Format 2015: what is new in pediatric allergic diseases

What is New in Pediatric Allergic Diseases 2015
Attilio Boner
University of
Verona, Italy
attilio.boner@univr.it
Diagnosis
Food Allergy
Atopic Dermatitis
Allergic Asthma
Allergic Rhinitis
Anaphylaxis
Urticaria & Angioedema
Risk & Protective factors
Burden

The predictive value of allergen skin prick tests and IgE
tests at pre-school age: The PACT study
Dorthea RA, PAI 2014;25:691–698
Background
•Sensitization toward allergens, as determined by SPTs or sIgE, is a
predictor for the later presence of allergy-related disease
(atopic eczema, allergic rhinoconjuctivitis and asthma).
•However, it is not known whether SPT or sIgE should be the
preferred test.
•The aim of this study was to compare the predictive ability of SPT
and sIgE when performed in a general population of 2-yr-old children.

 longitudinal population-based
study of children aged
2–6 yr
 SPTs and sIgE for 9 common
allergens performed at 2 yr
 allergy related disease
evaluated by clinical
examination and questionnaire
at 2 and 6 yr of age (n = 199)
40 –
30 –
20 –
10 –
.0
10.6%
21.1%
% children aging 2 yrs with
(+) SPTs (+) sIgE
Dorthea RA, PAI 2014;25:691–698

OR for subsequent allergic disease
by age 6 yrs
7.0 –
6.0 –
5.0 –
4.0 –
3.0 –
2.0 –
1.0 –
0.0
6.5
4.1
(+) SPTs (+) sIgE
Dorthea RA, PAI 2014;25:691–698
2–6 yr

by age 6 yrs
7.0 –
6.0 –
5.0 –
4.0 –
3.0 –
2.0 –
1.0 –
0.0
6.5
4.1
(+) SPTs (+) sIgE
Dorthea RA, PAI 2014;25:691–698
2–6 yr
Sensitization at
2 yr may be
useful predictors
of allergy-related
disease
later in childhood

by age 6 yrs
7.0 –
6.0 –
5.0 –
4.0 –
3.0 –
2.0 –
1.0 –
0.0
6.5
4.1
(+) SPTs (+) sIgE
Dorthea RA, PAI 2014;25:691–698
2–6 yr
Receiver operating
characteristic analysis
showed that SPT and
sIgE had comparable
predictive ability for
atopic eczema, asthma
or any allergy-related
disease, but sIgE had
better ability to
predict later allergic
rhinoconjunctivitis.
ns

Disagreement between skin prick test and specific IgE
in young children Schoos A. M. M. Allergy 2015;70:41
 389 children from the
Copenhagen Prospective
Study on Asthma in
Childhood
 SPTs and sIgE levels
assessed simultaneously
for 16 common inhalant
and food allergens at
age ½, 1½, 4, and 6 years
Inhalant allergens:
changes in prevalence over time

Inhalant allergens: changes in prevalence over time
The prevalence of inhalant allergen sensitization increased during childhood
diagnosed by both sIgE levels (p<0.0001) and SPT results (p<0.0001)

Inhalant allergens, agreement
between SPT and sIgE.
The numbers in the figure are
absolute numbers
Study on Asthma in
Childhood

Food allergens: changes
in prevalence over time
Study on Asthma in
Childhood

The Prevalence of food sensitization increased during childhood when diagnosed from
sIgE (p<0.0001), but decreased when diagnosed from SPT (p=0.05)
Food allergens: changes in prevalence over time

Food allerges, agreement between
SPT and SIgE.
absolute numbers
Study on Asthma in
Childhood

Food allerges, agreement between
SPT and SIgE.
absolute numbers
Study on Asthma in
Childhood
Overall, the agreement
between SPT and sIgE
levels was poor to moderate
(all κ-coefﬁcients≤0.60)
and decreased from
moderate to slight for food
allergens by increasing age
(κ-coefﬁcients: 0.46)

1) We observed that the agreement between SPT and sIgE levels for
diagnosing inhalant and food allergen sensitization during preschool
age was at best moderate with a striking decrease in agreement
with age for food sensitization
2) Increasing the cutoff level of sIgE to 1.0 kUA/l had no noteworthy
effect on agreement
3) The pattern observed for sensitization to food allergens measured
by sIgE, with increasing prevalence with age, suggests this does not
reﬂect clinical food allergy
4) Some commercial SPT extracts do not contain all the components
of the foods, which may result in a higher sensitization prevalence
using sIgE levels compared to SPT

5) In addition, cross-reactivity between inhalant and food allergens
could add to the disagreement, for example, cross-reactivity
between Bet v 1 in birch and Ara h8 in peanut would result in a
higher prevalence of positive sIgE measurements for peanut
compared to SPT, if the SPT extract does not contain Ara h8
6) An alternative explanation for the disagreeing test results might
be that the immune response is different in the skin and in the
blood
7) The disagreement between SPT and sIgE results emphasizes the
importance of careful interpretation of test results based on
assessment method, clinical history, age of the child, and the type
of allergen tested for.

5) In addition, cross-reactivity between inhalant and food allergens
could add to the disagreement, for example, cross-reactivity
between Bet v 1 in birch and Ara h8 in peanut would result in a
higher prevalence of positive sIgE measurements for peanut
compared to SPT, if the SPT extract does not contain Ara h8
6) An alternative explanation for the disagreeing test results might
be that the immune response is different in the skin and in the
blood
7) The disagreement between SPT and sIgE results emphasizes the
importance of careful interpretation of test results based on
assessment method, clinical history, age of the child, and the type
of allergen tested for.
SPTs may underestimate the prevalence
of mite, dog, grass, and birch allergy.

The effect of component-resolved diagnosis on specific
immunotherapy prescription in children with hay fever.
Stringari G, J Allergy Clin Immunol 2014;134:75-81
Background:
 Sensitization to profilins and other cross-reacting molecules might
hinder proper specific immunotherapy (SIT) prescription in
polysensitized patients with pollen-related allergic rhinitis (AR).
 In these patients, component-resolved diagnosis (CRD) might modify
SIT prescription by improving the identification of the
disease-eliciting pollen sources.

 It has been suggested that SIT to a pollen should be prescribed only
when serum IgE antibodies to major allergenic molecular components
of that pollen are detectable.
 Hence component-resolved diagnosis (CRD) should make it possible to
avoid either the isolated administration of irrelevant allergens or the
“dilution” of the relevant ones in an SIT preparation.
 For example, it was proposed that patients with SPT reactivity to
grass pollen extracts should receive SIT for grass only in the
presence of IgE antibodies to the major allergenic molecules
Phl p 1, Phl p 5, or both.
 Similarly, patients with SPT response positivity to the extract of
parietaria, mugwort, Betulaceae, or olive should receive SIT only if
they have IgE to Par j 2, Art v 1, Bet v 1, and Ole e 1, respectively.

No IgE to the respective major allergens
was detected in significant proportions of
patients with supposed clinically relevant
sensitization to
69%
60%
30%
Betulaceae Parietaria
70 –
60 –
50 –
40 –
30 –
20 –
10 –
00
Mugwort
artemisia
 Children (n = 651) with
moderate-to-severe pollen-
related AR recruited
16 Italian outpatient clinics.
 SPT to grass, Betulaceae,
cypress, mugwort, olive,
parietaria.
 IgE to Phl p 1, Phl p 5, Bet v 1,
Cup a 1, Art v 1, Ole e 1,
Par j 2, and Phl p 12 (profilin)
by ImmunoCAP.
(-) Art v 1
(-) Bet v 1
(-) Par j 2

28%
15%
10%
Cypress Grass
30 –
20 –
10 –
00
Olive
sensitization to
(-) Ole e 1
(-) Cup a 1
(-) Phl p 1
(-) Phl p 5
parietaria.
by ImmunoCAP.

parietaria.
by ImmunoCAP.
28%
15%
10%
Cypress Grass
30 –
20 –
10 –
00
Olive
sensitization to
(-) Ole e 1
(-) Cup a 1
(-) Phl p 1
(-) Phl p 5
IgE to panallergens:
profilins (Phl p 12),
polcalcins, or both
could justify
173 (37%) of 464
of these SPT
reactions.

