Allergies and Asthma

Paul Keith MD MSc FRCPC

McMaster UniversityPresident, Canadian Society of Allergy and Clinical Immunology

DISCLOSURE INFORMATION

I have the following financial relationship to disclose:

Consultant for: CSL Behring, GSK, Merck, Novartis, Takeda, Viropharma

Grant/Research support from: CSL Behring, GSK, Merck, Shire

Honoraria from: CSL Behring, GSK, Merck, Takeda

Name: Dr. Paul Keith

CSACI Mission:

“…is the advancement of the knowledge and practice of allergy, clinical immunology, and asthma for optimal patient care.

The Society is also dedicated to improving the quality of life of people with allergies through research, advocacy, and continuing professional development and public education."

TRUE or FALSE?

1. Intranasal steroids are first line for the treatment of rhinitis when moderate congestion is present

2. Exposure to hand sanitizer is associate with increased rate of allergen sensitization

3. Allergy specific IgE levels go up as you Vitamin D levels go down

Father's desperate screams spur CPR rescue

THE HAMILTON SPECTATOR Aug 27, 2010 Jordan Hertz, a 12-year-old asthmatic

boy from east Hamilton, "He has severe asthma, and during the

day he said, 'Dad, I can't breathe,'" said Hertz. "That's a sign for me to rush him to the hospital."

While racing to Hamilton General, Jordan began saying, "I can't breathe, I can't breathe." His father called 911 on his cellphone and went to pull over. Before he could stop and give his son a puff from a rescue inhaler, Jordan lost consciousness.

The patient was 'vital signs absent' upon arrival

Inverse Relation between the Incidence of Prototypical Infectious Diseases (Panel A) and the Incidence of Immune Disorders (Panel B) from 1950 to 2000.

Bach J. N Engl J Med 2002;347:911-920.

Age-adjusted Australian hospital admission rates for anaphylaxis

1993-2005

*Rate per million population

Mullens RJ. Med J Aust 2007; 186 (12): 618-621.

The atopic march

Baatenburg de Jong A et al. Pediatr Allergy Immunol 2009;20:735

Food

Inhalant

Age in yrs

miliaseptumturrbinate

Asthma

Before

10 Minutes After Allergen Challenge

Laitinen et al. J Allergy Clin Immunol. 1992;90:32-42.

Eosinophilic Esophagitis

Allergy skin prick testing

IgE-dependent Release of Inflammatory Mediators

Immediate ReleaseGranule contents:Histamine, TNF-, Proteases, Heparin

Over MinutesLipid mediators: ProstaglandinsLeukotrienes

Over HoursCytokine production:Specifically TNF-a, IL-4, IL-13

IgE

FcRI

FcRIbinding site

Cell recruitment

Sneezing Nasal congestionItchy, runny noseWatery eyes

WheezingBronchoconstriction

Priming:Increased

responsiveness to repeated

allergen exposure

IgE Ab

Mast cell

Release of histamine and

other mediators

Early-phase reaction

Sneezing, rhinorrhoea, congestion, eye

symptoms

Antigen

Eosinophils

Late-phase reaction

Cellular Infiltration

Allergic inflammation and priming

Naclerio R, manuscript in development.

Mould

• sampled 46 rooms in 4 urban elementary schools (northeastern United States) and from 38 student bedrooms

Sheehan WJ et al Ann Allergy Asthma Immunol 2009 Feb;102(2):125-30

Epidemiology of allergic rhinitis in adults

Bauchau V, Durham SR. Eur Respir J 2004;24:758–64.

0

10

20

30

Belgium France Germany Italy Spain UK

% g

ener

al p

op

ula

tio

n

Prevalence of allergic rhinitis (AR) in European adults during 2001

Do you have nasal congestion or nasal symptoms?

• 44% of eligible respondents reported either nasal congestion or nasal symptoms.

