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EPOS DEFINITION OF ACUTE AND CHRONIC RHINOSINUSITISWITH AND WITHOUT NASAL POLYPS
all'esperienza persona le Benedetta Biagioni School of Allergy and - - PowerPoint PPT Presentation
all'esperienza persona le Benedetta Biagioni School of Allergy and - - PowerPoint PPT Presentation
La Poliposi Nasale: dalla genetica alla terapia e all'esperienza persona le Benedetta Biagioni School of Allergy and Clinical Immunology La Poliposi Nasale: introduzione DEFINIZIONE EPOS DEFINITION OF ACUTE AND CHRONIC RHINOSINUSITISWITH AND
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EPOS CLASSIFICATION OF NASAL POLYPS
La Poliposi Nasale: introduzione
CLASSIFICAZIONE DEI POLIPI NASALI
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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
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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
- f 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
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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.
CRSwNP
Current or future LOWER AIRWAY INVOLVEMENT NO lower airway involvement
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Journal of Internal Medicine, 2012, 272; 133–143
La Poliposi Nasale: endotipi
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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
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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
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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
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La Poliposi Nasale: patogenesi
RUOLO DI S. AUREUS
- S. aureus enterotoxins (SAEs) act as superantigens
High local polyclonal IgE concentration
1/105 –1/106 T cells 1/5 T cells
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La Poliposi Nasale: patogenesi
RUOLO DI S. AUREUS
- S. 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
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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
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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
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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
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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
- ccurrence of CRSwNP.
La Poliposi Nasale: genetica
POLIPOSI NASALE ED EREDITARIETÀ
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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 rhinosinusitis
with 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
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- 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
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La Poliposi Nasale: genetica
GENETICA DELLA AERD
Aspirin-exacerbated respiratory disease (AERD)
> 50% NP associated Widal-Samter’s Triad LTC4S promoter SNP
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EPOS2012
La Poliposi Nasale: terapia
TRATTAMENTO DELLE FORME LIEVI-MODERATE
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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, 2012
Methods: 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
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Congestion score Sense of smell
JACI 2005; 116: 1275
La Poliposi Nasale: terapia
CORTICOSTEROIDI TOPICI
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CORTICOSTEROIDI TOPICI
La Poliposi Nasale: terapia
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EPOS2012
La Poliposi Nasale: terapia
TRATTAMENTO DELLE FORME SEVERE
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La Poliposi Nasale: terapia
CORTICOSTEROIDI ORALI
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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 normal before treatment, 1 week after the first injection, and 1 week after the last injection.
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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
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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 reduction in nasal polyp size, methylprednisolone causes an initial reduction in polyp size but complete recurrence after 2 months
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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
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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
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La Poliposi Nasale: terapia
FARMACI BIOLOGICI
J ALLERGY CLIN IMMUNOL MAY 2017
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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
10 20 30 40 50 60 70 80 W2 W4 W6 W8 W10 W12 W14 W16 W18 placebo
- malizumab
- 3
- 2,5
- 2
- 1,5
- 1
- 0,5
0,5 1 BL W2 W4 W6 W8 W10W12W14W16W18 placebo
- malizumab
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JACI 2013; 131:110-6
La Poliposi Nasale: terapia
OMALIZUMAB
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La Poliposi Nasale: terapia
ANTI IL-5: RESLIZUMAB
J Allergy Clin Immunol 2006
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La Poliposi Nasale: terapia
ANTI IL-5: MEPOLIZUMAB
J Allergy Clin Immunol 2011 Clin Immunol 2017
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La Poliposi Nasale: terapia
DUPILUMAB
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La Poliposi Nasale: terapia
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La Poliposi Nasale: terapia
“ For many patients with severe disease, uncontrolled with the current surgical and pharmacological possibilities, biotherapeutics soon will
- ffer a new and significant
treatment option,,
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La Poliposi Nasale: esperienza
Subject Disease CRS onset FESS Revision FESS Treatment start 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 Revision FESS Treatment start 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
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