
304,679 children aged 13-14 years from 106 centers in 56 countries
prevalence of eczema symptoms in children aged 6-7 years ranged from 2% in Iran to 22.3%
in Sweden
prevalence of eczema symptoms in adolescents aged 13-14 years ranged from 1.4% in China
to 21.8% in Morocco
Reference - Lancet 2006 Aug 26;368(9537):733, correction can be found in Lancet 2007 Sep
29;370(9593):1128
United States incidence/prevalence
estimated prevalence 0.8% in Wisconsin
based on 419 cases identified through electronic medical records with diagnoses of
atopic dermatitis or eczema at least twice 60 days apart in 2000 and 2001
Reference - Ann Intern Med 2003 Jul 1;139(1):1
7.4 million office visits for atopic dermatitis by children < 18 years old in United States
1997-2004
annual pediatric visits for atopic dermatitis increased from 620,000 in 1997 to peak of
1.7 million in 2003 then declined to 850,000 in 2004
Reference - Pediatrics 2007 Sep;120(3):e527
estimated prevalence 10.2% in adults in United States in 2010
based on cross-sectional National Health Interview Survey of 27,157 adults in United
States in 2010
overall 1-year prevalence of
atopic dermatitis was 10.2% (95% CI 9.7%-10.6%)
atopic dermatitis plus asthma and/or hay fever was 3.2% (95% CI 2.8%-3.3%)
atopic dermatitis was significantly higher in older persons, females, Hispanic persons,
birth in United States, higher education level, and persons currently employed (p ≤ 0.02
each)
Reference - J Allergy Clin Immunol 2013 Nov;132(5):1132, editorial can be found in J
Allergy Clin Immunol 2013 Nov;132(5):1139
Western Europe incidence/prevalence
reported incidence in children 16.5 per 1,000 person-years in Netherlands
based on study of 88,307 children seen in 104 Dutch general practices in 2001
Reference - BMC Dermatol 2006 Mar 21;6:4 full-text
prevalence of eczema in children and adolescents in Italy 2002
based on questionnaires completed by parents for 11,287 children aged 6-7 years and
completed by 10,267 adolescents aged 13-14 years
lifetime history of eczema reported in 17% children and 12.8% adolescents
eczema symptoms in past 12 months reported in 14.5% children and 11.2% adolescents
eczema symptoms in flexures in past 12 months reported in 10.4% children and 8.5%
adolescents
Reference - Pediatrics 2006 Jan;117(1):34
 prevalence of atopic dermatitis similar in preterm infants compared to term infants
based on cohort of 512 children followed for 2 years
atopic dermatitis in
18.6% of cohort
19.9% of children born premature
17.9% of children born at term
Reference - Arch Dis Child 2009 Mar;94(3):202
Likely risk factors
family history(1, 7)
about 70% of patients have family history of atopic diseases; odds of developing atopic
dermatitis are
2-3 times higher in children with 1 atopic parent
3-5 times higher in children with 2 atopic parents
maternal history of atopic dermatitis may be associated with higher risk of developing atopic
dermatitis
loss of function mutation in filaggrin (FLG) gene(1, 7)
FLG gene encodes epidermal structural protein
about 10% of persons of European ancestry have 1 null mutation in FLG, and they are
reported to have 3 times higher likelihood of developing atopic dermatitis
FLG null mutations may increase risk of earlier onset and more severe persistent atopic
dermatitis
however, FLG null mutations are absent in many patients with atopic dermatitis, and up to
60% of persons with the mutation do not develop atopic dermatitis
FLG mutation associated with increased risk of allergic sensitization or allergic
disorders
based on systematic review
systematic review of 24 genetic epidemiological studies evaluating association between
filaggrin gene (FLG) mutation and allergic sensitization or allergic disorders
FLG mutation associated with
allergic sensitization
atopic eczema
allergic rhinitis
asthma in people with atopic eczema
no studies investigated association between FLG mutation and food allergy or
anaphylaxis
Reference - BMJ 2009 Jul 9;339:b2433 full-text, editorial can be found in BMJ 2009
Jul 9;339:b1203
 othergenetic risk factors include mutations in genes involved in(7)
epidermal barrier functions, candidate genes include OVOL1, ETS1, ACTL9/ADAMTS10
environmental sensing, candidate genes include CD207, MICB, HLA-DRB1/HLA-DQA1,
CARD11
immune regulation, candidate genes include IL6R, IL18R1/IL18RAP, IL2/IL21, IL7R,
RAD50/IL13, IL15RA/IL2RA, IL22, PPP2R3C, CLEC16A
tissue response, candidate genes include C1orf51/MRPS21, LINC00299, INPP5D, GLB1,
CCD80/CD200R1L, TMEM232, GPSM3, ZBTB10, ZNF365, PRR5L, NLRP10, ZNF652,
LRRC32, RTEL1/TNFRSF6B, CYP24A1
reported environmental risk factors include(7)
"Western diet" - diet consisting of high amounts of sugar and polyunsaturated fatty acids
small family size
household high education level
living in urban settings
living in regions with low exposure to ultraviolet radiation and low humidity
possible triggers of atopic dermatitis in children include(2, 3, 7)
irritants
wool or synthetic clothing
soaps, detergents, disinfectants and topical antimicrobials
chemical reagents
contact allergens
latex
metals
preservatives in topical medications
perfume-based products
dietary factors
cow's milk
eggs
peanuts
tree nuts
wheat
soy
fish, shellfish
rarely others such as sesame, kiwi and legumes
inhalant allergens
house dust mites (Dermatophagoides pteronyssinus and D. farinae), cockroach
tree and grass pollens, molds
animal dander
microbial colonization and or infection
Staphylococcus aureus
Streptococcus species
Candida albicans
Pityrosporum yeasts
herpes simplex
environmental
hard water
cooking with gas, tobacco smoke, exposure to road traffic
climate - extremes of temperature and humidity
concurrent conditions
teething
lack of sleep
psychologic stress
Possible risk factors
 exposure to antibiotics in first year of life associated with increased risk of eczema in patients
≤ 25 years old
based on systematic review of observational studies
systematic review of 20 longitudinal or cross-sectional studies evaluating association between
antenatal or early postnatal (< 1 year old) antibiotic use and development of eczema in
patients ≤ 25 years old
comparing postnatal antibiotic exposure to no postnatal antibiotic exposure in first year of life
postnatal antibiotic exposure associated with increased risk of eczema (odds ratio 1.41,
95% CI 1.3-1.53) in analysis of 17 studies
results showed significant dose-response relationship, with 7% increase in eczema for
each additional antibiotic course
no significant difference in risk of eczema comparing antenatal antibiotic exposure to no
antibiotic exposure in analysis of 4 studies
Reference - Br J Dermatol 2013 Nov;169(5):983
 neonatal jaundice may increase risk of atopic dermatitis
based on prospective cohort
673,614 infants born between 1997-2006 in Denmark were assessed for perinatal risk factors
of atopic dermatitis and followed for 5 years
85,743 children (12.7%) had atopic dermatitis at age ≤ 5 years
atopic dermatitis diagnosed by 1st birthday associated with neonatal jaundice (risk ratio [RR]
1.13, 95% CI 1.06-1.21)
Reference - Pediatr Allergy Immunol 2016 Jun;27(4):368 full-text
 atopic dermatitis in first 6 months of life associated with black or Asian mother (compared to
white mother), male sex, increased gestational age at birth, and maternal history of atopic
disease
based on prospective cohort of 1,005 pregnant women and their offspring in United States
172 (17%) of infants had diagnosis of eczema or atopic dermatitis in first 6 months of life
atopic dermatitis at age ≤ 6 months associated with
black or African-American mother (compared to white or Caucasian mother) (odds
ratio [OR] 2.41, 95% CI 1.47-3.94)
Asian mother (compared to white or Caucasian mother) (OR 2.58, 95% CI 1.27-5.24)
males sex (OR 1.76, 95% CI 1.24-2.51)
gestational age (per week) (OR 1.14, 95% CI 1.02-1.27)
maternal history of any atopic disease (OR 1.99, 95% CI 1.43-2.78)
maternal history of atopic dermatitis (OR 2.67, 95% CI 1.74-4.1)
maternal history of asthma (OR 1.58, 95% CI 1.01-2.47)
Reference - Pediatrics 2004 Mar;113(3):468, commentary can be found in Pediatrics 2004
Oct;114(4):1129
 skin lesions by 18 months may predict atopic dermatitis by age 3 years in high-risk children
based on prospective cohort study
411 neonates born of mothers with history of asthma (48% of mothers also had history of
atopic dermatitis) were enrolled at age 1 month
356 children had complete follow-up data at age 3 years and were analyzed
cumulative incidence of atopic dermatitis was 31% at age 1 year, 41% at age 2 years and 44%
at age 3 years
skin lesions on specific body regions (arm, forearm, wrist, ankle, knee, elbow) by age 18
months associated with highest risks (odds ratio 7.5-11.8) for atopic dermatitis by age 3 years
skin lesions in any of 10 body regions by age 18 months had 90% sensitivity, 50% specificity,
