STATE-OF-THE-ART REVIEW ARTICLE

Management of Atopic Dermatitis in the Pediatric

Population
Andrew C. Krakowski, MDa,b, Lawrence F. Eichenfield, MDb,c,d, Magdalene A. Dohil, MDc,d,e

aDivison of Pediatric Dermatology, cDepartments of Pediatrics, and dMedicine, University of California, San Diego, California; and the eEczema Center and b Pediatric and
Adolescent Dermatology, Rady Children’s Hospital, San Diego, California

Financial Disclosure: Drs Eichenfield and Dohil have served as investigators and consultants for multiple pharmaceutical-sponsored studies on atopic dermatitis, but they have no personal or family equity
interest in any company; Dr Krakowski has indicated he has no financial relationships relevant to this article to disclose.

ABSTRACT
Atopic dermatitis, one of the most common skin disorders in young children, has a
prevalence of 10% to 20% in the first decade of life. It is a chronic illness that
requires a multifaceted treatment strategy in the setting of limited therapeutic www.pediatrics.org/cgi/doi/10.1542/
peds.2007-2232
options. Balancing safety concerns with efficacious treatment is of particular impor-
tance in the pediatric population. Parents of patients with atopic dermatitis turn to doi:10.1542/peds.2007-2232
their primary caregivers for guidance regarding this physically demanding and psy- Key Words
topical calcineurin inhibitors, atopic
chologically stressful condition. In addition to serving as a review of atopic dermatitis, dermatitis, atopy, management strategies,
this article delves into the state-of-the-art therapeutic options and includes a detailed topical steroids
review of the differences between topical corticosteroids and topical calcineurin Abbreviations
inhibitors. We also discuss new treatment strategies that are being used by atopic AD—atopic dermatitis
dermatitis specialists, such as comprehensive “education-as-intervention” models, IL—interleukin
TNF-␣—tumor necrosis factor ␣
wet wraps, bleach baths, and systemic immunomodulatory therapies. Pediatrics 2008; Th—T helper
122:812–824 IgE—immunoglobulin E
FDA—Food and Drug Administration
TCI—topical calcineurin inhibitor
EPIDEMIOLOGY FTU—fingertip unit
Atopic dermatitis (AD), well known among pediatricians as a chronic, highly pruritic, Accepted for publication Jan 23, 2008
inflammatory skin disease, is one of the most common skin disorders in children.1–3 Address correspondence to Magdalene A.
Dohil, MD, Eczema Center, Division of Pediatric
In developed countries, 10% to 20% of children and 1% to 3% of adults are and Adolescent Dermatology, 8010 Frost St,
estimated to be affected.4 Between 1997 and 2004, pediatric patients with AD Suite 602, San Diego, CA 92123. E-mail:
(newborn to 18 years of age) accounted for an estimated 7.4 million office visits in [email protected]

the United States alone.5 Disease onset typically occurs by 1 year of age in ⬃60% of PEDIATRICS (ISSN Numbers: Print, 0031-4005;
Online, 1098-4275). Copyright © 2008 by the
affected infants and by 5 years of age in ⬃85% of affected children.2 American Academy of Pediatrics

ETIOLOGY
The clinical manifestations of AD are thought to result from a complex interplay of genetic, immune, metabolic,
infectious, neuroendocrine, and environmental factors.6 Defects in the epidermal barrier function and cutaneous
inflammation are 2 hallmarks of AD. Defective epidermal barrier function is thought to be related to the downregu-
lation of cornified envelope genes such as the filament-aggregating protein, filaggrin, reduced ceramide levels,
increased levels of endogenous proteolytic enzymes, and enhanced trans-epidermal water loss.7,8 Barrier function can
be damaged further by a lack of certain endogenous protease inhibitors in atopic skin, exogenous proteases from
Staphylococcus aureus and house dust mites, and the use of soaps and detergents that can raise the local pH and increase
activity of endogenous proteases such as stratum corneum chymotryptic enzyme.9,10 The diminished epidermal
barrier function seen in patients with AD likely contributes to increased allergen absorption into the skin and
microbial colonization.11
Atopic skin inflammation is mediated, at least in part, by a complex, temporal-spatial expression of cytokines and
chemokines. Mechanical injury, from trauma, infection, or even simply the scratching of the itch associated with
atopic skin, stimulates the local production of primary proinflammatory cytokines such as interleukin 1 (IL-1) and
tumor necrosis factor ␣ (TNF-␣). These cytokines bind to vascular endothelium receptors, activate cellular signaling
pathways, induce vascular endothelial cell adhesion molecules, and lead to extravasation of inflammatory cells into
the skin.12 Expression of cytokines seems to differ for acute versus chronic AD. Acute AD is associated with the
production of T-helper type 2 (Th2) cytokines such as IL-4 and IL-13, which mediate immunoglobulin isotype
switching to immunoglobulin E (IgE) synthesis and upregulate expression of adhesion molecules on endothelial cells.
Acute AD lesions also contain increased levels of IL-17, a cytokine that induces the release of proinflammatory
mediators from macrophages and fibroblasts.13 In contrast, chronic AD lesions are associated with IL-5, which is
involved in eosinophil development and survival, production of the Th1-like cytokines IL-12 and IL-18, and several
remodeling-associated cytokines such as IL-11 and transforming growth factor ␤1.11,13 Ongoing research into the roles

