Difficult Cases: Chronic Rhinosinusitis

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Difficult CasesChronic Rhinosinusitis
Anita Trikha, MD Division of Allergy and
Immunology National Jewish Health and Todd
Kingdom, MD Director, Rhinology and Sinus
Surgery University of Colorado School
Medicine Staff Physician, National Jewish
Health AAAAI Houston, February 20, 2015
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Case 1 KD

• 27 year old woman referred by ENT after surgery
  for nasal polyposis for cough
• First sinus surgery at age 15 for nasal
  polyposis second in 2013
• Asthma diagnosed as a child with chronic cough
  for 10-20 years. On inhalers as a child, but off
  medications for years used a friends inhaler at
  work with improvement of dyspnea

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Case 1 (cont.)
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• Intermittent non-exertional chest pain
• Productive cough with greenish sputum - no change
  while on prednisone for 30 days prior to last
  sinus surgery
• Some nasal congestion
• Negative allergy testing
• Oophorectomy in 2009 for ectopic pregnancy

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Case 1 (cont.)

• Family history Mother with asthma, sister with
  thyroid disease and 13 year old son with AR
• Social Hx ex-smoker ages 14-22 1/2ppd
  occasional ETOH denies drug use
• Environmental Hx 2 dogs
• Current medications budesonide in nasal washes
  Ranitidine prn NSAIDs

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Case 1 (cont.)
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• Physical Exam O2 sat 95 on RA nasal mucosa
  edematous decreased air movement on lung exam
• Spirometry FEV1 2.48L or 69 predicted FVC
  3.82L or 91 predicted FEV1/FVC 65 (LLN 75)
  mild airflow limitation, no BD response

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Pansinusitis
Imaging prior to 2nd surgery
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Q1. Which of the following diagnoses is highest
on the differential ?

• AERD
• Cystic Fibrosis
• EGPA aka Churg-Strauss Syndrome
• Allergic Fungal Sinusitis

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Q1. Which of the following diagnoses is highest
on the differential ?

• AERD
• Cystic Fibrosis
• EGPA aka Churg-Strauss Syndrome
• Allergic Fungal Sinusitis

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Chronic RhinosinusitisDisease Definitions

• 2nd in prevalence amongst all chronic conditions
• 1/3 with NP- greater burden of disease
• Inflammation with symptoms

Ocampo CJ and Grammer LC. JACI Chronic
Rhinosinusitis. 2013. Settipane RA, Peters AT
and Chandra R. CRS. Am J of Rhinology and
Allergy. S11.
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Clinical Practice GuidelinesEPOS 2012

• Subjective 2 symptoms
• must have the 1st or 2nd, 12weeks
• Nasal obstruction/congestion
• Anterior or posterior discharge
• Facial pain/pressure
• Reduction or loss of smell
• Objective
• Endoscopy polyps, mucopurulence or edema of
  middle meatus
• and/or
• CT mucosal changes within OMC and/or paranasal
  sinuses

Fokkens et al., Rhinology 2012, EPOS 2012
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Phenotypes CRSsNP

• Histology fibrotic mucosa goblet cell
  hyperplasia mononuclear cell infiltrate Th1
  inflammation
• TGF-B implicated in remodeling via attraction of
  fibroblasts
• Excessive collagen deposition (different from
  CRSwNP)

Bachert and Zhang. Chronic Rhinosinusitis and
asthma novel understanding of the role of IgE
above atopy. J Int Med. 2012. Ocampo CJ and
Grammer LC. JACI Chronic Rhinosinusitis. 2013.
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CRSwNP

• Deficit in T reg cells and TGF-B expression
• In US/Europe NP typically eosinophilic (Th-2)
• In Asia NP pathology PMNs (Th-1)
• PMNs also typical in NP of CF patients (Th-1)

Bachert and Zhang. Chronic Rhinosinusitis and
asthma novel understanding of the role of IgE
above atopy. J Int Med. 2012. Settipane RA,
Peters AT and Chiu AG. Nasal Pokyps. Am J
Rhinology and Allergy 2013. Wilson KF, McMains
KC, Orlandi RR. The association between allergy
and chronic rhinosinusitis with an without nasal
polyps an evidence-based revew with
recommendations. Int Forum Allergy Rhinol.2014
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Nasal polyposisImaging and Nasal Endoscopy
Findings
fLeft Nasal Endoscopy
fCT Sinus
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PathophysiologyNo unifying mechanism