• 20 % had been diagnosed with AR by a physician

n=3,671

Allergies in Canada Survey: Symptom control in worst month ( n=1001)

Allergies in Canada Survey: symptoms during worst month (n=1001)

35

29

23

21

22

16

7

8

6

11

5

32

30

30

27

19

18

17

15

14

10

7

17

15

17

13

12

14

18

13

14

7

11

0 20 40 60 80 100

stuffed nose

sneezing

runny nose

watering eyes

itchy nose

post-nasal drip

headache

sleep loss

facial pain

loss of smell

ear symptoms

daily few days/week few days/month

Concomitant treatment in 6829 Canadians with SAR at baseline

Keith PK et al. Clin Ther 2007

30 352520151050% of patients

INS

Oral nonsedating antihistamine

Ophthalmic drugs

Immunotherapy

Oral sedating antihistamineTopical nasal decongestant

Oral nasal decongestant

Intranasal antihistamine

Oral corticosteroid

Cromolyn

Intranasal anticholinergic

INS, intranasal corticosteroid; SAR, seasonal allergic rhinitis

Visits for allergic rhinitis are infrequent

44% >1yearor never

12%13% 13%

16%

29%

15%

Past month Past 3 months Past 6 months Past 12 months Greater than 1 year ago Never

DISCUSSED ALLERGY WITH PHYSICIAN

Q11: When was the last time you discussed your allergies and/or allergy medication(s) with your physician?

Most patient’s symptoms are not at least mostly controlled

9%

16%

34%

37%

4%

Not at all A little Somewhat Mostly Fully

SYMPTOMS CONTROLLED

Q3: How well do you consider your allergy symptoms controlled?

Most patient’s symptoms are not at least mostly controlled

9%

16%

34%

37%

4%

Not at all A little Somewhat Mostly Fully

SYMPTOMS CONTROLLED

Q3: How well do you consider your allergy symptoms controlled?

59% not controlled

Impact of allergic rhinitis on patients’ daily life

1. Scadding G et al. EAACI 2007, Abstract 1408. 2. Reilly MC et al. Clin Drug Invest 1996;11:278–88. 3. Tanner LA et al. Am J Manag Care 1999;5(Suppl 4):S235–S247. 4. Blanc PD et al. J Clin Epidemiol 2001;54:610–18. 5. Juniper EF et al. J Allergy Clin Immunol 1994;93:413–23. 6. Marshall PS, Colon EA. Ann Allergy 1993;71:251–8.

SLEEP AND TIREDNESS• 46% of patients feel tired1

• 77% of patients have trouble falling asleep1

WORK AND SCHOOL PRODUCTIVITY

• ≤90% effectiveness at work4

• 93% impaired classroom performance3,5

EMBARRASSMENT• Adolescents embarrassed to

use inhalers6

Impact ofallergicrhinitis

DAILY ACTIVITIESIMPAIRED2,3

LEARNING AND COGNITIVEFUNCTIONS DISTURBED6

True or false?

l Asthma is more common in the population than allergic rhinitis

• Up to 40% of patients

with allergic rhinitis also

have asthma

• Up to 94% of patients

with allergic asthma also

have allergic rhinitis

AR-Asthma relationship

Allergic rhinitisalone

AR+

asthmaAsthma alone

True or false?

l Asthma is more common in the population than allergic rhinitis

FALSE

Risk of developing asthma over time

Shaaban R et al Lancet 2008; 372: 1049–57

First Line Therapies for Patients with Allergic Rhinitis and Asthma

Leukotriene receptor antagonists

Topical Corticosteroids

(nasal and pulmonary)

Adapted from Corren J AAAAI 2006

Anthistamines

INS vs LTRA vs LTRA+AH vs placebo started prior to season

Pullerits T et al. JACI 2002;109:949-55

FPANS= intranasal steroid, ML= LTRA, LT= antihistamine

Pullerits T et al. JACI 2002;109:949-55

Copyright ©1998 BMJ Publishing Group Ltd.