European American
42%
48% 47%
50 –
40 –
30 –
20 –
10 –
00
% of SIT prescription that was
changed after component resolved
diagnosis according to
Approach
Opinion of the
14 local pediatric
allergists
parietaria.
by ImmunoCAP.

parietaria.
by ImmunoCAP.
European American
42%
48% 47%
50 –
40 –
30 –
20 –
10 –
00
% of SIT prescription that was
changed after component resolved
diagnosis according to
Approach
Opinion of the
14 local pediatric
allergists
In children with
pollen-related AR,
applying CRD leads
to changes
in a large proportion of
SIT prescriptions as
opposed to relying
on clinical history
and SPT alone.

Criteria for SIT prescription
A. European Monosensitization or Not more than 3
polysensitization
B. American Monosensitization or As many as the clinically
polysensitization relevant sensitization
C. Monoallergenic Monosensitization or Only 1
polysensitization
D. Monosensitization Monosensitization Only 1
Model Patient's clinically
relevant sensitization
Number of allergenic
extracts

 In the European model, when 4 or more clinically relevant
sensitizations were detected, the 3 most relevant allergens
were selected on the basis of the opinion of the locally
recruiting doctor.
 In the American model the number of allergenic sources to be
mixed was unlimited.
 In the monoallergenic model only the most important allergenic
source was allowed.

Factors augmenting allergic reactions
Niggemann B, Allergy 2014;69:1582
 Augmenting factors may explain why certain
conditions lead to anaphylaxis.
 Augmenting factors may exhibit 3 effects:
1) lowering the threshold,
2) increasing the severity, and
3) reversing acquired clinical tolerance.
 Common augmenting factors are
•physical exercise,
•menstruation,
•NSAIDs,
•alcohol,
•body temperature,
•acute infections,
•antacids.

Therapeutic options may address causative, preventive,
pragmatic, or symptomatic considerations:
• avoid the eliciting food
• take an antihistamine before any situation with a possible
risk of augmentation
• separate food and sport (at least for 2 h)
• carry an adrenaline autoinjector at all times

Proposal for a new terminology of risk
factors for anaphylactic reactions

Different effects of augmenting factors
(A) Lowering the threshold
(B) Increasing severity
(C) Reversing acquired clinical tolerance

Possible interacting mechanisms of augmentation

Misuse of medical devices: a persistent problem in
self-management of asthma and allergic disease
Bonds Ann Allergy 2015;114:74
A. Asthma is likewise a critically important disease.
B. Up to 92% of asthmatic patients incorrectly use inhalers.
C. Even among medical personnel, rates of correct use are suboptimal.
D. This misuse translates into reduced clinical efficacy of therapy.

% MDI users demonstrating
perfect technique
7%
The most
commonly missed step
was exhaling to
functional residual
capacity or residual
volume before
actuating the canister
(66% of imperfect
users failed to
perform this step).
20 –
15 –
10 –
05 –
00
 Factors associated
with incorrect use of
metered-dose inhalers
(MDIs) and epinephrine
autoinjectors.
 102 patients using
epinephrine and
44 patients using MDIs
with spacers from adult
and pediatric clinics.

Device technique standards: MDI

Errors in metered-dose inhaler technique demonstration.
(C) Number of steps performed
incorrectly by patients with a MDI
(D) Frequency with which each step was
performed incorrectly (MDI).

1) Anaphylaxis is a concerning disorder because of its life-threatening
potential and increasing incidence.
2) It is well established that intramuscular epinephrine is a life-saving
therapy in anaphylaxis; however, patients frequently
do not understand how to self-administer
the medication.
3) The problem of incorrect epinephrine autoinjector
use is documented in the literature with rates of correct use
as low as 22%.
4) This misuse has been documented in cases of fatal anaphylaxis.

 Factors associated
with incorrect use of
metered-dose inhalers
(MDIs) and epinephrine
autoinjectors.
 102 patients using
epinephrine and
44 patients using MDIs
with spacers from adult
and pediatric clinics.
% patients used the epinephrine
autoinjector properly
20 –
15 –
10 –
05 –
00
16%
The most common
error was not
holding the unit in
place for ≥ 10
seconds after
triggering.
This error was
done by 76% of
patients.

Device technique standards: EpiPen

Errors in technique demonstration.
(A) Number of steps performed
incorrectly by patients with
epinephrine autoinjector.
(B) Frequency with which each step
was performed incorrectly
(epinephrine autoinjector).

Peanut allergens are rapidly transferred in human breast
milk and can prevent sensitization in mice
Bernard H., Allergy 2014; 69: 888
Ara h6 is detected as
soon as 10 min after
peanut ingestion, with
peak values observed
within the first hour
after ingestion.
The transfer is
long-lasting, small
quantities of peanut
allergens being detected
over a 24-h period
 Human breast milk was collected
from 2 non-atopic peanut-tolerant
mothers before and at different
time points after ingestion of 30 g
of commercial roasted peanut
 Ara h6, Ara h6 immune complexes,
and the IgE binding capacity of
breast milk samples were measured
using specific immunoassays
 Human breast milk obtained
before or after peanut ingestion
was administered intragastrically
to BALB/c mice, and mice were
further experimentally sensitized

Peanut
allergens
transferred in
milk are IgE
reactive and
can induce an
allergic
reaction
in vitro
Ara h6 is detected as
soon as 10 min after
peanut ingestion, with
peak values observed
within the first hour
after ingestion.
The transfer is
long-lasting, small
quantities of peanut
allergens being detected
over a 24-h period

Ara h6 is rapidly excreted in
human breast milk
24 hrs12 hrs10 min

However,
administration of
human breast milk to
young mice, notably
before weaning,
does not lead to
sensitization,
but instead to
partial oral tolerance

Randomized Trial of Peanut Consumption
in Infants at Risk for Peanut Allergy
Du Toit G, N Engl J Med 2014;372:803-13
 640 infants,
aged between 4 and 11 months,
with severe eczema,
egg allergy, or both.
 Randomly assigned to:
 dietary peanut consumption or
 dietary peanut avoidance.
 Randomly stratified into 2 study
cohorts on the basis of the results
of a skin prick test for peanut allergy:
 no measurable wheal
 a wheal measuring
1 to 4 mm in diameter.
20 –
15 –
10 –
05 –
00
Avoidance
Group
Consumption
Group
p<0.001
17.2%
3.2%
Prevalence of peanut allergy
(+OFC) at 60 months of age
in the whole cohort.
±

±
 640 infants,
with severe eczema,
20 –
15 –
10 –
05 –
00
Avoidance
Group
Consumption
Group
p<0.001
17.2%
3.2%
Increases in levels of
peanut-specific IgG4 antibody
occurred predominantly
in the consumption group.
A greater percentage of
participants
in the avoidance group had
elevated titres of
peanut-sIgE.
sIgE
sIgG4
Prevalence of peanut allergy
(+OFC) at 60 months of age
in the whole cohort.

Prevalence of peanut allergy (+OFC)
at 60 months of age
in the (+) SPT cohort.
40 –
30 –
20 –
10 –
0
Avoidance
Group
Consumption
Group
p=0.00435.3%
10.6%
 640 infants,
with severe eczema,
±

40 –
30 –
20 –
10 –
0
Avoidance
Group
Consumption
Group
p<0.001
13.7% 1.9%
at 60 months of age
in the (-) SPT cohort.
 640 infants,
with severe eczema,
±

±
40 –
30 –
20 –
10 –
0
Avoidance
Group
Consumption
Group
p<0.001
13.7% 1.9%
 640 infants,
with severe eczema,
Early introduction of peanuts
significantly decreased
the frequency of the
development of peanut allergy
among children at high risk
for this allergy
and modulated immune
responses to peanuts.
at 60 months of age
in the (-) SPT cohort.

