Chronic rhino sinusitis pathophysiology based on epos 2020

1. PATHOPHYSIOLOGY OF CHRONIC
RHINOSINUSITIS
MUHAMMED SAHIR C
DLO
SHRI

2. CONTENTS
• DEFINITION
• CLASSIFICATION
• PATHOPHYSIOLOGY OF CRS
INFLAMMATORY MECHANISMS
ENVIRONMENTAL FACTORS
HOST FACTORS
GENETIC FACTORS

3. CHRONIC RHINOSINISITIS
• DEFINITION
• >3months[12weeks]
• Rhinosinisitis= inflammation of the nose & PNS
characterised by 2 0r more symptoms ,one should
be either nasal blockage /obstruction /congestion
/discharge{anterior /posterior nasal drip}
• +/- facial pain/ pressure
• +/- reduction or loss of sense of smell
• And either

4. Endoscopic sign of :
• Nasal polyp and /or
• Mucopurulent discharge primarily from middle
meatus and/or
• Oedema/mucosal obstruction primarily in middle
meatus and/or
• CT changes :
• Mucosal changes within the OMC and /or sinuses

5. Classification of primary CRS
(Adapted from Grayson et al)

6. Classification of secondary CRS
(Adapted from Grayson et al).

7. CRSwNP vs CRSsNP
• CRSwNP
• Intense oedematous stroma
in the sinonasal
epithelium,Albumin
deposition.
• Pseudocyst formation and
subepithelial/perivascular
inflammatory cell
infiltration.
• Associated with a typical T-
helper 2 cell [TH2] skewed
eosinophilic
inflammation,high IL-5 and
eosinophilic cationic protein
[ECP] concentration in the
polyps.
• CRSsNP
• Fibrosis,basement
membrane
thickening,goblet cell
hyperplasia,subepitheli
al
oedema,mononuclear
cell infiltation.
• Exhibit a T –helper 1
cell[TH1]
milieu,increased IFN-
gama in inflamed sinus
mucosa
• Low ECP/
myeloperoxidase ratio

8. PATHOPHYSIOLOGY OF CRS
INFLAMMATORY MECHANISMS OF CRS
• Molecular pathways leading to the establishment
of the mucosal inflammation and tissue
remodeling –mechanisms for inflammation in
CRS
• Diverse inflammatory mechanisms are driven by
dysfunctional interactions at the mucosal surface
between the host and environmental stressors.
• From the host standpoint, genetic and epigenetic
variation of the mucosal immune system is
believed to play a key role in CRS.

9. • Environmental agents like cigarette smoke, fungi,
viruses, bacteria, pollutants and allergens have
been implicated.
• Most common microbial agent is Staphylococcus
aureus, but also due to dysbiosis of the microbial
community as a whole, rather than a specific
dominant pathogen.
• CRS is predominantly an adult onset disorder.
Duration, intensity and sequence of exposure,
including stochastic events such as viral infection,
may be key components of pathogenesis in CRS.

10. • In normal individual, the sinonasal mucosa acts as a
relative barrier, modulating environmental
stimulation including commensal organisms with a
specific, self-limited response.
• In cases of pathogen penetration, single or
combined Type 1, 2 and 3 immunological response
pathways are activated, generating cytokine,
chemokine, innate cellular and T helper (Th)
responses designed to eliminate the identified class
of pathogen with minimal collateral tissue damage.

11. Physiological immune response across
mucosal boundary

12. • Type 1 cytokines include IFN-gamma (IFN-g) and IL-12
with the response geared towards addressing viral
pathogens.
• Type 2 cytokines are IL-4, IL-5, and IL-13, which
promote anti-helminth immunity and regulate tissue
regeneration following injury.
• Type 3 cytokines include IL-17A and IL-22 with
immunologic effects directed against extracellular
bacteria and fungi.
• Each immune response pathway is mediated by
unique innate lymphoid (ILC) and T helper (Th) subsets
that secrete the majority of the key cytokines.
• In cases of CRS, mucosal barrier penetration by
environmental agents also activate Type 1, 2 and 3
pathways.

13. • CRS with Type 2 cytokines is most commonly
associated with asthma and resistance to current
therapies.
• The tissue inflammation is often associated with
remodeling patterns including fibrosis, polypoid
oedema, fibrin deposition and barrier failure.
• Loss of barrier results in greater antigenic
stimulation and more inflammation, further
damaging the barrier and potentially fostering
chronicity.