Weiner, J. M et al. BMJ 1998;317:1624-1629

Intranasal steroids vs oral antihistamines

Treatment of Allergic Rhinitis

Class IMild /

intermittent

Class IIModerate/intermittent

Moderate-severe / intermittent

Severe/ intermittent

Mild / persistent

Class III

Moderate / persistent

Class IVModerate – severe /

persistent

Severe/persistent

Surgery

Immunotherapy

Oral steroids

LTRAs

Intranasal corticosteroids

Oral H1 antihistamines

Allergen / irritant avoidanceSmall et al. J Otolaryngol. 2007

Strength of evidence for treatment of rhinitisARIA update 2007

intervention SAR PAR Persistent adult child adult child rhinitis

oral anti-H1 A A A A A

intranasal CS A A A A A**

intranasal chromone A A A A

anti-leukotriene A A A A**

Anti-IgE mab A A A A A**

Subcutaneous IT A A A A A**

Allergen avoidance D D A* B*

* Not effective in general population

** extrapolated from studies in PAR/SAR

Mea

n c

han

ge

in p

atie

nt-

rep

ort

ed n

asal

co

ng

esti

on

sc

ore

fro

m b

asel

ine

(%)

Days

1-15 16-30 31-45 46-60 61-75 76-90

Mandl et al. Ann Allergy Asthma Immunol. 1997;79:370.

Moderate to severe perennial allergic

Mean % Reduction in Patient-Rated Congestion* From Baseline

EndpointBaseline

† †

†

†

†

†

†

†

†

†

†

†

†

†

†

Mometasone

Growth in children with perennial allergic rhinitis taking nasal mometasone furoate

Mometasone 100 µg/day

Placebo

Month*p=0.02 (6.9 cm vs 6.3 cm)

Schenkel et al. Pediatrics 2000;105:E22

Mean change in height from baseline (mm)

*

Nasal Biopsies

Long-term treatment with mometasone:No evidence of nasal atrophy

Minshall et al. Otolaryngol Head Neck Surg. 1998;118:648.

Before mometasone treatment: After 12 Months of mometasone 200 µg/day treatment:

Disruption of epithelium

Eosinophil infiltration

Epithelium intact

No eosinophil infiltration

Pharmacologic management of mucosal congestion

Allergic Rhinitis Nasal Polyps

Acute Rhinosinusitis

Mucosal Congestion2 sprays OD 2 sprays BID

2-4 sprays BID

First and Second Line Therapies for Patients with Allergic Rhinitis and Asthma

Leukotriene receptor antagonist

Topical Corticosteroids

(nasal and pulmonary)

Anthistamines

Anti-IgE Immunotherapy

Immunotherapy(high dose Ag)

Th1

IFNg

IgG

Tr

IL-10 TGF-b

IgG4 IgA

APC

Natural exposure (low dose Ag) + IgE

Th2

B cell

Eosinophil

IgE

IL-4

IL-5

Allergy(-)

(-)

Robinson DS, Larche ML and Durham SR. J Clin Invest 2004; 114: 1389-97

SLIT = sublingual immuntherapy

SLIT for asthma, rhinitis, and conjunctivitis symptoms adults and

children

Calamita Z et al. Allergy 2006;61:1162

165

119

65

51

28

0

20

40

60

80

100

120

140

160

180

Respiratoryinfections

Hypertension Disorders oflipid

metabolism

Diabetesmellitus

Depressivedisorder

Source: Verispan PDDA 2004

Num

ber o

f com

mon

offi

ce

visi

ts (m

illio

ns)

