Session: 4819 Q & A Workshop

Respiratory Allergies

Chitra Dinakar, M.D., F.A.A.P. Professor of Pediatrics

University of Missouri-Kansas City

Faculty, Allergy, Asthma and Immunology

Children's Mercy Hospitals and Clinics

email address: cdinakar@cmh.edu

Section Of Allergy/Immunology

American Academy of Pediatrics

Disclosures

Astra Zeneca: Speakers Bureau

Aerocrine: Speakers Bureau Training

Learning Objectives

• To understand the most recent clinical

research findings in pediatric asthma,

eczema, food, drug and insect allergy

• To be able to apply recent advances in

pediatric allergy/immunology to clinical

practice

Course of Asthma Activity

• Ontario health data, 15-year follow-up study of

613,394 patients

• Primary outcome: active asthma (any physician

claim ICD9 493; ICD 10 J 45, J 46)

• Secondary outcome: gap in asthma activity of 2

years or more

• Persistent asthma: 2 year gap between asthma

claims not present

Gershon A, Guan J, Victor C, et al: The course of asthma activity: a population study. J Allergy Clin Immunol

2012;129:679-686.

Course of Asthma Activity

• 82.3% had active asthma during follow-up, with a

median of 4 asthma-related claims per person.

• 74.6% had at least a 2-year gap between claims.

• Factors associated with increased asthma activity:

– higher number of previous asthma claims;

– older and younger age, particularly 65 years or old

– presence of chronic obstructive pulmonary disease.

Gershon A, Guan J, Victor C, et al: The course of asthma activity: a population study. J Allergy Clin Immunol

2012;129:679-686.

Asthma 'Remissions‘ Are Common--But

Most Patients Have Active Disease

• Study limitations: individuals may or may not use

healthcare when disease is active (or inactive);asthma

definition; potential misclassification)

• Most patients have active asthma; periods of "remission"

occur and are prolonged

• 3/4 of patients had a gap of at least 2 years in their

asthma activity

• The natural course of asthma is to wax and wane--but

that it doesn't really resolve.

Gershon A, Guan J, Victor C, et al: The course of asthma activity: a population study. J Allergy Clin Immunol

2012;129:679-686.

Should ucontrolled asthmatic children

without overt GERD be treated?

Lansoprazole for children with poorly controlled asthma;

a randomized controlled trial. Writing Committee for the

American Lung Association Asthma Clinical Research

Centers.

JAMA. 2012 Jan 25;307(4):373-81.

Lansoprazole in children with uncontrolled

asthma

• Study of Acid Reflux in Children with Asthma (SARCA)

• Lansoprazole vs placebo with poorly controlled asthma

• Masked, PC RCT

• N=306, 19 USA academic centers f/u for 24 weeks

Lansoprazole in children with uncontrolled

asthma

• Primary outcome: ACQ (asthma control questionnaire)

• Secondary outcome measures: FEV1, asthma related

quality of life, or rate of episodes of poor asthma control)

• N=115 with esosphageal ph studies, GER =43%

• ↑AE: ↑ resp infections in lansoprazole group (RR: 1.3)

Lansoprazole for children with poorly controlled asthma; a randomized controlled trial. JAMA.

2012 Jan 25;307(4):373-81.

•No statistically significant difference in primary or

secondary outcomes

•No Rx effect in positive ph probe sub-group

Adverse events:

•No difference in activity related fractures

•↑ URTI, sore throats and bronchitis

•? Non-acid reflux worsening asthma

•Does not evaluate GER and cough

Lansoprazole for children with

poorly controlled asthma; a

randomized controlled trial.

JAMA. 2012 Jan

25;307(4):373-81.

Do children on ICS attain

predicted adult height?

NEJM 2012; 367; 904-12

ICS and Final Adult Height

• Transient decrease in height 1-4 yrs after initiation of ICS

Rx in pre-pubertal children; not thought to decrease final

adult height

• Continuation of the CAMP study; adult height of

participants measured

• Subjects were given budesonide 400 mcg, nedocromil

16 mg or placebo daily starting at age 5-13 yrs

• 943/1041 (96%) had final adult ht. measured at ~ 25 yrs

• Adjusted for demographic variables, initial height and

asthma features at trial entry

Mean adult ht was 1.2 cm lower in the budesonide

group than placebo (p=0.001; CI -1.9 to -0.5) )

and not stat. sig. different in Nedocromil group

NEJM 2012; 367; 904-12

• A larger daily ICS does in first 2 yrs was associated with

lower adult ht (p=0.007)