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 TABLE 1 Diagnostic Considerations for Pediatric AD6,14,15,90 well-being and as a disease that affects the family dy-
Essential features (must be present) namic.3,16 Pruritus, one of the most common symptoms
Pruritus of AD, often leads to an “itch-scratch” cycle that can
Eczematous dermatitis (acute, subacute, or chronic) compromise the epidermal barrier, resulting in increas-
Typical morphology and age-specific patterns ing water loss, xerosis, microbial colonization, and sec-
Chronic or relapsing history ondary infection. The physical changes of AD can affect
Important features (observed in most cases and providing support to diagnosis) pediatric patients in a variety of ways including lack of
Early age of onset sleep, poor school performance marked by an inability
Atopy to focus, behavioral problems, low self-esteem, being
Personal or family history
teased by other children, decreased participation in
IgE reactivity
sports and other social activities, stress, and anxiety. In
Xerosis
Associated features (suggest the diagnosis of AD but are too nonspecific to be children with AD, health-related quality-of-life impair-
used as defining/detection criteria for research and epidemiologic ment may at least equal that experienced with many
studies) other chronic diseases of childhood, including diabetes
Atypical vascular responses (eg, facial pallor, white dermatographism, delayed and cystic fibrosis.17,18 Families, too, may suffer signifi-
blanch response) cant physical, emotional, and functional effects and
Keratosis pilaris/hyperlinear palms/ichthyosis must be prepared to cope with lifestyle limitations im-
Ocular/periorbital changes posed by AD.19
Other regional findings (ie, perioral changes/periauricular lesions) From a public health perspective, the prevalence of
Perifollicular accentuation/lichenification/prurigo lesions
AD in children has increased steadily over the past sev-
Conditions to be excluded
eral decades and is paralleled by increases in the preva-
Contact dermatitis (allergic and irritant)
Seborrheic dermatitis lence of asthma, allergic rhinoconjunctivitis, and the
Scabies emerging entities of eosinophilic esophagitis and gastro-
Psoriasis enteritis.20,21 The epidemiologic linkage among AD,
Impetigo asthma, and allergic rhinitis (also known as the atopic
Drug eruptions triad) is particularly evident when evaluated in the con-
Perioral dermatitis text of increasing disease severity.22 The observation that
Ichthyoses and keratinization disorders (eg, Netherton syndrome) AD is frequently the first disorder of the atopic triad to
Cutaneous lymphoma manifest has led to the concept of the “atopic march,”
Immune deficiency syndromes (eg, Wiskott-Aldrich syndrome, hyper-IgE
the notion that infants with AD, through epicutaneous
syndrome, etc)
sensitization that leads to systemic allergic responses and
Zinc deficiency (acrodermatitis enteropathica)
Potential variants/associated characteristics of AD airway sensitization, are predisposed to developing
Ichthyosis vulgaris asthma and/or allergic rhinitis later in childhood.3,23–25 At
Keratosis pilaris least 1 long-term prospective study is investigating the
Nummular eczema notion that if AD arises early in life, then perhaps
Pityriasis alba prompt recognition and intervention may improve out-
comes with respect to the clinical course of AD and
influence the subsequent development of asthma and
of cytokines and the complex immunology of AD may allergic rhinitis.26 Alternatively, it has also been sug-
provide additional insight into the development and, gested that these atopic disorders may be independent
ultimately, treatment of this disease. coexpressions of a common phenotype.22

DIAGNOSING AD APPROACHES TO AD MANAGEMENT

Diagnosis is based on the presence of a combination of Successful management involves educating patients and
(1) essential, (2) important, and (3) associated clinical their families about AD, reducing signs and symptoms of
features (Table 1) and can present challenges because of the condition, preventing and decreasing the degree and
the broad differential diagnosis.14,15 Therefore, when di- frequency of flares, modifying the overall disease course,
agnosing AD, physicians must be careful to exclude the and, possibly, slowing the atopic march.27 A comprehen-
possibility of other skin conditions (Table 1).6 Once the sive long-term strategy that encompasses education, trigger
diagnosis has been established, we recommend frequent avoidance, excellent skin care, and treatment (pharmaco-
reevaluation during the clinical course to ensure the logic and nonpharmacologic measures) is vital.
accuracy of the diagnosis, to forestall morbidities such as Physicians should use their understanding of the
superinfection, to reinforce key management points variety of available treatment options to develop a per-
with parents and patients, and to evaluate and adjust sonalized therapeutic strategy that is tailored to the in-
treatment according to clinical response and tolerability. dividual child’s age and needs, extent and localization of
These measures are particularly important for very AD at presentation, and overall disease course (including
young patients. persistence, frequent flares, etc). To maximize compli-
ance with treatment recommendations, it is important
SIGNIFICANCE OF EARLY AND EFFECTIVE MANAGEMENT that physicians be sensitive to parental anxiety about the
It is important that clinicians recognize AD as a direct disease and any real or perceived potential adverse ef-
threat to an individual child’s overall physical and social fects of available treatments. For this reason, efficacy and

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safety profiles, indications, contraindications, and limi- TABLE 2 Online Resources for Patients With AD and Their Families
tations are important considerations for evaluating phar- Coping strategies and support groups
macologic treatments.14 Effective management is also National Eczema Association (www.nationaleczema.org)
based on close monitoring for changes in disease status Under My Skin: A Kid’s Guide to Atopic Dermatitis (www.undermyskin.com)
(eg, flares) and should entail stepwise treatment that is Images of Isolation (www.nationaleczema.org/Images-Of-Isolation/default.asp)
adjusted in tune with the clinical course to allow for Specialized AD care
transition from acute flare treatment to chronic mainte- The Eczema Center (www.eczemacenter.org)
nance therapy. Guiding the patient and his or her family National Jewish Medical and Research Center (www.njc.org)
along a sliding scale of treatment options may enable them EczemaNet (www.skincarephysicians.com/eczemanet/index.html)
Information on allergic triggers
to respond appropriately and promptly to minor disease
American Academy of Allergy, Asthma & Immunology (www.aaaai.org)
variations and may proactively promote compliance with
Food Allergy & Anaphylaxis Network (www.foodallergy.org)
prescribed therapy. Careful review of in-hand medications
(ie, the patient brings all current therapies to the office visit
for evaluation of quality/quantity of use) and diligent mon-
itoring of refills are also recommended to assess compliance ing and supporting patients with AD and their families
and potential medication overuse. (Table 2).

