Robert M' Naclerio, MD

1
Robert M. Naclerio, MD
2
Impact of Allergic Inflammation on Physiology

• Robert Naclerio
• University of Chicago

3
Pathophysiology
Antigen
IgE Ab
Late-Phase Reaction
Cellular Infiltration
Mast Cell
Hyper- responsiveness
Eosinophils (ECP)
Histamine Release
Priming
Early-Phase Reaction Sneezing, Rhinorrhea,
Congestion
4
Hyperresponsiveness After Allergen
Saengpanich S, Assanasen P, et al. Laryngoscope
200211247-52
30
5
Epithelial cells in nasal lavage fluids
ANOVA, p 0.01
70
60
p 0.03
50
Change from baseline in epithelial cells ( x
10-4/ml)
40
p 0.03
30
20
p 0.02
p 0.26
10
0
CDA
WMA
CDA
AG
DIL
challenge
CDA sensitive N 10
CDA insensitive N 10
Allergics N 10
group
6
Symptoms and mediators after cold, dry air and
allergen challenge
10
8
p 0.005
cold, dry air challenge (cold, dry air-sensitive
, N10)
6
rhinorrhea VAS score (cm)
p 0.008
4
allergen challenge (allergic rhinitis, N10)
2
0
BASELINE
CHALLENGE
25
20
p 0.03
15
p 0.03
tryptase (ng/ml)
10
5
0
CHALLENGE
BASELINE
7
Cold, dry air can induce mast cell mediator
release in nasal fluids
10
N10
8
p 0.005
rhinorrhea visual analog scale score (cm)
6
4
2
0
CHALLENGE
BASELINE
25
20
15
tryptase (ng/ml)
p 0.03
10
5
0
CHALLENGE
BASELINE
8
Nasal responsiveness to histamine
9
Secretory Hyporesponsiveness In Older Adults
30
Age lt 40 (N10)

Age gt 70 (N15)
25


20

Secretion weight (mg)
15

10
5
0
sham
0.06
0.2
0.6
2.00
6.0
20.0
Histamine (mg)
10
Hypothesis

• Water will evaporate from the epithelial surface
  and create a hyperosmolar milieu at the nasal
  epithelial surface. Individuals with water
  transport defects will not be able to replenish
  the evaporated water as fast and will therefore
  develop more hyperosmolar surface secretions.
  The hyperosmolar surface secretions stimulate
  nerves to activate the parasympathetic system,
  which activates glands to produce secretions and
  blood vessels to dilate and induce congestion.
  The more hyperosmolar the secretions become, the
  more neural stimulation occurs. The induced
  nasal congestion speeds airflow through the nasal
  cavity. As airflow increases, the temperature of
  air leaving the nose falls leaving more
  conditioning to occur in the lower airway.

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Comorbidities and Complications of Allergic
Rhinitis

• Complications
• Asthma exacerbation
• Increased sinusitis episodes
• Increased otitis episodes
• Sleep disorders
• Craniofacial abnormalities
• Decreased cognitive functioning

• Comorbidities

Secondary otitis
Secondarysinusitis
Asthma
Spector SL. J Allergy Clin Immunol.
199799S773-S780.
12
Health Impact of Olfactory Disease

• Approximately 2 million American adults with
  taste and smell disorders (National Advisory
  Neurological and Communicative Disorders and
  Stroke Council)
• National Health Interview Survey in 1994 reported
  prevalence of 2.7 million US adults (1.4) with
  an olfactory problem
• These diseases are associated with significant
  impact on quality of life and pose serious
  clinical consequences for patients

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CC-SIT

• Cross-cultural Smell Identification Test a 12
  item scratch and sniff smell test based on the
  UPSIT
• Validated in cross-cultural populations
• Test-retest reliability gt .70
• Takes 5 minutes to administer, inexpensive
• Age and sex norms available

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Population Statistics
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Results
P0.0013
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Ocular Symptoms of Allergic Rhinitis

• Tearing
• Redness
• Itching
• Mechanisms
• Direct contact of allergen with conjunctiva
• Nasal ocular reflex
• Combination of above