14. ENVIRONMENTAL FACTORS
• Acute viral infection has been implicated in both
the initial development and subsequent
exacerbations of asthma, yet the role of viruses in
CRS pathogenesis remains unclear.
• Studies on bacteria have revealed the abundance
and diversity of bacterial genera present in the
nose and sinuses, further suggesting alterations in
association with the presence of CRS. In particular,
the presence of S.aureus has been hypothesized to
potentiate certain inflammatory mechanisms of
CRS.

15. • Fungi seem to affect CRS at least in some sporadic
cases.
• Allergens and an array of other environmental
agents also pay a role in CRS.

16. VIRUSES
• RNA viruses that contribute to respiratory
infections include rhinovirus, respiratory
syncytial virus and influenza.
• RNA viruses have high mutation rates
compared to DNA viruses because viral RNA
polymerases lack the proofreading ability of
DNA polymerases.
• The common cold is caused by RNA viruses.

17. • Rhinovirus infection can be linked with exacerbations of
CRS, including increased bacterial adhesion; increased
susceptibility to secondary microbial infection (by
bacteria, fungi, or other viruses), reduction of epithelial
barrier integrity, respiratory exacerbations (as in
asthma, CF and bronchiectasis subjects); epithelial
damage, including necrosis; ciliary dysfunction; and
impairment of mucociliary clearance and mucus
overproduction.
• Cadherin-related family member 3 gene (CDHR3) is a
rhinovirus receptor and its rs6967330 risk allele has
been shown to be associated with childhood asthma
with severe exacerbations and adult CRS, suggesting a
role for aberrant rhinovirus effects in the pathogenesis
of both diseases.

18. • Virus infection activates TLR3 and TLR7-9 signaling
in human airway epithelium.
• Tengroth et al. showed defects in the TLR9
mediated microbial defence close to anatomical
origin of polyp, which explain virus induced polyp
growth.
• DNA-viruses in the head and neck region under
normal conditions and during cancer pathogenesis
are HHV, EBV, and HPV, yet their role in CRS
pathogenesis still needs more evidence from
research.

19. • Epithelial damage scores were significantly higher
for HSV1 and S.aureus co-infected explants
compared with control explants or S.aureus only-
infected explants, and significantly correlated with
HSV1-invasion scores, thus suggesting that HSV-1
infection facilitates invasion of S.aureus.

20. BACTERIA
• Resident microbiota embedded in respiratory
mucus effectively provide first line of defence.
• Commensal organisms prevent colonization of
pathogens and provide certain local metabolites
that enhance mucosal health
• Acute exacerbations of CRS have been more closely
linked to specific bacteria, perhaps following a viral
infection

21. • Dysbiosis is a term indicating microbial imbalance
and associated with the sinonasal microbiome of
CRS patients.
• Dysbiosis of the community as a whole, as opposed
to individual organisms, may trigger mucosal
inflammation.
• Prevalence of Gram negative aerobic and
facultative anaerobic bacteria was high in the non-
eosinophilic CRSwNP subgroup.
• Relative abundance of the Bacteroides phylum in
CRS has been associated with increased severity of
histopathological inflammation and presence of
mucosal ulceration.

22. • Biofilm consists of bacterial colony embedded
within an extracellular matrix of polymeric
substances, which makes it resistant to
environmental stress, host defences and
antimicrobial treatment
• H.influenzae, S. pneumoniae, Pseudomonas
aeruginosa, Moraxella catarrhalis and S. aureus can
all form sinonasal biofilms in CRS patients, some of
which have been associated with a worse
prognosis.
• S. aureus is most closely associated with a
subpopulation of CRS patients, specifically severe
CRSwNP and asthma patients exhibiting high tissue
eosinophilia

23. • Superantigen hypothesis-non invasive s.aureus in
nasal mucosa of CRS patients secrete exotoxins
which produce localised inflammatory response
• Exotoxin specific superantigen IgE ,eosinophils and
markers of chronic eosinophilic inflammation are
higher in CRSwNP than CRSsNP.

