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Cummings Chapter 40: Immunology of the Upper Airway and
Pathophysiology and Treatment of Allergic Rhinitis
Chapter 41: Physiology of Olfaction
December 3, 2014
Joshua Au
Key Points
• Immune system divided between the innate and
adaptive systems.
• Review of innate and adaptive immunity
• Allergic Rhinitis (AR) is a Type I, IgE dependent, mast
cell-mediated immune reaction
• AR impairs quality of life
• Treatment of AR
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Innate Immunity
• Immediate foreign recognition via pattern recognition
receptors
• Barrier mechanisms - epithelial cell layers, mucus
layers, epithelial cilia
• Soluble proteins and small bioactive molecules that
activate cells - cytokines, chemise, enzymes
• Activated phagocytes - PMN, macrophages.
3
Toll Like Receptors
• Identified first in drosophila.
• Transmembrane proteins with extracellular repeated
leucine rich motifs. Intracellular component similar to IL1 receptor induces cell signaling.
• Located on monocytes, B cells, T cells, and dendritic
cells.
• General specificity: Lipopolysaccharides (LPS) of
Gram Negative bacteria activate TLR4. Microbial
lipoproteins activate TLR2. TLR9 activated by bacterial
DNA. TLR5 bacterial flagella. TLR3 ds- RNA - induces
IFN-a IFNb for antiviral response. sRNA activate TLR7
TLR8.
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Antimicrobial Peptides AMPS
• Directly kill microbes
• Cathelicidins - found in neutrophil granules - undergo
extracellular proteolytic cleavage - release C-terminal
peptide- LL-37. Antimicrobial to pseudomonas, E Choli,
Staph. Chemoattractant for mast cells, PMN,
monocytes, T cells, induce histamine release.
• Defensins
• alpha
- expressed by PMN, nasal epithelial cells. Oxygen
independent killing of phagocytes microorganisms, increase
expression of TNF-a, and IL 1.
• Beta
- chemotactic, histamine release
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Adaptive Immunity
• Antigen specific receptors on T and B lymphocytes by
gene rearrangement of T cell receptor and B cell
receptors. Small number of cells with specificity,
increases with proliferation
• Self tolerance - recognize self and attach non self.
Human leukocyte antigen complex and Major
histocompatibility complex Chromosome 6. MHB class I
(HLA-A, B, C) Class II (HLA-DR, DQ, DP).
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MHC
• MHC-I on most somatic cells - present endogenous
antigens to cytotoxic T cells, allowing recognition of
virus infected cells. When recognized by TCR - T cell
proliferates and matures (CD8+). Killing only targeted
cells.
• MHCII expressed only on immunocompetent antigen
presenting cells (APCs) - macrophages, monocytes,
dendritic cells, B lymphocytes. Unregulated by IFNgamma, present exogenous antigens to CD4+ T
helper cells at sites of inflammation.
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Cell Differentiation
• Pluripotent stem cells to myeloid or lymphoid cells
• Lymphoid cells - T cells (80%) TCR recognize APCs,
thymus, B cells (10%) membrane bound
immunoglobulin, bone marrow, NK cells large granular
lymphocytes - no TCR or Ig, recognize virus infected or
tumor cells with complex cell surface receptors (10%),
bone marrow.
• Myeloid - erythrocytes, neutrophils, monocytes,
eosinophils, basophils, mast cells - differentiation in
bone marrow.
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T Cell Development
• Leave bone marrow to reach thymus. Recombination of
TCR gene segments of alpha, beta, gamma, delta.
• Ligand dependent selections when bind peptide
loaded MHC complex. If not bound they are eliminated
by apoptosis, and those that react too strongly to self
antigens also eliminated by apoptosis. Positive and
negative selection.
9
T Cell Differentiation
• CD4 T helper cells (65%) activate humoral (B cell)
immunity and delayed type hypersensitivity. Two types:
• TH1
- specialize in macrophage activation by IFN gamma
production and contact dependent stimulation in delayed type
hypersensitivity. directed by IFN generated by innate response
• TH2
- Recognize MHC II, CD4 cell stimulate B cells by IL4,
CD40 and CD40 ligand interaction. Important in IgE
production and eosinophilic inflammation - allergy and helminth
clearance.
• CD8 cytotoxic T Cells (35%)- granzymes - apoptosis and perforin - membrane disruption, targeted cell
killing. Fas binding - target cell apoptosis (negative
selection).
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T Cell Differentiation
• TH17 cells - inversely related to Th2 eosinophilic
direction. Mobilize neutrophil recruitment.
• Treg - suppress T cell responses, prevent
autoimmunity. Develop in thymus high affinity for IL2
receptor (CD25).
