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EPOS2020Inflammatory Mechanisms of
Chronic Rhinosinusitis
Robert C. Kern MDGeorge A. Sisson Professor of Otolaryngology
Chairman, Department of Otolaryngology-Head and Neck Surgery Northwestern University Feinberg School of Medicine Chicago,
Illinois
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Definition of CRS
• 12 consecutive wks of subjective sinonasal symptoms
• 4 cardinal symptoms: blockage, drainage, smell loss, pressure or pain
• Objective confirmation of inflammation via endoscopy or CT
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CRS Phenotypes
• Broad clinical syndrome
• Symptom complex with objective confirmation
• Historically, divided into CRS into 2 phenotypes: CRSwNP and CRSsNP
• Simplistic, multiple clinical patterns exist
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Advanced CRS Phenotypes in USA
• Total CRS 20,000,000• Total CRSsNP 16,000,000• Total CRSwNP 4,000,000
• AERD 400,000• AFS 500,000• Cystic Fibrosis 30,000• Autoimmune (GPA, EGPA) 10,000• Kartagener’s syndrome 7000
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Age: CRS Phenotypes
• Older onset CRS/asthmatics do poorly
• Early onset CRS patients do better
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CRS phenotypes
• Not usually very helpful in terms of patient counseling
• Not very helpful in terms of guiding treatment
• Research into causes of CRS for 20+yrs to make treatment more precise
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What is CRS?
• Broad clinical syndrome-not a disease
• 2 basic pathways to CRS:
– OMC blockage– Primary mucosal inflammation
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CRS Syndrome
OMC Inflammation Primary Inflammation Mixed
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Primary Mucosal inflammation in CRS
Causes ???
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Etiology and Pathogenesis of CRS
Environment• Fungal hypothesis• Superantigen
hypothesis• Biofilm hypothesis• Microbiome
hypothesis• Allergy
Host
• Eicosanoid hypothesis
• Immune barrier hypothesis
• EPOS 2012• Lam et al., 2015
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Nasal and Sinus Mucosa
• Site of Interface with the external environment
• In health, this occurs with minimal if any inflammation
• Mucosa serves as an “immune barrier”
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Mucosal ImmunityOverview
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CRS Etiology and Pathogenesis
Host
Barrier Penetration
Environment
CRS
• Host and Environment interact for 40+ years and then barrier is penetrated resulting in CRS
• With self perpetuating inflammation
Age 45
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CRS Etiology and Pathogenesis
Host
Barrier Penetration
Environment
CRS
• Typically, adult onset disorder• Early 40’s CRSsNP; Late 40’s CRSwNP
Age 45
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Nasal and Sinus Mucosa
• Cross talk between host and environment• Microbiome • Defense vs. symbiosis• Stochastic events such as viral infection at a young age
• Early life exposure protective; Hygiene Hypothesis• Strachan, BJM, 1989
• Gut/airway axis• Von Mutius, JACI 2016• Lynch and Boushey, Curr Opin Allergy Clin Immunol., 2016
• SCFA, other compounds-protective!
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Atopic March
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Early onset Atopic CRS?
CRS?
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Early Onset CRS Phenotype?
Host
Barrier Penetration
Environment
‘Atopic’ CRS
• Milder, atopic, progression of childhood disease• CRSsNP typically• Mild asthma or childhood asthma
Age 25
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CRS Etiology and Pathogenesis
Host
Barrier Penetration
Environment
CRS
• Host and Environment interact for 40+ years and then barrier is penetrated resulting in CRS
• More severe, probably more likely to need surgery• CRSsNP early 40’s; CRSwNP late 40’s
Age 45
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Host vs. Environment in CRS
Which are more important host factors or environmental factors in an individual patient?
Can we know in an individual patient?
Would it matter?
