Ray J. Rodríguez MD, JD, MPH, MBAFAAP, FACAAIa

United Airway: Implications for Treatment

United Airway: Implications for Treatment

• Allergic Rhinitis and Asthma– Linked in epidemiologic, pathophysiologic, clinical

studies– Rhinitis as a risk factor for asthma

• AR and otitis media: strong 2-way link in children• AR and sinusitis

– AR possible risk factor for sinusitis• Treatment of AR and its impact on other upper

and lower airways disease

Condiciones de Salud 2002*School of Public Health, Univ. of Puerto Rico & the Dept. of Health of Puerto Rico

Sistema Respiratorio 25.77

Sistema Circulatorio 18.90

Endocrinas, nutricionales y metabolismo

16.22

Impedimentos, defectos y deformidades

15.25

Sistema Digestivo 11.59

Sintomas, signos y hallazgos anormales clinicos y de laboratorios

9.46

Ojos y sus anexos 7.59

Sistema Nervioso 7.47

Trastornos mentales y del comportamiento

5.95

Sistema genitourinario 4.88

Piel y tejido subcutaneo 3.46

Infecciosas y parasitarias 2.68

Traumatismo, y envenenamiento 1.69

Tumores y neoplasia 1.65

Sistema Osteomuscular y del tejido

1.40

Sangre y organos hematopoyeticos y problemas de

inmunidad

1.33

Oido y de la apofisis 1.23

Malformaciones Congenitas y Cromosomicas

0.15

Embarazo, parto y puerperio 0.07

Afecciones del periodo perinatal 0.06

* Por cada 100 habitantes

Top Ten Chronic Conditions in Puerto Rico 2002

1. Hypertension2. Asthma3. Diabetes4. Arthritis5. Sinusitis6. Allergic Rhinitis7. Migraines8. Myopia/Astigmatism9. Cholesterol10. Circulatory Problems

• Public Health Reform Insurance– Asthma: 48,476– Diabetes: 117,766– Hypertension: 90,255– Congestive Heart Failure:

4,823

School of Public Health, Univ. of Puerto Rico & the Dept. of Health of Puerto Rico

Remission of Allergic Rhinitis

• 257 patients were seen in 1990 & 1998• 198 / 257 diagnosed with AR either to

pollen, animals and dust mites• Remission rates in 1998 (mean rate: 18%)

– 12% pollen– 19% animals– 38% for HDM

• AR is a persistent disease !!Bodtger et. al. JACI 2004;114:1384-88

Skin Test Reactivity by Age

05

1015202530354045

21-30 31-40 41-50 51-60 61-70

Age (years)

#

Trees

Grasses

Weeds

Molds

D. farinae

D.pterony.

Cockroach

Dog

Cat

Prevalence of Allergic Rhinitis by Age Group

Embriology & Histology

• Respiratory epithelium– Linked posteriorly

from the septum and lateral walls of the fossa to the nasopharynx, larynx, trachea, bronchi and bronchioles

Mast Cells in Allergic Rhinitis patientsMast cells in Non allergic patients

* JACI 2001;107:249-57

Nasal Biopsies

Rhinosinusitis

• Rhinosinusitis– Group of disorders characterized by

inflammation of the mucosa of the nose and the paranasal sinuses

• Divided in– Acute presumed bacterial rhinosinusitis– Chronic RS without polyps– Chronic RS with polyps– Classic AFRS

JACI 2004;114:S155-213

Immune System Development

TH1No allergies

TH2Allergies

AllergenExposure

Source: Busse WW, Lemanske RF. N Engl J Med 2001.

Birth:TH0

Pathogenesis of Allergic Rhinitis & Asthma

Antigen-presenting

cell

Allergen

Eosinophil

IL-4

TH2 GM-CSF

IL-3, IL-5

IgE

B lymphocyte

Mast cell

GM-CSFIL-4

IL-5

ActivationProlonged

survival

GM-CSF, CysLTsIL-3, IL-5

Bone marrow

GM-CSFCysLTs

Histamine CysLTs

PGs

CysLTsEotaxinMIP-1α

Chemoattraction

Allergic symptoms

Mast cell

GM-CSF, CysLTs, IL-3, IL-5

Blood

Transmigration Adhesion

Endothelium

IL-13

CysLTs

Neurotrophins

IL-4

Sensorynerves

Neuropeptides

Shared Pathophysiology of Allergic Rhinitis and Asthma

Early and Late Phase Response in AR & Asthma

Adapted from Varner AE, Lemanske RF Jr. In: Asthma and Rhinitis. 2nd ed. Oxford: Blackwell Science, 2000:1172-1185; Togias A J Allergy Clin Immunol 2000;105(6 pt 2):S599-S604.