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B Cell Development
• Develop in bone marrow.
• Pro Bcell to Pre B cell noted by recombinationn of Mu
heavy chain of Ig. Kappa or Lambda light chain
development links with heavy chain to IgM at surface for
immature B cell.
• B cell response - provides humoral immunity from
extracellular pathogens through production of
antibodies, neutralize pathogens and toxins, facilitate
opsonization, activate complement.
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B Cell Function
• IgM produced in absence of infection, lower affinity first line defense against bacterial infection. Primary
infection - production of high affinity specific Abs.
• Dendritic
cells present Ag in lymphoid organs via MHCII to Bcell
•B
cell migrates to T-B cell interface where they encounter
primed TH cells binding CD40L (Tcell) to CD40 (Bcell)- activate
B cell, promoting Ig class switch
• Cytokine
specific - IL10 -> IgG1, IgG3. IL 3, 13 -> IgE. TGF beta ->
IgA, IFN gamma -> IgG2.
• Activated
B cells to follicle initiate germinal center and
differentiate to Ig secreting plasma cells for 2-3 weeks. Some
cells exit germinal centers and provide memory.
13
Other Cell Types
• Natural Killer cells - large granular lymphocytes –not
restricted to recognition of target cells by MHC. Inhibited
by MHC I molecules presenting self antigens.
• Kill
cells that have down regulated MHC I expression - old or
infected by viruses (avoid Tcell killing).
• Monocytes and macrophages – APCs
• Names
depend on location - Langerhans cells epidermis,
Kupffer cells liver, microglial cells CNS, dendritic cells in
lymphatic tissue.
• Express
MHC I and MHCII recognition of antigen to TCR,
Phagocytose microbes - facilitated by opsonization, coats
foreign material with antibodies, phagocytose, vacillate infused
with lysosomal enzymes which destroys with nitric oxide.
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Other Cell Types
• Neutrophils - 60% of leukocytes
• Produce
reactive oxygen species, phagocytosis, cytokines for
inflammation.
• Eosinophils - 2-5% leukocytes
• Contains
granules - major basic protein, eosinophil derived
neurotoxin - against helminths. Stimulate histamine release.
Induce bronchoconstriction, airway hyperreactivity.
• Basophils and Mast cells
• Cell
surface IgE receptors- Type Ihypersensitivity responses
and response to helminths. Release histamine - cause tissue
inflammation, edema, smooth muscle contraction.
• Platelets - Produced from megakaryocytes.
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Lymphoid Organs
• Primary lymphoid organs
• thymus
and bone marrow - where lymphocytes differentiate and
mature
• Secondary lymphoid organs
• mature
lymphocytes reside and immune responses are
generated
• Systemic immune system- spleen and LNs
• Mucosal immune system - Peyer’s patches, tonsil,
intraepithelial lymphocytes.
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Lymph Nodes
• Receive antigens from blood and lymph
• Cortex - B cells predominate in germinal centers
expressing IgM or IgD. Ig class switching, development
of memory B cells.
• Parametrical region - contains T cells, macrophages,
dendritic cells, B cells.
• Medulla - center - Bcells, T cells, macrophages, plasma
cells - secrete Ig to efferent lymphatics.
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Mucosal Immune System
• Tonsils - Adenoids, palatine tonsils, lingual tonsils
• Develop
• Crypts
in childhood and involute around puberty
maximize surface area exposure to pharynx.
• Lobubles
B cells; surrounding lymphoid tissue contian T cells,
macrophages, dendritic cells, B cells.
• Peyers Patches - jejunum and ileum mucosa facilitate
Ag presentation from intestinal lumen to T and B cells.
• Lamina propria beneath epithelium secrete IgA –
neutralize toxins
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Humoral Immune Response
• T cell dependent
• Follicular
B cell presents MHC antigen to T cell that promotes
class switching, Ig production, memory.
• T cell independent
•B
cell response - Large antigens with repeating determinants
like carbohydrates in capsules and cell walls of bacteria cause
activation and secretion of IgM.
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Immunoglobulins
• Variable potion - heavy and light chain - binds to Ag.
• Constant portion - heavy chain - responsible for effector
function binding HC receptors and activate complement.
• IgG-
75% monomer - fix complement, neutralization,
opsonization, bacteriolysis, agglutination, hemolysis
• IgM
- 10% pentamer - earliest Ag receptor on B cells. early
humoral phase. efficient complement fixing. replaced by IgG
• IgA
- 15% monomeric or dimeric. mucosal immunity - excreted.
neutralize substances and prevent systemic access.