58% positive predictive value and 86% negative predictive value for atopic dermatitis by age
3 years
Reference - Arch Dermatol 2006 May;142(5):561
 atopic dermatitis associated with sensitization to house dust mites, grass pollen, cats, and
peanuts
based on prospective cohort study
1,456 infants born between January 1989 to February 1990 on Isle of Wight were followed
for ≥ 4 years
at age 4 years, 981 children (124 with atopic dermatitis) were assessed with skin prick tests of
12 common allergens
192 children were atopic (positive skin test to ≥ 1 allergens)
atopic dermatitis associated with sensitization to
house dust mite (odds ratio [OR] 1.95, 95% CI 1.04-3.66)
grass pollen (OR 2.92, 95% CI 1.49-5.72)
cats (OR 2.7, 95% CI 1.23-5.92)
peanuts (OR 4.65, 95% CI 1.02-21.34)
atopic dermatitis was nonsignificantly associated with egg sensitization (OR 6.08, 95% CI
0.88-42)
Reference - Pediatrics 2001 Aug;108(2):E33 full-text
 reduced vitamin D status in pregnancy may increase risk of eczema in first year of life in
infants at high risk for atopic disease
based on retrospective cohort study
231 infants at high risk for atopic disease were assessed for allergic outcomes at 12 months,
and by 25-hydroxyvitamin D3 (25[OH]D3) concentration from previously frozen serum cord
blood analyzed
maternal allergic disease reported for 86.1% of infants, with 51.9% of infants having both
parents with history of allergic disease
34.1% of infants had eczema
compared with cord blood 25(OH)D3 concentration ≥ 75 nmol/L (30 ng/mL), cord blood
25(OH)D3 concentration < 50 nmol/L (20 ng/mL) associated with increased risk of eczema
(odds ratio [OR] 2.66, 95% CI 1.24-5.72)
each 10 nmol/L (4 ng/mL) rise in cord blood 25(OH)D3 concentration associated with
decreased risk of eczema (adjusted OR 0.86, 95% CI 0.74-1)
Reference - Pediatrics 2012 Nov;130(5):e1128
 inconsistent evidence that introduction of solid foods before age 4 months may affect risk of
eczema
based on systematic review and cohort study
systematic review of 13 studies, only 1 controlled trial
5 studies found evidence for association between early solid feeding and eczema
4 studies found no association between early solid feeding and eczema
no strong evidence for association between early solid feeding and other allergic
disease
Reference - Arch Pediatr Adolesc Med 2006 May;160(5):502, commentary can be
found in Am Fam Physician 2006 Oct 15;74(8):1428
birth cohort of 5,991 children with 4,753 (79%) 4-year follow-up
no association found between solid food introduction in first year of life and eczema in
first 4 years in children
Reference - J Pediatr 2007 Oct;151(4):352
Factors not associated with increased risk
 standard vaccination schedule does not appear to affect risk of eczema or recurrent wheeze
based on prospective cohort study
2,764 families participated in birth cohort study to age 1 year
no differences in 1-year rates of eczema or recurrent wheeze comparing 77% infantswho had
standard vaccination schedule, 15% who had incomplete vaccination and 7% who were never
vaccinated
Reference - Pediatrics 2007 Feb;119(2):e367
 preterm birth and low birthweight each might be associated with decreased risk of atopic
dermatitis before age 5 years
based on prospective cohort
673,614 infants born between 1997-2006 in Denmark were assessed for perinatal risk factors
of atopic dermatitis and followed for 5 years
85,743 children (12.7%) had atopic dermatitis at age ≤ 5 years
reduced risk of atopic dermatitis associated with
preterm birth (risk ratio [RR] 0.74, 95% CI 0.68-0.81)
low birthweight (≤ 2,499 g) (RR 0.68, 95% CI 0.61-0.75)
Reference - Pediatr Allergy Immunol 2016 Jun;27(4):368 full-text
 Helicobacter pylori colonization associated with decreased risk for atopic eczema
based on epidemiological study of 3,347 school starters in Germany
H. pylori colonization (diagnosed with urea breath test) inversely associated with eczema
(adjusted odds ratio 0.31, p = 0.006) in children not predisposed to atopy
Reference - J Epidemiol Community Health 2007 Jul;61(7):638
 single episode of varicella zoster virus infection at age 0-8 years associated with decreased
risk of developing atopic dermatitis for up to 10 years
based on case-control study with 256 children aged 1-18 years with atopic dermatitis and 422
controls
single episode of varicella zoster virus at age 0-8 years associated with protection up to 10
years of age against atopic dermatitis (odds ratio [OR] 0.56, 95% CI 0.35-0.9), delayed onset
of atopic dermatitis symptoms (p < 0.0001), decreased risk of moderate (OR 0.08, 95% CI
0.04-0.15) or severe (OR 0.04, 95% CI 0.01-0.13) atopic dermatitis and fewer office visits
(OR 0.17, 95% CI 0.06-0.51)
Reference - J Allergy Clin Immunol 2010 Aug;126(2):300
 children with diabetes mellitus type 1 appear to have decreased prevalence of atopic
dermatitis
based on case-control study
920 children aged 3-15 years with insulin-dependent diabetes mellitus compared to 9,732
non-diabetic children
atopic dermatitis in 13.1% with diabetes vs. 19.8% controls (p < 0.0001)
Reference - Lancet 2001 Jun 2;357(9270):1749
Associated conditions
Allergic and respiratory conditions
"atopic march"(1,3, 7)
describes progression of atopic disorders in individuals genetically susceptible to IgE
sensitization to environmental allergens
thought to begin with atopic dermatitis, and progress to asthma , and then allergic rhinitis
allergic conjunctivitis (1, 3, 7)
evidence for association with asthma
eczema in early childhood may be associated with asthma in later childhood
based on systematic review of cohort studies
systematic review of 13 prospective studies including 4 birth cohort studies and 9
eczema cohort studies
in birth cohort studies pooled odds ratio (OR) for risk of asthma after eczema was 2.14
(95% CI 1.67-2.75) compared with children without eczema
in eczema cohort studies prevalence of asthma at age 6 years was 35.8% for inpatients
and 29.5% for combined group of inpatients and outpatients
Reference - J Allergy Clin Immunol 2007 Sep;120(3):565
eczema appears associated with asthma in adults
based on cross-sectional study
27,157 adults in United States were evaluated on 2010 National Health Interview
Survey
overall 1-year prevalence of eczema 10.2% (95% CI 9.7%-10.6%;
overall prevalence of eczema plus asthma and/or hay fever 3.2% (95% CI 2.8%-3.3%)
eczema in adulthood associated with
higher prevalence of asthma (p < 0.001)
more asthma attacks in past year (p < 0.001)
more persistent asthma (p = 0.02)
Reference - J Allergy Clin Immunol 2013 Nov;132(5):1132, editorial can be found in J
Allergy Clin Immunol 2013 Nov;132(5):1139
 acute bronchitis associated with atopic eczema
based on epidemiological study of 3,347 school starters in Germany
bronchitis associated with risk of eczema with adjusted OR 1.98 (p < 0.001)
Reference - J Epidemiol Community Health 2007 Jul;61(7):638 full-text
allergic contact dermatitis
food allergy (1,3, 7)
reported in about 30% of patients with early onset or severe atopic dermatitis
allergies to milk, egg, and wheat usually resolve during childhood, although allergies to nuts
and fish may persist
15.9% infants with mostly mild-to-moderate atopic dermatitis developed ≥ 1 IgE-mediated
food allergy in secondary analysis of randomized trial with 1,091 infants followed for up to 6
years (Pediatrics 2015 Dec;136(6):e1530)
37% children with refractory, moderate-to-severe atopic dermatitis had immunoglobulin E
(IgE)-mediated clinical reactivity to food proteins in series of 63 patients (Pediatrics 1998
Mar;101(3):e8)
increasing prevalence of IgE-mediated food allergy with increasing severity of atopic
dermatitis reported in birth cohort of 620 infants with family history of allergic disease
(Pediatr Allergy Immunol 2004 Oct;15(5):421 in Pediatrics 2005 Aug;116(2 Suppl):546)
among 51 consecutive infants 20-51 weeks old with moderate atopic eczema who were
referred to dermatology department, 44 infants (86%) had IgE food sensitivity by skin prick
test (J Pediatr 2007 Oct;151(4):359)
 atopic dermatitis might be highly prevalent in patients with either Wiskott-Aldrich syndrome
or hyper-IgE recurrent infection syndrome
based on prospective cohort study
128 children aged ≤ 16 years with primary immunodeficiency disorders were assessed for
skin manifestations
24 (19%) of all patients had eczema
all patients with Wiskott-Aldrich syndrome and all patients with hyper-immunoglobulin E
(IgE) recurrent infection syndrome had atopic eczema
Reference - Pediatr Dermatol 2011 Sep-Oct;28(5):494
Behavioral and psychiatric associations
sleep disturbance is very common in patients with atopic dermatitis(1, 7)
typically due to itch, but is reported to also be present in patients in clinical remission
review of sleep disturbances in eczema can be found in Sleep Med Rev 2010 Dec;14(6):359
psychiatric and behavioral disorders(1, 7)
