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Chronic Rhinosinusitis Flashcards

1
Q

√What are the etiologic factors for the development of sinusitis? 10

A

A. INFECTIOUS
1. Viral
2. Bacterial
3. Fungal

B. IMMUNE
1. Congenital
2. Acquired
3. Allergic

C. LOCAL
1. Craniofacial anomalies (choanal atresia, VPI, cleft palate)
2. Trauma
3. Surgery
4. Dental
5. Ciliary
6. Anatomic

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2
Q

√What are the anatomic variations influencing the incidence of sinusitis? 8

A
  1. Septal deviation and spur
  2. Concha bullosa
  3. Paradoxical middle turbinate (inferomedially curved middle turbinate edge with the concave surface facing the nasal septum, usually occurs bilaterally)
  4. Prominent Ethmoidal bulla
  5. Pneumatization or deviation of the uncinate plate
  6. Prominent agger nasi cells
  7. Complex frontal cells - supra-aggar/bullar
  8. Infraorbital ethmoid cell (Haller cell)
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3
Q

√What 7 histologic changes are seen in polyps/CRS?

A

Classification of Nasal polyposis:
1. Edematous, eosinophilic (most common, 85%)
2. Fibroinflammatory
3. Glandular

Features of edematous, eosinophilic polyps:
1. Edema + scattered fibroblasts
2. Infiltrates of inflammatory cells (e.g. neutrophils, mast cells)
3. Epithelial ulceration
4. Squamous metaplasia
5. Epithelial hyperplasia
6. Goblet cell hyperplasia
7. Eosinophilic infiltrates

I’m EGF Sue ME

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4
Q

√What are the etiologic factors for nasal polyps? 7

A

A. Inflammation
1. Nasal mastocytosis (increased mast cells in nasal mucosa)
2. Chronic infection
3. Allergy, including fungal
4. Samter’s triad

B. Ciliary problems
1. Cystic fibrosis
2. Kartegener’s syndrome
3. Young’s syndrome (bronchiectasis, rhinosinusitis, and reduced fertility)

Can also be divided as:
1. Eosinophilic: eGPA, AERD, Allergy, AFRS
2. Non-eosinophilic: CF, Antrochoanal polyp, Kartageners

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5
Q

List 6 different conditions that may be associated with nasal polyposis.

A
  1. Atopy (atopic dermatitis, asthma, allergic rhinitis)
  2. AERD
  3. NARES
  4. PCD
  5. Cystic Fibrosis
  6. eGPA (Curg-Strauss Syndrome)
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6
Q

Discuss two types of grading systems for polyp size

A

0-3 Grading:
1. Grade 0: No visible polyps
2. Grade 1: Polyps confined to middle meatus
3. Grade 2: Polyps extending beyond middle meatus but not obstructing nasal cavity
4. Grade 3: Polyps completely obstructing nasal cavity

0-4 Grading (Meltzer)
1. Grade 0: No visible polyps
2. Grade 1: Polyps not reaching inferior border of middle turbinate
3. Grade 2: Polyps reaching inferior border of middle turbinate
4. Grade 3: Polyps extending below middle turbinate, not obstructing nasal cavity
5. Grade 4: Polyps completely obstructing nasal cavity

Kevan Page 24

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7
Q

What are the CT and MRI findings of nasal polyps?

A
  1. CT: Low density
  2. MRI:
    - T1 Hypointense
    - T2 Hypertense (high water content)
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8
Q

What are the conditions that are associated with CRS?

A
  1. COPD
  2. N-ERD (NSAID-Exacerbated respiraotry disease)
  3. Hypogammaglobulinemia
  4. GERD
  5. Asthma
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9
Q

What is the difference between Eosinophilic CRS and Non-eosinophilic CRS?

A
  • eCRS and Non-eCRS = determined by the histologic quantification of the numbers of eosinophils
  • Number per high powered field = 10/hpf (400x)

Tissue eosinophil level and inflammation are closely related to treatment response
- 10-100/hpf in >2 areas of >100/hpf in >2 areas

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10
Q

What are the associations between CRS, polyps, and asthma?

A
  1. 20% of CRS have polyps
  2. 40% of CRS have asthma (Canadian guideline)
  3. 50% of polyps have asthma (35% of which have Samter’s triad)
  4. 10-20% of polyps have Samter’s triad
  5. 7% of asthma have polyps
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11
Q

What are the types of inflammatory responses?

A
  1. Type 1: Target viruses
  2. Type 2: Target parasites - characterized by IL-4,-5,-13; activation and recruitment of eosinophils and mast cells
  3. Type 3: Target extracellular bacteria and fungi
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12
Q

What are 4 groups of mediators important in CRS and asthma?