Tolerance to egg proteins in egg-sensitized infants
without previous consumption Alvaro M, Allergy 2014;69:1350
Background:
•Egg-sensitized infants who have never eaten egg may react at first
ingestion.
•We sought to determine the association between skin prick test
(SPT) and sIgE to egg proteins (EP) and oral food challenge (OFC)
outcomes to find cut-off points which can diagnose egg allergy.
±

Patient classification relating
SPT and outcomes after OFC
 154 infants up to 18 months, with
cow’s milk allergy (CMA) and/or
atopic dermatitis (AD) without
previous egg consumption
 Skin prick test (SPT) to egg
proteins (EP) were performed.
If it was positive, sIgE was
performed
 If positive SPT and/or sIgE
(n = 94), oral food challenge (OFC)
performed between 12 and 18
months
±

±
Patient classification relating
SPT and outcomes after OFC
performed
months
Egg white (EW)
and ovalbumin
(OVA) sIgE have
the best area
under the curve
(AUC)

Sensitized infants
but “cooked
egg tolerant”
performed
months
±

±
Sensitized infants
but “cooked
egg tolerant”
performed
months
In egg-sensitized infants
with egg white (EW)
SPT ≥8mm and/or EW
sIgE ≥8.36 KU/l,
egg diagnostic oral food
challenge (OFC) can be
avoided as there is
94% probability of
resulting positive

±
Sensitized infants
but “cooked
egg tolerant”
performed
months
In the other
patients, oral food
challenge (OFC)
should be
performed safely
and early to avoid
unnecessary diets

Predicting Outcomes of Oral Food Challenges by Using
the Allergen-Specific IgE–Total IgE Ratio
Gupta RS, J Allergy Clin Immunol Pract 2014;2:300-5
Background
 Although allergists typically use allergen-specific IgE (sIgE) levels or
skin prick test wheal sizes to identify food allergens that may provoke
IgE-mediated food-induced allergic reactions, both tests have high rates
of false positivity and mislabel patients who are tolerant as allergic to
the food allergen.
Objective
 To examine the accuracy of the ratio of sIgE to total IgE (“Ratio”) in
predicting the outcome of challenges performed to confirm the
development of tolerance.
Ratio = (sIgE/tIgE) × 100

 Children diagnosed
with food allergy.
 Oral food challenge.
 The Ratio was calculated
by using the following
formula:
Ratio = (sIgE/tIgE) × 100.
sIgE to total IgE (“Ratio”) %
0.49%
1.5 –
1.0 –
0.5 –
00
1.48%
(-) (+)
FOOD CHALLENGE

 Children diagnosed
with food allergy.
 Oral food challenge.
 The Ratio was calculated
by using the following
formula:
Ratio = (sIgE/tIgE) × 100.
sIgE to total IgE (“Ratio”) %
0.49%
1.5 –
1.0 –
0.5 –
00
1.48%
FOOD CHALLENGE
The Ratio was
significantly more
accurate than sIgE
alone in predicting
challenge outcome
(Ratio 0.69 vs sIgE
alone 0.55; P =0.03 ).
(-) (+)

Median Ratio (sIgE/tIgE) stratified
by outcome of oral food challenge
“Less persistent FA” refers to
milk, egg, wheat, and soy as a
group (red);
“more persistent FA” refers
to peanut, tree nuts, shellfish,
and seeds as a group (blue).

Median Ratio (sIgE/tIgE) stratified
by outcome of oral food challenge
“Less persistent FA” refers to
milk, egg, wheat, and soy as a
group (red);
“more persistent FA” refers
to peanut, tree nuts, shellfish,
and seeds as a group (blue).
The Ratio for participants
who failed their OFC was
higher than the Ratio for
those who passed,
especially for more
persistent allergens
(eg, peanut and tree nuts).

Differences in empowerment and quality of life among
parents of children with food allergy
Warren C, Ann Allergy Asthma Immunol, 2015;114:117-25
Psychological empowerment
has been defined as
“a process through which people
gain greater control over
decisions and actions affecting
their health.”
Psychological empowerment
is believed to facilitate
the appropriation of medical
knowledge and reinforce
psychosocial skills,
thus increasing self-efficacy
with regard to disease and
treatment-related behaviors.
 876 families of children
with food allergy.
 Food allergy defined
by stringent criteria.
 Parental empowerment and
Food Allergy-Related Quality Of
Life (FAQOL) assessed
by the adapted Family
Empowerment and
FAQOL-Parental Burden scales.

with food allergy.
Empowerment and
 Mothers reported
greater empowerment
(p < .001) and
lower FAQOL (p < .001)
compared with fathers.
 Greater effects
on FAQOL were seen
for milk and egg
compared with other
food allergies.

with food allergy.
Empowerment and
Although parents
of children with food
allergy might be
empowered to care
for their child,
they continue to
experience impaired
FAQOL owing to fears
of allergen exposure
beyond their control.
 Mothers reported
greater empowerment
(p < .001) and
lower FAQOL (p < .001)
compared with fathers.
 Greater effects
on FAQOL were seen
for milk and egg
compared with other
food allergies.

 305 caregiver
quality of life (QoL)
of children allergic
to milk, egg, peanut,
or tree nut.
Comparison of mean quality of life
(QoL) scores for each allergen and the
overall study population.
Increased scores indicate worse QoL.
What affects quality of life among caregivers
of food-allergic children?
Howe Ann Allergy 2014;113:69
p=0.001
p<0.0001

 305 caregiver
or tree nut.
p=0.001
p<0.0001Milk or egg allergy
and an income
< $50,000 was
associated with
worse QoL.

 305 caregiver
or tree nut.
Multiple food allergies
(p=0.007), accurate
reaction perception
(-0.37, p=0.04), eczema
(+0.49, p=0.004), and
caregiver report that the
child had anaphylaxis
(+0.48, p=0.02) were
significantly
associated with
worse QoL score.
p=0.001
p<0.0001

1. Food protein-induced enterocolitis syndrome (FPIES) is a pediatric
non-immunoglobulin E (IgE)-mediated allergic disorder triggered by
the ingestion of food, whether solid or liquid.
2. Up to 65% of patients with FPIES react to cow’s milk and soy;
however, FPIES also can be caused by a wide variety of solid foods
in up to 25% of these patients with soy and milk FPIES.
3. FPIES usually presents within the first 6 to 12 months of life with
some nonspecific symptoms along a spectrum of severity:
repeated debilitating vomiting is typical and often accompanied by
diarrhea, and in more severe cases hypotension can develop,
manifesting as signs of shock.
Clinical presentation and referral characteristics
of food protein-induced enterocolitis syndrome
in the United Kingdom
Ludman Ann Allergy 2014;113:290

4. The symptoms resolve once the offending food protein has been
removed from the diet and reoccur on re-exposure.
5. Unlike immediate-onset IgE-mediated allergies, FPIES typically
presents 2 to 6 hours after ingestion of the culprit food
(“acute” FPIES); this delay commonly leads to misdiagnosis and
presentation to an acute medical setting, where a diagnosis of
sepsis or gastrointestinal viral illness is typically entertained.
6. Unlike sepsis, in FPIES the blood inflammatory markers are not
increased, but the peripheral white cell count can be elevated,
peaking at 6 hours, adding to the clinical confusion surrounding
the diagnosis.

7. The diagnosis of FPIES is made on clinical grounds.
8. FPIES also can present with a subacute or chronic
presentation (“chronic” FPIES) that manifests as
intermittent vomiting, diarrhea, faltering growth,
and sometimes dehydration.
9. This subacute or chronic presentation has been attributed to
continuous exposure to the food trigger, such as cow’s milk or soy
formula.

 54 patients with FPIES
presenting over a 3-year
period (2010-2013) in a
tertiary pediatric allergy
clinic in London.
 Presenting symptoms.
Average age of onset
at 8 months.
They initially presented
to medical professionals
other than an allergist
or gastroenterologist.