children and adolescents with atopic dermatitis are reported to be have 1.5 times increased
risk for attention-deficit hyperactivity disorder (hypothesized to be partially caused by sleep
disturbance associated with atopic dermatitis)
severely affected children are reported to have increased prevalence of depression, anxiety,
conduct disorder, and autism
adults with atopic dermatitis are reported to have higher rates of depression
atopic eczema associated with increased risk of attention-deficit hyperactivity disorder
based on case-control study of 1,436 patients with atopic eczema (mean age 12.6 years)
and 1,436 matched controls
attention deficit hyperactivity disorder (ADHD) in children in 5.2% with atopic eczema
and 3.4% in controls (p = 0.02)
Reference - JAMA 2009 Feb 18;301(7):724
atopic dermatitis may be associated with increased risk of autism spectrum disorder in
children
based on systematic review of observational studies
systematic review of 18 observational studies (10 cohort and 8 case-control studies)
evaluating association between atopic dermatitis and autism spectrum disorder in
children
1 study also included adults ≤ 26 years old
meta-analyses not performed due to heterogeneity in study design, patient population,
and criteria used for definition of autism spectrum disorder
increased prevalence of autism spectrum disorder associated with
atopic dermatitis and other atopic disorders and comorbidities in 9 of 14 studies
allergic disease in 3 of 3 studies
maternal atopic dermatitis in 2 of 2 studies
Reference - Am J Clin Dermatol 2015 Oct;16(5):371
atopic dermatitis associated with increased risk of several psychiatric and behavioral
disorders in children and adolescents
based on cross-sectional analysis of 92,642 children and adolescents from 2007
National Survey of Children's Health survey
compared to no atopic dermatitis,atopic dermatitis associated with increased risk of
ADHD (adjusted odds ratio [OR] 1.87, 95% CI 1.54-2.27)
depression (adjusted OR 1.81, 95% CI 1.33-2.46)
anxiety (adjusted OR 1.77, 95% CI 1.36-2.29)
conduct disorder (adjusted OR 1.87, 95% CI 1.46-2.39)
autism (adjusted OR 3.04, 95% CI 2.13-4.34)
Reference - J Allergy Clin Immunol 2013 Feb;131(2):428 full-text
atopic dermatitis associated with increased prevalence of anxiety and depression in
adults
based on case-control analysis of cross-sectional data
428 adults (mean age 44 years) reporting atopic dermatitis in past year were compared
to 74,572 adults (mean age 46 years) without atopic dermatitis
all participants were respondents of 2013 National Health and Wellness Survey
(NHWS) in United States
individuals with atopic dermatitis were more likely to be female (64.4%) than controls
(51.8%), p < 0.0001
comparing adults with atopic dermatitis vs. controls in past year
anxiety in 42.5% vs. 21.3% (p < 0.0001)
depression 37.2% vs. 20.9% (p < 0.0001)
nasal allergies 46.4% vs. 19.8% (p < 0.0001)
asthma 22.4% vs. 7.9% (p < 0.0001)
lost work productivity 30% vs. 16.3% (p < 0.0001)
Reference - Curr Med Res Opin 2016 Jun 21 early online
Other associated conditions
other reported associated conditions include(7)
alopecia areata
vitiligo
rheumatoid arthritis
inflammatory bowel disease (see Crohn's disease in adults or children or ulcerative colitis)
cancer is inconsistently associated with atopic dermatitis(1)
atopic dermatitis is reported to decrease risk of glioma, meningioma, and acute lymphoblastic
leukemia(7)
association with cancer with borderline statistical significance
based on 2 cohort studies in Sweden
allergic conditions may be associated with increased risk of hematologic
malignancies
cohort of 16,539 Swedish twins born 1886-1925
self-reported information about allergic conditions collected in 1967
Swedish Cancer Registry followed 1969-1999
eczema during childhood associated with increased relative risk of non-Hodgkin
lymphoma with borderline statistical significance (relative risk 2.3, 95% CI 1-
5.3)
Reference - BMC Public Health 2004 Nov 4;4:51 full-text
hospitalized patients with atopic dermatitis might have subsequent increased risk
of cancer
register-based retrospective cohort of 15,666 hospitalized patients in Sweden
1965-1999 who had discharge diagnosis of atopic dermatitis
after exclusion of first year after discharge, 311 patients developed cancer based
on National Swedish Cancer Register records with standardized incidence ratio
1.13 (95% CI 1.01-1.25)
excess risks (often with borderline statistical significance) reported for cancers of
esophagus, pancreas, brain and lung and for lymphoma
Reference - Arch Dermatol 2005 Sep;141(9):1123
atopic dermatitis may be associated with increased risk of lymphoma
based on systematic review of observational studies
systematic review of 23 observational studies (5 cohort studies and 18 case-control
studies) evaluating association between atopic dermatitis and risk of lymphoma
atopic dermatitis associated with increased risk of lymphoma in analysis of 4 cohort
studies (risk ratio 1.43, 95% CI 1.12-1.82)
no significant association between atopic dermatitis and risk of lymphoma in analysis
of 18 case-control studies, results limited by significant heterogeneity
4 studies (2 cohort studies and 2 case-control studies) evaluated association between
topical atopic dermatitis treatments and risk of lymphoma
high-potency topical corticosteroid treatment associated with increased risk of
lymphoma (odds ratio 1.73, 95% CI 1.52-1.97) in analysis of 2 case-control
studies
no significant difference in risk of lymphoma with low-potency topical
corticosteroids (2 case-control studies) or topical calcineurin inhibitors
tacrolimus (4 studies) or pimecrolimus (4 studies)
Reference - J Am Acad Dermatol 2015 Jun;72(6):992
 atopic dermatitis associated with overweight or obesity in adults and children
based on systematic review of observational studies
systematic review of 30 observational studies evaluating association between atopic
dermatitis and overweight or obesity in 900,358 patients
overweight defined as body mass index (BMI) 25-30 kg/m2 or 85th-95th percentile,
obesity defined as BMI > 30 kg/m2 or > 95th percentile
23 studies included children and 7 studies included adults
overall prevalence of atopic dermatitis 5.1%
compared to normal weight, increased risk of atopic dermatitis associated with
overweight (odds ratio 1.25, 95% CI 1.11-1.41) in analysis of 18 studies
obesity (odds ratio 1.47, 95% CI 1.21 to 1.79) in analysis of 23 studies
consistent findings in adults and children
Reference - J Am Acad Dermatol 2015 Apr;72(4):606
Etiology and Pathogenesis
Causes
cause unknown, but postulated to result from interaction of genetic predisposition and
environmental risk factors(7)
mutations in FLG genes that encode filaggrin, an epidermal structural protein, or other genes
involved in epidermal structure or immune regulation have been associated with atopic
dermatitis
deficient or aberrant immune responses to environmental antigens, both IgE-mediated
(immediate hypersensitivity) and cell-mediated have been associated with atopic dermatitis
interaction of impaired structure and aberrant immune responses create a cycle of
sensitization to potential allergens and irritants, alterations in skin microbiome, inflammation,
and susceptibility to superinfections
Pathogenesis
mutually reinforcing disease mechanisms appear to include both of the following(1, 7)
epidermal barrier abnormalities in structure and function
cutaneous inflammation from inappropriate immune responses to antigens encountered on the
skin
epidermal barrier dysfunction(7)
stratum corneum abnormalities include decreased hydration and increased water loss, altered
lipid composition with reduced ceramide content and chain length, decrease of certain
ceramide classes, abnormal lamellar organization, increased skin pH, abnormal serine
proteases activity, and reduced skin microbiome diversity
possible contributors to barrier abnormalities and dysfunctions
filaggrin deficiency, which may occur due to inherited FLG null mutation or other
factors such as FLG copy number variants, mechanical damage, low humidity, and
cutaneous cytokine imbalance associated with atopic dermatitis
leads to impaired epidermal barrier function through disturbing keratinocyte
differentiation, impairing corneocyte integrity and cohesion, impairing tight-
junction formation, decreasing water retention, acidifying strateum corneum,
altering lipid formation, and enhancing cutaneous infectivity
associated with subclinical inflammation, increased permeability to certain
tracers, reduced inflammatory thresholds, and enhanced percutaneous allergen
priming
other inherited factors in varying combinations with exogenous factors are also thought
to cause atopic dermatitis, including
contributing environmental exposures such as soaps, detergents, exogenous