A
  1. Cells: Eosinophils, Th2 lymphocytes
  2. Cytokines: Interleukins (IL-1B predominant; also IL-4, 5, 13), PAF, TNF
  3. Prostaglandins and Leukotrienes
  4. Acute sinusitis - IL4 and 6
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13
Q

Discuss IL-4:
1. What does it do? List 5 things

A
  1. Stimulation of activated B-cell and T-cell proliferation
  2. Differentiation of B cells into plasma cells
  3. Key regulator in humoral and adaptive immunity
  4. Induces B-cell class switching to IgE
  5. Upregulates MHC class II production
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14
Q

List 5 functions of IL-5

A
  1. Stimulates B-cell growth
  2. Increase immunoglobulin secretion - primarily IgA
  3. Mediiator in eosinophil activation
  4. Two major signaling pathways of IL-5 in eosinophils:
    - A. Activates Lyn, Syk, and JAK2
    - B. Propagates signals through the Ras-MAPK and JAK-STAT pathways
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15
Q

List 6 functions of IL-13

A

Similar to IL-4

  1. Central regulator in IgE synthesis
  2. Goblet cell hyperplasia
  3. Mucous hypersecretion
  4. Airway hyperresponsiveness
  5. Fibrosis up-regulation
  6. A mediator of allergic inflammation in asthma
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16
Q

Discuss the Canadian Diagnostic Criteria for Chronic Rhinosinusitis. Outline the full criteria.

A

CANADIAN DIAGNOSTIC CRITERIA

Needs ALL THREE of the following:
1. 2 or more of CPODS:
a/ Congestion
b/ Pressure
c/ Obstruction
d/ Discharge (purulent rhinorrhea)
e/ Smell changes (hyposmia/ansomia)

  1. Lasting for more than 8-12 weeks
  2. Objective findings of inflammation:
    a/ Endoscopic findings; OR
    b/ CT findings (mucosal changes within OMC and/or sinuses)

ENDOSCOPIC SIGNS OF:
1. Nasal polyps, and/or
2. Mucopurulent discharge primarily from middle meatus, and/or
3. Edema/mucosal obstruction primarily in middle meatus

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17
Q

Regarding CRS: How has it been historically classified/divided into?

A

CRS has historically been divided into:
1. CRSwNP: Th2 predominant (more allergic)
2. CRSsNP: Th1 predominant
3. Then further divided into eosinophilic vs. non-eosinophilic
4. Then further divided into allergic fungal vs. non-allergic fungal
*This has changed from EPOS Classification in 2020 (previous classification too non-specific)

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18
Q

Discuss the EPOS classification 2020 of Chronic Rhinosinusitis

A

PRIMARY CRS:
1. Localized = unilateral
a/ Type 2 = e.g. AFRS
b/ Non-Type 2 = e.g. isolated sinusitis
2. Diffuse = bilateral
a/ Type 2 = e.g. CRSwNP, AFRS, CCAD (Central Compartment Atopic disease - variant of CRSwNP associated with inhalant allergy, characterized by polypoid changes in the central compartment ie. superior nasal septum, middle turbinates, and/or superior turbinates)
b/ Non-type 2 = non-eosinophilic CRS

SECONDARY CRS:
1. Localized = unilateral
a/ Local pathology, such as:
- Fungal ball
- Odontogenic sinusitis
- Sinonasal tumor
2. Diffuse = bilateral
- Mechanical = e.g. PCD or CF
- Inflammatory = e.g. GPA, eGPA
- Immunity = e.g. selective immunodeficiency

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19
Q

Discuss all the known contributing factors to chronic rhinosinusitis 6

A

A. HOST FACTORS
1. Genetic predisposition
2. Structural (anatomic) factors
3. Defects in innate or adaptive immunity

B. MICROBIAL FACTORS
1. Superantigens
- Exotoxins produced by infectious organisms that can activate a larger population of the T-lymphocyte pool
- Especially seen with Staph Aureus
2. Biofilms
- Biofilms are a community of bacteria adherent to a surface
- Extracellular matrix of biofilm protects against host defence systems

C. ENVIRONMENTAL FACTORS
1. Smoking
2. Allergies
3. Pollution

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20
Q

What systemic conditions predispose to CRS? 8

A
  1. Allergic rhinitis
  2. Recurrent viral URTIs
  3. Dental infections
  4. Primary ciliary dyskinesia
  5. Immunocompromised (HIV, IgG deficiency)
  6. Poor nutrition
  7. Chronic steroid use
  8. Diabetes
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21
Q

What are the most common organisms in Chronic Rhinosinusitis?

A
  1. Staph Aureus
  2. Anaerobes
    - Fusobacterium
    - Peptostreptococcus
    - Prevotella
    - Porphyromonas
    - Enterobacteriaceae
  3. Pseudomonas Aeruginosa
    - Most common in Cystic Fibrosis
    - More common in nosocomial infection or in immunocompromised host

UNCOMMON:
1. Pneumococcus
2. H. Influenzae
3. Beta-hemolytic streptococci
4. Coag-negative staph

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22
Q

What are 7 histopathologic findings in CRS?

A
  1. Submucosal gland formation
  2. Major basic protein deposition
  3. Eosinophilic and lymphocytic infiltration
  4. Goblet cell hyperplasia
  5. Mucous hypersecretion
  6. Abnormal Basement membrane thickening
  7. Subepithelial edema/fibrosis

SMEGMAS

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23
Q

How does sinonasal tissue get remodelled in Type 2 CRS?