• IgE
0.004% monomer - effects mast cells, basophils causing
immediate hypersensitivity reactions.
• IgD
0.2% monomer - membrane bound on B cell surfaces.
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Complement
Cleavage of C3
- C3a fragment anaphylatoxin, mast cell
degranulation, edema,
phagocytic recruiment.
- C3b binds antigen
- assembles membrane attack
complex (MAC - C6,7,8).
- Deficiency - pyogenic
infections
- deficiency of serum inhibitor of
C1 - mast cell independent
angioedema.
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Hypersensitivity Response
• Type I - Mast cell mediated - IgE-dependent
(anaphylaxis) or IgE-independent (iodine contrast)
• Type II - cytotoxic antibody - IgG and IgM bind to Ag of
target cell, destruction of cells - opsonization,
complement, cell lysis. Autoimmune hemolytic anemia.
• Type III - Immune complex - Ig and Ag form immune
complex deposited in normal tissues, activate
complement, inflammation, neutrophil influx, tissue
injury – vasculitis, lupus, RA
• Type IV - delayed hypersensitivity - T cell mediated,
antibody independent. PPD.
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Allergic Rhinitis
• Clinical hypersensitivity of the nasal mucosa to foreign
substances through IgE Ab.
• Prevalence 10-20% affects 20-40 million
• Genetics - Atopy predisposition to respond to
environmental allergens with production of IgE occurs
only in 13% in children without atopic parents, 29% in
one atopic parents or sibling and 47% with both
parents.
• 4-6x more likely in pts with asthma
• Sleep loss, learning, working deficiencies - productivity
loss $593 per year. Health care costs $2-5 billion/yr.
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Hygiene Hypothesis
• Observation - Increasing allergy, autoimmune disease,
insulin dependent diabetes in developed countries with
concomitant decrease in infections due to vaccinations,
antibiotics, hygiene.
• Infection response: TH1 cytokines IL2 and IFN gamma,
Allergy: TH2 cytokines IL4 and 5. Down reg of TH1 and
upreg of TH2.
• Decrease in antigenic stimulation from decreased
infections decrease IL10 and decrease Treg activity
which help to down regulate TH1 and TH2. So
increased TH1 and Th2.
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Pathophysiology of AR
• Ag deposited on nasal mucosa engulfed by APCs and
presented to helper T cells. Th2 CD4+ cells secrete
IL4,5, 13 -> B cells produce IgE -> recruit eosinophils.
• IgE bind mast cells and basophils and sensitize the
nasal mucosa. Subsequent exposure - Membrane IgE
receptors for Ag causing mast cells degranulation
• Early response - pruritus, sneezing, rhinorrhea, nasal
congestion. Increased mediators histamine, kinins,
tryptase, PGD2, leukotriene C4
• Late response 4-10 hrs – histamine – nasal congestion
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Evaluation and Diagnosis
• Symptoms
• Temporality – Seasonal, Perennial, Episodic;
Intermittent vs Persistent
• Severity
• Physical Exam – MEE, erythema/edema of
conjuntiva/NC; septal devation, CRS
• Tests – Skin testing – Wheal <15min +IgE
• Limitations
- antihistamine , children not able to tolerate, eczema
dermatographism preclude interpretation, systemic reactions
may occur
• Total
IgE elevated 40% in AR. Less sensitive than skin testing
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Therapy
• Avoidance
• Antihistamine – Sneezing, rhinorrhea, not congestion
• Phenylephrine, Afrin congestion, rhinitis
medicamentosa
• Ipratroprium – anticholinergic – rhinorrhea
• Mast cell stabilizers – Cromolyn, montelukast
• Intranasal steroids – Most potent – Decreased TH2
• Efficacy
after 8 hrs
• Systemic steroids – refractory pts, side effects
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Immunotherapy
• Subcutaneous immunotherapy SCIT -effective in pollen
allergy - rise in IgG, inc in IgG and IgA in nasal
secretion, reduced basophil reactivity of basophils,
reduced lymphocyte responsiveness to allergens,
recuded inflammatory cells in nasal mucosa, shift from
TH2 to TH1, spress seasonal rise in IgE. Onset of
action is slow 12 weeks increasing over 1 year, requires
compliance - multiple visits. Duration is 3-5 yrs.
• Sublingual immunotherapy (SLIT) - extracts
administered sublingually. Ease of administration - local
side effects - itching and swelling of lips. Not approved
by FDA.
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COCLIA
• R2
• 4.1.3
• What are the different types of hypersensitivity
reactions? Give examples of each?
• 4.1.4
• What are the different immunoglobulin types and what
is their typical structure?