• The reduction in adult height in budesonide group was

similar to placebo after first 2 yrs (-1.3 cm)

• During first 2 years decreased growth velocity occurred

primarily in pre-pubertal children

The initial decrease in height associated

with ICS use in pre-pubertal children

persisted as a reduction in attained adult

height of approximately half an inch,

though the decrease was not progressive

nor cumulative

ICS and Adult Height

NEJM 2012; 367; 904-12

• Previous pooled data (2003) from phase I to III studies of

omalizumab showed a numeric imbalance in

malignancies arising in omalizumab recipients (0.5%)

compared with control subjects (0.2%)

• Data from 67 phase I to IV clinical trials

• Prespecified primary analysis: incidence of primary

malignancy in 32 RDBPC trials

•Incidence rates per 1,000 patient-years were omalizumab

(4.14; 95% CI, 2.26-6.94), placebo (4.45) (95% CI, 2.22-7.94)

•No association was observed between Omalizumab treatment

and malignancy; the rate was below unity (0.93) JACI 2012; 129; 983-9

Hypertonic Saline

and Viral-induced Wheezing

• Rhinovirus: main cause of acute wheezing episodes in preschool

children; associated with decreased mucus clearance

• RCT evaluated inhaled hypertonic saline as a treatment option

• 41 children, mean age 32 months, seen in ED for wheezing

• X 1 albuterol, then 4 mL of inhaled hypertonic 5% saline, or normal

saline

• Both Rx given with 0.5 mL albuterol: x2 q 20 minutes, then x 4 in the

ED daily if the child was hospitalized.

Ater D, Shai H, Bar B-E, et al: Hypertonic saline and acute wheezing in preschool children.

Pediatrics. 2012;129:e1397-e1403.

Hypertonic Saline

improves viral-induced Wheezing

• Primary Outcome: Length of stay (LOS)

• Secondary outcomes: admission rate and clinical severity score

• LOS: Median length of stay : 2 (HS group) vs 3 days (NS group)

(p=0.027)

• Hospital admission rates were 62% versus 92%, respectively

• Improvements in clinical severity scores but not between the groups.

• Majority needed hospitalization (92%)- higher rate than before;

greater disease severity; milder severity improved after pre-

randomization albuterol

• Groups were younger (less than 4 years)

• Inhaled hypertonic saline can improve outcomes in preschool-aged

children with acute wheezing.

Ater D, Shai H, Bar B-E, et al: Hypertonic saline and acute wheezing in preschool children.

Pediatrics. 2012;129:e1397-e1403.

Hay Fever during Christmas?

• New onset of alder pollen allergies in 15-yr old children

attending a school in Grabs, a village in n Switzerland

• They had symptoms during the winter, a time when runny

noses are typically attributed to viral infections

• The genesis of this unusual occurrence was the

serendipitous planting of 96 hybrid trees with winter

resistance about 10 years ago along a commonly

commuted boulevard

• This resulted in exposure to alder pollen in December (the

geographical flowering season) and development of IgE

antibodies causing symptoms

• Grassnner M et al. NEJM 368;4:393.

Grassnner M et al. NEJM 368;393

High-dose SLIT with single-dose

grass pollen extract in children

• RCPCT: efficacy and safety of high-dose SLIT in

children allergic to grass pollen in 34 centers in Germany

and Polans

• After a baseline seasonal observation, 207 children aged

4 to 12 years with grass pollen-allergic rhinitis/

rhinoconjunctivitis with/without bronchial asthma (Global

Initiative for Asthma I/II) received either high-dose grass

pollen SLIT or placebo daily for 1 pre-/co-seasonal

period.

High-dose sublingual immunotherapy with single-dose aqueous grass pollen extract in children is

effective and safe: A double-blind, placebo-controlled study. Ulrich Wahn et al, SLIT Study Group. The

Journal of Allergy and Clinical Immunology - October 2012 (Vol. 130, Issue 4, Pages 886-893.e5,

High-dose SLIT with single-dose

grass pollen extract in children

• The primary end point: change of the area under the

curve of the symptom-medication score (SMS) from the

baseline season to the first season after start of

treatment.

• Secondary outcomes were well days, responders,

immunologic changes, and safety.