A
  1. Polyp formation
  2. Epithelial barrier abnormalities - greater permeability

Biologic agents that suppress Type 2 inflammation reverse remodelling and limit recurrence

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24
Q

Discuss the Kennedy Staging System for Chronic Rhinosinusitis

Not in Vancouver

A

Endoscopic Staging system for CRS

Stage 1:
- Anatomic abnormalities; OR
- Unilateral sinus disease only; OR
- Bilateral sinus disease confined to the ethmoids

Stage 2:
- Bilateral ethmoid disease + involvement of ONE dependent sinus

Stage 3:
- Bilateral ethmoid disease + involvement of TWO or more dependent sinuses on each side

Stage 4:
- Diffuse sinonasal polyposis

25
Q

Discuss the Lund-MacKay score for Chronic Rhinosinusitis
What are the scores for NPV and PPV?

A

Radiographic staging score for CRS
- Scored out of 24
- Individual sinuses on each side (left and right) are graded
- 0 = non-opacified, 1 = partially opacified, 2 = obstructed
- Ostiomeatal complex is scored 0 or 2 (non-obstructed vs. obstructed)
- Results in a total score of 12 per side, and 24 overall
- ≤2 excellent NPV, ≥5 excellent PPV

Components:
1. Anterior ethmoids (0/1/2)
2. Posterior ethmoids (0/1/2)
3. Frontal sinuses (0/1/2)
4. Sphenoid sinuses (0/1/2)
5. Maxillary sinuses (0/1/2)
6. OMC (0/2)

26
Q

Discuss the Lund-Kennedy Score for Chronic Rhinosinusitis

Not in Vancouver

A

Endoscopic staging system for CRS
- Similar to Lund-Mackay except looking at endoscopic features on the left and right side

  1. Polyps
    - 0: No polyps
    - 1: Polyps in middle meatus
    - 2: Polyps beyond middle meatus
  2. Edema
    - 0: Absent
    - 1: Mild
    - 2: Severe
  3. Crusting
    - 0: Absent
    - 1: Mild
    - 2: Severe
  4. Scarring
    - 0: Absent
    - 1: Mild
    - 2: Severe
  5. Discharge
    - 0: No discharge
    - 1: Clear, thin discharge
    - 2: Thick, purulent discharge

Total: 20 (10 per side)

27
Q

What is CRS Primary prevention suggested by EPOS 2020? 5

A
  1. Handwashing
  2. Stop smoking
  3. Vaccinations
  4. Treat LPR
  5. NS irrigation
28
Q

What is the definition of difficult-to-treat Rhinosinusitis according to EPOS guidelines?

A
  • Patients who do not reach an acceptable level of control despite adequate surgery, intranasal corticosteroid treatment
  • Up to two short courses of antibiotics or systemic corticosteroids in the last year can be considered to have difficult-to-treat rhinosinusitis
29
Q

Define “controlled”, “partially controlled”, and “controlled” CRS with respect to the following:
1. Nasal blockage
2. Rhinorrhea/post nasal drip
3. Facial pain/pressure
4. Smell
5. Sleep disturbance or fatigue
6. Nasal endoscopy
7. Rescue treatment (in last 6 months)

A

CONTROLLED: All of the following
1. Nasal blockage - Not present or not bothersome
2. Rhinorrhea/post nasal drip - Little and mucous
3. Facial pain/pressure - Not present/bothersome
4. Smell - Normal, or only slightly impaired
5. Sleep disturbance or fatigue - Not present
6. Nasal endoscopy - Healthy, or almost healthy mucosa
7. Rescue treatment (in last 6 months) - Not needed

PARTIALLY CONTROLLED: At least 1 of the following present
1. Nasal blockage - Present on most days of the week
2. Rhinorrhea/post nasal drip - Mucopurulent on most days of the week
3. Facial pain/pressure - Present on most days of the week
4. Smell - Impaired
5. Sleep disturbance or fatigue - Present
6. Nasal endoscopy - Diseased mucosa
7. Rescue treatment (in last 6 months) - Need of 1 course of rescue treatment

UNCONTROLLED: 3 or more present
1. Nasal blockage - Present on most days of the week
2. Rhinorrhea/post nasal drip - Mucopurulent on most days of the week
3. Facial pain/pressure - Present on most days of the week
4. Smell - Impaired
5. Sleep disturbance or fatigue - Present
6. Nasal endoscopy - Diseased mucosa
7. Rescue treatment (in last 6 months) - Symptoms (as above) persist despite rescue treatments

Vancouver 436

30
Q

What are the evaluation considerations in the patient with difficult to treat disease? 3

A
  1. Immunologic work-up: CBC, immunoglobulins, response to vaccines, HIV
  2. Autoimmune and granulomatous disease: CBC, ESR, CRP, RF, ANCA, ACE
  3. Allergy: Allergy testing
31
Q

What is the SNOT-22 score? What are the 5 domains and how is it scored?