• Staphlococcal Superantigen Hypothesis
• B and T cell stimulation with class switching and
  local polyclonal IgE production --gtTh2 mediated
  eosinophilic inflammation SA specific IgE
• colonization rates higher in patients with
  CRSwNP, asthma and aspirin sensitivity
• ?inhibition of Tregs - unopposed Th2 inflammation
  - harboring SA in nasal polyps

Bachert and Zhang. Chronic Rhinosinusitis and
asthma novel understanding of the role of IgE
above atopy. J Int Med. 2012. Settipane RA,
Peters AT and Chandra R. CRS. Am J of Rhinology
and Allergy. S11. Hulse et al. Pathogenesis of
Nasal Polyposis.
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PathophysiologyNo unifying mechanism

• Eicosanoid pathway defects
• Immune Barrier Hypothesis
• immunological defects innate immunity BAFF
  overproduction STAT3 dysregulation
• mechanical/epithelial unclear role of biofilms
• Underlying pathophysiology/biomarkers may help
  identify specific therapeutic options to consider

Bachert and Zhang. Chronic Rhinosinusitis and
asthma novel understanding of the role of IgE
above atopy. J Int Med. 2012. Settipane RA,
Peters AT and Chandra R. CRS. Am J of Rhinology
and Allergy. S11. Hulse et al. Pathogenesis of
Nasal Polyposis.
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Settipane RA, Peters AT and Chiu AG. Nasal
Pokyps. Am J Rhinology and Allergy 2013.
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Q2 What testing would you proceed with next?
(POLL)

• Sweat chloride test
• CT Chest
• PFTs
• Skin prick testing to environmental aeroallergens

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Q2 What testing would you proceed with next?
(POLL)

• Sweat chloride test
• CT Chest
• PFTs
• Skin prick testing to environmental aeroallergens

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CRS Evaluation

• Lab Culture from middle meatus 80 accuracy
  CVID/SAD if refractory (consider immune
  evaluation if associated bronchiectasis/sinopulmon
  ary infections)
• Nasal cytology less useful
• Nasal biopsy r/o vasculitis or malignancy or CD
• Sweat Chloride Test/Genetic screening
• Ciliary dysfunction analysis (low nasal NO)
• Allergy testing Grade C evidence
• Imaging unilateral extrasinus involvement no
  response to medical therapy (1/5 normal
  population)

Settipane RA, Peters AT and Chiu AG. Nasal
Polyps. Am J Rhinology and Allergy 2013.
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Cystic Fibrosis
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• Defect in CF transmembrane conductance regulator
  gene absence of normal cAMP-activated ion
  channel
• Most commondefective protein produced which does
  not traffic to apical membrane
• Decreased chloride secretion loss of inhibition
  of sodium channel increased sodium absorption
  depleted airway surface liquid and impaired
  mucociliary clearance

Davies JC et al. Recent advances in the
management of cystic fibrosis. Arch Dis Child
2014.
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Primary Ciliary Dyskinesia

• Autosomal recessive
• Abnormality in ciliary beating impaired
  mucociliary clearance recurrent upper and lower
  respiratory tract infections
• Consider in anyone you may consider CF testing in
• 50 with situs inversus (as embryonic cilia
  determine symmetry)
• Assessment of ciliary structure by EM /low NO

Lucas JS et al. Diagnosis and management of
primary ciliary dyskinesia. Arch Dis Child 2014.
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KD CT Chest Left lower lobe and lingular
bronchiectasis with significant degree of mucous
plugging/secretions.
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KD Further evaluation

• Labwork CBC without eosinophilia, eNO 7ppb,
  normal CRP/ESR/CMP/Quantitative Igs/IgE 2/ANCA
  and ANA negative/Alpha 1 AT level and phenotype
  normal
• Sweat test negative
• Tailored Barium Swallow abnormal
• Esophagram unremarkable
• She is awaiting a bronchoscopy, but it is
  suspected that bronchiectasis a result of past
  aspiration

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Treatment options

• Goal decrease inflammation/morbidity - not
  curative
• Address contributing factors Allergy testing
  Option
• Intranasal CS most off label good evidence FOR
  use in CRS
• Topical Therapy
• No benefit to hypertonic saline (may worsen)
• Steroids in nasal washes (off label use) Option
• Baby shampoo for biofilm no evidence
• Topical antibiotics (mupirocin) no data in
  routine CRS
• Antifungals in nasal wash no evidence
• Evidence favors large volume devices vs. low
  volume devices (particularly after surgery)

Ocampo CJ and Grammer LC. JACI Chronic
Rhinosinusitis. 2013. Adappa N et al. Nasal
Irrigation with or without drugsL the evidence.
Curr Opin Otolaryngolo Head Neck Surg 2012.
Alobid I and Mullol J. Role of Medical Therapy
in Management of NP. Curr Allergy Asthma Rep
2012. Kalish L et al. Topical Steroids for nasal
polyps. Cochrane Review. 2012. Orlandi RR,
Smith TL, Marple BF, et al. Update on
evidence-based reviews and recommendations in
adult CRS. Int Forum Allergy Rhinol. 2014.
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Treatment optionsWhat is the evidence?

