An Interactive Discussion of Balancing the Efficacy and Safety

of Inhaled CorticosteroidsBased on Patient Cases

Maci and Michael

Benefits Risks

David P. Skoner, MD

Director, Division of Allergy & Immunology,

Department of Pediatrics.

Professor of Pediatrics, West Virginia University

School of Medicine.

Grant/Research Support Greer Laboratories, Novartis, Genentech, Merck, GlaxoSmithKline, Sunovion, Teva, Boston Scientific

Consultant Merck, Mylan, Greer, Meda

Speaker’s Bureau Merck, Meda, Boehringer Ingelheim, Greer

Stock Shareholder Nothing to Disclose

Employee Nothing to Disclose

Other I reviewed charts and served as doctor and consultant for Maci’s family and expert witness for Michael’s family.

Learning Objectives

• Discuss the diagnosis of asthma in children.

• Review benefits and risks of ICS in children with asthma.

• Discuss the prevention and early recognition of systemic side effects of ICS.

Introducing—Michael

Lifestyle

Activities

Diagnosis

Prescription

• 16-year old male• Growing up in upper-middle class neighborhood in Pittsburgh• Intelligent parents—father is a mathematics professor and mother

is a teacher at Michael’s school

• Enjoyed playing soccer• Huge Penn State football fan• Well-liked by many friends

• Diagnosed with asthma years earlier• Experienced fall asthma symptoms yearly, always mild and persistent• Visited pediatrician annually• One visit to asthma specialist for allergy skin testing and spirometry• Never required emergency care

• Received prescriptions only for albuterol and cromolyn, both to be used as needed

• Albuterol always provided symptom relief

History of Events—Michael Fall weekend during football season in November 1999

Thursday Friday Saturday

Parents left town to celebrate their wedding anniversary

Michael's older sister (only sibling) attended school at Penn State University

Michael was left in care of his aunt, who had no knowledge of asthma

Michael developed his typical fall asthma symptoms and used albuterol

Michael awakened and struggled to catch his breath for the first time ever with no relief from albuterol

Parents called and instructed aunt to take Michael to his pediatrician, who knew him very well

Regular pediatrician was out-of-town and the office was covered by another physician not familiar with Michael

Saturday in the Office—Michael

10:30am

••At about 10:30AM, the office was very busy and needed to close at noon because the doctor had a “tee-time” for golf

••After a brief visit, pediatrician administered nebulized albuterol, which provided quick, but incomplete relief

Before12:00pm

••Left office before noon with prescription for a new albuterol inhaler and prednisone••While walking to the car, chest tightness redeveloped••Instead of going with his aunt to the pharmacy, asked to go home to watch the Penn

State football game on TV—Aunt granted request and dropped him off at home

Approximately45 minutes

later

••Upon return from the pharmacy about 45 minutes later, she found Michael dead on his favorite chair in front of the TV

••Autopsy revealed heavily remodeled airways

Saturday continued…

7

The child remained symptomatic and had diminished lung function despite high-dose oral steroid use for years

Grossly thickened basement membrane and edema within the lamina propria

Endobronchial Biopsy of a 16-year-old Male with Steroid-dependent Asthma

Reprinted with permission from Jenkins HA, et al. Chest. 2003;124:32-41.

In severe childhood asthma, significant airway remodeling can occur as early as 6 years of age, with little or no airway inflammation, and in spite of aggressive, long-term treatment with systemic and inhaled corticosteroids à need to look beyond inflammation in the treatment of severe asthma.

Pediatric Asthma Deaths:Patients With Mild Asthma Are Also At Risk*

05

10152025303540

Severe Moderate MildPatient Assessment

Patie

nt D

eath

s (%

)

Robertson et al. Pediatr Pulmonol. 1992;13:95-100.

*Findings from a cohort study reviewing all pediatric asthma-related deaths (n=51) in the Australian state of Victoria from 1986 to 1989.