Education as Intervention Avoidance of Triggers

Education is emerging as its own primary intervention Triggers vary among patients and should be avoided
and is critical in terms of creating realistic expectations when possible (Table 3). The role of aeroallergens, such
based on the knowledge that AD is a complex, chronic as dust mites and animal dander, remains unclear. Al-
disorder. A multicenter, randomized, controlled trial though total avoidance of environmental aeroallergens
compared children with AD whose parents had received is impossible, measures can be taken to reduce exposure
6 weeks of intensive AD education to those children to these factors for patients in whom aeroallergens are
whose parents did not. The investigators taught age- suspected of playing a causative role.33 Mattress covers,
appropriate interventions to the parents of patients with low-pile carpet (particularly in sleeping areas), and non–
AD at 7 hospitals in Germany. Educational classes were dander-producing pets may be beneficial, particularly for
organized according to age group, with separate once- children who have concomitant asthma and/or rhini-
per-week sessions for the parents of children aged 3 tis.34 Food allergens may also serve as triggers for some
months to 7 years, 8 to 12 years, and 13 to 18 years. patients, but parents should be cautioned against ex-
Compared with the children of parents who did not treme restriction diets, which may not only be unhelpful
receive any extra instruction, patients in all 3 treatment but also can lead to serious malnutrition.35 It should be
groups demonstrated improved subjective quality-of-life emphasized that eliminating specific triggers may not
scores and objective measures of eczema severity over result in clearance of AD; however, avoidance of known
the 12-month period.28 triggers is a reasonable approach.
Paralleling strategies shown to be effective in manag-
ing patients with asthma, new models of education are Breastfeeding
emerging as an essential component of long-term AD The impact of breastfeeding on the prevention of AD
management.29–31 Comprehensive “centers” combine remains under debate.36–38 Reasons for this controversy
several specialty services (dermatology, allergy, infec- include methodologic differences (eg, differences in cri-
tious disease, behavioral psychology, etc) with intensive
education as a direct intervention for improved care.
With longer patient appointments, focused educational TABLE 3 Potential AD Triggers1,8,33,34,90
curriculums, patient support networks, and the ability to Associated with direct contact
elicit patient feedback, the interventional education Toiletries containing alcohol, astringents, or fragrances
model may allow physicians to better impress on care- Harsh detergents/soaps
givers that living with AD should be equated to running Abrasive clothing (wool or synthetics)
a marathon rather than a sprint. Comparative evaluation Associated with physiologic/emotional stressors
is required to examine the cost-effectiveness and suit- Infections (especially from S aureus, viruses, fungi, etc)
ability of these educational programs.32 Overheating/sweating
When access to specialized eczema educational facil- Psychological stress
Associated with food
ities is impractical or unnecessary, primary care physi-
Food allergens found in
cians assume responsibility for educating patients and Cow’s milk
their families about AD. Topics ranging from trigger Eggs
avoidance to proper skin care should be addressed, and Peanuts
an explanation that AD has distinct phases that require Tree nuts (eg, walnuts, cashews)
different types of therapies during each phase should be Soy
made. In addition, flares, which may occur despite the Wheat
best of efforts, should be identified as short-term set- Fish
backs that can be overcome. Numerous resources exist Shellfish
on the Internet to assist health care providers in educat- Foods processed with any of the above

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 TABLE 4 Different Treatments for Features of AD1,3,6,16,34,90
AD Feature Treatment Option Mechanism of Action
Xerosis Emollients, moisturizers, and barrier devices Moisturize dry skin and help repair the defective skin barrier
Immune dysfunction Avoidance of triggers Helps prevent known allergic reactions and inflammatory response
Topical corticosteroids Broad-spectrum antiinflammatory activity
Topical Calcineurin Inhibitors (TCIs) Targeted antiinflammatory activity
Oral immunomodulating agents (eg, azathioprine, Systemic antiinflammatory activity
cyclosporine, mycophenolate, etc)a
Phototherapya Proposed: antiinflammatory activity
Infection Topical/oral antiinfective agents Treat cutaneous bacterial, fungal, or viral infections
Bleach baths Proposed: decrease microbial load on colonized and/or
superinfected skin
Other Antihistamines Proposed: Sedating effect may aid in sleeping, indirectly decreasing
night-time scratching and subsequent skin excoriation
a Reserved chiefly for severe and/or recalcitrant disease.

teria for hypoallergenicity and in AD diagnostic criteria), studies are necessary to document the long-term effect
flaws in study designs (eg, lack of control for confound- of dietary interventions on atopic disease.
ing factors, problems in blinding of study formula, and
insufficient adherence to prescribed dietary avoidance Probiotics
protocols), the immunologic complexity of breast milk As a result of greater understanding of immunologic
itself, and, possibly, genetic differences among patients reaction patterns in the skin, gut, and airways, there has
that would affect whether breastfeeding is protective been a resurgence of interest in probiotics. The findings
against the development of allergies or is, in fact, sensi- to date on their utility in preventing or modifying AD,
tizing.39,40 In January 2008, the American Academy of however, have been conflicting. A 2002 study by
Pediatrics Committee on Nutrition and Section on Al- Rautava et al44 revealed that the risk of developing AD
lergy and Immunology published breastfeeding guide- during the first 2 years of life in infants was significantly
lines that replaced their previous policy statement.41 The reduced if the mothers had received probiotics during the 4
new committee concluded that there is a lack of evi- weeks before giving birth and during breastfeeding. All
dence to support a major role in AD for maternal dietary women within this study had a family history of atopy.
restrictions during pregnancy or lactation. The commit- More recently, however, a placebo-controlled study by
tee also reported that for infants at high risk of develop- Taylor et al45 showed that early probiotic supplementation
ing atopic disease, exclusive breastfeeding for at least 4 did not reduce the risk of AD in infants at high risk but,
months (compared with feeding intact cow milk protein instead, was associated with increased allergen sensitiza-
formula) decreases the cumulative incidence of AD in tion in those infants who were receiving supplements. The
the first 2 years of life; exclusive breastfeeding beyond long-term significance of probiotics in the treatment of AD
this period did not seem to lead to additional benefit in warrants additional investigation.
the incidence of AD.42 More long-term prospective stud-
ies are necessary before a consensus about breastfeeding
Skin Care
recommendations can be reached.
Excellent skin care is a traditional cornerstone of AD
management. Although limited data exist to support the
Timing of Solid-Food Introduction notion that emollients and moisturizers improve AD
Zutavern et al43 performed a large, population-based, directly, these products are widely used because they
prospective birth cohort study and concluded that there improve the xerosis associated with AD (Table 4).46 In
was no evidence to support a delayed introduction of general, ointments contain high concentrations of lipids
solids beyond the sixth month of life on AD and atopic and are generally more effective than creams or lotions,
sensitization at 2 years of age. The findings were less which are water-based and, therefore, may dry the skin
clear when solids were introduced past the fourth month somewhat after evaporation.6 Ceramide-rich products
of life, and there was no evidence for a protective effect are also useful for retaining moisture in the skin.47 Re-
of a delayed introduction of solids on any outcome for cently, several novel barrier products have been cleared
children with atopic parents. The American Academy of for marketing by the US Food and Drug Administration
Pediatrics Committee on Nutrition and Section on Al- (FDA) as “510(k) medical devices” and contain ingredi-
lergy and Immunology published guidelines, in 2008, ents that their manufacturers claim in addition to mois-
stating that there is no convincing evidence that delay- turizing may help to relieve pruritus, burning, and pain
ing solid foods beyond 4 to 6 months of age has a associated with AD; studies are underway to evaluate
significant protective effect on the development of atopic the utility of these new products and their potential role
disease; this includes delaying introduction of those in helping to manage AD.48–51
foods thought to be highly allergic such as cow milk, With little evidence to recommend the use of one
fish, eggs, and peanut-containing foods.42 Additional emollient over another, we support the adage that “a