The most frequent
presenting symptom was
vomiting followed by signs
suggesting shock or
hypotension and diarrhea.
Differential diagnoses
included gastroenteritis,
sepsis, and surgical
abnormalities.
period (2010-2013) in a
clinic in London.

The main eliciting
foods were:
1) cow’s milk,
2) fish,
3) egg,
4) soy,
5) wheat.
period (2010-2013) in a
clinic in London.

Diagnostic criteria of food protein-induced enterocolitis syndrome
Van Sickle Gastroenterology. 1985;88:1915.
Leonard Curr Opin Pediatr. 2012;24:739.

Health practitioners seen by patients with
food protein-induced enterocolitis syndrome

Symptoms elicited from patient history
aIncludes melena, malodourous stools, pale stools, and sticky stools.

Clinical features and resolution of food protein-induced
enterocolitis syndrome: 10-year experience.
Caubet JC, J Allergy Clin Immunol 2014;134:382-9
 Food protein-induced
enterocolitis syndrome
(FPIES).
 160 subjects 6 months
to 45 years of age with
FPIES prospectively
recruited for oral food
challenges (OFCs).
 The diagnosis of FPIES was based on
Powell's clinical criteria:
1) exposure to the incriminated food
elicits repetitive vomiting, diarrhea,
or both within 4 hours without any
other cause for the symptoms;
2) symptoms are limited to the
gastrointestinal tract;
3) avoidance of the offending protein
from the diet results in resolution of
symptoms;
4) a standardized OFC or isolated re-
exposure elicits the typical symptoms.

 OFCs were performed after a minimum
of 12 months after the most recent
FPIES reaction to a specific food.
 A peripheral intravenous line was
placed before the OFC.
 Subjects were given from 0.06 g up
to 0.6 g of food protein per kilogram
of body weight (usually 0.3 g of
protein/kg body weight; maximum,
3 g of protein) in 3 equal doses over
a 45-minute period and remained under
observation for 4 to 8 hours after
the ingestion of the challenge food.
(FPIES).
FPIES prospectively
challenges (OFCs).

FPIES food triggers (number of patients)
65% reacted to 1 food,
26% reacted to 2 foods,
 9% reacted to ≥ 3 foods
(FPIES).
to 4.5 years of age with
FPIES prospectively
challenges (OFCs).

24%
25 –
20 –
15 –
10 –
05 –
00
% of subjects that in the
follow-up developed sIgE
to the food inducing FPIES
(FPIES).
FPIES prospectively
challenges (OFCs).
sIgE

4.7
years
7.0 –
6.0 –
5.0 –
4.0 –
3.0 –
2.0 –
1.0 –
0.0
4
years
5.1
years
6.7
years
Rice
Median age (years) when tollerance
was established (no FPIES)
Oat Soy Milk in pts
with no sIgE
for milk
(FPIES).
FPIES prospectively
challenges (OFCs).

(years) Median age when tollerance
4.7
years
7.0 –
6.0 –
5.0 –
4.0 –
3.0 –
2.0 –
1.0 –
0.0
4
years
6.7
years
Rice Oat Soy Milk in pts
with no sIgE
for milk
Whereas none of the
subjects with detectable
milk-specific IgE became
tolerant to milk during
the study (P=0.003).
(FPIES).
FPIES prospectively
challenges (OFCs).
5.1
years

(years) Median age when tollerance
4.7
years
7.0 –
6.0 –
5.0 –
4.0 –
3.0 –
2.0 –
1.0 –
0.0
4
years
6.7
years
Rice Oat Soy Milk in pts
with no sIgE
for milk
Whereas none of the
subjects with detectable
milk-specific IgE became
tolerant to milk during
the study (P=0.003).
(FPIES).
FPIES prospectively
challenges (OFCs).
5.1
years
FPIES typically resolves
by age 5 years.
Milk FPIES, especially
with detectable
food-specific IgE,
can have a protracted
course and eventually
transition to acute
reactions.

 A retrospective study.
 211 pediatric patients with
eosinophilic esophagitis
(EoE).
 Skin prick testing (SPT),
atopy patch testing (APT).
Pediatric eosinophilic esophagitis:
the Vanderbilt experience
Chadha Ann Allergy 2014;113:445
Younger patients showed
greater sensitization to foods
by SPT and APT. The most
common foods identified by
SPT were peanut, egg, and
soy. The most common foods
identified by APT were
potato, pork, and wheat.
Older patients with EoE
showed greater aeroallergen
sensitization; the most
common allergens were
pollens and dust mite.

Age distribution of presenting symptoms
of eosinophilic esophagitis
(EoE).

% subjects with (+) reaction to
80 –
70 –
60 –
50 –
40 –
30 –
20 –
10 –
00
65%
SPTs
77%
APTs
to foods
(EoE).

The impact of dietary therapy on clinical and biologic
parameters of pediatric patients with eosinophilic
esophagitis Colson D, JACIP 2014;2: 587-93
The updated consensus on EoE management recommends 3 dietary
methods:
1) an “elemental” diet, which removes all foods,
with an amino acid-based formula (AAF) as a substitute;
2) a 6 food elimination diet (SFED) that eliminates the most likely
food antigens, cow’s milk protein, wheat, soy, egg, peanut, nuts, and
fish and/or seafood;
3) an elimination diet based on multimodality allergy testing.

The updated consensus on EoE management recommends 3 dietary
methods:
1) an “elemental” diet, which removes all foods,
with an amino acid-based formula (AAF) as a substitute;
2) a 6 food elimination diet (SFED) that eliminates the most likely
food antigens, cow’s milk protein, wheat, soy, egg, peanut, nuts, and
fish and/or seafood;
3) an elimination diet based on multimodality allergy testing.
The modified SFED combined SFED with the
elimination of the foods that elicited a positive SPT
and/or APT.

2.2%
 111 ch. with eosinophilic esophagitis
(median age of 77.7 months)
 retrospective study in children
with EoE after a 2-month dietary
therapy
(6-food elimination diet,
avoidance of the 6 most
common allergenic foods,
plus avoidance of those eliciting
(+) SPTs, plus amino-acid formula
as replacement for diary products)
% children with dietary therapy
2.2%
60 –
50 –
40 –
30 –
20 –
10 –
0
7.46%
47.4%
59.3%
Normal endoscopic
appearance
Complete remission
<5 eosinophils/esophageal
HPF and disappearance
of symptoms

2.2%
therapy
2.2%
60 –
50 –
40 –
30 –
20 –
10 –
0
7.46%
47.4%
59.3%
Normal endoscopic
appearance
Complete remission
of symptoms
Post-diet blood
eosinophils counts
decreased in absolute
numbers
(P < 0.0001)

2.2%
therapy
2.2%
60 –
50 –
40 –
30 –
20 –
10 –
0
7.46%
47.4%
59.3%
Normal endoscopic
appearance
Complete remission
of symptoms
The nutritional status
of children with EoE
was mildly affected
and
not worsened by the
2-month
dietary therapy

2.2%
therapy
2.2%
60 –
50 –
40 –
30 –
20 –
10 –
0
7.46%
47.4%
59.3%
Normal endoscopic
appearance
Complete remission
of symptoms
Dietary therapy
with an amino-acid
formula as
a replacement for
dairy products is
nutritionally adapted
to the treatment
of EoE

 An amino-acid formula was prescribed as a replacement for dairy
products, Neocate or Nutramigen AA.
The recommended daily consumption of AAF was 500 mL or more, based
on the French pediatric feeding guidelines, which accounted for ≥30% of
total caloric intake.
 At the end of the 2-month period, the families reported whether or not
the child had followed the diet.
 Children were then prescribed a progressive reintroduction of eliminated
foods, 1 every 3 months, starting with foods for which they had tested
negative

 15 studies.
 Children undergoing
peanut, milk, and egg
oral immunotherapy
(OIT).
Relation between eosinophilic esophagitis and
oral immunotherapy for food allergy:
a systematic review with meta-analysis
Lucendo Ann Allergy 2014;113:624
Prevalence of
after OIT3.0 –
2.5 –
2.0 –
1.5 –
1.0 –
0.5 –
0.0
2.7%

 15 studies.
 Children undergoing
peanut, milk, and egg
oral immunotherapy
(OIT).
Relation between eosinophilic esophagitis and
oral immunotherapy for food allergy:
a systematic review with meta-analysis
Lucendo Ann Allergy 2014;113:624
Prevalence of
after OIT3.0 –
2.5 –
2.0 –
1.5 –
1.0 –
0.5 –
0.0
2.7%
Eosinophilic
esophagitis
often resolved
after OIT
discontinuation.

