Recalcitrant

Chronic
Rhinosinusitis
Michael S. Benninger, MD
Chairman
Head and Neck Institute
The Cleveland Clinic
Cleveland Clinic Abu Dhabi
The largest hospital project
in the world
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Rhinosinusitis
Allergic
Rhinitis
Chronic
Rhinitis
Asthma
Otitis
Media
Rhinosinusitis
Immune
deficiency
Rhinosinusitis
A group of disorders
characterized by
inflammation of the
mucosa of the nose
and paranasal
sinuses of at least 12
weeks duration
Benninger M. Ferguson BJ, Hadley JA, et al. Adult Chronic Rhinosinusitis: Definitions, Diagnosis,
Epidemiology, and Pathophysiology. Otolaryngol Head Neck Surg 2003;129(suppl 3):S1-32.
Definition endorsed in 2003 by AAO-HNS, ARS, AAOA, AAAAI & SAHP
Etiology of Rhinosinusitis
Acute Chronic
Bacterial
Viral
Allergy
? Fungal
? Superantigen
? Biofilm
mediated
? Osteitis

0
20
40
60
80
100
Time
P
e
r
c
e
n
t

o
f

P
a
t
i
e
n
t
s
710 Days 3 Months
Viral
Aerobes
Resistant aerobes,
anaerobes, and fungi
Causes of Rhinosinusitis Time
Course
Defining Chronic Rhinosinusitis
No antibiotics specifically approved by
FDA for CRS
No controlled randomized trials looking at
2 different antibiotics
Speculation on the relationship to fungi
Lack of prospective studies limited by lack
of clarity, multiple etiologies, and poor
definitions
10
Why does this happen?
Ostia are widely patent.
Sinus is well-ventilated.
Are our operations not
FUNCTIONAL?
Open antrostomies, Results vary
Mucostasis after surgery
Recalcitrant
Latin to be
stubbornly disobedient
Medical use: Not
responsive to
treatment
Quality of Life surveys:
SNOT, RSDI, CRS-SS
RSDI, Validated questionnaire to
evaluate the impact of nasal and sinus
disease on patent perception of quality
of life
Disease specific instrument measuring
health in three domains
Physical
Functional
Emotional
Does not require administration of SF36 or
other broad QOL survey
What makes the mucosa vulnerable?
Why did it not respond to surgical ventilation?
Normal mucosa Abnormal mucosa
Chronic Inflammatory
Rhinosinusitis
0
10
20
30
40
50
60
70
80
90
100
1 2 3 4 5 6 7 8 9 10
Eosinophilic
Weeks
Common Pathogens in
Chronic Rhinosinusitis:
Polymicrobial
Staphylococcus species, 51% (24-80%)
Staphylococcus aureus 20% (9-33%)
Anaerobes 5% (0-30%)
Streptococcus pneumoniae 5% (0-7%)
Mixed organisms 16%
Chronic Inflammatory
Rhinosinusitis with Acute Episodes
0
10
20
30
40
50
60
70
80
90
100
1 2 3 4 5 6 7 8 9 10
Neutrophilic
Eosinophilic
Weeks
CRS
Bacteria
Infection
Pathogenesis of Recalcitrant CRS:
Role of Bacteria - Infection
Benninger, et al. Otolaryngol Head Neck Surg, 2003;129:S1-32.
CRS
Bacteria
Infection
Pathogenesis of Recalcitrant CRS:
Role of Bacteria - Infection
Anatomy
Benninger, et al. Otolaryngol Head Neck Surg, 2003;129:S1-32.
CRS
Bacteria
Infection
Pathogenesis of Recalcitrant CRS:
Role of Bacteria Barrier disruption
Barrier Disruption
(Motojima S, Am Rev Respir Dis, 1989)
Anatomy
Benninger, et al. Otolaryngol Head Neck Surg, 2003;129:S1-32.
CRS
Bacteria
Infection
Post JC. Laryngoscope 2001;111:2083-94
Pathogenesis of CRS:
Role of Bacteria - Infection
Barrier Disruption
Anatomy
Biofilm
CRS
Bacteria
Infection
Kennedy, et al. Laryngoscope 1998;108:502-507,
Pathogenesis of CRS:
Role of Bacteria - Infection
Barrier Disruption
Anatomy
Biofilm
Osteitis
CRS
Bacteria
Infection
Pathogenesis of CRS:
Role of Bacteria - Inflammation
Inflammation
Benninger, et al. Otolaryngol Head Neck Surg, 2003;129:S1-32.
Types of Fungal Rhinosinusitis
Invasive
Fulminant
Indolent
Granulomatous
Non-granulomatous
Non-invasive
Fungal Ball (Mycetoma)
Saprophytic growth
Eosinophilic Fungal
Inflammation
IgE dependent fungal
inflammation
Classic AFRS
Non IgE-dependent fungal
rhinosinusitis
Eosinophilic Fungal
Rhinosinusitis (EFRS)
Meltzer EO, Hamilos D, Hadley, J et al. Rhinosinusitis: Establishing Definitions for Clinical
Research and Patient Care. Otolaryngol Head Neck Surg 131(6):S1-S62,2004.
Potential Etiologies for CRS
CRS
Bacteria
Super-
antigen
Allergy
Fungi
Etiology
Inflammation
Clinical Appearance
IL-5, IL-4
IL-8, IF-g
GM-CSF
Osteitis
Biofilm
Benninger, et al. Otolaryngol Head Neck Surg, 2003;129:S1-32.
Differentiation of CRS
Chronic
Rhinosinusitis
due to
Inflammation
CRS without
Nasal Polyps
CRS with
Nasal Polyps
Due to
Bacterial
Infection
Without
Bacterial
Infection
With Eosinophilic
Inflammation
No Eosinophilic
Inflammation
Meltzer EO, Hamilos D, Hadley, J et al. Rhinosinusitis: Establishing Definitions for Clinical Research and Patient
Care. Otolaryngol Head Neck Surg 131(6):S1-S62,2004.
Possible reasons for recalcitrant
disease after surgery
Polyps with asthma
Aspirin hypersensitivity
Significant allergies
Immunodeficiency
Fungal sinusitis
Biofilms?
Resistant organisms?
Wrong diagnosis
Incomplete operation obstructing cell