• Oral antibiotics no evidence for use, especially
  non-macrolide recommendation against use in
  routine CRS
• Oral anti-fungals recommendation against in
  routine CRS
• Oral steroids evidence supports in AFRS and
  peri-op in CRSwNP
• Option in CRSsNP used frequently
• Surgery evidence supports as option, less well
  defined in pediatric population

Ocampo CJ and Grammer LC. JACI Chronic
Rhinosinusitis. 2013. Adappa N et al. Nasal
Irrigation with or without drugsL the evidence.
Curr Opin Otolaryngolo Head Neck Surg 2012.
Alobid I and Mullol J. Role of Medical Therapy
in Management of NP. Curr Allergy Asthma Rep
2012. Kalish L et al. Topical Steroids for nasal
polyps. Cochrane Review. 2012. Orlandi RR,
Smith TL, Marple BF, et al. Update on
evidence-based reviews and recommendations in
adult CRS. Int Forum Allergy Rhinol. 2014 4
S1-15.
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Potency of Intranasal Steroids

• Triamcinolone and flunisolide are the least
  potent
• Beclomethasone is next most potent
• Budesonide is slightly gt beclomethasone
• Fluticasone is twice as potent as beclomethasone
• Mometasone may be slightly gt fluticasone

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Indications for Surgery for Chronic Rhinosinusitis
Absolute indications

• Sinusitis is causing a brain abscess or
  meningitis, a subperiosteal/ orbital abscess,
  cavernous sinus thrombosis, another contiguous
  infection, or an impending complication (e.g.
  Potts tumor)
• Sinus mucocele or pyocele
• Fungal sinusitis (all varieties)
• Nasal polyps (massive, i.e. causing obstruction
  of most or all of the nasal lumens)
• Neoplasm or suspected neoplasm (causing sinus
  obstruction)

Relative indications

• Failed medical treatment

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Take Home Points (Case 1)

• The is a team sport (collaboration critical)
• Each specialty has blind spots
• The single airway patient
• Evaluation and appreciation of the lower airway
  component
• Cough, reactive airway disease, recurrent
  pneumonia
• Systemic etiologies must be explored

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Take Home Points (Case 1)

• Disease definitions diagnostic classifications
• Infectious vs. inflammatory debate
• Objective evidence of sinonasal disease combined
  with symptoms
• Weakness of CRSwNP vs. CRSsNP classification of
  disease
• Understanding of molecular endotypes evolving

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Take Home Points (Case 1)

• Management considerations
• Focus on inflammation
• Failure analysis
• Medical
• Patient related / compliance
• Surgical (technical)
• Define treatment objectives careful patient
  selection

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Case 2 RC

• 32 year old woman with history of nasal polyposis
  s/p multiple surgeries (2006, 2007 and 2010) who
  presents for evaluation of asthma
• Known history of aspirin sensitivity severe
  asthma exacerbation after ingestion Alka-Seltzer
  and since then after NSAIDs

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Case 2 (cont.)

• No history of childhood asthma, eczema or
  allergic rhinits
• Current medications Budesonide in nasal washes,
  Advair 250/50 1 puff BID, Proair prn
• Family Hx Siblings with asthma
• Social Hx No tobacco use, no ETOH or drug use

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Case 2 (cont.)
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• Environmental Hx no pets
• Spirometry FEV1 1.97L or 65.2 predicted FVC
  3.18L or 88.8 predicted FEV1.FVC 61 (LLN 73)
  mild airflow limitation with BD response
• O2 sat 99 on RA
• Exam pertinent findings polyps in R nares

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Q3 In this patient, testing may be expected to
reveal

• Decreased LO-5 expression in tissue
• Decreased urinary LT C4
• Decreased LTC4 synthase expression in tissue
• Decreased production of PGE2

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Q3 In this patient, testing may be expected to
reveal

• Decreased LO-5 expression in tissue
• Decreased urinary LT C4
• Decreased LTC4 synthase expression in tissue
• Decreased production of PGE2