Is It Food Allergy or Frey Syndrome?
Betul Buyuktiryaki MD, JACI P 2015;3:269–270
 a 6-month-old boy with recurrent unilateral erythematous eruption
on his face after feeding
 symptoms were triggered by yoghurt, carrots, and fruit
(apples, pears, oranges) a few minutes after mastication
and would resolve spontaneously within 15 to 30 minutes
 the rash always appeared in the same area without pruritus, swelling,
respiratory, or gastrointestinal symptoms
 the child experienced the same manifestation with each newly added solid food
after chewing
 prick-to-prick tests and specific IgE levels were negative.

 an open challenge test with
yoghurt and pear on different
occasions resulted in flushing
within a few minutes, which
extended from the right cheek
across the preauricular and
temporal region to the forehead
scalp with no sweating and
disappeared over 20 minutes.

A: flushing on the left cheek after an open
challenge test with cucumber at 12 months of age
B: flushing on the right cheek after an open
challenge test with lemon at 12 months of age

 The child received a diagnosis of Frey syndrome, which is commonly
misinterpreted as a food allergy.
 Frey syndrome, otherwise named auriculotemporal nerve (ATN)
syndrome, is characterized by unilateral (rarely bilateral)
recurrent episodes of flushing and sweating over the parotid area
after gustatory stimulus.
 The syndrome most often occurs in adults after parotid surgery and very
uncommon in children. Because the disease often exhibits spontaneous resolution
within a few years in children, no treatment is recommended.
 It has been proposed that a perinatal birth trauma during delivery may be a
possible reason for damage to the auriculotemporal nerve.
 Although the majority of patients have flushing in the preauricular region
compatible with the cutaneous distribution of ATN, the reaction of our patient
expanded from the cheeks to the middle of the forehead.

The symptoms of Frey's syndrome are redness and sweating on the cheek area adjacent to
the ear (see focal hyperhidrosis). They can appear when the affected person eats, sees,
dreams, thinks about or talks about certain kinds of food which produce strong salivation.
Observing sweating in the region after eating a lemon wedge may be diagnostic.
Signs and symptoms include erythema (redness/flushing) and sweating in the cutaneous
distribution of the auriculotemporal nerve, usually in response to gustatory stimuli.
There is sometimes pain in the same area, often of a burning nature.
Between attacks of pain there is sometimes numbness or other alterred sensations
(anesthesia or paresthesia).
This is sometimes termed "gustatory neuralgia".

Milk allergy is associated with decreased growth
in US children.
Robbins KA, J Allergy Clin Immunol 2014;134:1466-68
 Anthropometric
measurements and
dietary intake of
calcium, vitamin D,
total calories, protein,
and fat between
children with and
without reported food
allergy by using National
Health and Nutrition
Examination Survey
(NHANES).
 6189 children aged
2 to 17 years.
6.3%
% children with
reported food allergy
10 –
09 –
08 –
07 –
06 –
05 –
04 –
03 –
02 –
01 –
00

in US children.
 Anthropometric
measurements and
dietary intake of
calcium, vitamin D,
and fat between
children with and
Examination Survey
(NHANES).
2 to 17 years.
Weighted box plots of anthropometric features for
children aged 2 to 17 years comparing children with
milk allergy versus those without milk allergy
(kg)/age (cm)/age (Kg/m2)/age

in US children.
 Anthropometric
measurements and
dietary intake of
calcium, vitamin D,
and fat between
children with and
Examination Survey
(NHANES).
2 to 17 years.
Weighted box plots of anthropometric features for
children aged 2 to 17 years comparing children with
milk allergy versus those without milk allergy
(kg)/age (cm)/age (Kg/m2)/age
Mean weight, height,
and BMI percentiles
were significantly
lower in those with
milk allergy

212
350 –
300 –
250 –
200 –
150 –
100 –
050 –
000
Mean total daily vitamin D
intake (D2+D3 [IU])
YES NO
Milk allergy
YES NO
in US children.
Mean total daily calcium intake (mg)
Milk allergy
308
802
1047p<0.001
p=0.053
1100 –
1000 –
0900 –
0800 –
0700 –
0600 –
0500 –
0400 –
0300 –
0200 –
0100 –
0000

Food allergies affect growth in children
Hobbs CB, J Allergy Clin Immunol Pract 2015;3:133-134
Weight for length and BMI
percentile of 4 groups of children
 245 children with real or
perceived food allergy
(RPFA)
(mean age 4.1 ± 2.9 yrs).
 Healthy and diseased
controls as patients with
celiac disease (CD) or
cystic fibrosis (CF).

(RPFA)
Children < 2 yrs with real
or perceived food allergy
(RPFA) had significantly
lower WFL percentiles,
and those ≥ 2 yrs had
significantly lower BMI
percentiles, compared to
healthy controls .
The adverse impact of
RPFA on WFL was less
than that of CD or CF.
Weight for length and BMI
percentile of 4 groups of children

(RPFA)
Growth percentiles per
number of food allergies

(RPFA)
Growth percentiles per
number of food allergies
Compared with those
with 1 or 2 RFPAs
children with
> 2 RFPAs had
significantly lower
mean weight p<0.001.

Decreased bone mineral density in young adult
IgE-mediated cow's milk-allergic patients.
Nachshon L, J Allergy Clin Immunol 2014;134:1108-13
 Densitometric measurements.
 Postpubertal patients
diagnosed with IgE-CMA
(group I, n = 33)
 Without IgE-CMA
(control group II, n = 24).
 IgE-CMA patients who after
desensitization consumed milk
for 12 to 39 months before
analysis (group III, n = 12).
Distribution of the severity of changes
in BMD in study participants

Participants' demographic characteristics
For continuous variables, data are presented as mean ± SD (median) and for categorical
variables data are presented as N (%). No statistical differences were noted between any
of the comparisons. H/W, Hours per week.

(group I, n = 33)
 Without IgE-CMA
Densitometric
measurements of
IgE-CMA patients
were significantly
lower than of those
in the control group
(P < 0.0001).

(group I, n = 33)
 Without IgE-CMA
IgE-CMA patients had a
severely reduced intake of
calcium than did controls
(335 vs 768; P <0.0001).
In addition, phosphorus
intake was significantly
lower in IgE-CMA
patients than in controls
(1004 vs 1295; P <0.0131)

(group I, n = 33)
 Without IgE-CMA
BMD measurements
in group III were
significantly greater
than in group I
(P <0.0001)
and unchanged from
the control group.

1) Even postpuberty, changes in the dietary habits of these patients, at
least by the introduction of dairy products, may indeed be successful
in reversing their risk for osteoporosis.
2) Milk provides a high concentration of bioavailable calcium; in contrast,
only 5% of the calcium in spinach is absorbed.
3) Working in concert with calcium intake, vitamin D, among its pleiotropic
actions, influences calcium absorption. In our study, the average vitamin
D levels were similar between patients and controls.
However, we noted a relatively high number of patients with suboptimal
vitamin D levels.

Conclusions:
 Patients with IgE-CMA have a significant risk of reduced BMD
and early osteoporosis, which appears to be reversible on milk
desensitization.
 Adequate calcium intake is not achieved while on a nondairy diet,
requiring investigation into optimal nutritional protocols for
these patients.