proteases from mite allergens, and mechanical damage from repetitive scratching
other genetic alterations that may contribute to changes in epidermal barrier
functions, environmental sensing, immune regulation, and tissue response (see
list in Risk Factor section above )
characteristics of cutaneous inflammation(7)
non-lesional skin of patients with atopic dermatitis shows subclinical inflammation with
increased numbers of pro-inflammatory cytokines, T-helper (Th)-2 cells, Th22 cells, Th17
cells, and Th2-cytokine-producing type 2 innate lymphoid cells
infiltrating T cells express various skin-homing adhesion molecules
antigen-primed T cells persist as effector memory cells and exert rapid recall responses
to encountered antigens
reduced microbial diversity in favor of Staphylococcus aureus
progressionto lesional skin associated with increased epidermal thickness with nerve fiber
sprouting, enhanced expression of immunostimulatory chemokines, and noticeable
infiltration; progressive steps include
upregulation of certain terminal differentiation genes (S100A7, S100A8, and S100A9)
while expression of others such as filaggrin remains low
Staphylococcus aureus population further thrives due to deficient epidermal barrier
despite induction of antimicrobial peptides
Staphylococcus aureus-derived proteases and enterotoxins (which act as T-cell-
activating superantigens) contribute to barrier dysfunction and inflammation
Staphylococcus aureus may also cause IgE-mediated sensitization and induce
degranulation of mast cells
Langerhans cells and inflammatory dendritic epidermal cells with specific high-affinity
receptors for IgE, and dermal dendritic cells take up any incidental allergens
IgE binding to these receptors classically causes immediate allergic reactions and
induces delayed type T-cell mediated reactions
local T effector memory cells are activated; Th2 and Th22 responses are amplified
while initial Th1 and Th17 responses are induced, the resultant proinflammatory
mediators further impair epidermal differentiation and integrity as well as activate
keratinocytes to release pro-inflammatory and pruritogenic mediators
characteristics of chronically lesional skin
epidermal hyperplasia progresses and corneocyte composition and adhesion is altered,
while intercellular lipids are reduced
Th2 and Th22 pathways are continuously activated and Th1 and Th17 pathways
become activated leading to further barrier functional impairment, accelerated local
inflammation, and promotion of cutaneous remodeling and neuroinflammation
History and Physical
History
Chief concern (CC)
chief concerns typically include(1, 7)
intense pruritus
erythema
xerosis and abnormally thick skin
excoriations (due to scratching)
History of present illness (HPI)
onset reported to occur by age 1 year in 60% of patients, but may start at any age, including into
adulthood(1, 7)
eczematous lesions usually do not present before age 2 months; early signs are skin dryness and
roughness(7)
disease course may be either(7)
continuous for long periods
consist of relapses and remissions with repeated flare-ups
ask patients and/or parents about(2, 7)
time of onset, pattern and severity of lesions
response to previous treatments
possible trigger factors such as allergies or irritants including components of emollients such
as preservatives, fragrances, emulsifiers, or antiseptics
dietary history, reactions and previous food manipulations
growth and development
ask about associated conditions, including(1, 3, 7)
allergic conjunctivitis
allergic rhinitis
asthma
food allergies, which are reported in about 30% of patients with early and severe atopic
dermatitis
foods that cause most significant allergic reactions are milk, eggs, wheat, soy, peanut,
tree nuts, shellfish, fish, and seeds (J Allergy Clin Immunol 2014 Nov;134(5):1016)
allergies to milk, egg, and wheat typically resolve during childhood
allergies to nuts and fish often persist
allergic contact dermatitis
depression or other psychiatric disorders
sleep disturbance
Family history (FH)
about 70% of patients have family history of atopic diseases(7)
ask about history of atopic disorders(1, 3, 7)
atopic dermatitis
asthma
allergic rhinitis
allergic conjunctivitis
Social history (SH)
ask patients and/or parents about impact on quality of life and psychosocial well-being, including
disturbed sleep (AAD Strength of Recommendation C, Level III)(1, 2)
 sleep disturbance due to pruritus appears common in young children
based on survey of parents of 300 children < 6 years old with atopic dermatitis
> 60% parents reported that dermatitis affected how they or their child slept
30% reported co-sleeping due to skin condition, 66% of parents bothered by co-
sleeping
sleep disturbance and co-sleeping associated with
severity of atopic dermatitis
child and family's happiness
Reference - Arch Pediatr Adolesc Med 2005 Aug;159(8):745
Physical
Skin
earliest skin signs in infants may include(7)
dryness
roughness
skin signs may vary(1, 7)
acute lesions typically appear as diffuse erythematous patches and plaques, papules, vesicles,
oozing, crusting
subacute lesions may appear as red, dry, and scaly skin
chronic lesions are typically poorly demarcated and appear as scaly patches or plaques with
excoriation and lichenification
Typical Age-related Morphology and Distribution of Atopic Dermatitis:
Age Morphology Distribution Patterns
Infants Diffuse erythematous patchesand oozing papulovesicles
Usually face and extensor
surface of limbs; may also
occur on trunk but “napkin”
area typically unaffected
Children aged 1-2 Years and
up
Polymorphous manifestations
and varying types of skin
lesions
Usually on flexural folds
including neck or knees
Adolescents and adults Typically lichenified andexcoriated plaques
Usually at flexures, wrists,
ankles, and eyelids. If head
and neck type, the upper
trunk, shoulders, and scalp
may be involved.
Other adult presentations
Adults may present with
Chronic hand-only
eczema
Pruigo-like lesions
N/A
Abbreviations: N/A, not applicable.
Reference - Lancet 2016 Mar 12;387(10023):1109
other signs may include
edema
erosions
hyperlinearity of palms or soles
morphological variants(7)
follicular type - densely aggregated follicular papules; frequently occurs in dark-skinned and
Japanese patients
prurigo type - erythematous, often excoriated papules and indurated nodules; sometimes seen
in patients with longstanding disease
nonspecific skin signs may include(3, 7)
ichthyosis (large scales)
keratosis pilaris (plugging of pores)
pityriasis alba (white lesions)
signs of atypical vascular response such as
white dermatographism
delayed blanch response
perifollicular accentuation ("goose skin")
rarely, lesions can generalize into secondary erythroderma(7)
Atopic dermatitis: Atopic dermatitis; marked dryness and lichenification, producing aged
appearance.
Atopic dermatitis: Atopic dermatitis; lichenification.
Atopic dermatitis: Atopic dermatitis; severe lichenification and excoriation.
 look for signs of secondary bacterial infection such as weeping, pustules, crusts, and
impetiginization of lesions(2)
other superinfections include(7)
eczema herpeticum manifests as monomorphic eruption of umbilicated and punch-out
vesicles
molluscum contagiosum infection, which typically occurs in flexural areas and consists of
flesh-colored hemispheric and slightly umbilicated papules sized 2-3mm; lesions may also
occur on non-inflamed skin and can spread by autoinoculation
eczema coxsackium, an atypical manifestation of hand-foot-and-mouth disease in children
with atopic dermatitis with a presentation that mimics herpes infection with monomorphic
eruption of umbilicated and punch-out vesicles (Curr Opin Pediatr 2015 Aug;27(4):486)
case report of eczema coxsackium in 10-month-old boy can be found in Arch Dis Child 2015
Apr;100(4):363
HEENT
facial pallor may be present, but is nonspecific(7)
ocular and periocular findings(3, 7)
common findings include Dennie-Morgan folds (prominent folds of skin under lower eyelid)
(7)
Atopic dermatitis: Atopic dermatitis; marked dry facial involvement, suggestive of dust mite
allergy.
atopic dermatitis may be complicated by cataracts, and has been reported present in up to
10% of juvenile patients
keratoconus (Lancet. 2003 Jan 11;361(9352):151-60.)
Herthoge’s sign - thinning or absence of lateral portion of eyebrows
rarely, upper lip cheilitis(1)
look for signs of allergic rhinitis
nasal findings of pale or bluish boggy nasal mucosa (edematous turbinates covered withthin
clear secretion), nasal airway obstruction, transverse nasal crease ("allergic crease")
pharyngeal findings of postnasal mucous discharge, cobblestoning (lymphoid hypertrophy of
posterior pharynx)
Atopic dermatitis: Atopic dermatitis; facial involvement.
Atopic dermatitis: Atopic dermatitis; early facial involvement.
Atopic dermatitis: Atopic dermatitis; facial involvement.
