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Infections and Allergies in Atopic Dermatitis: Myths versus Reality

Mercedes E. Gonzalez, M.D.

Medical Director, Pediatric Dermatology of Miami

Assistant Clinical Professor, Department of Dermatology, University of Miami Miller School of Medicine & Herbert

Wertheim College of Medicine, Miami, FL

F023: Translating Evidence into Practice: Atopic Dermatitis Guidelines

Mercedes E. Gonzalez, MD

F023: Translating Evidence into Practice: Atopic Dermatitis Guidelines, 07-30-2016

DISCLOSURES

Pierre Fabre Dermatologie: Speaker, Advisory Board – Honoraria

Anacor Pharmaceuticals, Inc.: Advisory Board – Honoraria

Encore Dermatology: Speaker – Honoraria

PuraCap Pharmaceutical, LLC: Speaker - Honoraria

DISCLOSURE OF RELATIONSHIPS WITH INDUSTRY

Eichenfield LF et al. J Am Acad Dermatol 2014

Clinical scenario 1:

• 11-month-old healthy girl

• Itchy, widespread eczematous plaques face, extensor extremities

• Rx: HCT 2.5%, Nutramagen

• Initially improved but now is bad again & not sleeping well

• Multiple new foods

• FH: Father had AD as a child

Mother asks you: What? Why? -Is this an allergy to the formula or a food? -Is there a blood test we can do? -Should I go to an allergist for allergy testing?

?

According to the revised Hanifin and Rajka criteria and the American Academy of Dermatology 2014 Atopic Dermatitis guidelines, which of the following is considered an essential diagnostic feature of atopic dermatitis?

A. Family history of atopic dermatitisB. PruritusC. Elevated IgE levelD. Presence since birthE. Skin biopsy showing spongiosis

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According to the revised Hanifin and Rajka criteria and the American Academy of Dermatology 2014 Atopic Dermatitis guidelines, which of the following is considered an essential diagnostic feature of atopic dermatitis?

A. Family history of atopic dermatitisB. PruritusC. Elevated IgE levelD. Presence since birthE. Skin biopsy showing spongiosis

Eichenfield LF, et al. J Am Acad Dermatol. 2014;70(2):338-351.

Atopic dermatitis: Clinical Diagnosis

?

Which of the following is the strongest risk factor for Atopic Dermatitis?

A. Family history of atopic dermatitisB. Living in a rural areaC. Early introduction of solid foodsD. Male sexE. A high total IgE level

Which of the following is the strongest risk factor for Atopic Dermatitis?

A. Family history of atopic dermatitisB. Living in a rural areaC. Early introduction of solid foodsD. Male sexE. A high total IgE level

Atopic dermatitis: Epidemiology

• Affects 20 % of children & 2-3 % of adults

• 60% develop AD in 1st year of life

• 90% by 5 years of age

• 10 -30% of patients persists into adulthood

• Strong risk factors

– (1) a family history of atopy and

– (2) the loss of function mutations in the FLG

Eichenfield LF et al. J Am Acad Dermatol 2014

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Atopic dermatitis: Risk Factors

Increased risk No effect

Black race Type of delivery (ie c/s or vaginal)

Higher level of parental education Male v Female sex

Higher socioeconomic status (*some studies)

Timing of solid food introduction

Living in urban areas Withholding of allergenic foods by infant and/or mother

Protective factors: Exposure to microbial endotoxin, farm animals and dogs, unpastuerized milk consumption (*not recommended)

Unclear: Daycare, pets

Eichenfield LF et al. Guidelines…Atopic Dermatitis. J Am Acad Dermatol 2014

AD Pathogenesis: Multifactorial

Genetic

Susceptibility

Epidermal

BarrierDysfunction

Immune

Dysfunction

Environmental Factors

Barnes KC. J Allergy Clin Immunol 2010Noda S et al J Allergy Clinical Immunol 2015

TLR, AMPsPRP

IL-4

IgE

iDC

CCL17CCL18CCL 22

IL-4, IL 13

AD: Complex PathogenesisCeramidesTEWL

AD Pathogenesis: Multifactorial

Genetic

Susceptibility

Epidermal

BarrierDysfunction

Immune

Dysfunction

Environmental Factors

Atopic dermatitis: Biomarkers

• Most commonly associated laboratory feature = elevated total and/or allergen specific serum IgE level– Not present in 20% of affected individuals

– Present in 55% of the general population

– May be a secondary phenomenon1

• Total IgE level does vary with disease severity– Not a reliable indicator

– Some with severe disease have normal values

• Similar inconsistent associations:– Mast cell & eosinophil counts, CD30, IL-12, -16, -18, -31,

thymus and activation regulated chemokine (TARC)

1 Kabashima K. J Dermatol Sci 2013

Recommendations for use of biomarkers:

• For patients with presumed atopic dermatitis, there are no specific biomarkers that can be recommended for diagnosis and/or assessment of disease severity.