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good product applied works better than a more expensive such as hydrocortisone ointment 1%.55 The vasocon-
product on the shelf.” In other words, because emollients strictor assay does not consider other factors that influ-
and moisturizers only work when they are actually used, ence desired therapeutic effect and unwanted adverse
patient and parental preference should be primary factors effects: the state of the skin barrier, the body site in-
in selecting a daily emollient or moisturizer. In general, volved, disease extent, the age of the patient, concomi-
patients should use a dye-free, fragrance-free moisturizer tant use of occlusion, the amount of steroid applied, and
and apply it at least twice per day subsequent to any topical the duration of treatment. However, it does correlate
pharmacologic therapies to allow active medications to well with clinical efficacy and provides a reasonable
reach the skin with full-effect. guide to the potential for adverse effects.
Tolerability and safety concerns regarding topical corti-
Bathing costeroids are well known and include local adverse effects
The value of bathing remains somewhat controversial. such as skin atrophy, striae, telangiectasias, hypopigmen-
The chief benefits of bathing are skin hydration and cleans- tation, rosacea, perioral dermatitis, acne, cataracts, and
ing. Bathing may also improve penetration of topical ther- glaucoma; these local adverse effects can occur more fre-
apies and may help debride infected eczema. The potential quently when topical corticosteroids are used on sensitive
drawbacks of bathing are drying of the skin and disruption areas of thin skin, such as the face, neck, or groin. Systemic
of the stratum corneum barrier during water evaporation, adverse effects such as hypothalamic-pituitary-adrenal axis
which can be minimized by using the “soak and seal” suppression (Table 5), growth retardation in children, and
method.6,33 With this technique, the child is bathed for reduced bone density have also been documented.1 A
several minutes in lukewarm water once or twice daily for recent review of topical therapies for AD showed, how-
mild or more severe AD, respectively. Use of a moisturizing ever, that although some systemic exposure to these
cleanser is preferred, and highly fragranced soaps or bubble topical agents does occur, physiologic changes seem to
baths should be avoided. After bathing, caregivers should be uncommon and systemic complications rare when
gently pat the child dry, being careful not to rub the skin medications are used properly.56 Also of concern is the
with a towel, which can be thought of as “scratching in risk of flare relapse after discontinuation of treatment
disguise.” Liberal quantities of emollients should then ap- and, rarely, steroid insensitivity. “Steroid phobia” among
plied to maximize moisture retention. caregivers is common, and suboptimal use of topical
corticosteroids as a result of concerns about adverse
effects can be impediments to effective management.33,52
PHARMACOLOGIC TREATMENT OF ACUTE AD It is important to anticipate these concerns and stress
Despite proper skin care and reasonable trigger avoid- that, despite these well-known potential adverse effects,
ance, most children will experience a flare and require topical corticosteroids remain the first-line treatment for
pharmacologic treatment. Flares of mild-to-moderate in- atopic flares in the pediatric population.
tensity are marked by itching, erythema, and excoriations, The extensive use of topical corticosteroids in clinical
papules, and lichenification. More severe or major flares practice is supported by an ever-expanding body of clin-
present with intense and persistent itching, substantial er- ical trial data, which help to provide physicians with
ythema, extensive excoriations, oozing/crusting, and li- sensible recommendations for the quantity, frequency,
chenification. Two major classes of therapeutic agents are and duration of topical corticosteroid therapy.56,57 Even
used for the treatment of AD: topical corticosteroids and with these recommendations, variation in topical steroid
topical calcineurin inhibitors (TCIs) (Table 4). Both classes prescribing habits among dermatologists is common.58
of agents inhibit the associated inflammatory response, Some clinicians opt to begin treatment with a more
albeit through distinct mechanisms of action. potent preparation to induce remission, followed by a
relatively quick tapering down of preparation potency as
Topical Corticosteroids the AD improves; a subsequent stepwise model allows
Topical corticosteroids, the predominant AD therapy for for as-needed management based on disease activity. A
more than 4 decades, provide effective flare control second approach is to use short bursts of a potent prep-
through their antiinflammatory, antiproliferative, im- aration followed by a steroid-free “holiday period” of
munosuppressive, and vasoconstrictive actions.52 They emollient use only until relapse occurs.1,33,52 Another
suppress the release of inflammatory cytokines, and they treatment regimen relies on more prolonged continuous
act on a variety of immune cells including T lympho- treatment with less-potent preparations. Regarding dos-
cytes, monocytes, macrophages, dendritic cells and their age frequency, 1 large systematic review revealed that
precursors.53 using twice-daily applications of topical corticosteroids
The current American system of classification strati- was no more effective than once-daily application.57 Ul-
fies topical corticosteroids into groups of roughly equal timately, providers should consider drug-specific FDA
potency on the basis of the vasoconstrictor assay, with indications when educating and instructing patients on
class I representing the most potent and class VII repre- topical corticosteroid usage.
senting the least potent.54 The difference in potency be-
tween classes is dramatic and is often misunderstood by Topical Calcineurin Inhibitors
both patients and their caregivers.52 Very potent, class I The 2 currently approved TCIs, tacrolimus and pimecroli-
preparations such as clobetasol propionate 0.05% are mus, provide an alternative to topical corticosteroids and
⬃1800 times more potent than a class VII preparation are approved by the FDA as second-line agents for the