Recommended calcium intake*
BSACI guideline for the diagnosis and management of
cow’s milk allergy Luyt D, CEA 2014;44:642-672

Calcium content in selected foods

Home reintroduction should not be attempted if
any of the following features are present
1) Previous cow’s milk allergy symptoms that significantly affected
breathing [cough, wheezing, or swelling of the throat, for example cough, stridor, or choking
sensation or throat tightness (in older children)], the gut (i.e. severe vomiting or diarrhoea),
or the circulation (faintness, floppiness or shock)
2) A less severe reaction with only trace exposure
3) Regular asthma preventative inhaler treatment and/or poorly controlled asthma.
4) Multiple or complex allergy
5) No significant reduction in SPT wheal diameter/sIgE level since diagnosis
6) High sIgE levels without history of any prior milk exposure
(e.g. exclusively breastfed or hypoallergenic formula fed infants withsevere eczema)
7) Parents who are unable to comprehend or adhere to the protocol
8) Children with any of these features should undergo a supervised challenge in hospital.
9) In children at highest risk, a supervised baked milk challenge is preferable

Classification of cow’s-milk-containing foods
(‘Milk ladder’)
UHT
ultra-heat
treatment
sterilizes
food by heating
it above 135°C

 124 neonates at high risk
for atopic dermatitis.
 Parents in the intervention
arm were instructed to
apply full-body emollient
therapy at least once per
day starting within 3 weeks
of birth.
 Parents in the control arm
were asked to use
no emollients.
 Incidence of atopic
dermatitis at 6 months.
Emollient enhancement of the skin barrier from birth
offers effective atopic dermatitis prevention
Simpson EL, J Allergy Clin Immunol 2014;134:818-23
with the use of
daily emollient
0.50
1.0 –
0.5 –
0.0
RR of atopic dermatitis
denvelopment
at 6 months of age

 124 neonates at high risk
for atopic dermatitis.
 Parents in the intervention
arm were instructed to
apply full-body emollient
therapy at least once per
day starting within 3 weeks
of birth.
 Parents in the control arm
were asked to use no
emollients.
 Incidence of atopic
dermatitis at 6 months.
with the use of
daily emollient
0.50
1.0 –
0.5 –
0.0
There were no
emollient-related
adverse events
RR of atopic dermatitis
denvelopment
at 6 months of age

Skin barrier
protection
might prevent
atopic
dermatitis
development.
FLG, Filaggrin.

 In the United Kingdom emollient choices were sunflower seed oil
(William Hodgson and Co, Congleton, United Kingdom), Doublebase
Gel (Dermal Laboratories, Hitchin, United Kingdom), and liquid
paraffin 50% in white soft paraffin.
 In the United States parents were offered the same sunflower
seed oil as used in the United Kingdom, Cetaphil Cream (Galderma
Laboratories, Fort Worth, Tex), or Aquaphor Healing Ointment
(Beiersdorf, Chester, Ohio).
 We used sunflower seed oil with a high ratio of linoleic/oleic acid
to optimize the positive skin barrier effects.
Danby S.G. et al Pediatr Dermatol. 2013;30:42–50.

Application of moisturizer to neonates prevents
development of atopic dermatitis
Horimukai K, J Allergy Clin Immunol 2014;134:824-30
 Emulsion-type moisturizer
applied daily during the first
32 weeks of life to 59 of 118
neonates at high risk for AD
(based on having a parent or
sibling with AD).
 Onset of AD (eczematous
symptoms lasting >4 weeks)
and eczema (lasting >2 weeks).
 Cumulative incidence of
(AD/eczema) at week 32
of life.
 Serum levels of allergen-
specific IgE.
Proportions of infants who did not have
AD/eczema during the first 32 weeks of life
-32%
p=0.012

sibling with AD).
of life.
specific IgE.
Proportions of infants who did not have
AD/eczema during the first 32 weeks of life
Approximately 32%
fewer neonates who
received the
moisturizer had
AD/eczema by
week 32 than control
subjects (P = 0.012)
-32%
p=0.012

in infants who had
AD/eczema
2.86
3.0 –
2.5 –
2.0 –
1.5 –
1.0 –
0.5 –
0.0
OR for sensitization
sibling with AD).
of life.
specific IgE.

sibling with AD).
of life.
specific IgE.
in infants who had
AD/eczema
2.86
3.0 –
2.5 –
2.0 –
1.5 –
1.0 –
0.5 –
0.0
We did not show a
statistically significant
effect of emollient on
allergic sensitization
based on the level of
IgE antibody against
egg white at 0.34 kUA/L

sibling with AD).
of life.
specific IgE.
in infants who had
AD/eczema
2.86
3.0 –
2.5 –
2.0 –
1.5 –
1.0 –
0.5 –
0.0
Daily application of
moisturizer during the
first 32 weeks of life
reduces the risk of
AD/eczema in infants.
Allergic sensitization during
this time period is
associated with the
presence of eczematous
skin but not with
moisturizer use.

Allergic sensitization at week 32
sibling with AD).
of life.
specific IgE.

Numbers of Infants with AD/eczema
and allergic sensitization at week 32
sibling with AD).
of life.
specific IgE.

 In our study we were not able to show the significant effect of
emollient on the prevention of allergic sensitization based on the level
of IgE antibody against egg white; similar proportions of infants were
sensitized in the intervention and control groups.
 However, we showed that a higher proportion of infants with
AD/eczema had allergic sensitization based on serum concentrations
of anti–egg white IgE compared with infants without AD/eczema.
 Collectively, these findings indicate that the presence of eczematous
skin, rather than a lack of emollient use, induces or promotes
sensitization to allergens, such as egg white, during the first 8 months
of life.

Natural history of allergic sensitization in infants with
early-onset atopic dermatitis: results from ORCA Study
Just J, PAI 2014;25:668–673
 229 infants with active
atopic dermatitis (AD)
 follow up at age 6 yrs
 sIgEs
40 –
30 –
20 –
10 –
.0
26.2%
37.1%
% infants with baseline
elevated blood
eosinophilia
(eosinophil blood count
≥470 eosinophils/mm3)
elevated
total IgE
(serum IgE
level ≥45 kU/L)

Just J, PAI 2014;25:668–673
% children with sIgE to
baseline
58%
34%
67%
17%
70 –
60 –
50 –
40 –
30 –
20 –
10 –
0
food allergens inhaled allergens
baseline6 yrs 6 yrs
 sIgEs

Just J, PAI 2014;25:668–673
OR for developing sensitization
to inhaled allergens at 6 yr
4.0 –
3.0 –
2.0 –
1.0 –
0.0
3.72
initial multiple sensitizations
to food allergens
(≥ 2 allergens)
 sIgEs

Just J, PAI 2014;25:668–673
OR for developing sensitization
to inhaled allergens at 6 yr
4.0 –
3.0 –
2.0 –
1.0 –
0.0
3.72
initial multiple sensitizations
to food allergens
(≥ 2 allergens)
 sIgEs
In the early-onset
AD phenotype,
multiple sensitization
to food allergens
conveys a higher risk
of sensitization to
inhaled allergens than
single sensitization

Atopic dermatitis increases the effect of exposure to
peanut antigen in dust on peanut sensitization and likely
peanut allergy.Brough HA, J Allergy Clin Immunol 2015; 135:164-70
Background
 History and severity of atopic dermatitis (AD) are risk factors for
peanut allergy. Recent evidence suggests that children can become
sensitized to food allergens through an impaired skin barrier.
 Household peanut consumption, which correlates strongly with peanut
protein levels in household dust, is a risk factor for peanut allergy.
Objective
 We sought to assess whether environmental peanut exposure (EPE) is
a risk for peanut sensitization and allergy and whether markers of an
impaired skin barrier modify this risk.