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CRS Etiology and Pathogenesis
Host
Barrier Penetration
Environment
CRS Endotypes
• Etiologic factors vary so…..the inflammation not the same in
all CRS patients: ENDOTYPES-mechanistic pathways, types/patterns
Age 45
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Personalized Medicine
• Genotype- genetic makeup that underwrites a disease
• Endotype-subtype of a disease defined by a distinct pathophysiologic mechanism
• Phenotype-observable clinical characteristics
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Chronic Rhinosinusitis
• Genotype-complex, multiple genes, ALOX 15, CFTR; Environmental factors probably more important
• Endotype-new classification systems
• Phenotype-clinical groupings; basis of most treatment at present
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Etiology and Pathogenesis of CRS
Genotype Epigenetic variation
Endotype(s)
Environmental factors
Phenotypes
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Etiology and Pathogenesis of CRS
Endotype
Host
Remodeling Phenotype
Natural historyoutcome
Barrier penetration
Environment
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Etiology and Pathogenesis of CRS
Endotype
Host
Remodeling PhenotypeNatural history
outcome
Barrier penetration
Environment
Lower airway disease?Asthma and Bronchiectasis
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Endotypes of CRS
• Endotypes: mechanistic pathway
• What are the endotypes of CRS?
• How can they help guide treatment?
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Fig 3
Journal of Allergy and Clinical Immunology 2016 137, 1449-1456.e4DOI: (10.1016/j.jaci.2015.12.1324) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions
Tomassen et al., JACI 2016
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Endotyping CRS
Tomassen et al., 2016
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1. Mucus/Cilia2. TJs3. HDM and sIgA4. ILC1, 2 and 35. Innate cells6. T cells 7. B cells
Sinonasal Immunity
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Innate Lymphocytes Guide Immune Responses
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Mucosal Immunity
• ILC1 → Type 1 inflammation; Th1Viruses, Intracellular organisms
• ILC2 → Type 2 inflammation; Th2Parasites, REPAIR
• ILC3 →Type 3 inflammation; Th17Extracellular organisms
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Mucosal Immunity
• ILC1 → Cytotoxic T cells, NK cells and neutrophils
• ILC2 → Eosinophils, mast cells, B cells and neutrophils
• ILC3 → Neutrophils
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CRS Endotypes
• Type 1 inflammation: IFN-γ• Type 2 inflammation: IL-4, IL-5, IL-13• Type 3 inflammation: IL-17
• So we can determine tissue patterns based on markers of Type 1, 2 and 3 inflammation in the tissue
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CRS Endotype Patterns
• T1• T2• T3• T1,2• T1,3• T2,3• T1,2 and 3• Non typeable
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Inflammatory endotypes in CRS
Kato A et al., unpublished. 2018 (updated)
T1sNP: total 21%
T2sNP: total 55%
T3sNP: total 27%
T1wNP: total 17%
T2wNP: total 87%
T3wNP: total 18%
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Kato A et al., unpublished. 2018 (updated)Wang X and Bachert C al., J Allergy Clin Immunol. 2016
(Adapted)
Similar inflammatory patterns in CRS are reported in Europe
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60+% of CRS in Chicago is T2
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Type 2 Inflammation
• Associated with treatment failure• Asthma • Eosinophilia
• Higher rate of polyp formation
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TYPE 2 Inflammation
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Type 2 Inflammation
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Endotype Drives Remodeling
Barrier Penetration
Host and Environment
CRS Endotypes
• Remodeling includes polyp formation, barrier changes, fibrosis, glandular hypertrophy
Remodeling
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Type 2 CRS
Barrier Penetration
Host and Environment
Type 2 CRS Endotype
• Polyps and barrier damage are remodeling changes secondary to the Type 2 inflammation
T2 Remodeling: Polyps and
barrier
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Nasal Polyp
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What are Polyps?