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Antigen (AG) challenge of the left nostril
releases histamine which causes stimulation of
sensory nerves. The histamine initiates a reflex
whose efferent arc involves parasympathetic
stimulation of both nostrils and both eyes.
Dashed arrowafferent limb and solid
arrowsefferent limb of the nasonasal and
naso-ocular reflexes.
Nasal Ocular Reflexes
Central Nervous System
Right Eye
Left Eye
Left Nostril AG
Right Nostril
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Sneezes
p0.01
NS
p0.04
15
10
Number
5
0
Diluent
Antigen
Diluent
Antigen
Placebo
Azelastine
19
Itchy Eyes
p0.01
p0.0009
NS
20
Watery Eyes
21
Nasal Secretion Weights Ipsilateral to Challenge
p0.0001
plt0.0001
NS
70
45
40
60
35
50
30
40
25
mg
mg
20
30
15
20
10
10
5
0
0
Diluent
Antigen
Diluent
Antigen
Azelastine
Placebo
22
Nasal Secretions Contralateral to Challenge
p0.0006
p0.0002
NS
45
60
40
50
35
30
40
mg
25
mg
30
20
15
20
10
10
5
0
0
Diluent
Antigen
Diluent
Antigen
Placebo
Azelastine
23
Ocular Secretion Weights Ipsilateral to Challenge
24
Ocular Secretion Weights Contralateral to
Challenge
25
Nasal Histamine Levels Ipsilateral to Challenge
NS
p0.008
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Summary

• Nasal challenge with antigen leads to an
  ipsilateral response and a contralateral
  nasonasal reflex, which is reduced by treatment
  with a topical H1 antihistamine.
• Histamine is released at the site of challenge
• Nasal challenge leads to ocular symptoms which
  are reduced by a topical intranasal
  antihistamine, suggesting that eye symptoms are
  induced by a nasal ocular reflex.
• Ocular secretion weights increase on both sides
  after challenge, but are not reduced by a topical
  intranasal antihistamine

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Mechanism By Which INS Reduce Eye Symptoms

• Nasal inflammation causes priming, which
  increases the naso-ocular response. Reducing
  nasal inflammation with intranasal steroids
  reduces the reflex and is the mechanism by which
  this class of medications reduces symptoms of
  conjunctivitis during the treatment of seasonal
  allergic rhinitis.

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United Airways
Sinusitis
Rhinitis
Asthma
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Similar Allergic Inflammation in the Middle Ear
and the Upper Airway

• Middle ear effusions and biopsies of taurus
  tubarius and adenoids obtained in 45 children at
  surgery.
• 11/45 (24) were atopic by skin prick test.
• Cells and cytokines were quantitated.

Nguyen LHP, et al. J Allergy Clin Immunol
20041141110-5.
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Eosinophils and T-lymphocytes
Same trend for IL-4 and IL-5
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The Allergic Rhinitis-asthma Connection Chronic
Respiratory Inflammation Syndrome
32
Allergic Rhinitis Predisposes to CRS Sinus
Surgery

• ENT Disqualifying Events in 465 Naval Flight
  Personnel with AR, compared over 5 years to
  12,628 without AR
• Condition Relative Risk
• Chronic Rhinosinusitis 4.5 X
• Need for Surgery (PET, sinus) 3.8 X
• Alternobaric Disease 1.6 X
• Nasal Polyp 1.2 X

Walker C. et al. Aviat Space Environ Med. 1988
69952
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Allergy and Sinusitis Mechanisms

• A local mucosal response to infection involving
  TH1 cells could be hindered by an ongoing local
  mucosal response to allergens involving TH2
  cells.
• In subjects with underlying anatomic defects,
  allergen-induced nasal congestion could obstruct
  sinus drainage and enhance a subsequent bacterial
  infection.
• The ciliary movement from the sinuses could be
  altered by allergic inflammation reducing
  clearance of bacteria.

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Allergy and Sinusitis Mechanisms

• Inflammatory mediators released by eosinophils
  during an allergic reaction could alter the
  epithelium so that bacteria bind better.
• Allergic inflammation could "prime" circulating
  leukocytes such that when there is recruitment of
  such primed cells to the sinus mucosa they
  release more inflammatory mediators, worsening
  the consequences of infection.
• Nasal allergic inflammation could induce
  neurogenic inflammation within the sinuses via
  neural reflexes.

