La Poliposi Nasale:dalla geneticaalla terapia e
all'esperienza personaleBenedetta Biagioni
School of Allergy and Clinical Immunology
EPOS DEFINITION OF ACUTE AND CHRONIC RHINOSINUSITISWITH AND WITHOUT NASAL POLYPS
DEFINIZIONE
La Poliposi Nasale: introduzione
EPOS CLASSIFICATION OF NASAL POLYPS
La Poliposi Nasale: introduzione
CLASSIFICAZIONE DEI POLIPI NASALI
EPIDEMIOLOGIA
Estimated prevalence of CRSwNP :
•In Europe � 2.1% (France) / 4.4% (Finland)
•In the USA � 4.2%
•In Asia � 1.1% (China) / 2.6% (Korea)
La Poliposi Nasale: introduzione
NP occur more frequently in asthma patients with aspirin sensitivity
Incidence of nasal CRSwNP :
• higher in men than in women
• increases after the age of 40 years
La Poliposi Nasale: fenotipi
CRSwNP:
Proinflammatory and neutrophil-
associated cytokines : interleukin (IL)-
1β, tumor necrosis factor (TNF)-α, IL-8
�increased neutrophil activation
Upregulation of TGF-β1 and TGF- β2 and
of their receptors TGF-βR1 and TGF-βR3
� collagen deposition
CRSsNP:
Eosinophil-rich, Th2-dominated cytokine
Downregulation of TGF-β1 protein and its
receptors R1 and R2 � no collagen
deposition
CRwNP vs CRSsNP
CRSwNP E ASMA
La Poliposi Nasale: fenotipi
CRSwNP frequently is found in association with asthma and nonspecific
bronchial hyperresponsiveness.
In patients with CRSwNP,
asthma was found in 20% to 70%.
In patients with CRSwNP and bronchial
hyperreactivity an eosinophilic
bronchial inflammation is observed in
the tissue, whereas in patients with
CRSwNP without bronchial
hyperreactivity, such inflammation is
absent.
CRSwNPCurrent or future LOWER AIRWAY INVOLVEMENT
NO lower airway involvement
ENDOTIPI INFIAMMATORI IN CRS
La Poliposi Nasale: endotipi
Multicenter case-control study patients with CRS and control subjects underwent surgery.
173 tissue analyzed for :
IL-5, IFN-γ, IL-17A, TNF-α, IL-22, IL-1β, IL-6, IL-8,ECP, MPO, TGF-β1, IgE,
Staphylococcus aureus enterotoxin-specific IgE and albumin.
J ALLERGY CLIN IMMUNOL nnn 2016
ENDOTIPI INFIAMMATORI IN CRS
La Poliposi Nasale: endotipi
10 clusters:
• 6 clusters with high concentrations of IL-5, eosinophilic cationic protein, IgE.
• 4 clusters with low or undetectable concentrations those markers
La Poliposi Nasale: endotipi
•IL5 negative clusters� Predominant CRSsNP phenotype
without increased asthma prevalence
•IL-5–positive clusters were divided into:
1. Moderate IL-5 levels � CRSsNP/CRSwNP and increased asthma phenotype
2. High IL-5 levels � almost exclusive nasal polyp phenotype
with strongly increased asthma prevalence
ENDOTIPI INFIAMMATORI IN CRS
In clusters with
the highest
concentrations of
IgE and asthma
prevalence
all samples
expressed
Staphylococcus aureus enterotoxin–specific IgE
La Poliposi Nasale: patogenesi
RUOLO DI S. AUREUS
� S. aureus enterotoxins (SAEs) act as superantigens
� High local
polyclonal IgEconcentration
1/105 –1/106
T cells1/5
T cells
La Poliposi Nasale: patogenesi
RUOLO DI S. AUREUSS. Aureus and its
pruduct evoke
the release of
epithelial
cytokines
IL-33, TSLP,
eotaxin
�EET
S. Aureus and staphylococcal proteins can
directly activate T-cells to release IL-5�EET
Direct contact between eosinophils
and S. aureus
� EET
BARRIER DYSFUNCTION
EOSINOPHIL EXTRACELLULAR TRAPS
La Poliposi Nasale: endotipi
CRSwNP: West vs Est
Western world:
Asian world :
Th2 signature in 80% of nasal polyps
Th2 signature between 20% (China and Korea) and 60% (Thailand)
Lower asthma comorbidity
Low risk of recurrence after surgery
Immunological heterogeneity among different regions within the same
disease phenotype
La Poliposi Nasale: endotipi
CRSwNP: West vs Est
IL-5-POSITIVE NASAL POLYPS mediators of eosinophilic inflammation associated with greater
Gram-positive bacterial colonization.