Bad Disease, Poorly controlled
Diplopia, proptosis,
telecanthus despite
NON-invasive dz
CT: High attenuation
w/in expanded
sinuses (fungus) and
hyperdense areas
(metals/calcium),
Bony erosion (98%)
Aspirin Sensitivity
Recurrent disease is common
Difficult to control multiple manifestation of
the disease
Asthma, pulmonary hypersensitivity
Diffuse ASA or similar inflammatory
environmental exposure.
ASA immunotherapy is difficult and hard to
stay on
Immunodeficiency
Immune Dysfunction in Refractory
Sinusitis

Retrospective review of 316 patients with sinusitis
referred to Allergy-Immunology clinic for
immunological evaluation from 1991-1997
79/316 patients were selected based on
following: sinus surgery and/or sinusitis dx by
endoscopy and/or CT at least 3x/previous year
14/78 (17.9%) with low IgG
13/78 (16.7%) with low IgA
4/78 (5.1%) with low IgM
CVID in 9.9%
Selective IgAdeficiency in 6.2%


Cheeet al. Laryngoscope 2001;111:233
CRS in Hypogammaglobulinemia

Objective: study bacteria and viruses when
asymptomatic
Prospective cross sectional study for 6 months
17 patients with hypogammaglobulinemia(16 with
CVID, 1 with X-linked agammaglobulinemia
MRI, maxillary sinus aspiration and lavage, culture
and PCR
9/17 (53%) had abnl MRI at time 0 and 6 months
13/15 had bacteria (>2 pathogens)
7/15 with viruses (5 Rhinovirus, 3 enterovirus, 1 RSV)

Kainulainenet al. Arch OtolaryngolH&N Surg2007;133:597
Types of Infections in Specific
Antigen Deficiency (SAD)
KuangChen et al. Ann Allergy Asthma Immunol2006;97: 306
SAD in CRS

Retrospective review
between 2002-2010 who
underwent FESS and
had immunodeficiency
evaluation
11.6% of patients with
SAD


Carr et al., Am J of RhinolAllergy, 2011
Cystic Fibrosis
Most common lethal Auto Recessive disease in
Caucasians
1:2,000 live births; carrier rate 1:20-25
Thick, exocrine mucus causing mucostasis
CFTR gene on 7q31 affecting chloride channel;
Delta-F508 70% of CF mutations
Chronic endobronchial infections, progressive
COPD, pancreatic insufficiency, male infertility,
and CRS +/- polyposis (up to )
Allergy Testing as a Measure in
Rhinosinusitis
Evidence of increased allergy prevalence
in both ABRS and particularly in CRS
Some correlation of testing an disease
severity in AR, ? in rhinosinusitis
Can assist in guiding treatment which
may effect outcome
Not specific measure of outcome
Biofilm Ultrastructure
Basic building block =
microcolony containing
sessile cells
Heterogenous nature
Matrix-enclosed towers and
mushrooms composed of
microcolonies
Open water channels
dispersed between
microcolonies