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Nasal and Sinus Reflexes
Central Nervous System
Right Maxillary Sinus
Left Maxillary Sinus
Left Nostril
Right Nostril
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Nasal and Sinus Reflexes
Central Nervous System
Right Maxillary Sinus
Left Maxillary Sinus
Left Nostril
Right Nostril
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Nasal and Sinus Reflexes
Central Nervous System
Right Maxillary Sinus
Left Maxillary Sinus
Left Nostril
Right Nostril
38
Nasal and Sinus Reflexes
Central Nervous System
Right Maxillary Sinus
Left Maxillary Sinus
Left Nostril
Right Nostril
39
Nasal and Sinus Reflexes
Central Nervous System
Right Maxillary Sinus
Left Maxillary Sinus
Left Nostril
Right Nostril
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Hypothesis

• Allergen stimulation of the nasal mucosa will
  lead to reflex neurogenic inflammation in the
  ipsilateral (same side) maxillary sinus.

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Sinoject
42
Number of Sneezes After Allergen and Control
Challenges
Allergen (n20)

plt0.05, plt0.01

Number





Pre
Dil
A1
A2
A3
1
2
3
4
5
6
7
8
Time (hrs)
43
Number of Sneezes After Allergen and Control
Challenges

plt0.05, plt0.01

Number





Pre
Dil
A1
A2
A3
1
2
3
4
5
6
7
8
Time (hrs)
44
Number of Sneezes After Allergen and Control
Challenges
EPR
Number


plt0.05, plt0.01
Control
Allergen

Number





Pre
Dil
A1
A2
A3
1
2
3
4
5
6
7
8
Time (hrs)
45
Number of Sneezes After Allergen and Control
Challenges
EPR
Number


plt0.05, plt0.01
Control
Allergen

LPR
Number

Number





Pre
Dil
A1
A2
A3
1
2
3
4
5
6
7
8
Time (hrs)
Control
Allergen
46
Albumin Levels in the Nasal Cavity After Allergen
and Control Challenges
EPR
4000
3500

Albumin (µg/ml)
plt0.01, plt0.05


Control
Allergen


LPR



Albumin (µg/ml)




Albumin (µg/ml)






Dil
A1
A2
A3
1
2
3
4
5
6
7
8
Time (hrs)
Control
Allergen
47
Eosinophils in the Nasal Cavity After Allergen
and Control Challenges
EPR
Eosinophils x10-3

NS

plt0.05, plt0.01
Control
Allergen

Eosinophils x10-3
LPR

4000
3500
3000


2500

Eosinophils x10-3
2000



1500

1000
Pre
Dil
A1
A2
A3
1
2
3
4
5
6
7
8
500
Time (hrs)
0
-500
Control
Allergen
48
Albumin Levels in the Maxillary Sinus After
Allergen and Control Challenges
6500
EPR
6000
Albumin (µg/ml)

plt0.05, plt0.01


Allergen
Control



LPR



Albumin (µg/ml)

Albumin (µg/ml)

Dil
A1
A2
A3
1
2
3
4
5
6
7
8
Time (hrs)
Allergen
Control
49
Eosinophils in the Maxillary Sinus After Allergen
and Control Challenges
EPR
125
100
75
50
Eosinophils x10-3
25
NS

0
plt0.05, plt0.01

-25
-75
Control
Allergen
-100


LPR
Eosinophils x10-3




Eosinophils x10-3

Time (hrs)
Control
Allergen
50
Eosinophils in the Peripheral Circulation and
Local Tissues During the Late Phase Response
51
Nasal Eosinophil Response

plt0.02 vs Dil N15

Eosinophilsx10-3





Time (hrs)
52
Influx of Eosinophils into the Maxillary Sinuses
After Nasal Allergen Challenge



plt0.05 vs Dil N15
Total Eosinophils




Time (hrs)
53
Eosinophils in the Peripheral Circulation and
Local Tissues During the Late Phase Response
plt0.02 vs Blood
Peak LPR Eosinophils



Blood
Nasal
Ipsilateral Sinus
Contralateral Sinus
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Possible Explanations

• Since the nose and maxillary sinuses are
  anatomically distinct cavities, our data suggest
  that a neurogenic reflex might be responsible for
  our observations
• Axonal and central on the ipsilateral side
• Central on the contralateral side
• Alternatively, allergen challenge of the nasal
  mucosa could lead to a systemic inflammatory
  response which manifests itself in other body
  cavities including the maxillary sinuses.