AsthmaAllergic rhinitis

Symptomscore

Time postchallenge (hr)

1Antigen challenge

3–4 8–12 24

Immediate (early) phase Late phase

FEV1(% change)

Time (hr)1 10 240 2 3 4 5 6 7 8 9

0

50

100

Inflammatory Mechanism in AR

• The inflammation that develops over the course of an allergy season is associated with an approximately 10 fold increase in the # of mast cells in nasal epithelia

• The more persistent the exposure will trigger PRIMING (less allergen will be needed to trigger MC)

Systemic Implications of Allergies

Allergen

Pollen, molds, DM,CR Pets

Lungs

Asthma

Nose

Allergic Rhinitis

Sinuses

Sinusitis

“Allergic Late Phase Response”

The central role of allergens in producing allergic

symptoms in the nose, sinuses and lungs

Clinical

Allergic rhinitis

Adapted from The Workshop Expert Panel. Management of Allergic Rhinitis and its Impact on Asthma (ARIA) Pocket Guide. A Pocket Guide for Physicians and Nurses. 2001; Bousquet J and the ARIA Workshop Group J Allergy Clin Immunol 2001;108(5):S147-S334; Sibbald B, Rink E Thorax 1991;46:895-901; Leynaert B et al J Allergy Clin Immunol 1999;104:301-304.

Asma y Rinitis Alergica : “Una sola vía unida”

Asthma

• Alrededor de un 80% de pacientes asmáticos tienen rinitis alergica

Epidemiologic Links Between Allergic Rhinitis and Asthma

Rinitis Alérgica es un factor de riesgo para desarrollar Asma

Rinitis Alérgica aumenta 3 veces más el riesgo de desarrollar asma

Slide 3SGA 2001-W-6472-SS08-03-SNG-02-(PR)EC-006-SS

23-year follow-up of college freshmen undergoing allergy testing; data based on 738 individuals (69% male) with average age of 40 years.Adapted from Settipane RJ et al Allergy Proc 1994;15:21-25.

12

10

8

6

4

2

0

% of patients

whodeveloped

asthma

10.5

Allergic rhinitisat baseline

(n=162)

3.6

No allergic rhinitisat baseline

(n=528)

p<0.002

Pacientes asmáticos identificados en MCS-HMO

2000 % 2001 %

ICD-9 para asma 19,145 8.5 24,863 8.6

Utilización de medicamentos

5,838 7,948

Total 22,227 9.8% 30,105 10.4%

Incidencia de asma en pacientes de La Reforma de Salud (MCS-HMO)

Se estima que hasta un 80% de los pacientes asmaticos padecen de rinitis alergica (30,105 x 0.8)= 24,084

Allergies in Chronic Rhinosinusitis

• 200 consecutive patients with chronic rhinosinusitis refractory to medical therapy who underwent functional endoscopy sinus surgery

• Allergy Skin Testing Prior to Surgery• 60% of patients had significant allergic

sensitivities• The predominant allergies were to perennial

allergens (DM) over seasonal allergens

Emmanuel et al. Otolaryngol Head Neck Surg 2000;123(6):687-91

Dil 1 hr 2hr 3hr 4hr 5hr 6hr 7hr 8hr

Ipsi SinusAllergen

challenge

55 55 483* 55* 55* 95 444* 111 278*

Contra Sinus

55 161 56 167 235* 606* 56 55 55

Nasal Allergy Challenge in AR and Sinuses (Central Reflex)

Baroody et. al. J Allergy Clin Immunol 2000;105 (Suppl):S70-1

15 allergic rhinitis patients (ragweed) were challenged off season

Nasal and bilateral sinus lavages checking for eosinophils were performed after each challenge and then hourly for 8 hrs