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 TABLE 5 Select Topical Corticosteroids and Their Hypothalamic-Pituitary-Adrenal Axis Suppression Studies: Pediatric Experience
Class Steroid Vehicle Dosage and Frequency Age Group Design Duration of Test HPA Studies Source
VII Hydrocortisone 1% Ointment 48.7–223.2 mg/m2 BSA per 3.1 to 10.7 y n ⫽ 14; moderate or severe 3 to 10 y (median: PC: no change in basal/peak plasma Patel et al98
d; 9 of 14 also AD; 58% median BSA 6.5 y) levels but earlier peak seen in
intermittently used affected patients with AD versus controls
moderate-potency
preparations
VII Hydrocortisone 2.5% Ointment 2 times per d n ⫽ 20; open label, parallel 4 wk CST: all normal Lucky et al99
VI Alclometasone Cream 2 times per d n ⫽ 39; open label 3 to 4 wk PC (AM): all normal Crespi100
dipropionate 0.05%
VI Desonide 0.05% Hydrogel 2 times per d 6 mo to 6 y n ⫽ 40; open label; 4 wk CST: normal in all patients without Eichenfield et al101
moderate-to-severe AD; protocol violations; 1 of 3 abnormal
51% mean BSA affected in patients with protocol deviations
VI Fluocinolone acetonide Protein-free 2 times per d Study 1: 3 mo to 2 y; Study 1: n ⫽ 24, open label, 4 wk CST: all normal Study 1: On file with
0.01% peanut oil study 2: 2 to 12 y moderate-to-severe AD, the FDA102; study
ⱖ20% BSA affected; 2: Paller et al103
study 2: n ⫽ 32, open
label, moderate-to-
severe AD, ⱖ50% BSA
affected
V Fluticasone propionate Cream 2 times/d (average amount 3 mo to 6 y n ⫽ 43; open label; 3 to 4 wk CST: 2 of 43 patients with abnormal Friedlander et al104
0.05% of drug used per d: 3.8 g moderate to severe AD; test results; 1 patient with 95% BSA
for ages 3–35 mo, 7.7 g 64% mean BSA treated affected normalized 12 d after last
for ages 36–70 mo) study dose; 1 patient with 35% BSA
was lost to follow-up
V Fluticasone propionate Lotion 2 times per d 3 mo to 6 y n ⫽ 42; open label; 3 to 4 wk CST: all normal Hebert et al105
0.05% moderate-to-severe AD;
65% mean BSA treated
V Prednicarbate 0.1% Cream 2 times per d 4 mo to 12 y n ⫽ 55; open label; mostly 3 wk CST: all normal Moshang106
moderate-to-severe AD
(1 “mild” enrolled);
46.7% mean BSA
affected
IV Mometasone furoate Cream 1 time per d 6 to 23 mo n ⫽ 97; open label; AD 3 wk CST: 16% of patients with abnormal On file with the
0.1% (severity not stated); tests (4 of 5 tested patients FDA107
41% mean BSA affected normalized 2–4 wk after treatment)

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III Fluticasone propionate Ointment n ⫽ 35; AD (severity not 3 to 4 wk CST: 4 patients with abnormal test On file with the
0.005% stated); ⱖ35% BSA results FDA108
affected
III Triamcinolone acetonide Ointment 4 times per d (average 7 mo to 8 y n ⫽ 7; open label; severe 6 wk PC (AM/PM): “no substantial difference” Rasmussen109
0.1% amount of drug used AD 24-HUC: “no notable depression”
per d: 13–46 g/m2)
II Mometasone furoate Ointment 1 time per d 6 to 23 mo n ⫽ 63; open label; AD 3 wk CST: 27% of patients with abnormal On file with the
0.1% (severity not stated); test results (5 of 8 tested patients FDA110
39% mean BSA affected normalized 2–4 wk after treatment)

817 PEDIATRICS Volume 122, Number 4, October 2008

 short-term and noncontinuous chronic treatment of
Schlessinger et al111
moderate-to-severe AD in immunocompetent patients

On file with the

Source

aged ⱖ2 years.59,60 TCIs block the production and release

FDA112
of proinflammatory cytokines after antigen-specific or
nonspecific activation of T cells and mast cells.61,62
The safety and efficacy of tacrolimus and pimecroli-
mus have been demonstrated in several short-term (6-
CST: cohort 1: 1 of 15 patients in twice-

abnormal test results (1 normalized

week) and long-term (⬎2-year) clinical trials.63–65 Data

cohort 3: 1 of 15 patients in twice-

patients in twice-daily group with

normalized 2 wk after treatment);

suppression (assessment method

result (suspected collection error;
daily group with abnormal test

daily group with abnormal test

from clinical trials have shown that pimecrolimus re-
results (normalized 2 wk after
treatment); cohort 2: 2 of 16

duces the number and severity of flares, extends the

9 of 14 patients with adrenal

8 d after treatment, and 1
HPA Studies

length of time between major flares, and decreases pru-

ritus and other cutaneous signs associated with AD.66
not suppressed) Likewise, long-term, intermittent (once-daily, 3-times-
weekly) maintenance use of tacrolimus ointment in pa-
not stated)
tients with stabilized AD has been shown to significantly
increase time between disease exacerbation and total
number of disease-free days versus vehicle.67 The inci-
dence of adverse effects (mostly transient application-
Duration of Test

site stinging) is generally low.68,69

In January 2006, the FDA added a boxed warning to
TCI labels noting that the long-term safety of these
agents has not been established. The warning was added
2 wk

