Nasal Polyps - Pathogenesis and Treatment Implications

1. Nasal Polyps - Pathogenesis and Treatment Implications Bastaninejad, Shahin, MD, Assistant Professor of ORL-HNS, TUMS, Amir’AlamHospital

2. Importance NPs have been shown to have a significant detrimental effect on the quality of life, which is similar in severity to COPD

3. Introduction • Nasal polyps appear as grape-like structures in the upper nasal cavity, originating from within the ostiomeatal complex • They consist of: loose connective tissue, oedema, inflammatory cells and some glands and capillaries, and are covered with varying types of epithelium, mostly respiratory pseudostratified columnar epithelium…

4. Eosinophilsare the most common inflammatory cells in nasal polyps (80%), but Neutrophils, mast cells, plasma cells, lymphocytes and monocytes are also present, as well as fibroblasts • IL-5 is the predominant cytokine in nasal polyposis, reflecting activation and prolonged survival of eosinophils

5. In the general population, the prevalence of nasal polyps is 4% (2.2/1 MF Ratio) • The average age of onset is approximately 42 years • In patients with asthma, a prevalence of 7 to 15% has been noted whereas, in NSAID sensitivity, nasal polyps are found in 36 to 96% of patients

6. Factors associated with NP • Allergy Only Kern state inhalant allergy as a risk factor for NP, but food allergy is significantly higher in NP patients (80%) • Asthma  NPs are present in 13% in non-atopic asthma (skin prick test and total and specific IgE negative) and 5% in atopic asthma • Aspirin sensitivity  In patients with aspirin sensitivity 36-96% have nasal polyps

7. Factors associated with NP • Genetics NP are frequently found to run in families… HLA-A74 , HLA-DR7 • Environmental factors  The role of environmental factors in the development of NP is Unclear

8. Hypotheses regarding the underlying mechanisms • Chronic infection (Fungal/Bacterial) • Aspirin intolerance (Samter) • Aerodynamics alteration with trapping of polutions • Epithelial cell defects / Epithelial disruptions • Gene deletions (CFTR genes in CF) • Inhalant or food allergens (discussed in previous page)

9. Chronic Rhinosinusitis Nasal Polyps The spectrum of sinus disease Nasal Polyps Chronic rhinosinusitiswith and without nasal polyps 20-33% of CRS Rhinosinusitis PMNEOS TH1TH17TH2 (INF-gama, IL-8) (IL-4, IL-5)

10. Histopathology • Frequent epithelial damage, a thickened basement membrane, and Edematous to sometimes fibrotic stromal tissue, with a reduced number of vessels and glands but virtually no neural structure • Among the inflammatory cells, Eosinophils are a prominent and characteristic feature in about 80% of polyps

11. H&E staining . Immunoperoxidase staining

14. Pathomechanism • Eosinophilic inflammation • IL-5 was found to be significantly increased in nasal polyps • Cytokine IL-5  Eos  ECP (E. cationic protein)  progression in pathology

15. Pathomechanism • Extracellular matrix regulation • Eos  TGF-β1&2  Fibroblast activity  progression in pathology (increase in extra cellular matrix formation)

16. Pathomechanism • Role of Staphylococcus aureus enterotoxins (SAE) • Multiclonal IgE antibody formation to SAE can be seen in nasal polyp tissue, but rarely in CRS • It is positive in about 30-50% of the patients with NP and in about 60-80% of nasal polyp subjects with asthma

17. Epithelial damage (barrier dysfunction) Hyper IgE  Cytokines  Polyclonal IgE chronic microbial trigger Albumin Superantigens Eosinophils  ( apoptosis) IL-5 Chemokines Eotaxin ECP T B Nasal polyposis: aetiology and pathogenesis S. Aureus enterotoxins: disease modifiers

18. Demo for Pathogenesis polyps B cell Mast cell eosinophil Y Y Y Y Arachydonic acid cytokines Y Y Y Cycloxygenase 5 lipoxygenase Leukotrienes Prostaglandin Histamine Interleukin Thanks from Dr. R. Cathcart for this demo

19. Differentials • Encephalocoeles • Gliomas • Dermoid tumours • Haemangiomas • Papillomas / transitional cell papillomas • Nasopharyngeal angiofibromas • Rhabdomyosarcomas • Lymphomas • Neuroblastomas • Sarcomas • Chordomas • Nasopharyngeal carcinomas

20. Medical Treatments • Corticosteroids • reduce airway eosinophil infiltration by preventing their increased viability and activation • Directily • Or via reducing the secretion of chemotactic cytokines by nasal mucosa and polyp epithelial cells • Topical Cort.: effect on poly size and also on symptoms associated with NP such as nasal blockage, secretion and sneezing but the effect on the sense of smell is not high

21. Postoperative treatment with topical corticoidsteriods • Postoperative effect on recurrence rate of NP after polypectomy with intranasal steroids is well documented and the evidence level is Ib • But in patients who undergone FESS operation did not showa positive effect of local corticostoroids over placebo (3mo-1yr-2yr)