Values represent medians of total Eos. *p<0.05 vs Dil. hr, Hour after allergen challenge

• To determine whether the middle ear compartment may be a component of the united airways in allergic disease

• 45 patients undergoing tympanostomy tube placement for OME and adenoidectomy for adenoid hypertrophy

• Samples of middle ear effusions, torus tubaris (Eustachian tube mucosa at the nasopharyngeal orifice), and adenoidal tissue were taken plus allergy skin testing

• Looking at the cellular and cytokine profiles of each site

United Airway Concept

Nguyen et. al. J Allergy Clin Immunol 2004;114:1110-5

United Airway Concept

• Eleven of the 45 patients with OME (24%) were atopic.

• The middle ear effusions of atopic patientshad significantly higher levels of eosinophils, T lymphocytes, and IL-4 mRNA1 cells (P < .01) and significantly lower levels of neutrophils and IFN-g mRNA1 cells (P < .01) compared with nonatopic patients.

Nguyen et. al. J Allergy Clin Immunol 2004;114:1110-5

United Airway Concept

Nguyen et. al. J Allergy Clin Immunol 2004;114:1110-5

Nguyen et. al. J Allergy Clin Immunol 2004;114:1110-5

Effect on Upper Airway on Lower Airway

• 18 atopic asthmatic children on inhaled steroids not properly under controlled (not on nasal steroids) “moderate asthma”

• Nasal endoscopy: diagnosed with chronic rhinosinusitis (mucopurulent rhinorrhea, nasal obstruction, PND & cough for > 3 months)

• Evaluation: PFT’s, symptom score, nasal endoscopy, nasal scraping, & Cytokine evaluation at days 1, 14 & 44

Tosca et. al. Ann Allergy Asthma Immunol 2003;91:71-78

• Treatment: – Amoxicillin/Clauvanate & Fluticasone Nasal

Spray for 14 days & a oral steroid for 4 days.• Results:

– Improvement in symptom score– Improvement in PFT’s– Reduction in IL-4 with an increase in g-INF

Effect on Upper Airway on Lower Airway

Tosca et. al. Ann Allergy Asthma Immunol 2003;91:71-78

Relationship of AR and Asthma• Cross-sectional epidemiological survey of the

management of rhinopathies in asthma patients seen by pulmonologists in France

• 1623 asthma patients• Mean asthma duration was 10 years (range 5–

20)• Patient’s opinion about the effectiveness of their

anti asthma treatment:– 47.8% stated that effectiveness was good or very

good– 52.3% that it was fair or poor.

Demoly et. al. Allergy 2003: 58: 233–238

Relationship of AR and Asthma

• 78.7% of patients felt that their asthma was allergic – House-dust mites (62.3%), pollens (57%), house dust

(46%), animals (29.9%)• Triggers of asthma according to patients

– Infections (57.7%)– Physical activity (52.6%)

• Asthma with rhinopathy had a greater negative impact on sleep than asthma alone

Demoly et. al. Allergy 2003: 58: 233–238

• According to the pulmonologists– 76.6% of the patients had a rhinopathy and

31.2% had conjunctivitis.– Rhinopathy was usually chronic (91%)– Allergic rhinitis in most cases (66.2%),

nonallergic rhinosinusitis in 17.5% of cases, and nasal polyposis in 10.1%.

Relationship of AR and Asthma

Demoly et. al. Allergy 2003: 58: 233–238

Treatment of AR & Asthma

• Children 6 to 15 years old with asthma and with 1 asthma-related visits to a GP during a 12-month follow-up period (n=9522)

• Asthma-related hospitalizations, GP visits, and prescription drug costs for patients with and without comorbid allergic rhinitis

• 19.7% had allergic rhinitis recorded in the GP medical records

• Patients with comorbid AR:– Higher GP visits – Higher asthma admissions– Higher costs: drugs

Thomas et. al. PEDIATRICS Vol. 115 No. 1 January 2005, pp. 129-134

United Airway: Impact of Rhinitis on Sleep

• Nasal Airway has less resistance than oral airway at night

• Nasal Obstruction may lead to oral breathing can trigger sleep disorders (non restorative sleep and drowsiness or sleep apnea)