24. FUNGUS
• Key roles in two CRS subtypes: fungal balls and
allergic fungal rhinosinusitis (AFRS)
• Aspergillus can cause a fungal ball, which is usually
unilateral, and is more prevalent in middle aged to
elderly females.
• Histologically-fungal balls are characterized by
entangled masses of fungal organisms or masses of
fungi embedded in fibrinous, necrotic exudate, with
minimal mucosal inflammatory reaction without
tissue invasion or granulomatous inflammation

25. AFRS
• 1) Type 1 hypersensitivity
• 2) Nasal polyposis
• 3) Characteristic CT changes
• 4) Eosinophilic mucus
• 5) Presence of non-invasive fungus in sinus content
• AFRS patients tend to be younger, express
consistently high serum IgE, and have milder
asthma in general.
• AFRS is also more common in humid climates with
a tendency to present unilaterally

26. • Innate immune defect (possibly in TLR4) may
account for fungal accumulation in the sinonasal
cavities of AFRS patients
• Intrinsic protease effects that induce Type 2
cytokine signaling leading to the accumulation of
eosinophilic mucin
• Histologically characterized by sloughed epithelial
cells, eosinophils, Charcot–Leyden crystals, and
scattered fungal hyphae

27. OTHER ENVIRONMENTAL FACTORS
• Allergens typically possess intrinsic protease activity
that can interact with epithelial cells through three
principle pathways: direct effects on junctional
proteins, reaction with cell surface protease-
activated receptors and toll-like receptor 4 (TLR4)-
dependent epithelial activation
• Protease activity of allergens may elicit the release
of epithelial-derived Type 2-driving cytokines and
chemokines
• Imbalance of proteases and protease inhibitors
within the epithelial barrier may contribute to the
pathogenesis of Type 2 diseases

28. SMOKING
• Exposure to tobacco smoke alters sinonasal mucosa
• Cigarette smoke exposure downregulates
expression levels of E-prostanoid receptors and
stimulates the production of prostaglandin E2, IL-8
and TNF-α
• Tobacco smoke alters the sinonasal composition of
dendritic cells

29. 0ZONE
• Air pollutant with known proinflammatory effects
on exposed epithelia
• Clara cell protein 16 (CC16) is produced by non-
ciliated Clara cells in the respiratory epithelium and
has an anti-inflammatory role in chronic upper and
lower airway eosinophilic inflammations
• Decreased levels of CC16 are found in the nasal
secretions and plasma of patients with chronic
eosinophilic inflammatory disorders, such as BA, AR
and CRSwNP and CRSsNP, and in people exposed to
high levels of air pollutants

30. • Vitamin D and its receptors involved in the
regulation of the immune system and may play
role in CRS
• Vitamin D3 deficiency has shown to cause
changes in murine sinonasal immunity as
measured by tissue immune cell infiltrate and
nasal lavage cytokine levels

31. HOST FACTORS
• 1.Innate immunity
• 2.Adaptive immunity

32. INNATE IMMUNITY
• Innate immunity is present in healthy individuals at
baseline to block the entry of microbes and to
rapidly eliminate microbes entering the host tissues
• The components of innate immune system include
epithelial barrier, sentinel mucosal cells (resident
macrophages, dendritic cells, mast cells etc.),
circulating and recruited phagocytes (monocytes
and neutrophils), innate lymphoid cells, NK cells, as
well as non-cellular components (e.g. complement
system)

33. EPITHELIAL BARRIER
• Sinonasal tract is covered by ciliated
pseudostratified columnar, olfactory, and to lesser
extent layered squamous epithelium (in the nostril
area).
• Mucociliary clearance (MCC) and apical junctional
complexes between epithelial cells comprise a
mechanical barrier between host and environment,
which provides the first line of host defence for the
nose and sinuses

34. • Disrupted mechanical barriers & deficiencies in
both innate and acquired immune system make the
sinonasal mucosa susceptible to antigenic exposure
and stimulation, leading to chronic inflammation
• Genetic and acquired defects in mucociliary flow
with increased mucus viscosity are associated with
a high incidence of CRS
• IFN-γ and IL-13 decrease differentiation of ciliated
epithelial cells and secondary reduction in ciliary
beat frequency
• Surfactant protein A gene expression was increased
in CRS and decreased in primary atrophic rhinitis