35%

31% 33%

Benefits of Low-dose ICS

The index date for case patients and matched controls was the date of each case patient’s death from asthma. The rate ratio is adjusted for the age and sex of the patient; the number of prescriptions for theophylline, nebulized and oral β-adrenergic agonists, and oral corticosteroids in the year before the index date; the number of canisters of inhaled β-adrenergic agonists, dispensed in the year before the index date; and the number of hospitalizations for asthma during the two years before the index date.

Suissa S, et al. N Engl J Med. 2000;343(5):332-336.

0

0.5

1

1.5

2

2.5

0 1 2 3 4 5 6 7 8 9 10 11Number of Canisters of ICSs per Year

Rat

e R

atio

for D

eath

Fro

m A

sthm

a

12

The regular use of low-dose ICS is associated with a decreased risk of death

from asthma (powerful benefit at low-doses portends side effects)

NAEPP Guidelines—Benefits of ICSs• ICSs are preferred in the treatment of mild persistent

asthma in children, while cromolyn is recommended as an alternative

• ICS:– anti-inflammatory;– most effective long-term therapy for mild,

moderate, or severe persistent asthma;– well tolerated and safe at “recommended” doses.

• ICS DO NOT modify natural history.

NAEPP. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. August 28, 2007. Available online at http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf. Accessed March 30, 2016.

ICS = inhaled corticosteroid

Lessons From Michael’s Case• Children with “mild” asthma can die during their first

asthma attack and can have unexpectedly heavily remodeled airways.

• Children with asthma flare-ups should never be left alone.

• Patients with acute asthma must be monitored for rebound bronchoconstriction after albuterol treatment.

• Inhaled corticosteroids reduce risk of asthma death.

Balancing Efficacy and Safety

EfficacyMichael

SafetyMaci

Introducing—Maci

History

• 6.5 years of age• Presented to Pediatric Allergist on

11/23/09• 3-years of runny nose, nasal congestion,

posterior nasal drainage • Cough during colds and occasionally with

exercise• No recent shortness of breath or wheezing• Recurrent infections (sinusitis, otitis media,

RSV, others)• Mother had allergy and asthma

Introducing—Maci

Current Medications(can’t tell if they helped)

Physical Examination

Allergy Skin Testing/Other

• Cetirizine l0 mg qd• Montelukast 5 mg qd• Fluticasone furoate – 2 sprays qd, started January, 2009• Albuterol inhaler prn• Multivitamin daily

• Height 43.5 in (5th %ile), Weight 41lbs (10th %ile) • Well-developed and well-nourished • Allergic shiners, pale, edematous nasal turbinates, watery

nasal discharge, and lymphoid hyperplasia of the posterior pharyngeal wall

• Remainder of exam normal

• Puncture skin tests – positive to tree and grass pollen, mold and house dust mite

• Chest radiograph – not done

Spirometry

Spirometry

Introducing—Maci

Diagnosis by the Allergist

Recommendations and Dosages

• Allergic rhinitis• Asthma (cough-variant)• Cough• Recurrent sinusitis

• Mometasone INCS - 2 sprays in each nostril qd(FDA-unapproved dose)

• Fluticasone MDI - 110 mcg 2 puffs bid with AeroChamber®

(FDA-unapproved dose, NIH asthma guideline “high-dose”)• Cetirizine and Montelukast and Albuterol• Asthma action plan using symptoms• Follow-up visit in 6 weeks

Follow-up—Maci1/14/10

(6 years, 9 months old)8/3/10

(7 years, 4 months old)2/21/11

(7 years, 10 months)

• No interval asthma symptoms• No albuterol or prednisone use• Medication compliance good (>90%)

• Physical examination unchanged• Poor spirometry technique• FEV1 63%-75%, ACT Score 23-25

• Continue medications • Return visit 6 months

• Continue medications• Return visit 6 months

• Slight cough today• Mother worried about weight

gain and easy bruising of skin• Height 3rd percentile• Weight slightly >25th

percentile

Height/weight Plot Changes Not Viewed as Significant

fff

Follow-up—Maci2/21/11 continued…

(7 years, 10 months)