A

SNOT-22 = Quality of life questionnaire for CRS

“REEPS”

5 domains:
1. Rhinologic symptoms
2. Extranasal rhinologic symptoms
3. Ear/facial symptoms
4. Psychological dysfunction
5. Sleep dysfunction

Ranges from 0-110 (each question is scored 0-5, 22x5 = 110)
- Mild 8-20
- Moderate 21-50
- Severe > 50

32
Q

What are the limitations of SNOT-22 score? 2

A

Doesn’t capture disease duration or medication usage

33
Q

Discuss treatment options for CRS according to the CRS Canadian Guidelines

List 4-5 things for each wNP and sNP.
What are 5 targeted options that could also be provided?

A

CRSwNP:
- Saline rinses
- INCS
- Short course of oral steroids
- Antibiotics if signs of infection
- Consider: Allergy testing, LRTAs, specialty referral
- Surgery if failure of maximal medical therapy after 2-4 months

CRSsNP:
- Saline rinses
- INCS
- Antibiotics (e.g. long-term low-dose macrolides)
- Surgery if failure of maximal medical therapy

Targeted options:
1. ASA desensitization if AERD
2. Antihistamines if AR (Can consider Dymista in CRS + AR)
3. Immunotherapy if AR
4. Atrovent if vasomotor rhinitis
5. Biologics

34
Q

What is the recommended treatment of non-eCRS? (ie. no polyps)

A

1-3 month trial of:

  1. Intranasal corticosteroids
  2. Saline irrigation
  3. ± Antibiotics - long term low dose
  4. ± Course of oral steroids (will typically be less steroid responsive)
  5. If fails to improve after this - consider FESS
35
Q

What is the recommended treatment of eCRS? (polyps) List 8 things

A

2-3 months trial of:

  1. Intranasal corticosteroids
  2. Saline nasal irrigation
  3. Short course of oral steroids (2 weeks - very steroid responsive)
  4. ± antibiotics
  5. ± leukotriene receptor antagonist - Montelukast (especially consider for patients with asthma), Singulair
  6. ± Allergy testing
  7. Biologic therapies (no useful biomarkers to predict response to treatment with monoclonal antibodies directed at Type 2 endotypes)
  8. If failure to respond - consider FESS

Note: Patients with pure or mixed type 2 endotype tend to be more resistant to current therapies

36
Q

What are possible additions to be added to Nasal saline irrigation to enhance biofilm disruption? List 3 of the most evidence based ones

A

Evidence for: “XSX”
1. Xylitol
2. Sodium Hyaluronate
3. Xyloglucan

Insufficient evidence:
1. Surfactant
2. Baby shampoo
3. Manuka honey
4. Dexpanthenol
5. Hot water
6. Hypertonic saline

37
Q

Discuss the use of long term low-dose macrolides in CRS:
1. How does it work? List 4 mechanisms of action
2. Side effects? 4
3. Treatment protocol?
4. Predictors of good response? 4
5. What should you check prior to initiation of macrolides?

A

Controversial approach to treatment of CRS

MECHANISMS OF ACTION:
1. Antibacterial
2. Anti-inflammatory/immunomodulatory
3. Down regulates pro-inflammatory cytokines (IL-6, IL-8, TNFa)
- Decreases neutrophils and inhibit chemotaxis
- Decreases cell adhesion and phagocytosis
- Increases neutrophil degranulation of microbes and neutrophil apoptosis

SIDE EFFECTS: “CORG” like the rock man from avengers
1. GI Upset (less with Clarithromycin vs. Erythromycin)
2. Ototoxicity (5%)
3. Cardiotoxicity with prolonged use is possible (Prolonged QTc - get ECG first!)
4. Resistance (not evident yet in CRS) - use in diffuse panbronchiolitis for years has no resulted in resistance

LENGTH OF TREATMENT:
- Clarithromycin 250mg OD x 12 weeks improves clinical symptoms, endoscopic and CT scores
- 5% improved at 2 weeks, 70% at 12 weeks, with improvement up to 12 months
- Need 6-8 weeks for significant result

PREDICTORS OF A GOOD RESPONSE (Most beneficial in Th1 mediated, non-eosinophilic CRS)
- Low serum and tissue eosinophilia
- Normal or low serum IgE
- Poor response to inhaled or systemic steroids
- Lack of childhood asthma, skin or eye symptoms

CHECK ECG
Check IgE prior to initiation, if low (< 200mg/mL) –> “neutrophilic”/Th1 disease –> more likely to respond to macrolides

38
Q

Discuss Aspirin Exacerbated Respiratory Disease (AERD):
1. What is the pathophysiology?
2. What are the classic symptoms? 3
3. What is the epidemiology?
4. How is it diagnosed?
5. What are the treatment options? 13

A

Pathophysiology:
- ASA and other NSAIDs can exacerbate inflammatory rhinitis in a susceptible subset of the population with altered arachidonic acid metabolism
- In patients with this, they have an underlying overproduction of leukotrienes and prostaglandins, which is exacerbated by COX-1 inhibition. This shifts the arachidonic acid metabolism towards more leukotriene production
- Balance tilted to decreased prostaglandin E2 (antiinflammatory) and increased leukotrienes (which cause inflammation)
- Polyp formation influenced by stimulation of 5-lipoxygenase, which causes leukotriene overproduction
- Rhinitis is part of a subset of symptoms called AERD
- Not a TRUE allergy to ASA or NSAIDs, as this is NOT an IgE mediated allergic mechanism. The most technically correct description is a non-allergic hypersensitivity reaction