Diagnosis
Making the diagnosis
diagnosis is made clinically based on history and physical(1, 7)
several published criteria exist to aid clinical diagnosis
American Academy of Dermatology (AAD) 2014 guidelines advise the following criteria to
diagnose atopic dermatitis in infants, children and adults (AAD Strength of Recommendation C,
Level III)(1, 7)
pruritus AND eczema must both be present
eczema is characterized by typical morphology and age-specific patterns
in infants and children may involve facial, neck, and extensor
in any age group current or previous flexural lesions may present
groin and axillary regions usually not affected
eczema is chronic or relapsing
supporting signs and symptoms for diagnosis of atopic dermatitis include
early onset
atopy, suggested by personal or family history or immunoglobin E (IgE) reactivity
xerosis (dry skin)
nonspecific features that may aid diagnosis include
atypical vascular responses (facial pallor, white dermographism, delayed blanch
response)
keratosis pilaris, pityriasis alba, hyperlinear palms, or ichthyosis
ocular or periorbital changes
perioral changes or periauricular lesions
perifollicular accentuation, lichenification, or prurigo lesions
National Institute for Health and Clinical Excellence (NICE) recommendations for diagnosis of
atopic eczema in children are based largely on United Kingdom diagnostic criteria and include the
following(2)
diagnose atopic eczema if itchy skin condition plus ≥ 3 of
visible flexural dermatitis involving skin creases, such as elbows or knees (or visible
dermatitis on cheeks and/or extensor areas in children ≤ 18 months old)
personal history of flexural dermatitis (or dermatitis on cheeks and/or extensor areas in
children ≤ 18 months old)
personal history of dry skin in last 12 months
personal history of asthma or allergic rhinitis (or history of atopic disease in first-degree
relative of children ≤ 4 years old)
onset of signs and symptoms before age 2 years (this criterion should not be used in
children < 4 years old)
variations in Asian, black Caribbean and black African children
may have atopic eczema on extensor surfaces rather than flexural surfaces
discoid or follicular lesions may be more common
Japanese Dermatological Association diagnostic criteria for infants, children, and adults include(3)
presence of pruritus
chronic or chronically relapsing course, without consideration of severity, which chronicity
defined as
> 2 months in infancy
> 6 months in childhood, adolescence, and adulthood
often presence of old and new lesions simultaneously
typical morphology and distribution described as
eczematous dermatitis
acute lesions - erythema, exudation, papules, vesiculopapular, scales, and crusts
chronic lesions - infiltrated erythema, lichenification, prurigo, scales, and crusts
symmetrical distribution
commonly located on - forehead, periorbital area, lips, periauricular area, neck,
joint areas of limbs and trunk
age-related features
infants - starts on scalp and face, frequently spreads to trunk and
extremities
children - neck, flexural surfaces of arms and legs
adolescents and adults - tendency to be severe on upper half of body (face,
neck, anterior chest and back)
cases that do not fulfill all 3 criteria should be evaluated on basis of age and clinical course
with tentative diagnosis of acute or chronic, nonspecific eczema
Severity scoring
several methods for rating severity of atopic dermatitis exist, including
SCORing Atopic Dermatitis (SCORAD) index (Dermatology 1993;186(1):23)
eczema area and severity index (EASI) (Exp Dermatol 2001 Feb;10(1):11)
patient-oriented eczema measure (POEM) (Arch Dermatol 2004 Dec;140(12):1513)
six area, six sign atopic dermatitis (SASSAD) severity score (Br J Dermatol 1996 Sep;135
Suppl 48:25)
three item severity score (TISS) (Acta Derm Venereol 1999 Sep;79(5):356)
American Academy of Dermatology (AAD) 2014 guidelines recommend(1)
for routine clinical practice, disease severity measurement scales not needed
ask patients about symptoms, including itch, sleep, and impact on daily activitives
consider using severity management scale if practical
SCORAD
commonly used in clinical studies, and includes assessment of
extent of skin area involved
presence and intensity of redness, swelling, oozing/crusting, excoriations, skin
thickening (lichenification), and xerosis
presence and intensity of patient's symptoms of itch and sleeplessness
scored 1-100
SCORAD < 25, corresponds to mild atopic dermatitis
SCORAD 25-50 corresponds to moderate atopic dermatitis
SCORAD > 50 corresponds to severe atopic dermatitis
Reference - Dent Update 1989 Sep;16(7):279 and DermNet New Zealand 2016
Differential diagnosis
consider other common dermatoses(3, 7)
seborrheic dermatitis in infants or seborrheic dermatitis in children and adults
in infants, presents as pink-red greasy scaly lesions on scalp ("cradle cap") and napkin
area; usually seen in first 6 weeks of life and resolves within weeks
in adults, presents as erythematous patches with yellow, white, or grayish scales on
scalp, central face, and/or anterior chest
nummular eczema - common in children and adults; typically presents without itch and as
coin-shaped scaly patches usually on legs and buttocks
contact dermatitis may exist with atopic dermatitis and is common in children and adults
irritant contact dermatitis presents after local exposure to irritants with acute to chronic
eczematous lesions usually confined to exposure site
allergen contact dermatitis presents after local exposure to irritants with eczematous
rash at sites of exposure but may spread
asteatotic eczema in adults - common; presents most often on lower legs and as scaly, fissured
patches overlying dry skin
rule out infectious skin diseases(7)
dermatophyte infection children and adults (such as tinea corporis) is common, and typically
presents with itchy demarcated scaly patch or patches with central clearing and slightly raised
reddened edge
impetigo in children is common, and presents as demarcated erythematous patches with
blisters or honey-yellow crusting
scabies in children is common particularly in developing countries, and presents as itchy
superficial burrows and pustules on palms, soles, between fingers, and on genitalia, and may
cause secondary eczematous skin changes
consider rare congenital immunodeficiencies in infants(7)
Hyper-IgE syndrome, presents as pustular and eczematous rash in first weeks of life and may
include staphylococcal infections of skin, sinuses, and lungs
Wiskott-Aldrich syndrome in boys, presents with microthrombocytopenia and rash identical
to atopic dermatitis in first weeks of life
Omenn syndrome (complication of severe combined immunodeficiency (SCID) and vary
rare), presents with early-onset erythroderma, diffuse scaly rash, and chronic diarrhea
less common skin disorders to consider include(7)
lichen simplex chronicus in adults, presents as ≥ 1 localized circumscribed lichenified plaques
caused by repetitive scratching or rubbing due to itch
ichthyosis vulgaris in infants and adults , may coexist with atopic dermatitis and presents as
dry skin with fine scaling usually on lower abdomen and extensor areas, perifollicular skin
roughening, and palmar hyperlinearity
Netherton syndrome in infants and adults is very rare, and presents with eczematous lesions
in serpiginous linear pattern with double-edges andscales and hair shaft anomalies such as
"bamboo hair"
consider nutritional deficiencies
zinc deficiency in children is uncommon, but presents with erythematous scaly patches
usually around mouth and anus, rarely accompanied by diarrhea and alopecia(7)
pyridoxine deficiency can be associated with seborrheic dermatitis in infants
niacin intake associated with pruritus and flushing
phenylketonuria (PKU) (Br J Dermatol 2002 Sep;147(3):426)
multiple carboxylase deficiency (Lancet 2003 Jan 11;361(9352):151)
consider neoplastic disease
cutaneous T-cell lymphoma in adults is uncommon, but presents with variable itch in early
stages, and erythematous pink-brown macules and plaques with fine scaling that does not
respond well to topical steroids(7)
Letterer-Siwe disease (Lancet 2003 Jan 11;361(9352):151)
other differential diagnoses may include
juvenile spring eruption (Br J Dermatol 2013 May;168(5):1066)
psoriasis
dermatomyositis (see Idiopathic inflammatory myopathy)
immediate-type hypersensitivity reactions such as urticaria
dermatitis herpetiformis
graft versus host disease (GVHD) (Lancet 2003 Jan 11;361(9352):151)
DiGeorge syndrome
systemic lupus erythematosus (SLE)(3)
systemic disease resulting in pruritus include
primary biliary cirrhosis
polycythemia vera
Hodgkin lymphoma (HL)
hyperthyroidism
hepatobiliary obstruction
uremia (see Acute renal failure, Chronic kidney disease (CKD) in adults)
paraneoplastic acrokeratosis in case report (Am Fam Physician 2008 Jul 15;78(2):257)
Testing overview
testing is unnecessary to diagnose atopic dermatitis, and there are no specific biomarkers for
detection(1, 2, 7)
consider tests to rule out other skin conditions if suspected by clinical history and risk factors, such
as(1)
potassium hydroxide (KOH) preparation to rule out tinea capitis or tinea corporis
biopsy to rule out psoriasis
skin patch testing to rule out allergic contact dermatitis
IgE serum level testing not needed for diagnosis or monitoring of disease severity
in patients with adult-onset or erythrodermic dermatitis with poor response to topical treatment,
conduct skin biopsy to rule out cutaneous T-cell lymphoma(7)
consider testing for allergies if clinical history of suspicious reaction after exposure to suspected
allergy, or persistent atopic dermatitis despite optimal treatment
consider assessment for associated conditions if suspected based on clinical history and exam, such
as(1, 6)
rhinitis/rhinoconjunctivitis
asthma
sleep disturbance
depression
consider bacterial and viral cultures if superinfections with microorganisms other than
Staphylococcus aureus are clinically suspected, or if bacterial superinfection with possible antibiotic
resistance suspected(2)
Blood tests
American Academy of Dermatology (AAD) 2014 guidelines do not recommend any specific
biomarkers for diagnosis or severity assessment of atopic dermatitis (AAD Strength of
Recommendation B, Level II)(1)
total and/or allergen-specific serum immunoglobulin E (IgE) levels reported to be elevated in about
80% of patients, but significance of elevations debated(1)
elevated total IgE levels(1)
total IgE levels may vary with disease severity in some patients with atopic dermatitis, but do
not appear to be reliable markers, and routine measurements are not recommended by
American Academy of Dermatology
some patients with severe disease show no elevation
IgE may be elevated in non-atopic conditions such as parasitic infection, certain
cancers, and autoimmune diseases
American Academy of Dermatology (AAD) 2014 guidelines recommend against monitoring
immunoglobin E (IgE) levels due to lack of specificity for atopic dermatitis (AAD Strength of
Recommendation A, Level I)(1)
serum-specific immunoglobulin E (IgE) for food allergens
in vitro testing for specific food allergies include common methods such as
radioallergosorbent (RAST) testing or ImmunoCAP testing(6)
American Academy of Dermatology recommends against using skin prick tests or blood tests
such as the radioallergosorbent test (RAST) for the routine evaluation of eczema (Choosing
Wisely 2015 Aug 19)
about 67% of infants with moderate to severe disease are reported to be sensitized to food
allergens in first 2 years of life, but only some show IgE-mediated food allergies with
immediate non-eczematous skin reactions(7)
diagnostic accuracy of specific IgE for identifying allergies is uncertain with ranges for
sensitivity of 20%-100% and 6%-93% for specificity(2)
consider food allergy testing for cow's milk, eggs, wheat, soy, and peanuts if child is < 5 years
old, has moderate to severe atopic dermatitis, and either (AAD Strength of Recommendation
B, Level II)(6)
persistent disease despite optimized management and topical therapy
history of allergic reaction immediately after ingestion of specific food
negative testing can help rule out allergy, but positive testing should be correlated with
clinical symptoms
review of in vitro allergen-specific IgE (sIgE) testing in childhood can be found in Pediatrics 2012
Jan;129(1):193
Biopsy and pathology
skin biopsy findings may show
clinically unaffected skin of patients with atopic dermatitis shows sparse perivascular T-cell
infiltrates
acute eczematous skin lesions characterized by
epidermal intercellular edema (spongiosis)
antigen-presenting cells (for example, Langerhans cells, inflammatory dendritic
epidermal cells, macrophages) have immunoglobulin E (IgE) molecules in lesional skin
(may also occur to lesser extent in skin without lesions)
infiltration of CD4 activated T-cells within dermis
chronic lichenified lesions characterized by
acanthotic epidermis with elongation of rete ridges
parakeratosis
minimal spongiosis
increased number of IgE-bearing Langerhans cells and inflammatory dendritic
epidermal cells
macrophages dominate mononuclear dermal cell infiltrate
eosinophilia
Reference - Lancet. 2003 Jan 11;361(9352):151-60.