• Considering Mom’s concerns and Maci’s improvement, “it was time to wean the Fluticasone MDI anyway”

• Continue medications, except decrease Fluticasone MDI 110 mcg to 2 puffs qhs after the cough resolves

• Rinsing, gargling, spitting and brushing after use appeared for the first time in the asthma action plan

• Return visit 6 months

BUT, SHE NEVER MADE IT TO THAT FOLLOW-UP VISIT!INSTEAD, SHE EXPERIENCED A “GAME-CHANGING” EVENT.

Endocrinologist—Maci

Evaluation by Endocrinologist

on 4/5/11(8 years, 0 months)

• Mother requested endocrine referral from pediatrician for short stature and fast weight gain

• Still on Fluticasone MDI 110 mcg 2 puffs bid and MometasoneINCS

• Physical examination: Round faces and cheek fullness, a fat pad on the back of the neck, and centripetal deposit of adiposity

• Serum cortisol <2 mcg/dL (normal 2.5-22.9), ACTH <5 pg/mL (normal 5-46)

• Urinary free cortisol <1 mcg/L (low) • Normal bone age

Endocrinologist—Maci

Diagnosis by Endocrinologist

• (Iatrogenic) Cushing’s Syndrome• But, there was still reluctance to attribute this to

the inhaled steroids because no one had ever seen it before. So, her mother didn’t know if the adrenal gland would recover function or not, and was concerned that her daughter would die (Dr. Skoner’s involvement)

What the Parents Were Told About the Cause* of Maci’s New Symptoms and Signs after Starting the Medications

Symptom/Sign FluticasoneMDI/Mometasone INCS

Maci’s Diet/Activity Level/Genetics/Idiopathic

Short Stature

Fast Weight Gain

Easy Skin BruisingBMI Increase

Loss of Adrenal Gland Function

XXXX

X

* = not the cause; = the cause. X

Tumor (Pituitary)

Three questions the family needed Dr. Skoner to answer

Question ResponseHave you seen cases like Maci’s before? Yes

Can the ICS cause adrenal suppression? Yes

Will Maci’s adrenal gland recover after withdrawal of ICS?

Yes

Endocrinologist—Maci

Resolution

• Discontinue Fluticasone MDI and Mometasone INCS• Begin ICS with low systemic activity and Olopatadine

Nasal Spray• Continue Montelukast, now viewed as “steroid-sparing” • “Stress” doses of Cortef• Adrenal (after being off Fluticasone MDI for 4 weeks):

• Cortisol 9.1 (normal 2.5-22.9)• ACTH 20 (normal 5-46)

• Six weeks later, ICS stopped successfully and permanently

• Bones• Bone fractures (9/11, 2/12, 2/13)• DEXA (5/7/12): osteopenia • Growth Hormone (since 7/1/12) and Vitamin D

• Eyes normal

Lessons From Maci’s CasevAsthma is difficult to diagnose in small children.vSome ICS have sufficient systemic activity to produce

Maci’s outcome (i.e. Cushing’s Syndrome, which was NOT caused by prednisone!).

vSystemic side effects begin to develop during the first 3 months of ICS therapy (good time for follow-up visit).

vChildren are unique: 1) NOT just little adults; 2) treatment risks; and 3) “at risk” when there is insufficient attention to ICS safety.

Skoner DP. Allergy Asthma Proc. 2016;37:1-12. Skoner DP. Ann Allergy Asthma Immunol. 2016;117:595-600.

Why Did This Happen to Maci? What Can We Do About This?

Raise awareness and learn how to more carefully balance safety and efficacy!

0%

10%

20%

30%

40%

50%

LOWDOSE(176UG/DAY)

HIGHDOSE(>880UG/DAY)

17%

43%

The Reason for Maci’s Adrenal Failure and FDA’s Lack of Approval of Fluticasone 110µg & 220µg for Children

“HPA Axis Suppression”

% with MorningSerum Cortisol<5.5 µg/dl

62 children with moderate to severe asthma followed for two years.Eid N et al. Pediatrics 2002; 109: 217-221.