Symptoms: Samter’s Triad:
1. Sensitivity to ASA and COX-1 inhibiting NSAIDs
2. Asthma
3. Nasal polyposis (CRSwNP)
4. *Chronic eosinophilic rhinosinusitis
*Upper or lower respiratory symptoms typically occur within 90 minutes of ingestion of the NSAID. Ingestion does not initiate disease but can exacerbate symptoms once the disease process is underway

Epidemiology:
- Most commonly occurs in early adulthood
- 3:2 F:M predilection
- 1% of general population
- 21% in asthmatics
- 30-40% in asthmatics with nasal polyps

Diagnosis:
- No reliable in-vitro test
- Gold standard: Oral aspirin challenge test (inhalation and intranasal challenge tests also possible)
- Sinus CT (Normal scan rules out the disease)

TREATMENT OPTIONS
Acute Exacerbations:
- Inhated beta-agonists
- Antihistamines
- Systemic steroids
- IM epinephrine if hypotension, urticaria, or other systemic symptoms

Chronic management:
- Leukotriene inhibitors (Montelukast, Singulair)
- INCS ± oral steroids as needed
- Saline riinses
- Avoidance of ASA and NSAIDs and alcohol
- Treatment of concomitant allergic rhinitis if present
- Respirology assessment for management of lower airway disease
- Endoscopic sinus surgery if refractory to medical management
- Biologics
- ASA Desensitization - should be considered in anyone with respiratory symptoms of confirmed AERD

Kevan Page 28
Vancouver 438

39
Q
  1. What are indications for ASA desensitization? 4
  2. How does aspirin desensitization work?
  3. What are the contraindications for ASA challenge test? 4
A

Process of ASA desensitization:
- Initial challenge to confirm (oral, bronchial, nasal or urine LTc4)
- Lysine aspirin drops given (aim for 625mg/day, then maintain 100-350mg/day)
- Follow with SNOT22, VAS, CT, Serum IL-4/10, eosinophils
- Most are improved at 6 months

Indications for ASA Desensitization (performed by allergist within 6 weeks after FESS, target up to 325-650mg BID):
1. Refractory airway symptoms despite maximal medical management
2. Patients who require an NSAID or ASA (e.g. cardiac patients)
3. Severe polyposis requiring frequent surgery
4. Requiring unacceptably high doses of PO steroids

Contraindications for ASA Challenge Test:
1. Anaphylaxis
2. Uncontrolled asthma
3. FEV1 < 70% of predicted value
4. URTI within 4 weeks

40
Q

Regarding biologics, discuss:
1. What are the targets?
2. Adverse effects?
3. Duration of treatment?

A
  • Eosinophilic CRS surgical failure rate 10-30% (5 years)
  • ~85% of nasal polyps are characterized by prominent eosinophilia
  • IL-5 is the key driver of eosinophilic differentiation and survival
  • Target components of the Th2 pathway: IL-4, IL-5, and IL-13, IL-5R, IL-33, IgE
  • Currently no biological markers to determine best agent to use

ADVERSE EFFECTS:
1. Headache
2. Nasopharyngitis
3. URTI
4. Oropharyngeal pain
5. Injection-site reactions
6. Arthritis

DURATION
- Short term use (12 months) considered safe
- Biologics shown to be safe long term in other Th2 disease

41
Q

Discuss Dupilumab:
1. What is the MOA?
2. What are its effects?

A

Mechanism of Action:
- Fully human monoclonal antibody to IL-4a receptor
- Inhibits IL-4 and IL-13

Effects:
- Significant improvement in the secondary endpoints: Total (SNOT-22) scores, LM score, objective olfactory scores

42
Q

Discuss Omalizumab:
1. What is the MOA?
2. How is it dosed?

A

MOA:
- Anti-IgE antibody
- Decreases free IgE in the serum
- Stops immune complex formation

Dosage:
- SC dosage every 2-4 weeks

43
Q

What are the various biologics that are investigated for eCRS?

A
  1. Anti-IgE: Omalizumab (Xolair)
  2. Anti-IL5: Mepolizumab (Nucala), Reslizumab (Cinqair)
  3. Anti-IL5 R-alpha: Benralizumab (Fasenra)
  4. Anti-IL4 R-alpha: Dupilumab (Dupixent)
  5. Anti-IL13: Dupilumab (Dupixent)
44
Q

According to the Canadian Consensus guidelines of 2023
1. Who qualifies for biologic therapy for CRS? 5
2. Who is excluded? 3

A

QUALIFICATIONS FOR CRS BIOLOGICS:
1. Need both subjective and objective findings consistent with CRSwNP
2. All endotypes of CRSwNP are considered eligible
3. Endoscopy must show BILATERAL polyps and moderate to severe symptoms (Validated metrics = Chronic sinusitis survey CSS, SNOT-22, Rhinosinusitis disability index RSDI, Visual analogue scale VAS)
4. Need to have undergone adequate sinus surgery and failed appropriate medical therapy
5. Patients unfit for surgery and failed appropriate medical therapy also qualify

Patients may try another biologic therapy if they fail to respond to an initial agent and continue to fit the inclusion criteria

EXCLUSION:
1. Insufficient evidence to make a recommendation for CRSsNP
2. Not for recurrent acute bacterial sinusitis (RABS)
3. Hamster protein allergy

45
Q

What are the indications for biologic therapy with CRSwNP?
Discuss the indications based on EPOS.
Discuss the indications based on the 2021 Canadian consensus guidelines.
What are the types of biologic therapies available?