Donlan RM, Costerton JW. Clin Microbiol Rev. 2002;15:167-193.
Biofilm Resistance to Host Defenses
Costerton JW et al. Science. 1999;284:1318-1322.
The antimicrobial agent is depleted to ineffectual
levels before it gets to the biofilm.
The antimicrobial agent is delivered to the
surface of the biofilm, but is not effectively
transported into the depth of the biofilm.
The antimicrobial agent permeates the biofilm,
but is unable to kill microorganisms because
they exist in a phenotypic state that confers
reduced susceptibility (Resistance)
Biofilm Resistance to
Antimicrobial Agents
What are superantigens?
Microbial virulence factors
Produced by bacteria (eg. staph) and viruses
Potent T-cell stimulus
10,000x more potent than conventional antigens
Act through specific T-Cell Receptor V
Domains
Acute response: Toxic Shock
Chronic response: Atopic dermatitis
May also stimulate conventional IgE response

Superantigens:
Microbial Toxins That Bind Simultaneously to Antigen-
Presenting Cells and T Cells
CDR = complementarity determining region; HVR = hypervariable region;
MHC = major histocompatibility complex; TCR = T-cell receptor.
Kotzin BL. Hosp Pract (Off Ed). 1994;29:59-63, 68-70.
Schubert MS. Ann Allergy Asthma Immunol. 2001;87:181-188.
S. aureus produces 19 different SAgs.

SEA
SEB
SEC1
SEC2
SEC3
SED
SEE
SEG
SEH
SEI
SEJ
SEK
SEL
SEM
SEN
SEO
SEP
SEQ
TSST
T cell
V
b
SAg
Superantigen Stimulation of T Cells
TCR binding area located on the outside of the b chain
variable (TCR V b) region
Many superantigens capable of binding to multiple TCR
V b gene motifs
Activate up to 30% of T cells in given individual versus <
0.01% with normal antigen-specific T-cell responses

Schubert MS. Ann Allergy
Asthma Immunol.
2001;87:181-188.
Polyclonal IgE
Staph aureus and nasal polyposis
Chemokines
Massive polyclonal
lymphocyte activation
T B
Cytokines Hyper IgE
Eosinophils
( apoptosis)
Superantigens
Epithelial damage
(barrier dysfunction)
colonisation
C Bachert et al, JACI, 1997
HU Simon et al, J Immunol, 1997
C Bachert, P Gevaert, Allergy, 1999
C Bachert, P Gevaert et al, Am J Rhinol, 2000
C Bachert, P Gevaert et al, JACI 2001
C Bachert et al, Allergy 2002
C Bachert et al, JACI 2003,
C Bachert et al, Curr Allergy Asthma Rep 2003
C Perez Novo et al, Int Arch Allergy Immunol 2004
Bachert C, van Zele T, Gevaert P. et al. Superantigens and nasal polyps.
Curr Allergy Asthma Rep. 2003 Nov;3(6):523-31.
ESS Failure?
Is it truly
recalcitrant disease
or were the prior
operations effective
in preventing
recurrences?
ESS Failures?
Empty Nose Syndrome
Common problem in the
early days of ESS
Over-resection of
normal tissues
prohibiting mucociliary
clearance and mucous
stasis and crusting
Gwaltney JM, Phillips CD, Miller RD, et al. Computed tomographic study of the common cold.
N Engl J Med. 1994;330:25-30.
Viral Rhinosinusitis
Recalcitrant sinusitis: Correct diagnosis?
What Is Not Sinusitis?
Sinus Headaches
2520 Patients with Sinus
Headache in Primary Care
10%
8%
82%
0% 20% 40% 60% 80% 100%
% of Patients
Other including
sinus
Migrainous
Migraine w or
w/o aura
SUMMIT Study
Reported Sinus HA Symptoms
0% 20% 40% 60% 80% 100% 120%
Weather associated
Nausea
Unilateral
Worsened by activity
Photophobia
Nasal Discharge
Nasal Stuffiness
Mod-severe pain
n=30
Schreiber CP, Cady RK. Poster 10
th
IHC, June, 2001 NYC.
In the sinus-like
presentation of migraine,
pain and pressure can
be felt in or near eyes
and sinuses.
In a Sinus-like Presentation of Migraine
Pain Can Be Perceived in the Maxillary and
Ophthalmic Regions of Trigeminocervical Network
No headache, no nasal symptoms
With migraine headache associated
with nasal stuffiness and pressure
and before treatment
Cady R. Schreiber C. Otolaryngol Clin N Am. 37:2004;267-288.
Presence of Nasal Congestion During a Migraine
Rhinosinusitis : Indications for Cultures
Surveillance for changes in bacterial pathogenesis
of ABRS
Controlled clinical trials of therapy for ABRS or
CRS, FDA requirement
Purulent sinusitis unresponsive to empiric therapy
CRS with poor medical/surgical control
Methods of Culture:
Endoscopic versus Antral Tap
Antral Tap via Canine Fossa
Antral Tap via Inferior Meatus
Middle Meatal
Culture via
Aspiration or
small Swab
Culture
Gentle technique