35. INNATE LYMPHOID CELL
• ILC1, ILC2 and ILC3 correspond to the Th1, Th2, and
Th17 subsets of CD4+ T cells, respectively
• ILC2 play a significant role in eosinophilic CRSwNP,
and possibly all CRS that exhibits Type 2
inflammation
• ILC2 cells target parasites, assist in tissue repair and
also mediate allergy
NEUTROPHIL
• The role of neutrophils in CRS pathogenesis is
uncertain, but these cells are capable of
degranulation with tissue damage including some
loss of barrier integrity

36. MONOCYTE
• 2types of activated macrophages, M1 and M2
• M1 activation is driven by Type 1 cytokines that
trigger a proinflammatory response to kill
intracellular pathogens
• M2-activation driven by type 2 cytokines and role in
defence against helminths,humoral immunity, and in
tissue repair
• M2 macrophages have an impaired ability to
phagocytose and secrete high levels of CCL18, a
chemotactic for dendritic cells, naïve T cells, and Th2
cells — all of which may contribute to the
pathogenesis of CRSwNP

37. • BASOPHILS
• Granulocytes found mainly in the circulation and
are known to have a role in allergic disease and
immunity against parasites.
• Implicated in Type 2 responses in general, possibly
serving as an early source of IL-4 driving
polarization in the Th2 direction.
• Elevated in aspirin tolerant polyps as opposed to
N-ERD polyps.

38. MAST CELLS
• Local IgE class switching directed against common
aeroallergens may mediate mast cell activation and
contribute to subsequent eosinophilic
inflammation in CRSwNP
• Mast cells, along with platelets ,may be sources of
proinflammatory leukotrienes (cysLTs) and
prostaglandins (PGD2) in CRSwNP and N-ERD
• Potential to induce, augment and maintain
eosinophilic inflammation through IgE-dependent
and IgE-independent processes.

39. EOSINOPHILS
• Significant role in tissue repair and immune
defence, in particular against helminths.
• Important cell type in asthma, AR and CRS.
• Tissue eosinophilia correlates with relatively poor
outcome independent of the presence or absence
of polyps
• Biomarker for severe, recalcitrant disease, and is
the cell that mediates this relatively poor prognosis

40. • Process of eosinophil recruitment, activation and
survival in CRS is driven largely by epithelial
cytokines, exogenous proteases, complement
proteins, eicosanoids, stem cell factor and Type 2
cytokine.
• Eosinophils are steroid responsive, which likely
explains at least some of the therapeutic effects of
glucocorticoids in CRS.

41. • NATURAL KILLER CELLS
• Type of cytotoxic lymphocyte
• On activation by (virus-) infected cells, NK cells
empty their cytoplasmic granules.Granule proteins
enter infected cells and induce apoptosis.
• PLATELETS
• Platelets are activated and a major source of
proinflammatory leukotrienes (cysLTs) and
prostaglandins (PGD2) in CRSwNP and, in particular
N-ERD.

42. MECHANISMS OF ADAPTIVE IMMUNITY
• ANTIGEN PRESENTATION, DENDRITIC CELLS AND T
CELL ACTIVATION
• Antigen presentation is a transition phase from the
innate to the adaptive response and is mediated
mainly by dendritic cell(DC).
• Plasmacytoid dendritic cells are decreased in
patients with a more severe type 2 profile.
• Antigen presentation is regulated by co-stimulatory
molecules. Programmed cell death-1 (PD-1) is a
negative regulator of T-cell responses.

43. T CELLS
• T cells activate & recruit effector cells including
phagocytes, kill infected cells and provide help for B
cells in immunoglobulin production.
• Loss of T-helper cell function leaves the body
vulnerable to a wide range of infections.
• Th1 cells stimulate phagocyte-mediated killing of
ingested microbes via secretion of interferon-γ (IFN-γ)
and tumor necrosis factor -α and –β (TNF-α and TNF–
β).
• Th2 cells are induced by parasitic worm infections and
promote IgE-, mast cell-, and eosinophil-mediated
destruction of these parasites with the help of ILC2
cells.
• Th17 cells develop in response to extracellular
bacterial and fungal infections and induce
inflammatory reactions destroying these organisms.