A

EPOS Guidelines Indications for Therapy:
1. Presence of bilateral polyps AND previous endoscopic sinus surgery
2. As well as 3/5 of the following:

A. Evidence of Type 2 inflammation
- Serum eosinophils ≥250; OR
- Tissue eosinophils ≥10/hpf; OR
- Total IgE ≥ 100

B. Need for systemic steroids or contraindication to systemic steroids
- ≥2 courses per year; OR
- Long term (>3 months) low dose steroids

C. Significantly impaired QOL
- SNOT-22 > 40

D. Significant loss of smell
- Anosmic on smell testing

E. Diagnosis of comorbid asthma
- Asthma needing regular inhaled steroids

CANADIAN CONSENSUS STATEMENT (2021)
Can be used in patients with CRSwNP with:
1. Moderate to severe symptoms after FESS + appropriate medical treatment
2. Another Type 2 condition is not required

TYPES OF BIOLOGICS
1. Dupilumab –> Dupixent
- Anti-IL4alpha –> Inhibits IL-4 and IL-13
- Only FDA approved treatment thus far for CRSwNP

  1. Mepolizumab –> Nucala
    - Inhibits IL-5
    - Approved for eGPA but not for CRSwNP
46
Q

What are the factors that affect mucociliary clearance or nasal ciliary motility? List 15 things.

A
  1. Primary ciliary dysmotility/abnormalities
  2. Mucous viscosity
  3. Temperature (< 18 degreesC)
  4. Airway humidity (< 50%)
  5. Cilia density
  6. Ciliary beat frequency
  7. pH (excessive acidic or basic environmenta; optimal ciliary function at pH 7.0)
  8. Thicker gel layer
  9. Thinner sol layer
  10. Allergy
  11. Rhinitis medicamentosa (chronic abuse)
  12. Infection (viral, bacterial)
  13. Hypertonic or hypotonic solutions
  14. Dehydration
  15. Mucosal to mucosal surface contact (coapting)

MATCHIES
Medicamentosa
Allergy
Temperature
Ciliary abnormalities, coapted mucosa
Humidity, hypotonicity/hypertonicity
Infection
Excess acid/base
Smoking

47
Q

What are 2 genetic diseases associated with nasal polyposis?

A
  1. Cystic fibrosis
  2. Primary ciliary dyskinesia
48
Q

Regarding Cystic Fibrosis, discuss:
1. Inheritance/Gene
2. Pathophysiology of nasal polyposis
3. Clinical presentation - list 4 features

A

INHERITANCE:
- Gene: Delta-F508 gene deletioin on chromosome 7q most common (90%)
- Protein: CTFR protein mutation (cystic fibrosis transmembrane conductance regulator)
- Autosomal recessive

PATHOPHYSIOLOGY:
- Defect in chloride channel leading to abnormal resorption of chloride and increased resorption of sodium into cellular space (trying to make up for trying to reabsorb more chloride too)
- Causes increases water resorption and thicker mucous secretions on epithelial linings - causing mucous plugging, obstruction pathology
- Nasal polyps: nasal mucin is 30-60 times more viscous, causing obstruction of ostea leading to overgrowth of bacteria and inflammation
- Polyps are Th1 mediated

CLINICAL PRESENTATION:
- Sinus: Nasal polyposis, sinusitis
- Respiratory: thick mucous secretions, pneumonias
- GI: Meconium ileus, bowel obstruction, biliary obstruction, pancreatic exocrine insuffiiciency (poor vitamin ADEK absorption), constipation, diarrhea
- GU: Infertility

Vancouver page 440

49
Q

Classes of CF?

Not in Vancouver

A

CLASSES:
1. Class 1: Nonsense, frameshift, or splice-site mutation, which leads to premature termination of the mRNA sequence. Causes total total absence of CFTR protein, 2-5% CF
2. Class 2: Abnormal post-translational processing of the CFTR protein.
3. Class 3: Diminished protein activity in response to intracellular signaling. Essentially a fully formed protein channel that is non-functional
4. Class 4: Protein is produced and correctly localized to the cell surface. However, the rate of chloride ion flow and the duration of channel activation after stimulation is decreased from normal.
5. Class 5: Net decreased concentration of CFTR channels in the cellular membrane as a result of rapid degradation by cellular processes. It includes mutations that alter the stability of mRNA and others that alter the stability of the mature CFTR protein.