 Peanut protein in
household dust
(in micrograms per gram).
 History and severity of
AD, peanut sensitization,
and likely allergy
(peanut-specific IgE,
≥5 kUA/mL).
with an increase in 4 log2
environmental peanut exposure
(EPE) units OR for
Peanut SPT
sensitization
Likely peanut
allergy
2.5 –
2.0 –
1.5 –
1.0 –
0.5 –
0.0
1.71
2.10
p=0.01 p<0.01
sIgE ≥5 kUA/mL

household dust
and likely allergy
≥5 kUA/mL).
(EPE) units OR for
Peanut SPT
sensitization
Likely peanut
allergy
2.5 –
2.0 –
1.5 –
1.0 –
0.5 –
0.0
1.71
2.10
p=0.01 p<0.01
sIgE ≥5 kUA/mL
The effect of EPE on
peanut SPT sensitization
was augmented in children
with a history of AD
(OR, 1.97 P <0.01) and
augmented even further in
children with a history of
severe AD
(OR, 2.41 P <0.01)

household dust
and likely allergy
≥5 kUA/mL).
(EPE) units OR for
Peanut SPT
sensitization
Likely peanut
allergy
2.5 –
2.0 –
1.5 –
1.0 –
0.5 –
0.0
1.71
2.10
p=0.01 p<0.01
sIgE ≥5 kUA/mL
The effect was also
augmented in children with
a history of AD
OR 2.34
P < 0.01

Predictive probability for the effect of
environmental peanut exposure (EPE)
(displayed in log2 [microgram per gram] units
and untransformed [microgram per gram]
units) for peanut SPT sensitization (PS)
Predictive probability for the effect of EPE
(displayed in log2 [microgram per gram] units
and untransformed [microgram per gram]
units) for likely peanut allergy (PA)

Epidemiological link between wheat allergy and exposure
to hydrolyzed wheat protein in facial soap
Fukutomi Y, Allergy 2014;69:1405
Background:
 Recent studies have highlighted the importance of extra-intestinal
routes of sensitization to food-related allergens as the cause of
epidemics of food allergy.
 Instances of Japanese women developing food allergy to wheat
after exposure to hydrolyzed wheat protein (HWP) present in
facial soap have been reported.
 However, the epidemiologic impact of these ingredients as a cause
of food allergy has not been well studied.

 Case–control study
of Japanese women
aged 20 – 54 years
with self - reported
wheat allergy (WA)
(cases, n = 157) and
controls (n = 449)
OR for food
allergy to wheat
3 –
2 –
1 -
0 -
2.6
current use of an hydrolyzed
wheat protein (HWP)-
containing facial soap

 Case–control study
of Japanese women
aged 20 – 54 years
with self - reported
wheat allergy (WA)
(cases, n = 157) and
controls (n = 449)
3 –
2 –
1 -
0 -
2.6
current use of an hydrolyzed
wheat protein (HWP)-
containing facial soap
This study implicates
a possible role of
contact exposure to
food-derived protein
hydrolysates as a
risk factor for the
development of food
allergy manifesting
itself as anaphylaxis
OR for food
allergy to wheat

Randomized trial of vitamin D supplementation for
winter-related atopic dermatitis in children
Camargo CA Jr, J Allergy Clin Immunol 2014;134:831-5
 104 Mongolian children
with winter-related AD
(age 2 to 17 years).
 AD score 10 to 72 using
the Eczema Area and
Severity Index (EASI).
 Oral cholecalciferol
(1000 IU/day) versus
placebo for 1 month.
Improvement in EASI score
mean after 1 month
-6.5
-3.3
Vitamin D Placebo
p=0.04
-.-0
-1.0 –
-2.0 –
-3.0 –
-4.0 –
-5.0 –
-6.0 –
-7.0 –

Randomized trial of vitamin D supplementation for
winter-related atopic dermatitis in children
Camargo CA Jr, J Allergy Clin Immunol 2014;134:831-5
 104 Mongolian children
with winter-related AD
(age 2 to 17 years).
 AD score 10 to 72 using
the Eczema Area and
Severity Index (EASI).
 Oral cholecalciferol
(1000 IU/day) versus
placebo for 1 month.
-6.5
-3.3
Vitamin D Placebo
p=0.04
-.-0
-1.0 –
-2.0 –
-3.0 –
-4.0 –
-5.0 –
-6.0 –
-7.0 –
The AD improvement from
vitamin D supplementation
has strong biological
plausibility :
 Importance of vitamin D
for epidermal barrier
function.
 Production of the
antimicrobial peptide
cathelicidin.
Improvement in EASI score
mean after 1 month

Lower vitamin D status is closely correlated with
eczema of the head and neck.
Noh S, J Allergy Clin Immunol 2014;133:1767-69
 82 patients with AD,
38 asthmatic patients,
and 49 healthy control
subjects (HCs).
 25-hydroxyvitamin D.
Mean serum 25-hydroxyvitamin D
(25[OH]VitaminD) concentrations

 82 patients with AD,
38 asthmatic patients,
and 49 healthy control
subjects (HCs).
 25-hydroxyvitamin D.
Mean serum 25-hydroxyvitamin D
(25[OH]VitaminD) concentrations
Patients with AD
have much lower
25 (OH) VitaminD
concentrations than
HCs (P <0.001)
or asthmatic patients
(P =0.001).

The correlation study showed a statistically significant negative correlation
between the 25(OH) Vitamin D concentration and eczema involvement of:
the total area and the head and neck area

 In this study there were much lower VitD levels in patients with AD than
in asthmatic patients or HCs.
 In our data VitD levels were significantly inversely associated with eczema
area rather than with severity of AD.
 Even in asthmatic patients, in whom the skin is unaffected by inflammation,
there were no significantly lower VitD levels compared with those seen in
HCs in our study.
 We herein propose that patients with AD have lower serum VitD levels
because VitD production in the skin is impaired as a result of cutaneous
inflammation.
 Because the head and neck type of AD is frequently sensitized to
Malassezia species yeasts, the possibility that metabolites of colonizing
Malassezia species in the head and neck might be modified by UV and
cause alteration in VitD metabolism should be further studied.

Association between childhood atopic dermatitis,
malnutrition, and low bone mineral density:
A US population-based study
Silverberg JI, Pediatr Allergy Immunol. 2015;26:54-61
 3049 children (8–19 yrs)
from the 2005–2006
National Health and
Nutrition Examination
Survey.
 Questionnaire,
dual energy X-ray
absorptiometry, and
blood samples.
Atopic Dermatitis was
associated with:
• higher odds of
25-OH vitamin D
deficiency
OR = 4.81
• lower bone mineral
density (BMD)
Z-score
and

Association between childhood atopic dermatitis,
malnutrition, and low bone mineral density:
A US population-based study
Silverberg JI, Pediatr Allergy Immunol. 2015;26:54-61
 low BMD in AD appear to be related to malnutrition as judged by low BMI
and albumin levels.
 Malnutrition may be related to avoidance diets in AD patients with
suspected food allergies or perceived exacerbation of their skin disease
by foods.
 Diets that avoid milk products and other essential foods may result in
severe malnutrition.
 AD was associated with vitamin D deficiency, which is consistent with
previous studies that found correlations between AD severity and
vitamin D levels.
 It may be that vitamin D levels are decreased secondary to food
avoidance and malnutrition, rather than inflammation per se.

 52 homes of patients
with AD.
 Water damage by
thermal assessments
using an infrared
camera.
% homes with water damage
60 –
50 –
40 –
30 –
20 –
10 –
0
59.6%
Infrared camera-proven water-damaged homes
are associated with the severity of atopic dermatitis
in children Seo Ann Allergy 2014;113:565

with AD.
 Water damage by
thermal assessments
using an infrared
camera.
% homes with water damage
60 –
50 –
40 –
30 –
20 –
10 –
0
59.6%
Concentrations of
airborne mold were
significantly higher in
water-damaged homes
than in undamaged
homes (p=0.0013).