• Can be exacerbated by the use of first generation antihistamines

United Airway Concepts

• Activation of the nasopharyngeal-bronchial reflexes

• Loss of nasal function due to obstruction or exertion

• Aspiration of mediators from the upper airways to lower airways

• Nasal and bronchial mucosal eosinophilia correlate in nonatopics as well in atopic patients

Allergic March

• PEAK Study (Prevention of Early Asthma in Kids)

• Looking at the atopic profile of children with recurrent wheezing at a high risk of developing asthma

• 285 patients between 2 – 3 years of age• Frequent intermittent wheezing but without

persistent symptoms

Guilbert et. al. J Allergy Clin Immunol 2004;114:1282-7

Allergic March

Sensitization by Allergen Class

39%

7%28%

26%

Neither FoodAero-Allergen Both

•60% with POSITIVE skin test

•Male > Female

•Blood eosinophil >4%

•Total IgE > 100 IU/ml

•Personal History of Atopic Dermatitis is more predictive of sensitization than parental history of asthma

Guilbert et. al. J Allergy Clin Immunol 2004;114:1282-7

Natural History of Childhood Asthma

Age (Years)

Whe

ezin

g Pr

eval

ence

Non-atopicwheezers

Transient earlywheezers

IgE-associatedwheeze/asthma

0 3 6 11

Martinez. J Allergy Clin Immunol 1999;104:S169-S174.

Prematurity, daycare, maternal smoking (NOT ASSOC TO ATOPY or

Family history at age 11)

Linked to RSV

Atopy and Asthma

Wheeze Period(years)

N(%) Not tested PositiveSPT

No wheeze 0 - 6 425 (51.5)

317 33.8%

Transient early

0 – 3 164 (19.9)

125 38.4%

Late Onset 3 - 6 124 (15.0)

97 55.7%

Persistent 0 – 6 113 (13.7)

90 51.1%

Martinez et. al. N Eng J Med 1995;332:133-38

A Clinical Index to Define Risk of Asthma Year 2 and 3

Mayor Criteria• Parental Asthma• Eczema

Minor Criteria• Allergic Rhinitis• Wheezing apart from

colds• Eosinophilia (>4%)

Loose Index: Early wheezer + at least one major or two minor criteria

Stringent Index: Early frequent wheezer + at least one major or two minor criteria

Castro Rodriguez et. al. Am J respir Crit Care Med 2000; 162:1403-06

Atopic March: AR to Asthma• Leynaert et. al. at the European Community

Respiratory Health Survey questioned 90,478 patients 20-40 years of age in Europe, US & New Zealand

• 10,210 completed the survey, skin testing, spirometry, methacoline challenge and total IgE

• Prevalence of asthma: 2% of patients without rhinitis v 13% of patients with rhinitis

• Seventy percent of patients with asthma reported rhinitis

Leynaert et. al. J. J Allergy Clin Immunol 2004;113:86-93

Atopic March: AR to Asthma

• Leynaert et. al. – In a population of patients without asthma:

Bronchial hyperresponsiveness was found to be two times more common in patients with rhinitis (19.3%) compared with patients without rhinitis (8.7%)

Leynaert et. al. J. J Allergy Clin Immunol 2004;113:86-93

Relationship between AR & Asthma

Relationship between Childhood and Adult Asthma

• Childhood-onset asthma relapsing in adulthood was associated with the following factors:

• Male sex• More frequent asthma attacks• Lower spirometric values, especially

those related to small airways and especially if childhood asthma was severe

• Allergy being a factor in the initial onset of asthma and a trigger for asthma attacks

• Personal history of allergy with youngerage at onset

• More frequent sensitization to domestic airborne allergens such as D. pteronyssinus, D. farinae, and dog hair, and to grass and tree pollens

• Maternal history of atopic dermatitis and perennial rhinitis.

Segala et. al. Allergy Volume 55 Issue 7 Page 634 - July 2000

Treatment of allergic rhinitis indirectly improves asthma symptoms and decreases bronchial

hyperreactivity.

