United Airway: Implications for Treatment

United Airway: Implications for
Treatment
Ray J. Rodríguez MD, JD, MPH, MBA
FAAP, FACAAIa
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
Piel y tejido subcutaneo
3.46
Infecciosas y parasitarias
2.68
16.22
Traumatismo, y envenenamiento
1.69
Impedimentos, defectos y
deformidades
15.25
Tumores y neoplasia
1.65
1.40
Sistema Digestivo
11.59
Sistema Osteomuscular y del
tejido
Sintomas, signos y hallazgos
anormales clinicos y de laboratorios
9.46
Sangre y organos
hematopoyeticos y problemas de
inmunidad
1.33
Ojos y sus anexos
7.59
Oido y de la apofisis
1.23
Sistema Nervioso
7.47
0.15
Trastornos mentales y del
comportamiento
5.95
Malformaciones Congenitas y
Cromosomicas
Embarazo, parto y puerperio
0.07
Sistema genitourinario
4.88
Afecciones del periodo perinatal
0.06
* Por cada 100 habitantes
Top Ten Chronic Conditions in Puerto
Rico 2002
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
Hypertension
Asthma
Diabetes
Arthritis
Sinusitis
Allergic Rhinitis
Migraines
Myopia/Astigmatism
Cholesterol
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
45
40
35
30
25
20
15
10
5
0
Trees
Grasses
Weeds
Molds
D. farinae
D.pterony.
Cockroach
21-30
31-40
41-50
Age (years)
51-60
61-70
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
Nasal Biopsies
Mast cells in Non allergic patients
Mast Cells in Allergic Rhinitis patients
* JACI 2001;107:249-57
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
Birth:TH0
Allergen
Exposure
TH1
No allergies
Source: Busse WW, Lemanske RF. N Engl J Med 2001.
TH2
Allergies
Pathogenesis of Allergic Rhinitis & Asthma
Bone marrow
GM-CSF, CysLTs, IL-3, IL-5
GMCSF
IL-3, IL5
TH2
Allergen
Mast
cell
Neurotrophins
Antigenpresenting
cell
IL4
IL-13
Sensory
nerves
GM-CSF
GMIL-4
IL- CSF
CysLTs
5
Eosinophil
IL-4
IgE
Mast
cell
GM-CSF,
B lymphocyte Neuropeptides CysLTs
Histamine
IL-3, IL-5
CysLTs
CysLTs
PGs
Activation
Prolonged
survival
Allergic symptoms
CysLTs
Eotaxin
MIP-1α
Transmigration
Chemoattraction
Blood
Adhesion
Endothelium
Shared Pathophysiology of Allergic Rhinitis and Asthma
Early and Late Phase Response in AR &
Asthma
100
FEV1
(% change) 50
0
0
1
2
3
4
5
6
7
8
9
10
24
Time (hr)
Asthma
Allergic rhinitis
Late phase
Immediate (early) phase
Symptom
score
Antigen
challenge
1
3–4
8–12
Time postchallenge (hr)
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.
24
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
Nose
Pollen, molds,
DM,CR Pets
Allergic Rhinitis
“Allergic Late
Phase Response”
Sinuses
Sinusitis
Lungs
Asthma
The central role of allergens
in producing allergic
symptoms in the nose,
sinuses and lungs
Clinical
Asma y Rinitis Alergica :
“Una sola vía unida”
Allergic
rhinitis
Asthma
• Alrededor de un 80% de pacientes
asmáticos tienen rinitis alergica
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.
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
12
p<0.002
10
% of
patients
who
developed
asthma
10.5
8
6
4
2
3.6
0
No allergic rhinitis
at baseline
(n=528)
Allergic rhinitis
at baseline
(n=162)
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.
SGA 2001-W-6472-SS
08-03-SNG-02-(PR)EC-006-SS
Slide 3
Incidencia de asma en pacientes de La
Reforma de Salud (MCS-HMO)
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
Total
22,227
7,948
9.8%
30,105
Se estima que hasta un 80% de los pacientes asmaticos
padecen de rinitis alergica (30,105 x 0.8)= 24,084
10.4%
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
Nasal Allergy Challenge in AR and Sinuses
(Central Reflex)
Baroody et. al. J Allergy Clin Immunol 2000;105 (Suppl):S70-1
Dil
1 hr
2hr
3hr
4hr
5hr
6hr
7hr
8hr
Ipsi Sinus
Allergen
challenge
55
55
483*
55*
55*
95
444*
111
278*
Contra
Sinus
55
161
56
167
235*
606*
56
55
55
Values represent medians of total Eos.
*p<0.05 vs Dil. hr, Hour after allergen challenge
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
United Airway Concept
• 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
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 patients
had 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
Effect on Upper Airway on Lower
Airway
• 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
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
Relationship of AR and Asthma
• 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%.
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 12month 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
•60% with POSITIVE skin test
•Male > Female
•Blood eosinophil >4%
26%
39%
28%
7%
Neither
Aero-Allergen
•Total IgE > 100 IU/ml
•Personal History of Atopic
Dermatitis is more predictive of
sensitization than parental history of
asthma
Food
Both
Guilbert et. al. J Allergy Clin Immunol 2004;114:1282-7
Natural History of Childhood Asthma
Wheezing Prevalence
Transient early
wheezers
0
Prematurity, daycare,
maternal smoking (NOT
ASSOC TO ATOPY or
Family history at age 11)
Non-atopic
wheezers
3
Linked to RSV
IgE-associated
wheeze/asthma
6
11
Age (Years)
Martinez. J Allergy Clin Immunol 1999;104:S169-S174.
Atopy and Asthma
Wheeze
Period
(years)
N(%)
Not tested
Positive
SPT
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 younger
age 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
•
•
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)
Retrospective cohort study of a HMO from 1991-94
Patients over 5 years of age
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
Asthma
Treatment
Nasal Steroid
(+)
Nasal
Steroid (-)
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
•
•
Antihistamines (+) Antihistamines (-)
OR
Retrospective cohort study of a HMO from 1991-94
Patients over 5 years of age
Frequency Rates (rate per 100 person years)
Treating subclinical asthma with an orally inhaled
glucocorticoid may improve allergic rhinitis
• In a placebo-controlled, doubleblind, 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
Allergic Rhinitis
Asthma
Daytime Nasal Symptom Score*
0
Change –0.1
from
baseline –0.2
score
(LS –0.3
mean)
–0.4
Mean ± SE FEV1*
15
Montelukast
10 mg once daily
(n=408)
Morning
FEV1 10
mean %
change
from
5
baseline
Placebo
(n=352)
Placebo
(n=273)
0
–0.5
Montelukast
10 mg once daily
at bedtime (n=348)
0
3
6
9
Weeks
12
15
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.
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 60minute 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.