• Monitoring of immunoglobulin E levels is not recommended for the routine assessment of disease severity.

– Strength of recommendation: A

Atopic dermatitis: Biomarkers

Eichenfield LF et al. Guidelines…Atopic Dermatitis. J Am Acad Dermatol 2014

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?

This parent is concerned that a food allergy is causing her child’s atopic dermatitis. On questioning there have been no hives, no lip swelling, and no other signs of immediate hypersensitivity. What is the best next step in management?

A. Check a full food immunoglobulin E (IgE) panelB. Check a limited food IgE panel, including peanut, soy,

fish, egg, and wheatC. Patch testing with food chemicals D. Limited skin prick for foodsE. Treat with topical therapies and follow clinically,

allergy testing is not indicated

This parent is concerned that a food allergy is causing her child’s atopic dermatitis. On questioning there have been no hives, no lip swelling, and no other signs of immediate hypersensitivity. What is the best next step in management?

A. Check a full food immunoglobulin E (IgE) panelB. Check a limited food IgE panel, including peanut, soy,

fish, egg, and wheatC. Patch testing with food chemicals D. Limited skin prick for foodsE. Treat with topical therapies and follow clinically,

allergy testing is not indicated

Atopic dermatitis & Food Allergies

• 15-30% of children with moderate to severe AD also have food allergies

• “An adverse health effect arising from a specific immune response that occurs reproducibly on exposure to a given food.”

– IgE mediated: rapid onset ( 1 – 6 hrs) Urticaria, flushing, Respiratory and/or GI symptoms, anaphylaxis

– Non-IgE mediated: delayed onset (6 - 48hrs) eczematous dermatitis

• May be a trigger in a small subset of moderate-severe AD patients

Bergmann MM et al J Allergy Clin Immunol 2013Eichenfield LF et al. Guidelines…Atopic Dermatitis. J Am Acad Dermatol 2014

Food elimination diet x 4- 6 weeks

Atopic dermatitis & Food Allergies

Sidbury R et al. Guidelines…Atopic Dermatitis. J Am Acad Dermatol 2014

Most common: Egg, milk, peanut, soy & wheat Older children: tree nuts, fish, shellfish

Unlikely that food is a trigger

AD stable/ increased severity

Record intake & symptoms

Oral Food challengeConsider allergy testing

Consistent correlation

Improvement in symptoms

Recommendations:

• If significant concerns for allergy are identified (iehives, urticaria, etc) assessment can be undertaken. Allergy testing independent of history is not recommended.

• Consider limited food allergy testing (ie. cow’s milk, eggs, wheat, soy and peanut) in children < 5 yrs with moderate to severe AD if:

– Persistent moderate –severe AD in spite of optimized topical treatment, and/or

– History of immediate and reproducible reaction after ingestion of a specific food

Atopic dermatitis & Food Allergies

Sidbury R et al. Guidelines…Atopic Dermatitis. J Am Acad Dermatol 2014

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Recommendations:

• Food elimination diets based solely on the findings of food allergy test results are not recommended for the management of AD.

• If a patient has a true immunoglobulin E mediated allergy, he or she should practice avoidance to prevent potential serious health sequelae.

Atopic dermatitis & Food Allergies

Sidbury R et al. Guidelines…Atopic Dermatitis. J Am Acad Dermatol 2014

Atopic dermatitis & Food Allergies

• Tests: Skin Prick Test (SPT) and serum-specific IgE levels

• High negative predictive values (>95%) and low specificity and positive predictive values (40-60%)

• Positive tests need verification

– Food elimination diet or oral food challenge

• Most children develop tolerance over time and should be retested

Sidbury R et al. JAAD 2014

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The mother of an infant with severe atopic dermatitis asks whether she should delay introduction of peanuts because there is a family history of eczema and food allergies. What is the most appropriate response?

A. Yes, early introduction increases the risk of developing a peanut allergy

B. Yes, given her family history she is at high risk of anaphylaxis

C. No, current evidence now supports early introduction of peanuts

D. No, current evidence shows that timing of introduction does not matter

The mother of an infant with severe atopic dermatitis asks whether she should delay introduction of peanuts because there is a family history of eczema and food allergies. What is the most appropriate response?