KEY CYTOKINE-NEGATIVE NASAL POLYPS mediators of neutrophilic inflammation associated
with Gram-negative bacterial load
La Poliposi Nasale: endotipi
CRSwNP: West vs Est
Journal of Allergy and Clinical Immunology (2017)
These differences in type-2 signatures all over the world would stay over time or would be matter to change ?
� several publications show a dramatic change in the expression of eosinophilic
disease within the CRSwNP population in Thailand and Korea
EOSINOPHILIC SHIFT accompanied by higher
S. aureus carriage
Chronic rhinosinusitis (CRS) is a complex disease, with a pathophysiology
that is likely to be affected by multiple genetic and environmental factors
Family and twin studies:
100 patients with NP and 102 controls from the general population,
13.3% of the patients and none of the controls had a history of polyps in the family,
224 CRSwNP patients 52% had a positive family history of NP
Studies of monozygotic twins have NOT shown that
both siblings always develop polyps,
environmental factors are likely to influence the
occurrence of CRSwNP.
La Poliposi Nasale: genetica
POLIPOSI NASALE ED EREDITARIETÀ
A variety of cytokines, cytokine receptors, immunity and mucosal
airway remodeling related molecules have been associated with CRS.
Among them only three polymorphisms have been replicated :
IL1 alpha: •Karjalainen et al. The IL1A genotype is associated with nasal polyposis in asthmatic adults.
Allergy 2003
•Mfuna et al Association of IL1A, IL1B, and TNF gene polymorphisms with chronic rhinosinusitiswith and without nasal polyposis: A replication study. Archives of otolaryngology--head & neck
surgery 2010
TNF alpha:
•Erbek et al. Proinflammatory cytokine single nucleotide polymorphisms in nasal polyposis. Archives of otolaryngology-- head & neck surgery 2007
•Bernstein et al. Genetic polymorphisms in chronic hyperplastic sinusitis with nasal polyposis.
The Laryngoscope 2009
AOAH: •Mfuna-Endam et al. Genetics of rhinosinusitis. Current allergy and asthma reports 2011
•Zhang et al. Polymorphisms in RYBP and AOAH genes are associated with chronic rhinosinusitis in a Chinese population: a replication study. PloS one 2012
POLIPOSI NASALE E STUDI DI ASSOCIAZIONE
La Poliposi Nasale: genetica
• IL-33
• IL-22 receptor a
• IL-1 receptor a
• IL-1 receptor –like 1
• Matrix metalloproteinase 9
• Matrix metalloproteinase 2
• TSLP
• TGFbeta1
• TLR2
• OSF- 2
• IL-4 promoter
etc etc…..
La Poliposi Nasale: genetica
POLIPOSI NASALE E STUDI DI ASSOCIAZIONE
The other susceptibility genes and loci reported to be associated
could not be replicated:
EPIGENETIC ROLE?
?
??
?
??
?
heterogeneity and poor repeatability of the genetic findings
The differentiation of CRS into endotypes rather than phenotypes will offer
further opportunities to discover genetic and epigenetic patterns
La Poliposi Nasale: genetica
GENETICA DELLA AERD
Aspirin-exacerbatedrespiratory disease (AERD)
> 50% NP associated
Widal-Samter’sTriad
LTC4S promoter SNP
Forest plot of randomized controlled trials evaluating
topical steroids in patients with nasal polyposis. CI ¼
confidence interval; RR ¼ risk ratio.
Laryngoscope, 122:1431–1437, 2012Methods: randomized, placebo controlled
trials, nasal polyposis, and topical steroid
therapy.
Results: A total of 12 studies were combined
for quantitative analysis and demonstrated a
pooled risk ratio of 1.72 (95% confidence
interval, 1.41–2.09), indicating a significant
improvement in nasal symptoms.
All three topical steroid preparations
(fluticasone, mometasone, and budesonide)
resulted in symptom improvement.
Conclusions: Topical nasal steroid therapy
improves nasal symptoms in CRS patients
with nasal polyposis.