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Hypersensitivity Response
• Type I - Mast cell mediated - IgE-dependent
(anaphylaxis) or IgE-independent (iodine contrast)
• Type II - cytotoxic antibody - IgG and IgM bind to Ag of
target cell, destruction of cells - opsonization,
complement, cell lysis. Autoimmune hemolytic anemia.
• Type III - Immune complex - Ig and Ag form immune
complex deposited in normal tissues, activate
complement, inflammation, neutrophil influx, tissue
injury – vasculitis, lupus, RA
• Type IV - delayed hypersensitivity - T cell mediated,
antibody independent. PPD.
30
Immunoglobulins
• Variable potion - heavy and light chain - binds to Ag.
• Constant portion - heavy chain - responsible for effector
function binding HC receptors and activate complement.
• IgG-
75% monomer - fix complement, neutralization,
opsonization, bacteriolysis, agglutination, hemolysis
• IgM
- 10% pentamer - earliest Ag receptor on B cells. early
humoral phase. efficient complement fixing. replaced by IgG
• IgA
- 15% monomeric or dimeric. mucosal immunity - excreted.
neutralize substances and prevent systemic access.
• IgE
0.004% monomer - effects mast cells, basophils causing
immediate hypersensitivity reactions.
• IgD
0.2% monomer - membrane bound on B cell surfaces.
31
COCLIA
• R3
• 4.1.6
• What are medical therapy options for allergic rhinitis
(different classes of medications and their effects)?
• 4.1.7
• What are the common allergens and the times of year
(seasonal vs. perennial) that patients are most
affected?
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Therapy
• Avoidance
• Antihistamine – Sneezing, rhinorrhea, not congestion
• Phenylephrine, Afrin congestion, rhinitis
medicamentosa
• Ipratroprium – anticholinergic – rhinorrhea
• Mast cell stabilizers – Cromolyn, montelukast
• Intranasal steroids – Most potent – Decreased TH2
• Efficacy
after 8 hrs
• Systemic steroids – refractory pts, side effects
33
Allergens
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COCLIA
• R4
• 4.1.12
• Review humoral vs. cell-mediated immunity. What are
natural killer cells?
• B cell/Ab vs T cell
• Natural Killer cells - large granular lymphocytes –not
restricted to recognition of target cells by MHC. Inhibited
by MHC I molecules presenting self antigens.
• Kill
cells that have down regulated MHC I expression - old or
infected by viruses (avoid Tcell killing).
35
COCLIA
• 4.1.16
• Describe a typical history and physical findings in a
patient with allergic rhinitis.
36
Evaluation and Diagnosis
• Symptoms
• Temporality – Seasonal, Perennial, Episodic;
Intermittent vs Persistent
• Severity
• Physical Exam – MEE, erythema/edema of
conjuntiva/NC; septal devation, CRS
• Tests – Skin testing – Wheal <15min +IgE
• Limitations
- antihistamine , children not able to tolerate, eczema
dermatographism preclude interpretation, systemic reactions
may occur
• Total
IgE elevated 40% in AR. Less sensitive than skin testing
37
COCLIA
• R5
• 4.1.18
• Educate us on immunotherapy…SET vs. RAST based
treatment.
• 4.1.17
• Describe MQT and how it is used.
38
SET vs RAST
• Skin Endpoint Titration (SET) aka Intradermal Dilutional
Testing (IDT)
• Sequential
• Wheal
• Low
administration of fivefold diluted antigens
>7mm in <10min, positive
systemic response, in office, reproducible, high cost
• Radioallergosorbent Test (RAST) React serum with
serios of known allergens, radiolabeled anti-IgE
identifies specific antigen-IgE complexes (older)
• Takes
weeks, more expensive than skin
39
MQT – Modified Quantitative Testing
Highly correlated with IDT, lower cost, less time.
40
Cummings Chapter 41: Physiology of Olfaction
December 3, 2014
Joshua Au
Key Points
• Olfactory epithelium – peudostratified columnar
neuroepithelium with supporting cells, bipolar olfactory
receptor neurons.
• Receptor neurons coalesce into bundles CNI through
the cribriform plate to olfactory bulb
• Most common reasons for olfactory loss are CRS,
polyps, URI, head trauma, neurologic disorders.
• Treatment for olfactory disorders are limited.
42
Anatomy of Olfaction
• Nasal cavity airflow – 50% middle meatus, 35% inferior
meatus, 15% olfactory region.
• Odorant molecules are trapped by mucus
• Bipolar Neuron at posterior superior NC activated by
stimuli through dendrites and cilia. Synapse to olfactory
bulb at skull base.