Other diagnostic testing
Diagnostic criteria
United Kingdom diagnostic criteria requires itchy skin condition (or parental report of scratching or
rubbing in a child) plus ≥ 3 of
visible dermatitis of flexural areas (or cheeks, forehead and/or outer limbs in children < 4
years old)
history of involvement of skin creases such as elbows, knees, ankles or around neck
(including cheeks in children < 10 years old)
history of dry skin within last 12 months
history of asthma or allergic rhinitis (or history of atopic disease in first-degree relative in
child ≤ 4 years old)
onset before age ≤ 2 years (not used if child ≤ 4 years old at presentation)
Reference - Br J Dermatol 1994 Sep;131(3):406
 United Kingdom diagnostic criteria is most studied criteria for diagnosis of atopic dermatitis
based on systematic review of 15 case-control and 11 cross-sectional validation studies
evaluating diagnostic criteria for atopic dermatitis
United Kingdom criteria evaluated in 19 studies; various reference standards used, but 15
studies included clinical diagnosis as reference standard
Hanifin and Rajka diagnostic criteria (3 major and 3 minor of 27 criteria) evaluated in 2
studies with clinical diagnosis as reference standard
Schulz-Larsen criteria (≥ 50 points with 6 criteria) evaluated in 2 studies with Hanifin and
Rajka criteria and clinical diagnosis as reference standard in 1 study each
Diepgen criteria (≥ 10 points with 8 criteria) evaluated in 1 study with clinical diagnosis as
reference standard
Kang and Tian criteria (1 basic and 3 minor of 5 criteria) evaluated in 1 study with Hanifin
and Rajka criteria as reference standard
International Study of Asthma and Allergy in Childhood questionnaire (ISAAC score ≥ 3
with 7 criteria) evaluated in 1 study with clinical diagnosis as reference standard
no studies found validating Millennium criteria, Danish Allergy Research Centre criteria,
Lillehammercriteria, or Japanese Dermatology Association criteria
Hospital-Based Validation Studies of Diagnostic Criteria for Atopic Dermatitis:
Diagnostic
Criteria
Number of
Studies Sensitivity Specificity PPV NPV
United
Kingdom 8 10%-95.5% 90.4%-98.3%
28.6%*-
97.8% 76.7%-96.7%
Hanifin and
Rajka 2 93.1%-96% 77.6%-93.8% 83.1%*-97% 90.5%*-91.8%
Schulz and
Larsen 2 88%-94.4% 77.6%-95.9% 60.7%-88.9% 95.9%-97.4%
Diepgen 1 83%- 87.7% 83.9%-87% NA NA
Kang and Tian 1 95.5% 100% 100% 96%
Abbreviations: NA, not available; NPV, negative predictive value; PPV, positive predictive
value.
* Number calculated, total results of whole group described.
Population-Based Validation Studies of Diagnostic Criteria for Atopic Dermatitis:
Diagnostic
Criteria
Number of
Studies Sensitivity Specificity PPV NPV
United
Kingdom 12 42.8%*-100%* 89.3%-99.1% 18.4%**-96.6%*** 89.3%*-100%*
Schultz and
Larsen 1 88% 89% NA NA
ISAAC 1 NA NA 48.8% 91.1%
Abbreviations: NA, not available; NPV, negative predictive value; PPV, positive predictive
value.
* Number calculated.
** Adjusted for 1 year period prevalence.
*** Based on lifetime prevalence.
Reference - Br J Dermatol 2008 Apr;158(4):754
 Reliable Estimation of Atopic dermatitis of ChildHood (REACH) criteria help rule out atopic
dermatitis in children and outperforms ISAAC (level 1 [likely reliable] evidence)
based on diagnostic cohort study with independent derivation and validation cohorts
derivation cohort of 1,129 children from 2 elementary schools and 3 preschools responded to
parental-report REACH questionnaire, International Study for Asthma and Allergies in
Childhood (ISAAC), and were assessed at 1 year for prevalence of atopic dermatitis
validation cohort was 1,191 children (aged 4-12 years) from 2 elementary schools and 3
preschools
prevalence of atopic dermatitis at 1 year was 13.5% in derivation cohort and 11.8% in
validation cohort by reference standard of 2 dermatologists' exams
REACH questionnaire was based on 2 major criteria questions and 9 minor criteria questions
with best sensitivity and specificity and highest Youden index (sensitivity + specificity - 1)
2 major criteria were "recurrent skin rash in last year" and "itchy rash on
antecubital/popliteal fossae"
9 minor criteria questions involved 1 question for familial atopy history, 6 for localized
eczema, and 2 for environmental factors ("unusually dry skin" and "itchy while
sweating")
atopic dermatitis with eczema on antecubital or popliteal fossae diagnosed if 2 major
criteria positive
for atopic dermatitis without eczema on antecubital or popliteal fossae diagnosed if 1
major criteria and ≥ 4 minor criteria positive
in validation cohort REACH detected prevalence of 12.3% atopic dermatitis with
sensitivity 75.2%
specificity 96%
positive predictive value 72.1% and negative predictive value 96.6%
in validation cohort ISAAC questionnaire detected prevalence of 14.4% with
sensitivity 68.8%
specificity 92.9%
positive predictive value 56.4% and negative predictive value 95.7%
Reference - Allergy Asthma Immunol Res 2016 May;8(3):230 full-text
Assessment of allergies
American Academy of Dermatology (AAD) 2014 recommendations for allergen testing for patients
with atopic dermatitis(6)
physicians should assess for environmental and food allergies during history taking as
patients with atopic dermatitis have increased risk of these allergies (AAD Strength of
Recommendation B, Level II)
if significant concerns for allergy are identified during history taking (such as hives or
urticaria), allergy assessment can be completed (AAD Strength of Recommendation B, Level
II)
allergy testing independent of history of reaction after consumption of food or exposure to
environmental allergen is not recommended
American Academy of Dermatology recommends against using skin prick tests or blood tests
such as the radioallergosorbent test (RAST) for the routine evaluation of eczema (Choosing
Wisely 2015 Aug 19)
consider food allergy testing for cow's milk, eggs, wheat, soy, and peanuts if child is < 5 years
old, has moderate to severe atopic dermatitis, and either (AAD Strength of Recommendation
B, Level II)
persistent disease despite optimized management and topical therapy
history of allergic reaction immediately after ingestion of specific food
for food allergy testing
consider skin prick testing or serum-specific IgE in vitro testing
if severe or extensive dermatitis, dermatographism, or antihistamine use, serum-specific
IgE testing preferred
negative tests help rule out food allergy
positive tests must be correlated to clinical history
atopy patch testing
measures type IV hypersensitivity
involves application of suspected allergens to unaffected skin, usually the
patient's back, for 48-72 hours with evaluation of reaction at time of patch
removal and again up to 7 days later
not used in United States for food allergy testing, but more commonly used in
Europe
food challenge may be needed to confirm results
consider aeroallergens(2, 6)
most commonly associated aeroallergens include house dust mites, pollens, animal
dander, and fungi
reactivity to aeroallergens increases as age
inhalation of aeroallergen or cutaneous exposure may aggravate atopic dermatitis
diagnosis of allergic reaction supported by findings of
seasonal flares of atopic dermatitis
asthma or allergic rhinitis
dermatitis mainly affects exposed surfaces of face (especially around eyes), neck,
arms, legs, and ‘‘V’’ area of the chest
for diagnosis, consider skin prick testing or serum-specific IgE in vitro testing
atopy patch test using aeroallergens reported to be positive in 30%-50% of patients
with atopic dermatitis and usually negative in healthy volunteers or patients with
respiratory allergy only, but clinical utility with airborne allergens is uncertain
consider diagnosis of allergic contact dermatitis if(2, 6)
exacerbation of previously controlled atopic eczema
reactions to topical treatments
persistent/recalcitrant disease
history or physical exam findings consistent with allergic contact dermatitis
for allergic contact dermatitis, consider atopy patch testing for evaluation
 electrodermal testing (Vegatest) does not appear effective for diagnosing allergies in atopic
dermatitis (level 2 [mid-level] evidence)
based on small diagnostic cohort study
15 atopic patients with positive skin prick tests and 15 non-atopic volunteers had
electrodermal testing with blinded and randomly allocated samples containing house dust
mite extract, cat dander or distilled water (54 tests completed per patient)