50
Q

Regarding Cystic fibrosis:
5. Diagnostic tests - 4
6. Imaging features - 5
7. Treatment - 3 categories of treatment

A

INVESTIGATIONS:
1. Sweat-chloride test (most common): >60mEq/L = positive; 40-60 is borderline
2. Nasal potential difference
3. Genetic testing
4. Rarely done: Pancreatic function analysis (72-h stool collection for fecal fat); PFT and bronchoalveolar lavages

IMAGING FEATURES (Usually bilateral):
1. Nasal polyposis
2. Hypoplasia and poor pneumatization of the maxillary and ethmoid sinuses
3. Opacification of maxillary sinuses and medial displacement of lateral nasal wall into middle meatus (mucocele-like state)
4. Uncinate process demineralization
5. Poor development of the frontal sinus (adolescents often have no frontal sinus)

“PHOUF”
Polyposis
Hypoplasia and poor pneumatization of maxillary and ethmoid sinuses
Opacification of maxillary sinuses and medial displacement of lateral nasal wall into middle meatus (mucocele-like state)
Uncinate process demineralization
Frontal sinus poorly developed

TREATMENT:
1. Nose: sinus irrigation, antibiotics, nasonex, FESS only for severe cases
2. Lungs: Chest physio, hypertonic saline, puffers, chronic antibiotics (especially antii-pseudomonas), lung transplant
3. GI: Pancreatic enzymes, Vitamin ADEK replacement
4. New systemic therapies: Ivocafter/Tezocafter - CFTR correctors (selective)

51
Q

Describe the diagnostic criteria for cystic fibrosis

Not in Vancouvers

A

A. Presence of clinical symptoms of cystic fibrosis in at least one organ system

AND

B. Objective evidence of CF transmembrane conductance regulator (CFTR) dysfunction, based on ONE of the following:

a) Elevated sweat chloride > 60 mmol/L on two occasions
- Induce sweat (using pilocarpine iontophoresis-soaked gauze on skin)
- Apply current
- Collect sweat (chloride concentration will be determined from this)
- Results (> 6 months old)
1. Normal < 39 mmol/L (CF unlikely)
2. Intermediate 40-59mmol/L (CF possible)
3. Abnormal > 60mmol/L (diagnostic of CF)
If sweat chloride above is intermediate, perform a DNA analysis:
- If two CFTR mutations not identified, then repeat the sweat chloride test
- False positive reasons: lab error, malnutrition, dehydration, adrenal insufficiency, hypothyroidism, hypoparathyroidism, mucopolysaccharidosis, nephrogenic Diabetes insipidus
- False negative reasons: lab error, skin edema

b) Presence of two disease-causing CFTR mutations on DNA testing

c) Abnormal nasal potential difference
- Take 3 measurements of potential difference across the nasal epithelium (place on turbinate)
1. Basal state: high potential difference is abnormal (normally potential is balanced by equal sodium and chloride transport)
2. After nasal perfusion with amiloride (blocks sodium transport), a large decline in potential difference (hyperpolarization) is abnormal
3. After nasal perfusion with chloride-free solution containing isoproterenol (cAMP agonist-stimulates CFTR chloride transport), a minimal response is abnormal

52
Q

Discuss Primary Ciliary Dyskinesia:
1. What are the genetics/inherence?
2. What are the features? 4
5. What is the recommended treatment? Name 4

A

GENETICS:
- Autosomal recessive; or
- Multigenic

FEATURES:
- Immotile cilia of the respiratory tract, fallopian tubes, flagellated sperm
- 50% children with PCD also have Kartagener syndrome (situs inversus, bronchiectasis, CRS)
- Sinonasal disease most common manifestation
- Otitis media / recurrent OM
- Respiratory: recurrent pneumonia, bronchiectasis
- GU: Fallopian tubes and sperm flagella abnormal –> infertility

TREATMENT OPTIONS:
1. Aggressive infection control (antibiotics) - long term low dose macrolides (cover H. flu, S. Pneum, pseudomonas)
2. Chest physiotherapy to clear airways
3. Nasal irrigation
4. Consider FESS to improve sinus drainage (Gravity dependent over natural ostia)
5. New systemic therapies: Ivocafter/Tezocafter - CFTR correctors (selective)
6. If treating pulmonary disease, important to eradicate gram negative bacteria to improve sinonasal outcomes (Treat with topical antibiotics in nose)

Kevan Peds Question 211

53
Q
  1. What are the structural variations for cilia in PCD? 4
A

STRUCTURAL VARIATIONS: Normal flagella has a 9+2 microtubule structure
Abnormal variations include:
1. Absent/deformed outer dynein arms (most common)
2. Absent/deformed inner dynein arms
3. Absent/deformed outer + inner dynein arms
4. Among others (e.g. microtubule defects, absent central core, etc.) - RAD CAT variations

54
Q
  1. What are the diagnostic tests for PCD? Other tests that should be done? For each tests, what are the abnormal variables?
A