44. • Numbers of regulatory T cells (Tregs) are generally
reduced in CRS and this has been interpreted as
diminished Treg activity leading to chronicity.
• CD8+/ CD4+ T cell ratio is also higher in CRS,
indicating particular enhancement of the cytotoxic
T cell population.
• Increased expression of intercellular adhesion
molecule-1 (ICAM-1) in activated eosinophils is
associated with eosinophil extravasation and
infiltration into NP tissue, and seems to initiate also
mucosal remodeling of NP.
• VCAM expression was higher in CRSsNP, and highest
in CRSwNP, while ICAM expression was elevated in
both CRS subtypes.

45. • L-selectin ligand, peripheral lymph node addressin
(PNAd), was preferentially induced in the nasal
vasculature of eosinophilic CRS facilitating tissue
recruitment from blood.
• B cells and immunoglobulins have been implicated in
CRS and antibody defects are the most common
immunodeficiencies, typically associated with CRSsNP.
• B cell activation with excessive local antibody
production has more commonly been associated with
CRSwNP.
• Polyp tissue from CRSwNP patients has been found to
contain high levels of B cells, plasma cells, follicles that
resemble germinal centres, and high levels of IgA, IgM,
IgG and IgE that indicate local production of
immunoglobulins.

46. • Anti-BP180 antibodies were elevated in CRSwNP
patients, suggesting autoimmune targeting of the
epithelial barrier.
• Local IgE has been the most commonly implicated
antibody in the pathophysiology of CRSwNP.
• IgE in nasal polyps is polyclonal and can trigger mast
cell degranulation, suggesting a significant role for
IgE in the pathophysiology of this subset of CRSwNP
patients.
• Local IgG4 expression is high in serve eosinophilic
CRS.

47. OTHER INFLAMMATORY MECHANISMS
• In CRS, remodeling also takes place and observed
changes include fibrosis, basement membrane
thickening (BMT), goblet cell hyperplasia, epithelial
barrier abnormalities and polyp formation, osteitis and
angiogenesis.
• Inflammation leads to remodeling with cytokines,
mediators, enzymes and other factors determining the
remodeling pattern.
• Duration and type of inflammation would determine
the outcome.
• Periostin , IL-13 and osteopontin has been suggested
as a marker for BMT and fibrosis.

48. • Concept of a remodeled, immature, very leaky
barrier is most closely associated with Type 2 CRS
and may account for the higher treatment failure
rate using conventional therapy.
• Nasal polyposis is associated with marked tissue
oedema, diminished collagen and extracellular
matrix degradation, possibly due to imbalances in
metalloproteinase activity

49. • Downregulated pro-osteoblastic mucosal BMP
signaling is strongly and significantly associated
with increased osteitis in CRSwNP
• Different signaling pathways are involved in osteitis
in CRS and are activated by the TGF-β/Smad
signaling pathway in CRSwNP versus the TGF-
β/Smad-independent signaling pathway in CRSsNP.

50. LEUKOTRIENE HYPOTHESIS
• Defects in eicosanoid pathway most closely
aasociated with aspirin intolerance are also key
components in pathogenesis of eosinophilic
subtypes of CRS

51. GENETICS OF CRS
• First-degree family members of affected are 4.1
times more likely to develop CRSwNP and 2.4 times
more likely to develop CRSsNP
• A classic example is cystic fibrosis, where
homozygous mutations in the CFTR gene lead to
defects in cl transport and yield the clinical
manifestations of the disease.
• CRS, preferentially affecting the maxillary sinuses, is
a consistent feature of CF
• Defect in gene involved of the epithelial barrier lead
to poor epithelial regeneration following viral insult,
thereby yielding the same result

52. • S. aureus carriage in CRSwNP patients is associated
with a number of genes .
• Reduced engulfment of bacteria, modulation of
inflammatory response, and genes of barrier
elements
• TAS2R38 polymorphisms have been associated with
CRS. TAS2R38 codes for a type of bitter taste
receptor, which is expressed in the airway and is
implicated in innate immune defence
• In CRSsNP- non-tasting (or non-protective) TAS2R38
genotype is associated with higher rate of gram –ve
bactial carriage & poor outcome

53. REFERENCE
• European Position Paper on Rhinosinusitis and
Nasal Polyps 2020 [EPOS 2020]
• Scott-Brown’s otorhinolaryngology head and
neck surgery[8th edtn]
• Pathophysiology of CRS [journal] omassen,
Van Zele, Zhang, et al.
• Disease of ear nose and throat by Dhingra [7th
edtn]

54. THANK YOU