Vegatest results were not significantly different between atopic and non-atopic groups
Reference - BMJ 2001 Jan 20;322(7279):131 full-text
Treatment
Treatment overview
use a stepwise approach to improve symptoms and achieve long-term disease control based on
disease severity(7)
assess disease severity by extent of skin involvement, presence of active lesions and
lichenification, and severity of patient symptoms of itch and sleeplessness
provide structured education regarding disease course and treatments to patients and, if
patients are children, their parents or guardians
for all patients (step 1)
advise emollients (moisturizers) as a mainstay of treatment to enhance continuous repair of
epidermal barrier (AAD Strength of Recommendation A, Level I; JDA Grade A, Level II)
apply moisturizers soon after bathing to improve skin hydration (AAD Strength of
Recommendation B, Level II)
replace soaps, bubble baths, and shower gels with non-soap fragrance-free cleaners
with neutral to low pH helps prevent irritant or allergic reactions
assess for environmental and food allergies if suspected and advise avoidance of triggers or
irritants if clear clinical reaction after exposure, and positive allergy testing if available for
specific trigger(7)
foodavoidance is recommended in patients with true immunoglobulin E-mediated
allergy (AAD Strength of Recommendation A, Level I)
allergen-specific immunotherapy may be associated with improved symptoms in
patients with atopic dermatitis and allergy to house dust mite (level 2 [mid-level]
evidence)
use topical steroids on flaring areas as first-line treatment (AAD Strength of Recommendation
A, Level I)
select potency of topical steroid based on severity and location of atopic dermatitis
use low potency, such as desonide (Desonate) 0.05% gel, cream or ointment, or foam;
or fluocinolone (generic) 0.01% cream twice daily for mild atopic dermatitis
use medium potency, such as betamethasone valerate (Beta-Val) 0.1% cream or lotion;
or fluticasone propionate (Cutivate) 0.05% cream twice daily for moderate atopic
dermatitis
use a topical calcineurin inhibitor, such as tacrolimus ointment (0.03% and 0.1% strengths) or
pimecrolimus cream (1%) twice daily on flaring areas for any of following clinical situations
(AAD Strength of Recommendation A, Level I)
recalcitrance to steroids
sensitive areas (face, anogenital, skin folds)
steroid-induced atrophy
long-term uninterrupted topical steroid use
discuss black-box warning on the use of topical calcineurin inhibitor for patients with atopic
dermatitis as warranted (AAD Strength of Recommendation C, Level III)
topical calcineurin inhibitors appear to have similar efficacy as moderate-potency
corticosteroids, but may be associated with more adverse effects, particularly burning at site
of application
consider crisaborole, approved by FDA in December 2016, which improved mild to moderate
atopic dermatitis in 2 trials of short-term (28 days) treatment in patients aged ≥ 2 years with
mild to moderate atopic dermatitis
for patients with recurrent flares of atopic dermatitis or moderate atopic dermatitis (step 2)
continue recommendations for all patients (step 1)
advise proactive maintenance treatment with topical steroid (1-2 times/week) or topical
calcineurin inhibitor (2-3 times/week) at sites that typically flare to help prevent relapses, and
is more effective than emollients alone (AAD Strength of Recommendation A, Level I)
consider combination topical steroid plus topical calcineurin inhibitor, concomitantly or
sequentially, as steroid-sparing regimen (AAD Strength of Recommendation B, Level II)
consider bleach in bath water to improve symptoms, for patients with frequent secondary
bacterial infections (AAD Strength of Recommendation B, Level II)
consider wet wrap therapy with topical steroids
consider adding phototherapy
for patients with severe atopic dermatitis (step 3)
continue step 1 and consider therapies of step 2
consider systemic treatment with
cyclosporine (AAD Strength of Recommendation B, Level II)
azathioprine (AAD Strength of Recommendation B, Level II)
dupilumab 300 mg subcutaneously once weekly or every other week for adults with
moderate to severe atopic dermatitis inadequately controlled by topical medications
(level 1 [likely reliable] evidence)
most antimicrobial interventions do not appear effective for patients with noninfected atopic
dermatitis
therapies with insufficient or limited evidence include
topical antihistamines - not routinely recommended (AAD Strength of Recommendation B,
Level II)
oral antihistamines - not routinely recommended (AAD Strength of Recommendation A,
Level II)
probiotics - not routinely recommended (AAD Strength of Recommendation B, Level II)
specific laundering products or techniques - not recommended (AAD Strength of
Recommendation C, Level III)
other interventions with some evidence of efficacy
dietary supplements with limited evidence of benefit for atopic eczema include fish oil, and
vitamin D plus vitamin E (level 2 [mid-level] evidence)
some Chinese herbal medicines may improve symptoms and may be more effective than
Western medicines in patients with atopic eczema (level 2 [mid-level] evidence); but herbal
creams may contain potent steroids
clothing made with silk or silver-coated textiles associated with improved symptoms of atopic
dermatitis (level 2 [mid-level] evidence)
Diet
Dietary exclusions
American Academy of Dermatology (AAD) 2014 guidelines(6)
recommends food avoidance in patients with true immunoglobulin E-mediated allergy to
prevent potential serious health sequelae (AAD Strength of Recommendation A, Level I)
does not recommend food elimination diets based solely on food allergy test results (AAD
Strength of Recommendation B, Level II)
 dietary exclusions appear ineffective in unselected patients with atopic eczema, egg-free diet
may be beneficial in infants with suspected egg allergy (level 2 [mid-level] evidence)
based on Cochrane review of trials with methodologic limitations
systematic review of 9 randomized trials evaluating dietary exclusions in 421 patients with
medically-diagnosed atopic eczema
methodologic limitations included poor concealment of allocation, lack of blinding, and high
dropout rates without intention-to-treat analysis; no trial had clearly adequate allocation
concealment
no evidence of benefit in unselected patients with
egg and milk free diet (6 trials with 288 patients)
elemental diet (2 trials with 48 patients)
few-foods diet (1 trial with 85 patients)
egg-free diet may be beneficial in infants with suspected egg allergy who have positive
specific IgE to eggs (1 trial with 55 patients)
Reference - Cochrane Database Syst Rev 2008 Jan 23;(1):CD005203 (review updated 2008
May 22), commentary can be found in Evid Based Med 2008 Oct;13(5):138, also published
in Allergy 2009 Feb;64(2):258
 avoidance of food additives may be helpful in adults with allergy to ≥ 1 common aeroallergen
and elevated IgE levels (level 3 [lacking direct] evidence)
based on case series
50 adults with atopic dermatitis and allergy to ≥ 1 common aeroallergen and mean IgE level
1,900 kilounit/L treated with low-pseudoallergen diet consisting of reduction of foods
containing food additives, histamine, and naturally-occurring salicylates, benzoates and
aromatic compounds for 6 weeks
26 (63%) had improvement in skin disease severity
24 responders were rechallenged with pseudoallergen-rich diet for 2 days, 19 had
worsening of rash after 24-hour delay
10 nonresponders were rechallenged and none worsened
15 who responded to open challenge underwent double-blind challenge with food additives
6 developed increased rash after 24-hour delay
10 initial nonresponders had no response to controlled food additive challenge
Reference - Clin Exp Allergy 2000 Mar;30(3):407
 partially hydrolyzed cow's milk formula might reduce severity of atopic dermatitis in infants
(level 2 [mid-level] evidence)
based on randomized trial with high dropout rate
113 infants < 6 months old with atopic dermatitis were randomized to partially hydrolyzed
cow's milk formula vs. conventional cow's milk formula
27 infants (24%) dropped out by 12 weeks, 86 infants (76%) analyzed
partially hydrolyzed cow's milk formula group had significantly reduced atopic dermatitis
severity scores compared to conventional cow's milk formula group at 12 weeks (p < 0.05)
Reference - Pediatr Allergy Immunol 2011 Nov;22(7):688