Culture/
Catheter
Insertion
Culture/
Catheter
Insertion
Easy
Catheter
Removal
Endoscopically
Directed Middle Meatal Cultures
Versus Maxillary Sinus Taps in
Acute Bacterial Rhinosinusitis: A
Meta-analysis.
Benninger MS, Payne SC, Ferguson BJ,
Ahmad N, Hadley J. Otolaryngol Head
Neck Surg 134:3-9,2006.
What Findings are Meaningful?
Acute Rhinosinusitis
Rarely needed failure of empiric treatment or
complications
Chronic Rhinosinusitis
Culture data may be of little value in routine
CRS:
Polymicrobial
Not clear of the relationships between bacteria and
the inflammation (superantigens, biofilms, osteitis?)
Acute exacerbation of CRS identify the acute
pathogens
CRS recalcitrant to non-antibiotic therapy
Therapy to Break Cycle
Normal mucosa Abnormal mucosa
Treatment options in recalcitrant
Chronic rhinosinusitis
Intranasal steroids twice a day
Higher concentration special formulations
Intranasal antihistamines
Combined nasal sprays
Allergy immunotherapy
Leukotriene modifiers
Antibiotic irrigations
Antifungal irrigations
Systemic steroids
Nasal Cleansing solutions
Courtesy: Jim Hadley
Adjunctive Medical Management
of Rhinosinusitis
Treatment options
Nasal Hygeine and irrigations
Reduce bacterial and fungal load and thereby
reduce inflammatory response to these
colonizing pathogens
Avoid mucous stasis and obstruction
Re-establish mucociliary transport
Hypertonic saline may be bacteriotoxic and
fungotoxic
Surfactants and Biofilms

Disrupt microbial
binding to cell surface
receptors
Alter biofilm
microenvironment
Orthopedic studies
demonstrated
effectiveness in animal
wound models

Sinonasal mucosal biofilm
Johnsons Baby Shampoo
3 chemical surfactants that are a
combination of anionic and zwitterionic
Cocamidopropyl Betaine
Sodium Trideceth Sulfate
PEG 80 sorbitan laurate
1% Baby shampoo demonstrated in
vitro ability to inhibit pseudomonas
biofilm formation
1% Baby Shampoo was effective in
nearly 50% of post-op recalcitrant
patient population, with greatest
benefit as a mucoactive agent



Intranasal Corticosteroids
Reduce inflammation
Reestablish more normal nasal physiology
Reduce polyp size
Reduce obstruction of sinus ostia
Position may be important
Effects of Corticosteroids
CS
Effector

Eosinophils

Basophils

Mast Cells

Vascular
permeability
Director

T-cells

B-cells

APCs
Cytokines


IgE
Inflammatory
Mediators
INS in Nasal Polyposis:
Reduction in Bilateral Polyp Grade
*P0.001 vs placebo.

P<0.05 vs placebo.
Small et al. J Allergy Clin Immunol. 2005;116:1275.
Stjarne et al. Arch Otolaryngol Head Neck Surg. 2006;132:179.
-1.4
-1.2
-1.0
-0.8
-0.6
-0.4
-0.2
0.0
Baseline: 4.21
Study 1 (N=354) Study 2 (N=310)
4.00
*

4.10 4.17 4.27 4.25
MFNS 200 g qd
MFNS 200 g bid
Placebo
Change in Bilateral Polyp Grade at 4 Months vs Baseline
Systemic steroids
The most effective treatment for CRS
Limited by steroid side effects
Justifies the premise that CRS is primarily
an inflammatory disease and not a classic
infectious disease.
1mg/kg/day prednisone for 6-7 days
without or with a taper
Pulsed or chronic steroid therapy?
Leukotriene Modifiers
Known effectiveness in AR and asthma
Many of the inflammatory mediators are
similar to those in CRS
Some patients with CRS, particularly those
with polyps, have a response to LM
Length of antibiotic treatment
PK/PD Therapeutic Goals
Time Above MIC
0
2
4
6
8
10
0 1 2 3 4 5 6 7 8
Time (hours)
A
n
t
i
b
i
o
t
i
c