CRSwNP UT
Nasal polyp
Control UT CRSsNP UT
PicrosiriusRed
Takabayashi et al., Am. J. Resp. Crit. Care Med., 187:49, 2013
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Fibrin deposition in nasal polyps in CRS
Nasal polyp Nasal polyp Isotype control
Control UT CRSsNP UT CRSwNP UT
Takabayashi et al., Am. J. Resp. Crit. Care Med., 187:49, 2013
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Professor Shimizu from Shiga University first suggested importance of coagulation cascade and polyps
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Takabayashi et. al., Am J RCCM, 2013
Type 2 cytokine: IL-13
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Tissue TPA levels vary! Type 2 cytokine: IL-13
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Regulation of pathways of fibrin deposition by IL-13
Imoto et al., JACI, in press 2019
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SCFA
t-PA
SCFA Increase Epithelial t-PA
Imoto, Kato, Takabayashi, Sakashita et al., Clin Exp Allergy, 2018
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Type 2 Remodeling: Polyps
Barrier Penetration
Host and Environment
Type 2 CRS Endotype
• Type 2 Polyp formation is the results of fibrin crosslinking when t-PA is suppressed by sufficient IL-13
Remodeling: polyps
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Type 2 Remodeling: Barrier Damage
Barrier Penetration
Host and Environment
CRS Endotypes
• Barrier damage is also a type of remodeling seen with Type 2 inflammation
Remodeling:Barrier damage
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Type 2 Inflammation and Barrier
• Weakened and Immature epithelial barrier
• Chronic immature EMT state
• Barrier failure
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CRSwNP
Kuhar et al. IFAR 2017
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Control Uncinate
Nasal Polyp
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Abnormal Repair in Type 2 CRS
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Barrier Failure and Type 2 CRS
Jacqi summary of OSM story
Pothoven et al., 2015
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Hypothetical progression in Type 2 CRS
Schleimer, R. Ann. Rev. Path., 12:331, 2017
Barrier Penetration Barrier Failure
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Type 2 CRS
T2 Endotype
Host Environment
Remodeling:Polyps and
barrier failure
PhenotypeNatural history
outcome
Barrier penetration
Barrier Failure is probably distinct from barrier penetration
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Type 2 Inflammation and Recurrence
• Chronically weak barrier• Predisposes to recurrence
• Need steroid maintenance• Severe cases need a biologic
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Not all CRS is Type 2!
• T1• T2• T3• T1,2• T1,3• T2,3• T1,2 and 3• Non typeable
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What about Non-Type 2 Remodeling?
• T1• T2• T3• T1,2• T1,3• T2,3• T1,2 and 3• Non typeable
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Takabayashi et. al., Am J RCCM, 2013
Type 1 cytokine: IFN-γ
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Type 1 and 3 Remodeling: Polyps
Barrier Penetration
Host and Environment
Type 1 and 3 CRS
Endotype
• Type 1 and 3 Polyp formation is also the result of fibrin crosslinking when t-PA is suppressed but less common in Western Societies
Remodeling: polyps
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Non-Type 2 Inflammation
• Barrier more intact so recurrence less
• Polyps still fibrin
• Polyps less common because t-PA suppression weaker with T1/3 cytokines and no feed-forward mechanism because barrier more intact
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Nasal polyps
• Polyps are mostly a fibrin matrix in all CRS endotypes
• More common in T2 inflammation because IL-13 more effective at suppressing t-PA than Type 1 and 3 cytokines
• Also more common in T2 because Barrier Failure more likely to drive T2 cytokine levels
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Barrier Penetration
EnvironmentT1/T3
T2
Asthma
Fibrin Polyps, less fibrosis
Barrier failure
Bronchiectasis
Intact barrier
Fibrosis, less fibrin Polyps
Host
CRS Endotypes
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Barrier Penetration
EnvironmentT1/T3
T2
Biologics
Surgery
Corticosteroids (strong)
Surgery
Corticosteroids (weak)
Antibiotics
Host
Treatment of CRS Endotypes
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Thank you
73