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 WITHOUT NASAL POLYPS
La Poliposi Nasale: introduzione CLASSIFICAZIONE DEI POLIPI NASALI EPOS CLASSIFICATION OF NASAL POLYPS
La Poliposi Nasale: introduzione EPIDEMIOLOGIA Incidence of nasal CRSwNP : Estimated prevalence of CRSwNP : • higher in men than in women • In Europe � 2.1% (France) / 4.4% (Finland) • In the USA � 4.2% • increases after the age of 40 years • In Asia � 1.1% (China) / 2.6% (Korea) NP occur more frequently in asthma patients with aspirin sensitivity
La Poliposi Nasale: fenotipi CRwNP vs CRSsNP CRSwNP: Eosinophil-rich, Th2-dominated cytokine Downregulation of TGF-β1 protein and its receptors R1 and R2 � no collagen deposition CRSsNP : 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
La Poliposi Nasale: fenotipi CRSwNP E ASMA 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. Current or future LOWER AIRWAY INVOLVEMENT CRSwNP NO lower airway involvement
La Poliposi Nasale: endotipi Journal of Internal Medicine, 2012, 272; 133–143
La Poliposi Nasale: endotipi ENDOTIPI INFIAMMATORI IN CRS 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
La Poliposi Nasale: endotipi ENDOTIPI INFIAMMATORI IN CRS 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 ENDOTIPI INFIAMMATORI IN CRS • 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 In clusters with with strongly increased asthma prevalence 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 IgE concentration 1/10 5 –1/10 6 1/5 T cells T cells
La Poliposi Nasale: patogenesi RUOLO DI S. AUREUS S. Aureus and its pruduct evoke the release of epithelial cytokines IL-33, TSLP, eotaxin � EET Direct contact between eosinophils and S. aureus � EET BARRIER DYSFUNCTION S. Aureus and staphylococcal proteins can directly activate T-cells to release IL-5 � EET EOSINOPHIL EXTRACELLULAR TRAPS
La Poliposi Nasale: endotipi CRSwNP: West vs Est Western world: Th2 signature in 80% of nasal polyps Asian world : 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 accompanied by higher EOSINOPHILIC SHIFT S. aureus carriage
La Poliposi Nasale: genetica POLIPOSI NASALE ED EREDITARIETÀ 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 E STUDI DI ASSOCIAZIONE 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
La Poliposi Nasale: genetica POLIPOSI NASALE E STUDI DI ASSOCIAZIONE The other susceptibility genes and loci reported to be associated could not be replicated: • IL-33 • IL-22 receptor a ? • IL-1 receptor a ? • IL-1 receptor –like 1 ? • Matrix metalloproteinase 9 ? EPIGENETIC ROLE? • Matrix metalloproteinase 2 • TSLP • TGFbeta1 ? ? • TLR2 ? • OSF- 2 • IL-4 promoter heterogeneity and poor repeatability of the genetic findings etc etc….. 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 Widal-Samter’s Aspirin-exacerbated Triad respiratory disease (AERD) > 50% NP associated LTC 4 S promoter SNP
La Poliposi Nasale: terapia TRATTAMENTO DELLE FORME LIEVI-MODERATE EPOS2012
La Poliposi Nasale: terapia CORTICOSTEROIDI TOPICI 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. Forest plot of randomized controlled trials evaluating Level of Evidence : 1a topical steroids in patients with nasal polyposis. CI ¼ confidence interval; RR ¼ risk ratio.
La Poliposi Nasale: terapia CORTICOSTEROIDI TOPICI Congestion score Sense of smell JACI 2005; 116: 1275
La Poliposi Nasale: terapia CORTICOSTEROIDI TOPICI
La Poliposi Nasale: terapia TRATTAMENTO DELLE FORME SEVERE EPOS2012
La Poliposi Nasale: terapia CORTICOSTEROIDI ORALI
La Poliposi Nasale: terapia INIEZIONE LOCALE DI CORTICOSTEROIDI 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. 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.
La Poliposi Nasale: terapia MACROLIDI Anti-inflammatory effects of macrolide antibiotics. Efficacy in CR patients with • neutrophilic inflammation, • not elevated IgE • Low CT score Cervin & Wallwork Curr Allergy Asthma Rep (2014)
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