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Conclusions

• Chronic inflammation is an important feature of
  chronic rhinosinusitis
• Many similarities between allergic inmflammation
  and that seen in chronic rhinosinusitis
• Systemic inflammation as well as neural
  interactions between the nose and the sinuses
  probably contribute to the close link between
  allergic rhinitis and sinusitis

56
United Airways
57
Allergic Rhinitis As Risk Factor For
Asthma Copenhagen Allergy Study
of Subjects
OR 46.5
OR 18.9
OR 8.2
ANIMAL
MITE
POLLEN
No rhinitis at baseline
rhinitis at baseline
Linneberg Allergy 571048, 2002
58
Epidemiological Associations Of Duration Of
Severity Of Rhinitis And Asthma.
Guerra JACI 109419-25, 2002
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Allergic Rhinitis As A Risk Factor For Asthma

• Allergic Sensitization precedes Asthma

Diagnosis Study Population
Asthma at 23yr follow up (n)
17(10.5)
Allergic Rhinitis (Seasonal and Non Seasonal)
162
19 (3.6)
528
No Allergic Rhinitis
690
36 (5.2)
Total
Settipane Allergy Proc. 1521-25, 1994
60
Nose/Lung Interaction
Nose

• 24 hrs after SBP
• Increase in Eosinophils in nasal lamina propria
• Increase in eotaxin-pos cells in nasal lamina
  propria
• Enhanced expression of IL-5 in the nasal
  epithelium

Braunstahl et al. AJRCCM 20001612051.
61
Nose/Lung Interaction
Bronchus

• Nonasthmatic subjects with allergic rhinitis and
  normal controls underwent segmental bronchial
  provocation
• Bronchial biopsies taken before and 24 hr after
  SBP
• Nasal biopsies taken before, 1hr and 24 hrs after
  SBP

Braunstahl et al. AJRCCM 20001612051.
62
Nose Lung Interaction
Similar response exists if the nose is challenged
with allergen and the lung is biopsied 24 hrs
later
Braunstahl GJ. JACI 2001107469.
63
Intranasal Steroids and the Risk of Emergency
Departments Visits for Asthma
Adams JACI 109636-42, 2002
64
Intranasal Steroids for Asthma Control in People
with Coexistent Asthma and Rhinitis (Cochrane
Review 2005)

• Randomized controlled trials comparing INS to
  placebo. Asthma outcomes monitored.
• 14 trials involving 477 people
• Duration of Rx relatively short (1-8 wks)
• There was a trend of INS treatment to improve
  asthma symptom score and FEV1 which did not reach
  statistical significance.
• More studies encouraged.

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Mechanisms Of Pathologic Relationships Between
Nose And Lungs
66
Comorbidities and Complications of Allergic
Rhinitis

• Complications
• Asthma exacerbation
• Increased sinusitis episodes
• Increased otitis episodes
• Sleep disorders
• Craniofacial abnormalities
• Decreased cognitive functioning

• Comorbidities

Secondary otitis
Secondarysinusitis
Asthma
Spector SL. J Allergy Clin Immunol.
199799S773-S780.
67
Impact of Allergic Inflammation on Physiology

• Robert Naclerio
• University of Chicago

68
Question 1

• The most important aspect of the pathophysiology
  of allergic rhinitis
• 1 early reaction
• 2 late reaction
• 3 hyperresponsiveness
• 4 reflex activation

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Question 2

• Eye symptoms of allergic rhinitis are caused by
• Direct antigen exposure
• Nasal ocular reflexes
• Blockage of the nasolacrimal duct
• 1 and 2
• 1, 2 and 3

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Question 3

• Sinusitis associated with allergic rhinitis is
  caused by
• Ostial obstruction
• Nasal sinus reflexes
• Enhanced bacterial infection
• Systemic activation of immune cells
• Antigen deposit in the sinuses
• Skewing of immune response

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Question 4

• The cause of olfactory dysfunction associated
  with allergic rhinitis is
• Hereditary
• Associated with sinusitis
• The results of conduction problems
• The result of inflammation in the olfactory cleft
• Unknown