2 wk

in response to widespread off-label use in the infant

population (⬍2 years of age) and concerns about a po-
(cohort 1, twice daily) to
moderate-to-severe AD;

tential cancer risk based on 3 factors: (1) a shared mech-

severe AD; ⱖ20% BSA
43% (cohort 4, once

anism of action with systemic calcineurin inhibitors; (2)

n ⫽ 14; moderate-to-
mean BSA affected
n ⫽ 126; open label;

ranged from 34%

animal toxicology studies; and (3) rare postmarketing

Design

case reports of malignancy (skin cancer and lympho-

affected

mas). It is important to note that none of the reported

HPA indicates hypothalamic-pituitary-adrenal; BSA, body surface area; PC, plasma cortisol; CST, Cosyntropin; 24-HUC, 24-hour urinary cortisol.
daily)

lymphomas were characteristic of the posttransplant

lymphoproliferative disease type observed with systemic
immunosuppression.59,60 Clinical studies have indicated
Cohort 1: 12 to ⬍18 y;

y; cohort 3: 2 to ⬍6
y; cohort 4: 3 mo to

minimal systemic absorption and, considered together,

cohort 2: 6 to ⬍12

the available data do not suggest that the use of TCIs is

Age Group

associated with systemic immunosuppression, impacts

the delayed-type hypersensitivity response, or has an
12 to 17 y
⬍2 y

increased association with skin cancer.65,70,71

Accordingly, the FDA has not requested that ongoing
studies with TCIs in pediatric patients be halted. Official
indications for use, however, were changed from “short-
Dosage and Frequency

term and intermittent long-term therapy in the treat-

ment of patients with moderate to severe AD in whom
1 or 2 times per d

the use of alternative, conventional therapies are

2 times per d

deemed inadvisable because of potential risks, or in the

treatment of patients who are not adequately responsive
to or are intolerant of alternative, conventional thera-
pies” to the current indication of “second-line therapy for
the short-term and noncontinuous chronic treatment of
Vehicle

moderate to severe AD in nonimmunocompromised

Cream

Lotion

adults and children who have failed to respond ade-

quately to other topical prescription treatments for AD,
or when those treatments are not advisable” in children
aged ⱖ2 years.59,60
Clobetasol propionate

TCIs may be particularly valuable for patients with

Fluocinonide 0.1%
Steroid
TABLE 5 Continued

AD in whom the clinical course is marked by disease

persistence and/or frequent flares, which would other-
0.05%

wise result in an almost continuous need for topical

corticosteroid treatment. TCIs may also be of significant
benefit for those patients affected in sensitive skin areas
such as around the eye, face, neck, and genital area,
Class
I

where systemic absorption and the risk of skin atrophy

818 KRAKOWSKI et al
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are of special concern. The safety data for TCIs in the evaluated rigorously in large, randomized, double-blind,
pediatric population are still accumulating and will be placebo-controlled trials, and the drowsiness that may
helpful in guiding physicians in the use of these partic- be associated with daytime use is a legitimate concern
ular agents. for school-aged children.75,76 Second-generation anti-
histamines are less useful in managing AD, but they
may benefit patients with allergic triggers and, with
TOPICAL CORTICOSTEROID AND TCI USE IN DISEASE
chronic use, may help decrease the rate of atopic
MANAGEMENT
disease.77–79 Doxepin, a tricyclic antidepressant with
Both acute flare treatment and overall disease manage-
anxiolytic effects, has the highest H1-receptor antag-
ment must be tailored to the individual patient, and
onist activity among the tricyclic antidepressants and
disease severity (including disease persistence and fre-
is the most sedating. It is generally reserved for pa-
quency of flares) must be considered. Recognizing the
tients with severe AD and has an adverse-effect profile
risk/benefit profile of both topical corticosteroids and
that includes daytime sedation, hypotension, and tol-
TCIs allows for optimal individualized patient care using
erance.80
a sliding disease/treatment scale or stepwise therapeutic
approach.72 We have adopted the use of short-term
Antimicrobial Agents
bursts of mid- to high-potency topical steroids, typically
AD lesions provide a favorable environment for bacterial
applied twice daily for 7 to 10 days (versus the long-term
colonization and proliferation, and Staphylococcus aureus
use of less-potent agents), followed by a close reexami-
can be isolated in up to 90% of AD skin lesions.11 This
nation of the patient, as part of our current treatment
high prevalence of colonization is most likely multifac-
approach for children with rapid flares. After achieving
torial; proposed mechanisms include increased adher-
control of a flare, we shift therapy to a less-intense
ence of bacteria to inflamed skin, defective skin barrier
treatment and focus on a maintenance regimen with
function, decreased innate antibacterial activities, re-
moisturization (optimally, at least twice daily) at its
duced immune responses against bacteria, and skin-sur-
core. If a topical corticosteroid has been used to treat
face pH changes toward alkalinity.81 Patients with AD
a flare, it can be tapered to a lower-potency agent and
can have sudden exacerbations of AD attributable to
from daily to intermittent (eg, thrice- or twice-
overgrowth of S aureus that can be independent of true
weekly) application.6 Patients with a history of flare
secondary bacterial infection, a notion supported by the
recurrence after discontinuation or tapering of topical
clinical response of patients with severe AD to anti-
corticosteroids may benefit from transition to TCI
staphylococcal antibiotics.82,83 Honey-colored crusting,
therapy at that point.3,67 Some physicians advocate the
folliculitis, and pyoderma are signs of overt infection,
use of TCI monotherapy to control flare recurrence
and topical and/or oral antibiotic therapy, typically of
while limiting patients’ long-term exposure to corti-
short duration to avoid the development of bacterial
costeroids.72
resistance, is indicated.1,6 Obtaining skin cultures should
Irrespective of treatment strategy, physicians should
be considered before treatment, because methicillin-re-
monitor patient progress and disease course regularly
sistant Staphylococcus aureus may be an important patho-
(eg, evaluations at 2, 6, and 12 weeks) and evaluate the
gen in some patients. Recurrent, deep-seated S aureus
efficacy and tolerability of therapy. This evaluation
infections should raise the possibility of an immunode-
should include an assessment of medication use (eg,
ficiency syndrome such as hyper-IgE syndrome.11 Di-
type, quantity applied, refills made, etc), which allows
luted bleach baths (Table 6), analogous to swimming in
the physician to gauge compliance and medication risks.
a chlorinated pool, are an adjuvant antiinfective treat-
The fingertip unit (FTU), defined as the amount of top-
ment that can help decrease the number of local skin
ical medication extending from the tip to the first joint
infections and reduce the need for systemic antibiotics
on the palmar aspect of the index finger, is a guideline
for patients with AD with heavily colonized and/or su-
for estimating the amount of topical medication needed
perinfected skin.84
to cover a given area: it takes ⬃1 FTU to cover the hand
Patients with AD are also prone to recurrent viral
or groin, 2 FTUs for the face or foot, 3 FTUs for an arm,
infections, perhaps because of local defects in T-cell
6 FTUs for the leg, and 14 FTUs for the trunk.73
function. Molluscum contagiosum, a common cutaneous
viral infection, may often manifest as small, dome-
Adjunctive Therapy shaped papules that characteristically show a central
Pruritus is one of the defining features of AD, with umbilication. They typically affect the trunk, axillae,
associated scratching that leads to excoriated, often su- antecubital and popliteal fossae, and crural areas. Le-
perinfected lesions, bleeding, lichenification, and/or sions tend to be most numerous at sites of active derma-
nodular changes. In addition, pruritus can cause signif- titis and can induce pruritus as well as dermatitis around
icant sleep disturbance and affect the patient’s and car- the Molluscum papules.25 Eczema herpeticum, also
egiver’s quality of life.74 Identifying and removing trig- known as Kaposi’s varicelliform eruption, is a serious
gers of pruritus is appropriate. Although they do not risk in patients with widespread AD and may be easily
have direct effects on the pruritus associated with AD, misdiagnosed as bacterial superinfection.85 After an in-
sedating systemic antihistamines such as hydroxyzine cubation period of 5 to 12 days, these patients can
and diphenhydramine may be useful for improving sleep present with multiple, itchy, vesiculopustular, dissemi-
in patients with flare-ups. This practice has not been nated lesions and painful, “punched-out” erosions that