High-dose sublingual immunotherapy with single-dose aqueous grass pollen extract in children is

effective and safe: A double-blind, placebo-controlled study. Ulrich Wahn et al, SLIT Study Group. The

Journal of Allergy and Clinical Immunology - October 2012 (Vol. 130, Issue 4, Pages 886-893.e5,

High-dose sublingual immunotherapy with single-dose aqueous grass pollen extract in children is effective

and safe: A double-blind, placebo-controlled study. Ulrich Wahn et al, SLIT Study Group. The Journal of

Allergy and Clinical Immunology - October 2012 (Vol. 130, Issue 4, Pages 886-893.e5,

•Mean changes in area under the curve of the SMS were -

212.5 (active group) and -97.8 (placebo group (P =0.0040).

• Rhinoconjunctivitis SMS (p=0.002), separated symptom

(p=0.012) and medication scores (p=0.022) were statistically

different

•The number of well days and the percentage of responders

were greater in the active group.

High-dose sublingual immunotherapy with single-dose aqueous grass pollen extract in children is effective

and safe: A double-blind, placebo-controlled study. Ulrich Wahn et al, SLIT Study Group. The Journal of

Allergy and Clinical Immunology - October 2012 (Vol. 130, Issue 4, Pages 886-893.e5,

•Changes in allergen-specific IgE and IgG levels indicated a

significant immunologic effect (increase in IgG1 and IgG4).

•The treatment was well tolerated, and no serious treatment-

related events were reported.

•Significant improvement on symptoms, well tolerated, and

viable option in children with grass-pollen rhinoconjunctivitis

•Responder analysis: patients with 40 decrease in SMS from

baseline at end of 1 treatment period: 50% responders in

active group versus 33% in placebo group

•High dose SLIT in children allergic to grass pollen aged 4-

12 years is safe and efficacious

Summary: Suggested Practice

Changes • Counsel families:

– that while some patients with asthma have periods of

clinical remission, the majority continue to have active

disease

– there is an initial decrease in height of about ½ inch

associated with ICS use in pre-pubertal children, though

not progressive or cumulative

• There is no increased risk of malignancy with use of Xolair

Suggested Practice Changes

• Consider administration of inhaled hypertonic saline, along

with albuterol, in preschool-aged children with acute

wheezing

• Be aware of ‘out of season’ seasonal allergic rhinitis due to

geographical and climate changes

• Consider SLIT as an option in children with uncontrolled

grass pollen rhinitis/rhinoconjunctivitis

Thank You

For

Your

Attention!

Asthma Medications during

Pregnancy and Risk of Birth Defects

• Association between maternal asthma medication use and the risk

of birth defects in offspring; a population-based, case control study

of 2,853 infants using data from the National Birth Defects

Prevention Study

• Periconceptional use (from 1 month before pregnancy through the

third month of gestation) of asthma medications (bronchodilators or

anti-inflammatory drugs)

• Most birth defects were unrelated to use of asthma medications.

• However, significant positive associations: isolated esophageal

atresia and bronchodilators, adjusted odds ratio (OR) 2.39; isolated

anorectal atresia and anti-inflammatory drugs, OR 2.12; and

omphalocele and either type of asthma medication, OR 4.13.

• Further studies are needed to clarify whether the associations are

attributable to asthma medications or the severity of asthma itself.

• Lin S, Munsie JPW, Herdt-Losavio ML, et al: Maternal asthma medication use and the risk of selected

birth defects. Pediatrics. 2012;129:e317-e324.

Are Inhaled Glucocorticoids Safe

during Pregnancy?

• Data from a Danish national birth cohort study to assess the

association between ICS during pregnancy and disease risk

• 4,083 live singleton offspring born to pregnant women with asthma

Of 1,231 pregnant mothers receiving ICS, 79.9% used budesonide.

• Offspring were followed up to a median age of 6.1 years.

• Most categories of disease not significantly increased in offspring.

• Exception: increased risk of endocrine, metabolic, and nutritional

disorders: hazard ratio 1.84 (similar for mothers using budesonide).

• The possible association with endocrine, metabolic, and nutritional

disorders warrants further study.

• Currently only budesonide has a class B indication for pregnancy;

approximately 80% of this study cohort was treated with budesonide

Tegethoff M, Greene N, Olsen J, et al: Inhaled glucocorticoids during pregnancy and offspring pediatric

diseases: a national cohort study. Eur Respir J. 2012;185:557-563.