C
o
n
c
e
n
t
r
a
t
i
o
n

(
m
c
g
/
m
L
)
Drug A

Time Above MIC
Drug B

Time Above MIC
MIC
b-Lactams Time-dependent Time above MIC
Macrolides >40% - 50% of dosing interval
Agent Mechanism Goal PD Parameter
Long Term Low Dose Macrolide
Therapy
Non antibiotic effect
Macrolides reduce binding of viruses
Macrolides have anti-inflammatory effects
Some evidence of efficacy in CRS
Biaxin 500 mg/day for 2 months
Antibiotic Irrigations
Useful in post-operative infected cavities
where culture postive bacteria are present
Useful if positive staph cultures
bactroban
Not much evidence of the usefulness of
fungal cultures except in allergic fungal
sinusitis
Int Forum Allergy Rhinol, 2013; 3:129132.
Bacterial interference
Promising role in ABRS. CRS?
Probiotics have been shown to be effective in
preventing and in treating ABRS
Is there a role for probiotics in CRS?

Benninger et al, Otolaryngol Head Neck Surg, 2011
Probiotics in CRS in an animal
model
Rats randomized to receive intranasal
infusions of balanced saline (BE), staph
aureus (SA), staph epidermidis (SE) or
combination of SA+SE
Goblet cell concentration used as measure
of inflammation and epithelial response
3 days after infusion, goblet cell
concentration: BE=SE>SA+SE>SA
Does LPR play a role in CRS
Strong evidence supporting role of LPR in
recurrent upper respiratory tract infections
and adenoiditis in children, Some in adults
Anectdotal evidence that treating LPR may
improve treatment of recalcitrant CRS
May be reasonable to consider a trial of LPR
therapy in patients with recalcitrant CRS
3 month trial of bid PPI before breakfast and
dinner and nighttime H2 blocker
SURGERY
Indicated in many patients
Indications:
Failure of medical management
Impending complications
Recalcitrant/severe symptoms
Concern for neoplasm
Unilateral or disproportionately unilateral disease
There may be patients who require planned
repetitive/staged surgery
? Earlier initial surgery after diagnosis
Pathogenesis of Inflammatory
Rhinosinusitis
Antigen-
presenting
cell
Allergen
Eosinophil
IL-
4
T
H
2
GM-CSF
IL-3, IL-5
IgE
B lymphocyte
Mast
cell
GM-CSF
IL-4
IL-5
Activation
Prolonged
survival
GM-CSF,
CysLTs
IL-3, IL-5
Bone marrow
GM-
CSF
CysLTs
Histamine
CysLTs
PGs
CysLTs
Eotaxin
MIP-1
Chemoattraction
Inflammatory symptoms
Mast
cell
GM-CSF, CysLTs, IL-3, IL-5
Blood
Transmigration
Adhesion
Endothelium
IL-13
CysLTs
Neurotrophins
IL-
4
Sensory
nerves
Neuropeptides
Unanswered questions
Are antibiotics necessary?
Under which circumstances?
Is there a need for antifungals?
Role for topical applications for antibiotics?
Novel treatment strategies that interfere with
formation and maintenance of biofilms?
Can other anti-inflammatory medications
affect CRS?
Consider LPR therapy?
Anti-eosinophilia treatment?
Are there alternate ways in which to attenuate
the inflammatory process?

Benninger, et al. Otolaryngol Head Neck Surg, 2003;129:S1-32.
Sinusitis in Zero Gravity
Normal air filled sinus: Overlying skin and bone are readily
seen, the air in the sinus cavity is seen as an echolucent
area in the midportion of the image
Air-fluid interface in the porcine maxillary
sinus following instillation of 1cc of a viscous
fluid during 1 G conditions
Effect of microgravity on fluid contained in the porcine
maxillary sinus. Fluid rapidly dispersed along the walls of
maxillary sinus with a central area of air. This process
occurred rapidly and stabilized during microgravity -
returned to classic air-fluid level during gravity conditions.
Ultrasound examination of a frontal sinus obtained
on the International Space Station using the
Human Research Facility ultrasound machine. The
image was obtained by a non-physician crew
member using remote, expert guidance.