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 TABLE 6 A Bleach Bath Primer
Explain to patients that their skin may benefit from “swimming in pool water.” Then, give them these instructions for making a pool right in their very own bathroom.
Add lukewarm water to fill the tub completely (about 40 gallons of water).
Depending on the size of the tub/amount of water used, add 1⁄4 to 1⁄2 cup of common bleach solution to the bath water. Any sodium hypochlorite 6% solution will do
(for example, Chlorox liquid bleach); the goal is to make a modified Dakin’s solution with a final concentration of about 0.005%.
Stir the mixture to ensure that the bleach is completely diluted in the bath water.
Have patients soak in the chlorinated water for 5 to 10 minutes.
Thoroughly rinse skin clear with lukewarm, fresh water at the end of the bleach bath to prevent dryness and irritation.
As soon as the bath is over, pat the patient dry. Do not rub dry, as this is the same as scratching.
Immediately apply any prescribed medications/emollients.
Repeat bleach baths 2–3 times a week or as prescribed by the physician.
The following restrictions apply
Do not use undiluted bleach directly on the skin. Even diluted bleach baths can potentially cause dryness and/or irritation.
Do not use bleach baths if there are many breaks or open areas in the skin (for fear of intense stinging and burning).
Do not use bleach baths in patients with a known contact allergy to chlorine.

fail to respond to oral antibiotics.11 Before treatment, wraps (Table 7), which were first touted as a relatively
herpes infection should be documented (via culture safe and effective treatment ⬎20 years ago.88 Although
and/or direct fluorescent antibody), and antiviral ther- time consuming, wet wraps can be a useful tool in the
apy should be initiated as soon as possible. Similarly, intensive treatment of AD. Wet wraps increase skin hy-
eczema vaccinatum is a severe, potentially fatal wide- dration and serve as an effective barrier to scratching,
spread eruption caused by the live-virus smallpox vac- which helps promote more restful sleep. Likewise, they
cination or even exposure to vaccinated people such as act as an occlusive barrier that promotes penetration of
military personnel who receive smallpox vaccination topical corticosteroids into the skin, thereby increasing
in preparation for overseas deployment.86 For this rea- the amount of medication delivered to the affected areas
son, smallpox vaccination is contraindicated for pa- of inflammation. A recent review of the literature re-
tients who have ever been diagnosed with AD, even if vealed a wide variety in wet-wrap methodology. On the
the condition is not currently active. In addition, per- basis of currently available evidence, the authors of the
sons with household contacts who have a history of study found wet wraps with once-daily application of
AD, irrespective of disease severity or activity, should topical corticosteroids to be an efficacious and safe short-
not be vaccinated.87 Fungal infections such as those term intervention for children with severe and/or refrac-
caused by Trichophyton rubrum are also more common tory AD; temporary systemic bioactivity of the cortico-
in patients with AD. Antifungal therapy has been steroids was the only reported serious adverse effect.89
shown to reduce the severity of AD lesions exacer- Wet wraps may cause maceration of the skin and sec-
bated by Malassezia furfur, particularly in the sebor- ondary infections if overused or used incorrectly. Para-
rheic areas of the skin and scalp.11 doxically, they may promote skin dryness if sufficient
emollients are not part of the regimen.90 Because of
Wet Wraps these concerns, it is imperative that patients be super-
Patients with severe AD or disease that is refractory to vised closely by a physician who has expertise in the use
standard topical treatment may require the use of wet of wet wraps.