Respiratory infections are the # 1 reason for physician office visits

1.9 Million patient visits (96.6% treated with drugs)

MAT Dec 2008 IMS CDTI

1.4 Million patient visits (80.1% treated with drugs)

Therapeutic Profile

Acute Sinusitis Chronic Sinusitis

NIS MT4%

Other21%

NIS Adjunct

18%

Antibiotics54%

Nasal Steroids

23%

Other17%

Antibiotics60%

Untreated3%

Macrolide-resistant Pneumococci: Canadian Bacterial Surveillance Network, 1988-

2008

0

5

10

15

20

25

Per

cent

age

of I

sola

tes

Res

ista

nt t

oE

ryth

rom

ycin

1988

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

Canadian Bacterial Surveillance Network, Feb 2009

Rates of Penicillin and Amoxicillin Resistance Canada: 1988-2008

0

1

2

3

4

5

6

7

8% Penicillin Resistance% Amoxicillin Resistance

Canadian Bacterial Surveillance Network, March 2008

Figure 2 Kaplan Meier curves presenting the probability of asthma hospitalization in 30,675 children from the DNBC, who were exposed to maternal use of antibiotic for nonrespiratory infection during pregnancy (N=162) versus children who were not exposed to maternal antibiotic use during pregnancy (N = 1036).

Use of Antibiotics during Pregnancy Increases the Risk of Asthma in Early Childhood

Graff L et al. The Journal of Pediatrics 2012; Nov 6. pii: S0022-3476(12)01141-9

Figure 3 Asthma hospitalization in children from the DNBC presented in a dose-response curve per number of antibiotic prescriptions for nonrespiratory infection the mother received during pregnancy. The risk of asthma increased significantly with increasing number of prescriptions analyzed as a continuous variable, adjusted P value =.01. Number of prescriptions in each category: 27 244 (88.8%) mothers had no prescriptions in pregnancy, 2608 (8.5%) had 1 prescription, 569 (1.9%) had 2 prescriptions, 160 (0.5%) had 3 prescriptions, and 99 (0.3%) mothers had ≥4 prescriptions. Upright bars represent the HR estimates and 95% CI.

Use of Antibiotics during Pregnancy Increases the Risk of Asthma in Early Childhood

Graff L et al. The Journal of Pediatrics 2012; Nov 6. pii: S0022-3476(12)01141-9

Fig 1 Predicted probability of sensitization with 95% CIs by urinary triclosan levels. A, Aeroallergen sensitization for all subjects. B, Food sensitization for male and female subjects .

Savage JH et al. JACI 130;2012;453

Urinary levels of triclosan and parabens are associated with aeroallergen and food sensitization

Primary Efficacy Endpoint: Mean Change in Daily Mean Symptom Score

-5.5

-5

-4.5

-4

-3.5

-3

-2.5

-2

-1.5

-1

-0.5

0

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 EP

Mea

n C

han

ge

in D

aily

MS

S

DAYS

placebo

FF 110mcg QD

FF 110mcg BID

Keith PK et al. Prim Care Resp J 2012

Role of vitamin D?

67Camargo CA JACI 2007;120:131-6

Role of vitamin D?

Risk of recurrent wheeze

68Camargo CA et al Am J Clin Nutr 2007;85:788 –95

Vitamin D and s-IgE levels vs season

69Hollams EM et al. ERJ Express. May 12, 2011

Risk of atopy – positive relationship only in males 6-14 yo

70Hollams EM et al. ERJ Express. May 12, 2011

Vitamin D supplementation in children 5 to 18 years old may prevent asthma exacerbations

71Majak P et al JACI 2011 May;127(5):1294-6.

ACE inhibitor angioedema

ACE inhibitor use in Canada

Total volume of prescriptions dispensed from Canadian pharmacies for 1 year ending October 2010 (+ compared to year ending October 2009

Total Scripts Change1. Atorvastatin 15,768,000

+2.7%2. Levothyroxine 14,964,000

+5.1%3. Metformin 10,637,000

+8.4%4. Ramipril 9,349,000 -

1.6%47. Perindopril 2,690,000

+17.3%

( IMS Brogan, Canadian Compuscript)

TRUE or FALSE?

1. Intranasal steroids are first line for the treatment of rhinitis when moderate congestion is present TRUE

2. Exposure to hand sanitizer is associate with increased rate of allergen sensitization TRUE

3. Allergy specific IgE levels go up as you Vitamin D levels go down TRUE

Allergies and Asthma

Paul Keith MD MSc FRCPC

McMaster UniversityPresident, Canadian Society of Allergy and Clinical Immunology