A. Yes, early introduction increases the risk of developing a peanut allergy

B. Yes, given her family history she is at high risk of anaphylaxis

C. No, current evidence now supports early introduction of peanuts

D. No, current evidence shows that timing of introduction does not matter

Consensus communication on early peanut introduction in high-risk infants

• Provide interim guidance based on current evidence supporting early peanut introduction

• Learning Early About Peanut Allergy (LEAP) Trial

• 5 year RCT of 640 high risk infants ages 4 – 11 months

– High risk – history of egg allergy, severe eczema

– Most (542) with negative skin prick test, 98 had minimally positive responses to peanut

• Two arms – Avoidance versus peanut ingestion three times weekly

Fleischer DM et al Pediatrics 2015DuToit G, et al. Randomized trial of peanut consumption in infants at risk for peanut allergy. N Engl J Med. 2015

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• Results:

– 17.2% (peanut avoidance grp) vs. 3.2% (peanut consumption grp) had peanut allergy at 5 years of age

– 14% absolute risk reduction & number needed to treat of 7.1

– 81% relative risk reduction

• Interim guidance:

– Recommend introduction of peanut products into diets of “high-risk” infants in countries where peanut allergy is prevalent

– Infants with egg allergy or severe eczema might benefit from evaluation by allergist or dermatologist familiar with these guidelines to assist in implementing these suggestions

Consensus communication on early peanut introduction in high-risk infants

Fleischer DM et al Pediatrics 2015DuToit G, et al. N Engl J Med. 2015

Clinical scenario 1: Answers• What? Atopic dermatitis

• Why? Father with AD, right genetics and environmental triggers

• Is this an allergy to the formula or a food? No, more likely to also have a food allergy but not the cause

• Is there a blood test we can do? No

• Should I go to an allergist for allergy testing? No, no reproducible reaction

• Treatment: Fluticasone cream twice daily until clear, moisturizer, once clear, reintroduce regular formula

Clinical scenario 2:• 12-year-old boy with AD

• Thick eczematous plaques on arms and legs

• In past year, “always flaring”

• Current Rx: Cephalexin x 10 days, completed 1 month ago, hydrocortisone butyrate lotion once a day, vaseline

• Hx of furuncules but not now

Father asks you:My wife says he needs antibioticsHis eczema is always flared up, is this an infection?

AD and Infections

• Increased susceptibility to viral, bacterial and fungal infections

– Molluscum contagiosum

– Herpes simplex

– Smallpox

– Staphylococcus aureusEczema herpeticum

Staphyloccocus aureus and AD

• Highly prevalent in atopic dermatitis

– Pooled data from 95 studies1

• Lesional skin – 70% prevalence of S. aureus colonization; odds ratio (OR) versus control: 19.74

• Nonlesional skin - 39% prevalence of S. aureus; OR: 7.7

• Nares - 62% prevalence of S. aureus; OR: 4.5

• Prevalence of colonization increased with disease severity

• Eczema clinical severity α S. aureus density3

• 100-1000-fold > density of S. aureus on lesional compared to non-lesional2

• Clinical relevance is patient dependent

– No morbidity in most patients1 Totte JE, et al. Br J Dermatol 2016

2 Lin YT, et al. Clinic Rev Allerg Immunol 2007;33:167-1773 Gilani SJ, et al. Clin Exp Dermatol. 2004;30:10

Staphyloccocus aureus and AD

• Barrier and innate immunity defects promote S. aureuscolonization

• S. aureus derived ceramidase increases the permeability of the stratum corneum

• S. aureus produces exotoxins that act as superantigens

– Antigen-independent activation of T-cell receptor promotes inflammation

– S. aureus superantigens (SEB) applied to intact nonlesional skin of AD patients can induce erythema and dermatitis

• Sensitization: high levels of anti-staphylococcal IgE in AD

Strange P, et al. Arch Derm 1996; 132Skov L, et al. J Allergy Immunol 2000; 105

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Staphyloccocus aureus and AD

PathogenInfection

Inhabitant Colonization

?

The father of this 12-year-old boy asks you to prescribe an antibiotic because the culture taken by his pediatrician grew Staphylococcus aureus. You inform the father that with the use of topical corticosteroids prescribed, the density of Staphylococcus aureus is expected to:

A. Increase B. DecreaseC. Stay the sameD. Increase or decrease depends on the person

The father of this 12-year-old boy asks you to prescribe an antibiotic because the culture taken by his pediatrician grew Staphylococcus aureus. You inform the father that with the use of topical corticosteroids prescribed, the density of Staphylococcus aureus is expected to:

A. Increase B. DecreaseC. Stay the sameD. Increase or decrease depends on the person

• Oral antibiotics alone do not lead to satisfactory clinical improvement

• The addition of oral or topical antibiotics to topical anti-inflammatory treatments in uninfected eczema, reduces S. aureus density (temporarily) but does not lead to superior clinical improvement 1-4

• Both groups (TCS or TCI alone and TCS or TCI + Antibiotic) had decreased colonization rates and same clinical improvement1-4

• Patients quickly recolonize with S. aureus2

• S. aureus develops resistance4

Antibiotics in Atopic Dermatitis

1 Ewing C et al Br J Dermatol 19982 Boguniewicz M et al J Allergy Clin Immunol 2001

3 Gong JQ, et al. Br J Dermatol 20064 Hung SH et al Ann Asthma Immunol 2007

S. aureus and Atopic dermatitis

• Treatment of uninfected AD with topical anti-inflammatory medications improves barrier and decreases bacteria1-3