22. Systemic steroids : • Is effective in polyp reduction and nasal symptoms associated with NP, even on sense of smell • Oral corticosteroids for 10 days (20-40mg)  there are reports with 21 days and also higher doses (up to 50mg) of prednisolone • The benefit of oral steroids, however, remains less definitive with little randomized data available and the risk of systemic effect from oral steroids  use in severe cases

23. Antibiotics: • There is also increasing evidence in vitro of the anti-inflammatory effects of macrolides • The exact mechanism of action is not known, but it probably involves down regulation of the local host immune response as well as a downgrading of the virulence of the colonizing bacteria

24. Regimens (12wk also you can try 6wk): • Erythromycin Ethylsuccinate: 400 q6h up to 2wk, then 400 q12h up to 10wk • Clarithromycin: 500 q12h up to 2wk, then 500 daily up to 10wk • AZM  2011  lack of efficacy in treatment of CRS with or without NP

25. Antihistamines: • Cetirizine in a dose of 20 mg/day for three months, significantly reduced sneezing, rhinorrhoea and obstruction compared to placebo but with no effect on polyp size • So it is recommended in allergic patients with NP

26. Antileukotrienes: • There are a few case controlled trials indicate that antileukotriene treatment may have beneficial effect on nasal symptoms in patients with chronic/persistent rhinosinusitis and nasal polyposis

27. Capsaicin: • It is a neurotoxin that depletes substance P with some other neurokinins and neuropeptides, leading to long-lasting damage to unmyelinated axons • Tested in Eosinophilic non allergic non asthmatic NP • capsaicin significantly increased NSAV (nose-sinuses air volume) and very significantly improved subjective and endoscopy scores, but did not significantly alter ECP

28. Method of Capsaicin delivery: • for 3 consecutive days patients received: 0.5 ml 30 mmol/L capsaicin solution sprayed into each nostril, and 100 mmol/L of capsaicin solution on days 4 and 5, respectively

29. Furosemide: • It exhibited an anti-inflammatory effect • Also it acts on Na/Cl transporter and reduce tissue edema, too • Passali (2003) - RCT-n=177, post polypectomy furosemide vs. placebo vs. mometasone. Results after 5yr F/U: 17% recurrence with furosemide 30% recurrence with placebo 24% recurrence with mometasone

30. Method of furosemide delivery: • Furosemide diluted in physiological solution (2 ml of furosemide in 2 ml of saline) administered as nasal puffs (2 puffs per nostril a day, each puff corresponding to 50 micg) for 30 days. • Frist 2yrs: every other mounth (12/24mo) • Next 2yrs: 1mo on, 2mo off (8/24mo) • In 5thyr: 2mo in a year (2/12mo)

31. Strength of evidence for treatment of CRS vs. NP InterventionChronic rhinosinusitisNasal polyps Corticosteroids Topical A A  Systemic / C  Antibiotics Oral short term < 2w C D Oral long term (12w) C C  Antimycotics Topical / Systemic D D Antihistamines D B Anti-leukotrienes / C  Nasal saline douche C D  Decongestants D D Allergen avoidance D  D

32. Guideline in our country • INCS for undisclosed time  ? • Macrolide administration for 6 to 12wks • Oral corticosteroids for 10-20 days (20-40mg) • Montelukast (10mg/day) • In allergic patients: Cetrizine 20mg/day for 3mo

33. 2 3 1 5 Scheme for experimental polyp treatment polyps B cell Mast cell eosinophil Y Y Y Y Arachydonic acid cytokines Y Y Y Cycloxygenase 5 lipoxygenase Leukotrienes Prostaglandin Histamine Interleukin 4

34. Anti IgE Anti IL-5 Future therapies in nasal polyposis Anti-CCR3? Anti-IgE? Eotaxin IgE Tacrolimus? Anti-IL-5? IL-5 Corticosteroids? Anti-LTs? ECP Antibiotics?Anti-fungal?

35. Surgical Treatments • Surgical treatments, including Polypectomy alone or in combination with FESS, rarely result in long term control of polyposis and are typically combined with medical treatment • When hyposmia is the primary symptom, no additional benefit seems to be gained from surgical treatment. If nasal obstruction is the main problem after steroid txy, surgical treatment is indicated

36. When to proceed with surgical therapy? • when medical therapy fails to control symptoms • when the patient is not suitable for oral steroids • when total nasal obstruction occurs • when there is persistent infection or complications

37. Simple polypectomy vs. FESS!? Dalziel (2003) - meta-analysis : Symptom improvement Recurrence FESS 78-88% 28% Simple 43-84% 35% 7% difference!!

38. When is it logical to perform FESS instead of a simple polypectomy operation? • Severe and extensive disease • Underlying diseases (Asthma, Samter, Allergic fungal, CF,…) • Revision cases when pathology is not localized

40. Thank You! Bastaninejad MD