Level of Evidence: 1a
CORTICOSTEROIDI TOPICI
La Poliposi Nasale: terapia
Congestion score
Sense of smell
JACI 2005; 116: 1275
La Poliposi Nasale: terapia
CORTICOSTEROIDI TOPICI
Group A: oral prednisolone 1 mg/kg/day tapering by 5 mg/day, for 2 weeks
Group B: endoscopic intrapolyp steroid injection weekly (40 mg/mL triamcinolone, 1 mL) for up to five times
In both groups the treatment was followed by fluticasone propionate nasal drops 40 mg twice a day for 12
weeks.
decrease in symptom score and polyp score with no significant
difference between groups.
La Poliposi Nasale: terapia
INIEZIONE LOCALE DI CORTICOSTEROIDI
decrease in Lund-Mackay staging and
no significant difference was found between two groups.
Plasma cortisol and ACTH levels of the injected patients were normalbefore treatment,
1 week after the first injection,
and 1 week after the last injection.
La Poliposi Nasale: terapia
MACROLIDI
Cervin & Wallwork
Curr Allergy Asthma Rep (2014)
Anti-inflammatory effects of
macrolide antibiotics.
Efficacy in CR patients with
•neutrophilic inflammation,
•not elevated IgE
•Low CT score
Doxycycline
Doxycycline reduces local inflammation in terms of ECP and MPO
• effect on eosinophilic inflammation• effect on neutrophilic (may be related to the effect on S.aureus)
• Doxycycline has a sigificant effect on remodeling (MMP-9)
La Poliposi Nasale: terapia
DOXICICLINA
J ALLERGY CLIN IMMUNOL
MAY 2010
J ALLERGY CLIN IMMUNOL
MAY 2010
Doxycycline causes a
long-term reductionin nasal polyp size,
methylprednisolone
causes an initial
reduction in polyp
size but complete
recurrence after 2
months
389 CRS patients who had undergone bilateral 3–5 years prior to the study.
Postal questionnaire asking for control items according to EPOS control criteria, visual analogue scale (VAS)
scores for total and individual sinonasal symptoms, sinonasal outcome test (SNOT)-22 and Short Form (SF)-
36 questionnaires.
La Poliposi Nasale: terapia
POLIPOSI NASALE NON CONTROLLATA
Subgroup analysis
revealed that
female gender,
aspirin intolerance and
revision ESS were associated with
higher prevalence of
uncontrolled CRS,
whereas allergy, asthma
and smoking status d
id not alter the
percentage of patients
in each category of
control
La Poliposi Nasale: terapia
POLIPOSI NASALE NON CONTROLLATA
La Poliposi Nasale: terapia
Improvement in total nasal polyp score: Omalizumab (n=15) versus placebo (n=8)
OMALIZUMAB
Int Arch Allergy Immunol 2009; 148:87–98
0
10
20
30
40
50
60
70
80
W2 W4 W6 W8 W10 W12 W14 W16 W18
placebo
omalizumab
-3
-2,5
-2
-1,5
-1
-0,5
0
0,5
1
BL W2 W4 W6 W8 W10W12W14W16W18
placebo
omalizumab
La Poliposi Nasale: terapia
“ For many patients with
severe disease,
uncontrolled with the
current surgical and
pharmacological
possibilities,
biotherapeutics soon will
offer a new and significant
treatment option,,
La Poliposi Nasale: esperienza
Subject Disease CRS onset FESS RevisionFESS
Treatmentstart
Outcome
SM (m) EGPA 1995 yes > 1 2017 Qol
DR (m) EGPA 2013 no no 2017 Stationary
QM (f) EGPA 2010 no no 2011 Stationary
DF (m) EGPA 2009 no no 2015 Stationary
MS (f) EGPA > 10 years yes > 1 2013 Recurrence
PS (f) EGPA 1995 yes > 1 2016 TC
improvement
TS (f) EGPA 2009 yes 1 2014 Stationary
Subject Disease CRS onset FESS RevisionFESS
Treatmentstart
Outcome
RR (m) EGPA 2016 no no 2017 Recurrence
GS (f) asthma 2007 yes >2 2013 Stationary
PA (f) asthma 2006 yes no 2010 Stationary
NR (m) asthma 2006 yes no 2014 Recurrence
Mepolizumab in CRSwNP patients
Omalizumab in CRSwNP patients