• Double-blind cross-over study, children were treated with intranasal aqueous beclomethasone dipropionate (BDP)

• BDP treatment: rhinitis and asthma symptom scores were lower and bronchial hyperresponsiveness to methacholine improved significantly

Simons J Allergy Clin Immunol 1993;91:97-101

Intranasal steroids & the risk of ER visits for asthma Adams et. al J Allergy Clin Immunol 2002;109:636-42

• Retrospective cohort study of a HMO from 1991-94• Patients over 5 years of age

Age (n) Nasal Steroid (+) (n=2276)

Nasal Steroid (-) (n=11568)

Antihistamines (+) (n=3718)

Antihistamines (-) (n=10126)

6-17 (3888) 35(6.9) 336 (9.9) 43 (7.1) 328(10)

18-34 (5314) 36(4.1) 342 (8.1) 99 (5.8) 279 (8.2)

>35 (4822) 27(3.1) 27(3.1) 57(4.1) 225 (6.6)

All (13844) 98 (4.3) 933 (8.1) 199 (5.4) 832 (8.4)

Frequency Rates (rate per 100 person year)

Intranasal steroids & the risk of ER visits for asthma

Adams et. al J Allergy Clin Immunol 2002;109:636-42

• Retrospective cohort study of a HMO from 1991-94• Patients over 5 years of age

Frequency Rates (rate per 100 person years)

Asthma Treatment

Nasal Steroid (+)

Nasal Steroid (-)

OR Antihistamines (+) Antihistamines (-) OR

+ ICS (n=6110)

47 (6.8) 558 (10.3) 0.66 103 (7.6) 505(10.6) 0.72

- ICS (n=7734)

51(3.2) 375 (6.1) 0.52 97 (4.1) 321(6.1) 0.67

Treating subclinical asthma with an orally inhaled glucocorticoid may improve allergic rhinitis

• In a placebo-controlled, double-blind, parallel-group 7-week study during the birch pollen season,

• Patients with allergic rhinitis and bronchial hyperresponsiveness to methacholine, but no clinical asthma, orally inhaled budesonide 600 µg twice daily

• Budesonide prevented seasonal development of increased bronchoconstrictor response to methacholine (P < .05), and also reduced nasal symptoms.

•Greiff et al. Eur Respir J 1998;11:1268-74

Antihistamines treatment for AR may also improved asthma symptoms

Grant et. al. J Allergy Clin Immunol1995;95:923

Use of Montelukast in Seasonal Allergic Rhinitis and Asthma

Multicenter, 12-week double-blind, randomized trial in patients 15 to 81 years with seasonal allergic rhinitis. Multicenter, randomized, 12-week double-blind trial of montelukast vs. placebo in patients 15 years and older with asthma

*p<0.001 montelukast vs. placebo

Adapted from Reiss TF et al Arch Intern Med 1998;158:1213-1220; Malmstrom K et al. Poster presentation at the 57th AAAAI Annual Meeting, March 16–21, 2001.

3

15

10

5

0

0 6 9 12 15

Placebo(n=273)

AsthmaMean ± SE FEV1*

0

–0.1

–0.2

–0.3

–0.4

–0.5Montelukast

10 mg once dailyat bedtime (n=348)

Allergic RhinitisAllergic RhinitisDaytime Nasal Symptom Score*

Placebo(n=352)

Montelukast10 mg once daily(n=408)

Changefrom

baselinescore(LS

mean)

MorningFEV1

mean %change

from baseline

Weeks

Protective effect of Montelukast on Lower and Upper respiratory tract

• Random crossover study, double-blind treatment periods, separated by a 1-week washout period treated patients with montelukast vs placebo during two 2-week

• After each treatment period, patients underwent a 60-minute or less exposure to high levels of airborne cat allergen.

• Lower and upper airway responses were measured by spirometry and symptom scores

Perry et. al. Ann Allergy Asthma Immunol. 2004 Nov;93(5):431-8.

Protective effect of montelukast on lower and upper respiratory tract responses

• Montelukast provided significant (p = .001)protection against allergen challenge in the lower airway coprimary end point of area under the curve during challenge (AUC0-60min) for percentage decrease in FEV1

• Nasal congestion during the challenge and NSS (nasal symptom score) during recovery showed statistically significant (p = .048) protection by montelukast.

Perry et. al. Ann Allergy Asthma Immunol. 2004 Nov;93(5):431-8.