Nasal Polyps - Pathogenesis and Nasal Polyps - Pathogenesis and Treatment ImplicationsTreatment Implications

Bastaninejad, ShahinBastaninejad, Shahin, , MD, Assistant Professor of MD, Assistant Professor of ORL-HNS, TUMS, ORL-HNS, TUMS, Amir’Alam Amir’Alam HospitalHospital

ImportanceImportance

NPs have been shown to have a significant

detrimental effect on the quality of life, which

is similar in severity to COPD

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…

• Eosinophils are 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

• In the general population, the prevalence of nasal

polyps is 4% 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

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

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

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)

Chronic rhinosinusitiswith and without nasal

polyps

Chronic Rhinosinusitis Nasal Polyps

Nasal Polyps

The spectrum of sinus disease

Rhinosinusitis PMNPMN EOSEOS

20-33% of CRS

TH1 TH17 TH2

(INF-gama, IL-8) (IL-4, IL-5)

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

. Immunoperoxidase

staining

H&E staining

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

Pathomechanism

• Extracellular matrix regulation

– Eos TGF-β1&2 Fibroblast activity

progression in pathology (increase in extra

cellular matrix formation)

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

Nasal polyposis: aetiology and pathogenesis

Chemokines

TB

Cytokines Hyper IgE

Eosinophils ( apoptosis)

SuperantigensIL-5

ECP

Albumin

Eotaxin

Polyclonal IgE

Epithelial damage (barrier dysfunction)

chronic microbial trigger

S. Aureus enterotoxins: disease modifiers

Demo for Pathogenesis

polyps

eosinophil B cellMast cell

Arachydonic acid

5 lipoxygenase

Leukotrienes

Interleukin

Prostaglandin

Histamine

Cycloxygenase

cytokines

Thanks from Dr. R. Cathcart for this demo

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

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 but the effect on the sense of smell is not highon the sense of smell is not high

• 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 show a positive effect of local

corticostoroids over placebo (3mo-1yr-2yr)

• 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) 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

• Antibiotics:

– There is also increasing evidence in vitro of the

anti-inflammatory effects of macrolidesmacrolides

– 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

• 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

• 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

• 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

• Capsaicin:

– It is a neurotoxin that depletes substance P with some other neurokinins and neuropeptides, leading leading to long-lasting damage to unmyelinated axonsto 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 very significantly improved subjective and endoscopy scores, but did not significantly alter ECP

• Method of Capsaicin delivery: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

• 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 furosemide30% recurrence with placebo24% recurrence with mometasone

• Method of furosemide deliveryMethod of furosemide delivery:

– Furosemide diluted in physiological solution (2 (2 ml of furosemide in 2 ml of saline) 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 5th yr: 2mo in a year (2/12mo)

Strength of evidence for treatment of CRS vs. NP

Intervention Chronic rhinosinusitis Nasal polyps

Corticosteroids TopicalA A Systemic / C

Antibiotics Oral short term < 2w C D Oral long term (12w) C C

Antimycotics Topical / Systemic D DAntihistaminesD BAnti-leukotrienes / C Nasal saline doucheC D Decongestants DDAllergen avoidance D D

Guideline in our countryGuideline 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

Scheme for experimental polyp treatment

polyps

eosinophil B cellMast cell

Arachydonic acid

5 lipoxygenase

Leukotrienes

Interleukin

Prostaglandin

Histamine

Cycloxygenase

cytokines

1

2

3

45

Anti IgEAnti-IgE?

Antibiotics? Anti-fungal?

IL-5

ECP

Eotaxin

IgE

Anti IL-5 Anti-IL-5?

Corticosteroids? Anti-LTs?

Anti-CCR3?

Tacrolimus?

Future therapies in nasal polyposis

Surgical Treatments• Surgical treatments, including PolypectomyPolypectomy

alone or in combination with FESS, rarely rarely result in long term control 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

• When to proceed with surgical therapy?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

• Simple polypectomy vs. FESS!? Simple polypectomy vs. FESS!? Dalziel (2003) - meta-analysis :

Symptom improvementSymptom improvement Recurrence Recurrence

FESS 78-88% 28%Simple 43-84% 35%

7% 7% difference!!difference!!

• When is it logical to perform FESS instead of a When is it logical to perform FESS instead of a

simple polypectomy operation?simple polypectomy operation?

– Severe and extensive disease

– Underlying diseases (Asthma, Samter, Allergic fungal,

CF,…)

– Revision cases when pathology is not localized

Bastaninejad MDBastaninejad MD