TABLE 7 Keeping Eczema Under Wraps: Recommendations for Applying Wet Wraps
Gather your supplies.
Topical steroid ointment and/or emollient prescribed by your physician.
The wraps themselves consist of a bottom (wet) and top (dry) layer. Gauze wrap (eg, Kerlex) or cotton sleepers, pajamas, or long johns may be used. It will be
necessary to have two of the material chosen. Alternatively, it is possible to use the “daddy sock” method for wrapping extremities. Simply cut a small hole in the
toes of any adult-sized pair of 100% cotton socks to create a pair of tubular cotton bandages that fit easily over an extremity, can be moved up or down as needed,
and can be washed and reused.
Warm water in a sink or a basin.
Apply the steroid ointment directly to the patient’s inflamed skin using tongue depressors or popsicle sticks (similar to how a spatula is used in cooking). Using a
“spatula” helps to avoid direct contamination of the medication supply, allows large areas to be covered quickly and evenly, and prevents the caregiver from being
unnecessarily exposed to topical corticosteroids.
Apply emollient to the rest of the patient’s skin.
Take a layer of the wrap (e.g., gauze or one sock) and soak it in warm water.
Wring out any excess water until this bottom wet layer is only very slightly damp.
Wrap the affected area with the wet layer material. Make sure the wet layer is not too tight.
Immediately put the dry layer over the wet layer. Do not use plastic as the dry layer (it is too occlusive and may be a choking hazard).
Make sure the wrapped patient remains in a warm environment, which helps to promote a higher degree of humidity and ensures that the child does not get too cold
as the evaporation process occurs.
Wet wraps are generally left in place overnight and may be applied for 5 to 7 days in a row. As always, follow the advice of the physician for frequency of change and
duration of use.
Maintain close contact with the physician while undergoing the use of wet wraps. Report any suspected adverse effects immediately.

820 KRAKOWSKI et al
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Systemic Therapies CONCLUSIONS
Systemic immunomodulatory therapies such as photo- AD is a common, chronic skin disease that starts early in
therapy, cyclosporine, azathioprine, and mycophenolate life and can adversely affect a child’s overall health and
have gained acceptance in recent years as treatment for development. Topical corticosteroids remain the corner-
refractory AD that does not respond to topical thera- stone of therapy, and recent studies continue to help
pies.91 Phototherapy, which evolved as a treatment for assuage concerns about potential long-term adverse ef-
AD on the basis of the observation that many patients’ fects, especially in young children. TCIs have been
conditions seem to improve during the summer months shown to provide an effective, steroid-sparing alterna-
with increased exposure to natural light, has been tive for appropriate patients, particularly those who are
shown to be an effective modality. Multiple treatments prone to frequent flares and need AD treatment in sen-
are usually required to be effective, but they can be sitive skin areas. In conjunction with these pharmaco-
inconvenient for patients and their families depending logic treatments, overall management depends on (1)
on location and accessibility to a suitable light source. educating caregivers about AD’s chronic, unpredictable
Adverse effects can include erythema, pruritus, and pig- course characterized by flares that can occur despite best
mentary changes. Likewise, UV light is known to cause efforts, (2) appreciating the compromised epidermal bar-
premature skin aging and cutaneous malignancies.90 Al- rier and the importance of proper skin care, (3) ap-
though further study in the pediatric population is nec- proaching trigger avoidance carefully and with the un-
essary, it seems that phototherapy is a valuable and safe derstanding that, in general, AD is a multifactorial
therapeutic option for selected children whose condi- disease, and (4) using a team-oriented approach that
tions do not respond to other treatments.92 Cyclosporine includes primary care physicians, specialists, nurses, psy-
may be used as a short-term treatment or as a bridge chologists, behavioral therapists, and other health care
between other steroid-sparing alternatives. The safety professionals to better achieve long-term success for pa-
and efficacy of cyclosporine in the treatment of adult and tients with AD.
childhood AD is well documented, although hyperten-
sion and renal toxicity are limitations to long-term ther- ACKNOWLEDGMENTS
apy.93 Azathioprine, dosed according to thiopurine We are grateful for the generous contributions of Albert
methyltransferase genotype/levels, is also an effective Yan, MD, Jon Hanifin, MD, Therese Cosan, RN, Ann
monotherapy; blood cell counts and liver function tests Funk, RN, and the entire staff of the Eczema Center at
should be monitored closely, and drug hypersensitivity Rady Children’s Hospital, San Diego. We also thank the
and gastrointestinal disturbances have been report- National Eczema Association and the patients and their
ed.94–96 Mycophenolate mofetil, an inhibitor of purine families, who inspire us on a daily basis.
synthesis, has a good safety profile and represents a
promising therapeutic alternative for severe, refractive
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SCIENTISTS FIND WAY TO CREATE RED BLOOD CELLS

“New York—Scientists say they’ve found an efficient way to make red blood
cells from human embryonic stem cells, a possible step toward making
transfusion supplies in the laboratory. The promise of a virtually limitless
supply is tantalizing because of blood-donor shortages and disappointments
in creating blood substitutes. Red blood cells are an important component of
blood because they carry oxygen throughout the body. Experts called the
new work an advance, but cautioned that major questions had yet to be
answered. The research, published online Tuesday by the journal Blood, was
reported by scientists at Advanced Cell Technology in Worcester, Massachu-
setts, the University of Illinois at Chicago and the Mayo Clinic in Rochester,
Minnesota. The researchers said the cells they made behaved like natural red
blood cells in lab tests, and that their process could be used in large-scale
production. The results suggest that embryonic stem cells could someday supply
type O-negative ‘universal donor’ red cells for transfusion, they wrote.”
Associated Press. Wall Street Journal. August 20, 2008
Noted by JFL, MD

824 KRAKOWSKI et al
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 Management of Atopic Dermatitis in the Pediatric Population
Andrew C. Krakowski, Lawrence F. Eichenfield and Magdalene A. Dohil
Pediatrics 2008;122;812
DOI: 10.1542/peds.2007-2232

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 Management of Atopic Dermatitis in the Pediatric Population
Andrew C. Krakowski, Lawrence F. Eichenfield and Magdalene A. Dohil
Pediatrics 2008;122;812
DOI: 10.1542/peds.2007-2232

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pediatrics.aappublications.org/content/122/4/812

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