• Olfactory epithelium 1cm2 bilaterally of pseudostratified
columnar epithelium on a vascular lamina propria.
• Four cell types: ciliated olfactory receptors, microvillar
cells, supporting (sustentacular) cells, basal cells.
43
Neural Anatomy of Olfaction
• Olfactory Bulb – frontal cortex. Primary nerves
synapses at glomeruli. Possible mapping of the bulb
into spatial pattern to the glomerular activation elicited
by odorants.
• Olfactory connections in the brain – Central connections
between the olfactory tubercle, amygdala,
hypothalamus – connections between food intake,
temperature regulation, sleep, vision, memory, taste.
• Common Chemical sense – Free nerve endings of
trigeminal, glossopharyngeal, vagus provide additional
chemoreceptivity to the respiratory tract.
44
Olfactory Transduction and Coding
• Odorant molecule dissolved in mucus, bound by soluble
binding proteins, esp hydrophobic molecules; bind to
receptor proteins on surface olfactory cilia. cAMP and
IP3 pathways transduce signal to depolarize the cell.
Electrical signal to olfactory bulb
• Adrian’s Proposal
• Olfactory Odor Map – Four zones – each contains
different olfactory receptor subtypes
• Odor memory 1 yr vs visual memory 5 mo.
45
Stimulation and Measurement of Olfaction
• Detection threshold – most dilute concentration of
particular odorant detectable.
• Test
restest reliability low.
• Identification test – name correctly. Suprathreshold
test
• Simple detection test – smell alcohol pad
• Objective tests
– electrode on olfactory epithelium detect
negative voltage shift with odorant stimulation
• Electro-olfactogram
evoked potentials – summated percutaneous brain
electrical activity averaged after exposure to odorant.
• Brain
46
Factors affecting Olfaction
• Obstruction
• Head Trauma
• Aging
• Congenital Disfuction
• Toxic Exposures
• Neoplasm
• Neurologic disorders
• Surgery
47
Diagnosis and Management
• Dx – H&P, endoscopy, radiology. Biopsy considered
research tools.
• Management – at level of disruption – obstruction
treatable. Other non-anatomic etiologies have no
proven therapy.
• Reassure patient – regarding food, appreciate in other
ways than taste – texture, color. Safety to gases.
48
COCLIA
• R2 4.3.1 Describe the basic physiology of olfaction.
• 4.3.6 What is the differential diagnosis of anosmia?
• R3 4.3.5 What is the alcohol sniff test?
• R4 4.3.3 What is the mechanism by which individual
odorants chemicals are encoded as distinct?
• R5 4.3.12 How does septoplasty and turbinate
reduction influence olfaction?
49
4.3.1 Describe the basic physiology of
olfaction.
• Odorant molecule dissolved in mucus, bound by soluble
binding proteins, esp hydrophobic molecules; bind to
receptor proteins on surface olfactory cilia. cAMP and
IP3 pathways transduce signal to depolarize the cell.
Electrical signal to olfactory bulb
50
4.3.6 What is the differential diagnosis of
anosmia?
• Obstruction
• Head Trauma
• Aging
• Congenital Dysfuction
• Toxic Exposures
• Neoplasm
• Neurologic disorders
• Surgery
51
R3 4.3.5 What is the alcohol sniff test?
• Detection threshold – most dilute concentration of
particular odorant detectable.
• Test
restest reliability low.
• Identification test – name correctly. Suprathreshold test
• Simple detection test – smell alcohol pad
• Objective tests
– electrode on olfactory epithelium detect
negative voltage shift with odorant stimulation
• Electro-olfactogram
evoked potentials – summated percutaneous brain
electrical activity averaged after exposure to odorant.
• Brain
52
4.3.3 Mechanism by which individual odorants
chemicals are encoded as distinct?
• Adrian’s Proposal - Odorant selective sensitivity of
receptors, incoming odorants excite different patterns of
receptos along mucosal surface. Receptors of like
sensitivity are aggregated into particular regions of the
mucosa giving different spatial representation for each
odorant. Each odorant with different solubility properties
spread differentially across the mucosal sheet.
• Olfactory Odor Map – Four zones – each contains
different olfactory receptor subtypes, axons converge
on specific glomeruli in the olfactory bulb. Unknown
central processing of olfactory information, but
dominated by right hemisphere.
53
How does septoplasty and turbinate reduction
influence olfaction?
• Damm et al. ann Otol Rhinol Laryngol 2003
• After septoplasty inferior turbinate reduction – 87%
increased airflow, 80% improved odor identification,
70% pts improved odor discrimination (suprathreshold
tests). 54% improved odor thresholds
• Anosmia rare complication per literature
54
THANK YOU!
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