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AERD
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Natural History
Szczeklik Eur Respir J 2000 Berges-Gimeno Ann
Allergy Asthma Immunol 2002
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AERD Clinical Features

• Samters triad (really a tetrad)
• Chronic eosinophilic rhinosinusitis
• Nasal polyposis
• Asthma
• ASA/NSAID induced reaction
• Progressive disease despite careful avoidance of
  NSAIDs and ASA
• Chronic congestion, rhinitis, anosmia
• Sinusitis intermittent evolves in to chronic
• Persistent asthma, usually moderate to severe
  related to severity of sinus disease
• Abnormal sinus imaging pansinusitis

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Pathophysiology

• Aberrant arachidonic acid metabolism
• IMBALANCE of pro and anti-inflammatory factors
• Inhibition of COX-1 decreased PGE2
  unregulated activity of 5-LO
• Increased expression of 5-LO and LTC4Synthase
• Overproduction of cysteinyl LT (LTC4, D4, E4)
• Elevated baseline levels of urine LTE4, BAL
  samples and exhaled condensate
• ASA is only NSAID which irreversibly inhibits
  both COX-1 and COX-2 more potent against COX-1
  vs COX-2
• Type 1 reaction

Steinke JW, et al. J of Allergy. Jan 2012.
Okunishi K, et al. Biochimica et Biophysica
Acta. Feb 2011 Ocampo CJ and Grammer LC. JACI
Chronic Rhinosinusitis. 2013.
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Pathophysiology (cont.)

• ASA shunts AA ? life threatening LT surge

Middletons
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Diagnosis of AERD

• ASA challenge gold standard Oral, inhalational
  (bronchial), nasal challenge
• NASAL LYSINE faster, safer not FDA approved
• ORAL every 2 hours protocols based on Scripps
  Research
• Premedication to reduce severity of reaction
• REACTIONS TO ORAL ASA CHALLENGE
• Classic 20 or gt decline FeV1, nasoocular
• Pure lower no naso-ocular reaction
• Partial Asthma decline in FEV1 between 15-20
  with naso-ocular reaction
• Laryngospasm
• Negative no reaction following 650mg ASA
  consider repeat if high suspicion

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Evidence-Based Medical ManagementLimited data
specific to AERD

• Topical corticosteroids Access delivery
  methods may be factors extrapolate from CRS data
• Oral corticosteroids single study short term
  benefit (medical poylpectomy)
• Leukotriene modifiers
• EPOS review recommends against routine use as ¾
  studies with negative effect
• 2013 meta-analysis with limited data with
  comparable effect to INCS/possible benefit in
  atopic patients

Han, Smith, Kingdom unpublished IFAR
review Fokkens, Lund, et al. Rhinology 2007 EPOS
2012, Rhinology 2012 Wentzel JL et a.
Leukotriene antagonists in nasal polyposis A
meta analysis and systematic review. Am J Rhinol
Allergy 2013.
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Leukotriene Modifiers in CRSwNPsZileuton

• Hyperplastic rhinosinusitis with asthma
• Placebo-controlled, blinded study
• 40 patients with ASA-intolerant asthma
• Zileuton added to regimen for 16 weeks
• Pulmonary function improved
• Nasal outcomes
• Improved smell (plt0.01)
• Decreased rhinorrhea (plt0.05)
• Decreased congestion (p0.63)

Dahlen et al. Am J Respir Crit Care Med
1571187-1194, 1998
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Long-term treatment with aspirin desensitization
in asthmatic patients with aspirin-exacerbated
respiratory disease

• Long term studies of pts who underwent
  desensitization and treated with daily ASA
• Reduced upper airway congestion
• Reduced nasal polyp formation
• Improved asthma control
• 172 pts desensitized 1995-2000 treated with 650
  bid for 1-5 years, 1st 6 mons of ASA
• ?sinus infection
• ?Pred burst
• ?smell
• Decreased rhinitis
• Increased asthma control

1. Berges-Gimeno etal J Allergy Clin Immunol
2003 111 180-186. 2. Sweet et al JACI
19908659-65. 3. Stevenson DD, et al JACI
199698751-8. 4. Stevenson DD. JACI 2003..
Slide courtesy of Rohit Katial
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Optimal Dosage of ASA for treatment of AERD?