Photographs of a home with water
damage. Photographs of same areas taken
by the infrared camera, showing water
damage (darker areas)
with AD.
 Water damage by
thermal assessments
using an infrared
camera.

OR for moderate to severe
Atopic Dermatitis
in water-damaged homes
14.5
15 –
10 –
05 –
00
p=0.0025
with AD.
 Water damage by
thermal assessments
using an infrared
camera.

Background:
 National and international AD
guidelines address AD care in a
stepwise fashion.
 Wet wrap therapy (WWT) is a
therapeutic intervention for
moderate-to-severe AD.
Wet Wrap Therapy in Children with Moderate to Severe
Atopic Dermatitis in a Multidisciplinary Treatment Program
Nicol NH, JAllergy Clin Immunol Pract 2014;2:400

Objective:
This cohort study evaluated the effectiveness of
WWT as part of a multidisciplinary AD treatment
program to improve disease severity.
Patients treated in this unique outpatient program
had moderate-to-severe AD and had multiple
therapies that failed.

Severity of the AD by
-Scoring Atopic Dermatitis
(SCORAD)
-AD Quickscore (ADQ).
Severity classifications are
determined from SCORAD
index scores:
-mild (<25)
-moderate (25-49)
-severe (>50).
ADQ was scored at admission,
discharge, and 1 month
after discharge from the
Atopic Dermatitis Program.
72 children with a mean
age of 4.6 ± 3.12 yrs
SCORAD at admission
and at discharge

age of 4.6 ± 3.12 yrs
and at discharge
mean SCORAD score
admission
60 –
50 –
40 –
30 –
20 –
10 –
0
49.7
14.8
discharge
P<0.001

age of 4.6 ± 3.12 yrs
and at discharge
mean SCORAD score
admission
60 –
50 –
40 –
30 –
20 –
10 –
0
49.7
14.8
discharge
P<0.001
None of these
patients required
systemic
immunosoppressive
therapy

WWT protocol

SCORAD on admission (blue bars)
and at discharge (red bars)
P < 0.001
Mean ADQ
(Atopic Dermatitis Quickscore-black)
vs SCORAD (red)

SCORAD on admission (blue bars)
and at discharge (red bars)
P < 0.001
Mean ADQ
(Atopic Dermatitis Quickscore-black)
vs SCORAD (red)
Patient were treated with
WWT for a minimum of
2 days and for a maximum
of 16 days, with the
mean stay of 7.5 days

Are the concepts of induction of remission and treatment
of subclinical inflammation in atopic dermatitis clinically
useful? Tang TS, J Allergy Clin Immunol 2014;133:1615-25
Background
 Atopic dermatitis (AD) treatment is often initiated by symptoms or visible
erythema.
 The role of induction of remission or treatment of inflammation that is not
visible is unclear.
Objective
 We investigated whether
1) the notion of subclinical inflammation is scientifically sound,
2) treatment corrects subclinical inflammation,
3) different strategies for initial clearance of AD affect long-term disease
control.
Methods
 We conducted a systematic review based on searching.

 26 studies
 20 of 26 included studies presented
evidence of subclinical inflammation, with
a continuum of changes in skin barrier
dysfunction, the proinflammatory cytokine
milieu,
and
 lymphocytic infiltration from
normal-appearing skin to post-treatment
lesional skin to active skin lesions
in patients with AD.

 26 studies
 Failure to achieve control of AD symptoms
with initial therapy was associated with
a higher risk of relapse in 14 randomized
controlled trials
with fluticasone: risk ratio, 1.31;
with tacrolimus: risk ratio, 1.36).

 26 studies
 3 trials on systemic
therapy/phototherapy suggested that
induction of remission resulted in
long-term remission without
maintenance therapy in approximately
15% of patients.

 26 studies
 3 trials on systemic
therapy/phototherapy suggested that
induction of remission resulted in
long-term remission without
maintenance therapy in approximately
15% of patients.
Induction of
remission followed by
maintenance therapy
might prove to be an
integral part of a
disease-modifying
strategy for treating
atopic diseases.

Putative diagram (top) illustrating
what might currently happen when
the initial induction of remission
treatment period (started at point
A) ceases once signs and symptoms
have reduced (clinical remission or
point B) as opposed to what might
happen (bottom) if initial
induction of remission extended
to clear subclinical disease
(subclinical remission or point C).
Each induction of remission period
is followed by maintenance or
proactive treatment, requiring
2 consecutive days of treatment
per week to previously active
sites (points D).

Optimum predictors of childhood asthma:
persistent wheeze or the Asthma Predictive Index?
Amin P, J Allergy Clin Immunol Pract 2014;2:709-15
 The Asthma Predictive Index (API) is a validated clinical model for
childhood asthma originally developed with the Tucson Children's
Respiratory Study.
 In this study, parents were asked whether their child had chest
wheezing or whistling and to indicate on a Likert scale (1 to 5, from
“very rarely” to “on most days”) how frequently the child had wheezed;
early frequent “wheezers” were defined as children with a score ≥ 3.
 This API used major (ie, parental asthma and eczema) and minor
clinical criteria (ie, allergic rhinitis, wheezing apart from colds
and peripheral eosinophilia) to predict asthma later in childhood
(ie, age 6 and older) in age 3 early frequent “wheezers.
Castro-Rodriguez, J.A. et al. Am J Respi Crit Care Med. 2000; 162: 1403–1406

 A similar index, the modified API (mAPI) (herein defined as the
“University of Cincinnati API or ucAPI) was developed by Guilbert et al.
in the Prevention of Asthma in Kids (PEAK) trial in 2004.
Guilbert, T.W. Et al. Control Clin Trials. 2004;25:286–310
 The mAPI uses criteria similar to that of the API to predict childhood
asthma, albeit early frequent wheezing was defined as ≥ 4 wheezing
episodes per year during the first 3 years.
The major criteria of the mAPI added a third criterion of allergic
sensitization to ≥ 1 aeroallergen and replaced physician-diagnosed
allergic rhinitis in the minor criteria of the original API with allergic
sensitization to milk, egg, or peanuts.

defined as the “University of Cincinnati API (ucAPI)
A positive ucAPI at age 3 in our study was defined as having ≥ 2 episodes of wheezing in the
previous 12 months at the age 3, and 1 of the 3 major criteria
(parental asthma, allergic sensitization to 1 or more aeroallergens, or a history of eczema)
or 2 of the 3 minor criteria (wheezing without a cold, physician-diagnosed allergic rhinitis,
or allergic sensitization to milk or egg).

 Cincinnati Childhood
Allergy and Air
Pollution Study.
 A high-risk
prospective birth
cohort (n=589).
 modified API
(mAPI) (herein
defined as the
“University of
Cincinnati API
(ucAPI)
17.5%
20 –
15 –
10 –
05 –
. 0
% children with asthma
at age 7 years

Positive
ucAPI
13.3
p<0.01
9.8
p<0.01
10.4
p<0.01
5.4
Persistent
wheezing
Allergic
persistent
wheezing
Nonallergic
persistent
wheezing
15 –
10 –
05 –
01 –
at age 3 yrs
p<0.01
OR for asthma at age 7 years
Allergy and Air
Pollution Study.
 A high-risk
prospective birth
cohort (n=589).
 modified API
(mAPI) (herein
defined as the
“University of
Cincinnati API
(ucAPI)

Allergy and Air
Pollution Study.
 A high-risk
prospective birth
cohort (n=589).
 modified API
(mAPI) (herein
defined as the
“University of
Cincinnati API
(ucAPI)
Positive
ucAPI
13.3
p<0.01
9.8
p<0.01
10.4
p<0.01
5.4
Persistent
wheezing
Allergic
persistent
wheezing
Nonallergic
persistent
wheezing
15 –
10 –
05 –
01 –
at age 3 yrs
p<0.01
Both a positive ucAPI
and persistent wheeze
at age 3 were
associated with
objectively confirmed
asthma at age 7;
however, the highest
risk was associated
with ucAPI.
OR for asthma at age 7 years

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