Guideline: High Dose is >352 µg/dayMaci received 440 µg/day (110µg)

Duration of Side Effect

The Reason for Maci’s Growth Suppression and Long-Term Growth Hormone Treatment

“Systemic Activity”

Kelly HW et al. N Engl J Med. 2012;367(10):904-912.

Effect of Low-Dose Budesonide (Turbuhaler 200 µg bid) on Adult Height*Height Difference, Budesonide vs Placebo

Mean Age (yr) 9 11 13 25No. of ParticipantsBudesonidePlacebo

311418

296396

281383

281377

Treatment period(400 µg/day)

3 –

2 –

1 –

0 –

-1 –

-2 –

-3 –0 2 4 6 8 10 12 14 16

Years Since Randomization

Bud

eson

ide

vs P

lace

bo

Hei

ght D

iffer

ence

(cm

)

* Adherence steadily declined and was only about 50% at end of treatment period. J Allergy Clin Immunol 2012;129:112-8.

Duration of Benefit

*

RAISE AWARENESS AND EDUCATE

T = TeachingE = EveryoneA = AboutM = MedicationS = Safetywww.macisteams.org(site under construction)

CME coming soon.Patient Education.

More to come!Thankfully, able to

be selected by::

Two Cases Illustrate the Importance of Balancing Efficacy and Safety of ICS in Children

(Keys to Using ICS and INCS Wisely and Safely)

Efficacy1,2

§ Unquestioned, unparalleled.

Safety3,4

§ Make sure diagnosis is correct,§ Consider non-steroid alternatives, § Pick the safest steroid, § Use the lowest effective dose, § Optimize steroid sparing strategies,§ Treat comorbidities such as allergies, § Monitor growth, appearance, and behavior,§ Proactively discuss safety.1. NAEPP. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. August 28, 2007. Available online at http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf. Accessed March 30, 2016. 2. Suissa S et al. N Engl J Med. 2000;343(5):332-336. 3. Skoner DP. Pediatrics 2002: 109(2):381-392. 4. Skoner DP. Allergy Asthma Proc. 2016;37:1-12.

The Swinging Pendulum of ICS Safety

1990’sFearUnderuseMichael

2000’sNo fear

OveruseMaci

Stop Here

Stop Here

The Safety Landscape Has ChangedRead about how to pick the safest INS/INCS!

Skoner DP. Allergy Asthma Proc. 2016;37:1-12.

Michael’s and Maci’s Case(Perfect Storms and Opposing Forces)

Maci Michael

Age 6 years 16 years

High Level of Family Education and Resources?

Yes Yes

Allergic? Yes Yes

Asthma (Severity)? Not confirmed (Mild) Yes (Mild)

Failure of Doctors to Follow Guidelines?

Yes Yes

Role of ICS? Yes, too much* Yes, too little!

Life Threatening Event? Yes (Adrenal) Yes (Asthma)

Fatal Outcome? No Yes

*Use of high, FDA-unapproved doses of both inhaled and intranasal corticosteroids with systemic activity, with high adherence, lack of step-down over 18 months, and failure to acknowledge that evolving cushingoid features were drug-related.

Most likely, both would have had better outcomes on low-dose ICS!

1

SavetheDate12th AnnualNemacolinInternationalAsthmaConference

“LikebeingcourtsideatanNBAbasketballgame”

November 9–11, 2017

www.ahn.org/nemacolin-asthmaConference Directors

Deborah Gentile, MDTemple University

Paul O'Byrne MB, FRCP(C), FRSCMcMaster University

Giovanni Piedimonte, MD Cleveland Clinic Pediatric Institute

David P. Skoner, MDTemple University and West Virginia University

Sally E. Wenzel, MDUniversity of Pittsburgh