1 Stadler JF et al. Br J Dermatol 19942 Pournaras CC et al. J Invest Dermatol 20013 Hung SH et al. Ann Allergy Immunol 2007

Tacrolimus 0.1% ointment BID on S.aureus density

Tacrolimus 0.1% ointment BID on TEWL

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S. aureus returns to baseline levels after treatment

Mean

Pro

po

rtio

n

Kong HH Genome Res 2012

• Mean relative abundance of bacterial families at baseline flare and post-flare

Topical steroids suffice to decrease bacteria

a Total Bacteria

Log 1

0A

mpl

icon

copi

es

TCS + Bleach

(n=27)

TCS alone

(n=27)

TCS + Bleach

(n=9)TCS alone

(n=9) (n=44)

b Staphylococcus

Log 1

0A

mp

lico

nco

pie

s

TCS + Bleach(n=27)

TCS alone(n=27)

TCS + Bleach(n=9)

TCS alone(n=9) (n=44)

Log 1

0A

mpl

icon

copi

es

c S. aureus

TCS + Bleach(n=15)

TCS alone(n=19)

Lesional

TCS + Bleach(n=2)

TCS alone

(n=6)

Nonlesional

(n=11)

Control

d Streptococcus

Log 1

0A

mpl

icon

copi

es

TCS + Bleach

(n=19)

TCS alone

(n=19)

TCS + Bleach

(n=7)TCS alone

(n=7) (n=36)

e Corynebacterium

Log 1

0A

mpl

icon

copi

es

TCS + Bleach

(n=27)

TCS alone

(n=27)

TCS + Bleach

(n=9)TCS alone

(n=9) (n=32)

Log 1

0A

mpl

icon

copi

es

TCS + Bleach

(n=24)

TCS alone

(n=24)

Lesional

TCS + Bleach

(n=8)

TCS alone

(n=8)

Nonlesional

(n=32)

Control

f PropionibacteriumLesional Nonlesional Control

Gonzalez ME et al. JAAD 2016, In press

• Both groups: TCS alone & TCS + twice weekly bleach baths led to significantly decreased bacteria and Staphylococcus

• RCT of children with moderate to severe, infected AD treated with cephalexin x 2 weeks

• Greater EASI score reduction with BB (2x/week) and intranasal mupirocin ointment (5 day/month) vs simple bathing at 3 months1

• Improved clinical severity but did not eradicate S. aureus

Bleach baths in Atopic Dermatitis

1 Huang J et al Pediatrics 2009

Changes in mean EASI scores over time

Antimicrobials in Atopic Dermatitis

Recommendation:

•The use of systemic antibiotics in the treatment of noninfected atopic dermatitis is not recommended.

– Strength of recommendation: B/II

•Systemic antibiotics are appropriate and can be recommended for use in patients with clinical evidence of bacterial infections in addition to standard and appropriate treatments for atopic dermatitis disease itself (which may include the concurrent use of topical corticosteroids).

– Strength of recommendation: A/I and C/II

Recommendation:

• Except for bleach baths with intranasal mupirocin, no topical antistaphylococcal treatment has been shown to be clinically helpful in patients with AD, and is not routinely recommended.

– Strength of recommendation: A/I

• In patients with moderate to severe AD and clinical signs of secondary bacterial infection, bleach baths and intranasal mupirocin may be recommended to

reduce disease severity.

– Strength of recommendation: B/II

Antimicrobials in Atopic Dermatitis Wet wrap therapy in AD

• Method to quickly reduce AD severity

• Significant flares and/or recalcitrant disease

• Technique:

– (1) TCS or TCI

– (2) Moist layer: Tubular bandages, gauze, cotton suit, PJs

– (3) Dry layer

• Increased penetration, decreasing water loss, and providing a physical barrier against scratching

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Clinical scenario 2: Answers• My wife says he needs

antibiotics? – Antibiotics are not indicated because

there is no clinical evidence of infection, can have side effects, and may contribute to development of resistant bacteria

• Is this an infection?

– No, S. aureus is more prevalent on his skin because he has atopic dermatitis

• Treatment: mometasoneointment + Wet wrap therapy short term, moisturizer

• Atopic dermatitis is a chronic inflammatory skin disease with a complex pathogenesis; new insights into inflammatory pathways new therapeutic targets

• No biomarkers yet

• Food elimination diets (including elemental formula use), and allergy testing without a history of a reproducible reaction are not recommended

• S. aureus is a known colonizer on AD skin, oral and topical antimicrobials provide no additional clinical benefit are not recommended for the treatment of routine non-infected AD flares

Summary

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