Dietary supplementation
insufficient evidence to recommend treatment of atopic dermatitis with fish oils, evening primrose
oil, borage oil, multivitamin supplements, zinc, or vitamins D, E, B12, and B6 (AAD Strength of
Recommendation B, Level II)(6)
 dietary supplements with limited evidence of benefit for atopic eczema include fish oil, and
vitamin D plus vitamin E (level 2 [mid-level] evidence)
based on Cochrane review
systematic review of 11 randomized trials evaluating dietary supplements in 596 patients with
established atopic eczema
fish oil significantly reduced degree of itching (in analysis of 2 trials with 139 patients)and
improved quality of life compared to placebo (in 1 trial with 23 patients), but results of
questionable clinical significance
vitamin D plus vitamin E significantly reduced eczema severity on Scoring Atopic Dermatitis
score compared to placebo (mean difference -9.8, 95% CI -17.21 to -2.39) in 1 trial with 11
patients, but results of questionable clinical significance
single trials reporting no significant differences (but underpowered to detect outcome
differences) included
zinc vs. placebo
selenium vs. selenium plus vitamin E vs. placebo
vitamin D vs. placebo
pyridoxine hydrochloride vs. placebo
sea buckthorn oil vs. sea buckthorn pulp oil vs. placebo
hempseed oil vs. placebo
sunflower oil (linoleic acid) vs. fish oil vs. placebo
Reference - Cochrane Database Syst Rev 2012 Feb 15;(2):CD005205
 oral vitamin E 400 units/day may improve symptoms but may take up to 8 months for effect
(level 2 [mid-level] evidence)
based on randomized trial without blinding of patients
96 patients with moderate-to-severe atopic dermatitis (and uncontrollable itching) were
randomized to natural vitamin E 400 units vs. placebo orally once daily for 8 months
comparing vitamin E vs. placebo
great improvement in itching and thickened skin in 46% vs. 2.2% (NNT 3)
almost complete remission in 14% vs. 0% (NNT 8)
Reference - Int J Dermatol 2002 Mar;41(3):146
DynaMed commentary -- natural vitamin E (D-alpha tocopherol, used in this study)
significantly more biologically active than synthetic vitamin E (D,L-alpha tocopherol) so 2
products both providing 400 units of vitamin E may not have similar activities
DynaMed commentary -- this trial not mentioned in Cochrane review CD005205, not listed as
excluded
 vitamin D supplementation may decrease symptom severity in patients with atopic dermatitis
(level 2 [mid-level] evidence)
based on systematic review limited by clinical heterogeneity
systematic review of 9 randomized trials evaluating oral vitamin D supplementation for
atopic dermatitis in 576 patients
heterogeneity included differences in amounts and duration of vitamin D supplementation
(oral cholecalciferol in different dosages, sun exposure in 1 study), age of patients (adults,
children), and outcome measures of disease severity (including SCORAD index, Eczema
Area and Severity Index [EASI], and Investigator Global Assessment [IGA])
comparing vitamin D vs. control, vitamin D associated with decreased severity of atopic
dermatitis in analysis of 4 trials with 254 patients (mean difference -5.8 points, 95% CI -9 to
-2.6 points, p = 0.0004)
Reference - Nutrition 2016 Sep;32(9):913
fatty acid supplementation (gamma-linolenic acid, evening primrose oil, borage oil)
evening primrose oil and borage oil orally not associated with global symptom
improvement in patients with eczema (level 2 [mid-level] evidence)
based on Cochrane review of trials with methodologic limitations
systematic review of 27 randomized trials evaluating oral evening primrose oil or
borage oil in 1,596 patients with eczema
all trials had ≥ 1 limitation including
lack of or unclear allocation concealment
high dropout rate and/or lack of intention-to-treat analysis
small sample size
comparing oral evening primrose oil to placebo
no significant difference in patient-reported global symptom improvement in
analysis of 7 trials with 176 patients
evening primrose oil nonsignificantly increased physician-reported global
symptom scores in analysis of 8 trials with 289 patients
no significant difference in adverse events in 7 trials with 436 patients
comparing oral borage oil to placebo, no significant differences in
patient-reported global symptom improvement in 2 trials with 34 patients
physician-reported global symptom improvement in 5 trials with 240 patients
adverse events in 2 trials with 298 patients
Reference - Cochrane Database Syst Rev 2013 Apr 30;(4):CD004416
evening primrose oil may have beneficial effect on itch in patients with atopic dermatitis
who are not using high-potency steroids (level 2 [mid-level] evidence)
based on systematic review of trials with allocation concealment not stated
systematic review of 17 parallel and 9 crossover studies evaluating Efamol Evening
Primrose Oil 2-16 capsules/day (500 mg/capsule) orally vs. placebo (liquid paraffin,
olive oil, safflower oil or sunflower oil) for 3-16 weeks
evening primrose oil associated with
reduced pruritus at 8 weeks (p < 0.05) in analysis of 26 studies in patients taking
no, mild or moderately potent steroids
reduced pruritus at 12 weeks (p = 0.01) in analysis of 26 studies in patients
taking no, mild or moderately potent steroids
no reduction in pruritus at 12 weeks (not significant) in analysis of 26 studies in
patients taking potent steroids, analysis limited by significant heterogeneity
crusting, edema, redness, excoriation, sleep loss, dryness, and overall impression
associated with trend in favor of primrose oil in patients using low steroids
Reference - Curr Pharm Biotechnol 2006 Dec;7(6):503
supplemental docosahexaenoic acid (DHA) may improve atopic eczema severity scores
(level 2 [mid-level] evidence)
based on small randomized trial with high dropout rate
53 adults aged 18-40 years with atopic eczema randomized to DHA 5.4 g/day and
eicosapentaenoic acid 0.37 g/day orally vs. isoenergetic control of saturated fatty acids
for 8 weeks
25% in treatment group excluded for noncompliance
clinically significant reduction in severity scoring of atopic dermatitis from baseline in
DHA group at 8 weeks
Reference - Br J Dermatol 2008 Apr;158(4):786
Dietary considerations during breastfeeding
dietary changes for breastfeeding mothers
maternal dietary antigen avoidance during lactation may not improve or prevent atopic
dermatitis in children (level 2 [mid-level] evidence)
based on Cochrane review with limited evidence and cohort study
systematic review of 5 randomized trials evaluating maternal dietary antigen avoidance
in 952 pregnant or lactating women with history of atopic disease
all trials had ≥ 1 limitation including
inadequate or unclear allocation concealment
lack of intention-to-treat analysis
2 trials evaluated maternal antigen avoidance during lactation
comparing maternal antigen avoidance during lactation vs. usual diet
incidence of atopic eczema at ≤ 18 months old 41.7% vs. 57.1% (not significant)
in 1 trial with 26 infants
no significant difference in positive skin prick test results, except for increased
risk of egg allergy at 2 years in avoidance group (11.6% vs. 6%, p = 0.04, NNH
17) in 1 trial with 473 infants
no significant difference in infant eczema severity in 1 crossover trial with 17
infants
Reference - Cochrane Database Syst Rev 2012 Sep 12;(9):CD000133
cohort study of 65 children with family history of atopy whose mothers adhered to diet
excluding eggs, cow's milk, and fish during first 3 months of lactation compared to 50
matched children whose mothers did not practice similar diet
all children followed until age 10 years
high rates of atopic symptoms occurred in both groups at age 10 years, but
no significant differences between groups
Reference - Acta Paediatr 1999 Jan;88(1):7
 discontinuing breastfeeding associated with improvement in atopic dermatitis in infants (level
2 [mid-level] evidence)
based on prospective cohort study
100 Finnish infants with moderate-to-severe atopic dermatitis had skin symptoms evaluated
before and after cessation of breastfeeding
41 infants also had gastrointestinal symptoms (mainly vomiting, loose stools, diarrhea)
some improvement was achieved by maternal elimination diet prior to cessation of
breastfeeding
on discontinuing breastfeeding, infants were weaned to synthetic amino acid derived formula
severity of eczema decreased after discontinuation of breastfeeding assessed by Scoring
Atopic Dermatitis (SCORAD) reduction