DIAGNOSTIC TESTS FOR PCD
Must rule out Cystic Fibrosis

A. IN-VIVO TESTS (human level) - Mucociliary transport measurement
1. Saccharine Test (test mucociliary clearance)
- Particle of sugar placed 1cm behind the anterior end of the inferior turbinate, normally the saccharin will be swept backwards to nasopharynx and sweet taste will be perceived
- Count how long it takes for patient to taste sugar
- Normal time = 10-30 min (< 30 minutes)
- Abnormal if > 30 minutes
- Severe prolonged = 30-60 min
- Grossly prolonged > 60 minutes
2. Nuclear Testing
- Tc-99 labeled particles placed on inferior turbinate
- Migration is followed with a gamma particle
- Majority of radioactivity should disappear from nasal cavity within 30 minutes
- Essentially the same as a saccharine test except with a radiotracer

B. IN-VITRO TESTS (lab level)
1. Electron Microscopy (may be normal in some cases) - test of structure
- Examination of ciliary ultrastructure with electron microscopy
- Cytology brushings or biopsy taken from inferior turbinate in inferior meatus
- Request “electron microscopy for ciliary ultrastructure”
- Samples are stored in glutaraldehyde (not formalin!) on ice
- High percent of anomalous cilia, such as: (1) Absent or reduced dynein arms, (2) Absent radial spokes, (3) Translocation of microtubular doublets, or (4) Altered central pairs
2. Ciliary Beat Frequency - test of function
- Light microscopy with high-speed video analysis
- Abnormal beat frequency = < 11 beat/s

C. ADDITIONAL TESTING
1. Nitric Acid Testing
- Nasal NO (expelled by nasal mucosa) is 10 times lower in patients with PCD than in control patients
- Can be a useful screening test for PCD, but cannot be used definitively to rule in PCD (if low < 77nL/min) then proceed to inferior turbinate brushings
- Elevated NO: asthma, eosinophilic airway inflammation, CF, smoking, pulmonary HTN, bronchopulmonary dysplasia
2. Genetic Testing
- Multiple possible genes (DNAH5/I1 testing)
- X-linked PCD is caused by mutations in the RPGR gene
- Must rule out cystic fibrosis
3. Sinus CT
4. CXR

55
Q

In what situations do you have high nasal NO? 4
What situations would you have low nasal NO?5

A

High NO: acute inflammation
1. Acute inflammation (antimicrobial properties)
2. Inflammatory conditions (antiinflammatory properties)
3. Allergic rhinitis (due to inflammation)
4. Exercise induced NO (due to increased blood flow for vasodilation)

Low NO: chronic inflammation conditions
1. Chronic inflammation with eosinophilia (does not stimulate NO as much)
2. Persistent infections (damage to nasal epithelium)
3. Nasal obstruction (obstruction affects airflow and alter production/distribution of NO in the nasal passages)
4. Steroid use
5. Cystic fibrosis/PCD (CFTR mutation and impaired ciliary function may impair NO levels)

56
Q

Regarding Young’s Syndrome, discuss:
1. Genetics and inheritance
2. Triad of Features - 3

A

Young’s Syndrome - type of immotile cilia syndrome

GENETICS:
1. Autosomal recessive, multigenetic

TRIAD OF FEATURES:
1. Obstructive Azospermia
2. Bronchiectasis
3. CRS

Key differences with Kartagener’s:
- No situs inversus
- Pathophysiology is unknown but thought to be related to cilia dysfunction

57
Q

Regarding Kartagener Syndrome, discuss:
1. What is it?
2. Genetics and inheritance. What is the primary problem?
2. Features 6

A

KARTAGENER SYNDROME:
- Immotile cilia syndrome

GENETICS & INHERITANCE:
- Autosomal recessive, multigenetic
- Inherited lack of Dynein arms in A-tubules (9+2 microtubule structure)

Features:
1. Primary Ciliary Dyskinesia
2. Dextrocardia (right ward displaced heart) & Situs Inversus
3. Otitis media
4. Bronchiectasis (chronic cough)
5. CRS
6. Male infertility (immotile sperm)

58
Q

Describe Secondary Ciliary Dyskinesia, what it is and how it is diagnosed.

A

= Acquired nasal ciliary transport abnormalities, such as due to infection, inflammation, etc.

  • Functionally similar to PCD, but ultrastructurally different
  • Usually occurs during or after a respiratory illness
  • Often reversible

Characterized by a low percentage of anomalous cilia and pattern of secondary ultrastructural changes:
1. Compound cilia
2. Peripheral microtubule addition or deletion
3. Disorganized axonemes (the central strand of a cilium or flagellum)
4. Ciliary disorientation
5. Discontinuity of axoneme membrane
6. Swollen cilia with excess cytoplasm

59
Q

Six possible findings in immotile cilia?

A
  1. Lack of dynein arms
  2. Lack of central core structures
  3. Radial spoke defect
  4. Microtubule translocation
  5. Microtubule altered in length
  6. Ciliary aplasia

RAD CAT
Radial spoke defect
Aplasia of cilia
Dynein arms lacking
Central core structures lacking
Altered microtubule length
Translocation of microtubule

Vancouver 441

https://www.researchgate.net/publication/359948429/figure/fig2/AS:1144787214319631@1649949949806/Motile-cilia-ultrastructure-Motile-cilia-are-microtubule-based-structures-dynein-arms.png

Rhinology (11 decks)

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