• Mechanism exploit refractory period
• Consider co-morbidities
• 325 mg BID effective for responder patients after
  1 year at 650mg BID
• 325 mg q.d. higher prevalence of breakthrough
  nasal congestion in older studies
• Single study found a benefit in control of the
  upper airways with 300mg ASA q.d.1

Rozsasi A. et al. Long-term treatment with
aspirin desensitization a prospective clinical
trail comparing 100 and 300 mg aspirin daily.
Allergy 2008 63 1228-1234
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Reasons for Discontinuing ASA Treatment 46/172
(27) discontinued in 1st year

• 52 due to side effects
• 37 discontinuation unrelated to side effects
• 11 discontinuation unrelated to Rx response
• Planned pregnancy (1) Elective surgery (4)
• TIMING

Berges-Gimeno MP et al. J Allergy Clnic Immunol
2003111180-6
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Novel TherapiesAnti-IgE

• Omalizumab limited data, small contradictory
  studies
• NOT approved for AERD

Pinto JM et al. Rhinology 2010 EPOS 2012,
Rhinology 2012 Gevaert, et al. JACI 2013
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Novel TherapiesAnti-IL-5

• Mepolizumab and reslizumab
• Preliminary experience
• Improved NP scores
• Improved CT scores
• Data suggests potential role

Gevaert P, et al. JACI 2006 Gevaert P, et al.
JACI 2011 EPOS 2012, Rhinology 2012
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RC Patient Course

• ANCA negative IgE 228
• Singulair added
• Aspirin challenge and desensitization performed
  approximately 3 months post op with nasal
  symptoms noted after 81mg dose
• On 650mg BID of ASA, she reported persistent
  nasal symptoms.

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Q4 What treatment option would you proceed with
next?

• Stop aspirin
• Refer to ENT for further surgical intervention
• Trial of Zileuton
• Start Mepolizumab

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Q4 What treatment option would you proceed with
next?

• Stop aspirin
• Refer to ENT for further surgical intervention
• Trial of Zileuton
• Start Mepolizumab

54
Take Home Points (Case 2)

• AERD is an important consideration
• ENTs may miss this but often in best position to
  detect
• Evidence supports ASA desensitization as adjunct
  approach
• It is a team sport

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Take Home Points (Case 2)

• Role of surgery in CRSwNPs AERD
• Experience matters
• Clearance of irreversible mucosal disease
• Create access for topical therapy
• Patient selection critical
• Set expectations (allergist, rhinologist, patient)

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Take Home Points (Case 2)Surgical Outcomes in
CRSwNPs AERD

• Prospective cohort design
• Explore impact of AERD on outcomes

Endoscopy QOL scores, mean f/u 18 months
Similar proportions of each group showed
improvement after ESS
Robinson et al. Laryngoscope 2007
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Endoscopy Scores
Robinson et al. Laryngoscope 2007
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QOL scores
Robinson et al. Laryngoscope 2007
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Take Home Points (Case 2)Surgical Outcomes in
CRSwNPs AERD

• Analyze determinants of outcomes after ESS
• Prospective cohort design N 302 with CRS
• 39 patients with AERD
• Worse pre-op and post-op absolute
  measures
• Equivalent or greater magnitude of
  improvement
• Presence of AERD was not found to be a
  determinant in outcome after ESS

Smith et al. Otolaryngol Head Neck Surg 2010
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Take Home Points (Case 2)Surgical outcomes
whats the evidence where do we stand?

• Outcomes of Surgery

Predicting Outcomes
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Case 3
Cavanna C, et al. Allergic Fungal Sinusitis due
to Curvilaria lunata. New Microbiologica 2014.
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AFS

• Southeastern US up to 32 of patients who
  undergo FESS have been reported to have AFS
• African American patients with greater incidence
  and severity
• Nasal polyps on exam but in severe cases
  proptosis
• Imaging dense material in sinuses, with
  characteristic metallic densities on soft tissue
  windows metal salt chelation by fungii mucin
  may be seen eroding surrounding bony structures
• Surgical Debridement Peanut Butter
• Saline irrigation with steroids oral steroids
  post op (duration controversial), 0.5 mg/kg/
  daily for 2 weeks, then QOD with gradual tapering
  over several weeks
• Possible role of IT
• No significant role for oral anti-fungals

Laury AM and Wise SK. Allergic Fungal
Rhinosinusitis. Am J Rhinology and Allergy. 2013
63
Take Home Points (Case 3)

• Allergic Fungal Sinusitis
• Much debate and controversy continues with
  fungal sinusitis
• Surgery and corticosteroids mainstay of therapy
• No role for topical anti-fungal therapy
• Very limited role for oral anti-fungal therapy
• Long term surveillance (and patience) is critical