Appendix of Trio Thesis: The Role of Allergy and
Smoking in Chronic Rhinosinusitis and Polyposis
Steven M. Houser, MD, FACS*, Kevin J. Keen, PhD, PStat**
*MetroHealth Medical Center, Cleveland OH, USA, and **University of Northern British
Columbia, Prince George, BC, Canada
Corresponding author: Steven M. Houser, MD, FACS
MetroHealth Medical Center, 2500 MetroHealth Dr., Cleveland OH 44109
O: 216-778-8890, f: 216-778-7868, e: shouser@metrohealth.org
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Appendix I: Supplementary Literature Review
Pathophysiology of Allergic Rhinitis
The mechanism of allergic disease is through a Gell and Coombs type I, or IgE mediated,
reaction. The subject must first be exposed to a potential allergen, the antigen is taken up
by the body, and the host generates IgE antibodies towards the antigen via a Th2 cell line;
this phase is referred to as sensitization. Upon re-exposure to the particular antigen, the
specific IgE antibodies situated on the surface of mast cells can elicit an immediate
response toward the offending allergen; preformed mediators (histamine, leukotrienes,
etc.) can be released into the milieu of the allergic response. Late inflammation can then
take place as the preformed mediators induce a recruitment of inflammatory cells
(eosinophils, etc.) to the active site and more mediators are formed and released
(leukotrienes, etc.). Priming can also take place, whereby increasingly smaller amounts
of antigen exposure can lead to allergic manifestations.(1)
Defining Rhinosinusitis
Rhinosinusitis is not as clearly defined as allergic rhinitis. The Task Force on
Rhinosinusitis of the American Academy of Otolaryngology-Head and Neck Surgery has
attempted to clarify this issue in 1997 and 2003.(6,7) They replaced the term sinusitis
with rhinosinusitis to better reflect the inflammation of the sinuses that occurs in
conjunction with inflammation of the nose. The 1997 report created five categories of
rhinosinusitis based upon the duration of a patient’s symptoms:

Acute rhinosinusitis (symptoms present for less than 4 weeks)
2

Subacute rhinosinusitis (symptoms present for more than 4 weeks, but less than
12 weeks)

Chronic rhinosinusitis (symptoms present for greater than 12 weeks)

Recurrent acute rhinosinusitis (more than 4 acute episodes over 1 year)

Acute exacerbation of chronic rhinosinusitis (acute infection, with new acute
symptoms, superimposed over a chronic infection, with a constant baseline level
of symptoms)
In 2003 the task force further refined the definition of rhinosinusitis. A diagnosis of
CRS may be suggested by patients’ symptoms and the duration of the illness (greater
than 12 weeks of symptoms), but it should be confirmed by physical evidence of
mucosal swelling or discharge.
The 2003 clinical criteria for diagnosing chronic rhinosinusitis include:

Duration of disease is qualified by continuous symptoms or findings for more
than 12 consecutive weeks.

The physician should be able to identify at least one physical sign of
inflammation (e.g. discolored nasal drainage, edema or erythema of the middle
meatus or ethmoid bulla, generalized or localized erythema, edema, or granulation
tissue, computed tomography scan or plain sinus radiograph suggesting
inflammation).
3
Steinke and Borish (2004) presented an alternative scheme for categorizing chronic
sinusitis.(A1) They divided chronic (i.e., greater than 6 weeks) sinusitis into 4 groups
based upon the underlying disease process:

Chronic infectious sinusitis includes infection with some immunologic, or other
issue prohibiting clearance of the infection (e.g. immune deficiencies, ciliary
dyskinesia).

Chronic inflammatory sinusitis is seen in patients whose sinus ostia are
repetitively insulted by some disease process (e.g. viral infections, allergic
rhinitis, and/or anatomic restrictions). The inflammatory cells seen in this
situation are those which are commonly seen in infection (e.g., mononuclear
cells). Nasal polyps may develop as a result of the inflammation.

Chronic hyperplastic eosinophilic sinusitis (CHES) is characterized by
eosinophilic inflammation and often nasal polyposis.

Allergic fungal sinusitis may represent a severe form of CHES with fungal
colonization and an IgE inflammatory reaction.
In 2004 a joint committee of the American Academy of Allergy, Asthma and
Immunology, the American Academy of Otolaryngic Allergy, the American Academy of
Otolaryngology-Head and Neck Surgery, the American College of Allergy, Asthma and
Immunology, and the American Rhinologic Society met to discuss and find common
ground for defining sinusitis.(5) Consensus definitions were produced for 4 classes of
rhinosinusitis:
4

Acute (presumed bacterial) rhinosinusitis is an inflammatory condition of the
nasal and sinus lining lasting up to 4 weeks.

Chronic rhinosinusitis without polyposis is an inflammatory condition of the nasal
and sinus lining lasting 12 or more weeks. Examination reveals signs of
inflammation, but not polyposis.

Chronic rhinosinusitis with polyposis denotes bilateral nasal polyposis seen on
examination.

Classic allergic fungal rhinosinusitis is defined as meeting the criteria of CRS
with or without polyposis, as well as allergic mucin and evidence of allergic
hypersensitivity to fungal antigens.
Thoughts as to the origins of CRS, and how AR fits into the picture
Sinusitis cycle
The development of rhinosinusitis is often thought of as a wheel, or cycle of events, that
conspire to cause the disease initiation and promotion (Figure A 1, modified from
Reilly).(A2) Some insult (e.g., viral, bacterial, fungal, allergic, genetic) to the nasal and
sinus mucosa results in inflammation. Prolonged inflammation of the nasal mucosa in the
region of the ostiomeatal complex can cause obstruction of the paranasal sinus outflow
tracts. When the sinus ostia are obstructed there is decreased oxygen tension in the sinus.
The stagnant secretions in the sinus become more viscous and acidic, further damaging
the respiratory epithelium. This is an ideal environment for bacteria to proliferate and
perpetuate tissue insult, causing a cycle of chronic inflammation. The process may then
5
expand to involve adjacent sinuses. The initiating insult, or a propagating one, may be
allergic inflammation.
6
Figure A1. Rhinosinusitis Cycle.
Particulates/smoke
Mucus stasis
Allergic
Viral
Viscous, acidic mucus
Inflammation at ostia
Fungal
Bacterial
Bacterial proliferation
(possibly fungal proliferation)
Rhinosinusitis cycle denoting the initiation and promotion of the disease.
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Inflammatory cascade
The pathophysiology of allergic rhinitis may explain how this relationship develops
between PAR and chronic rhinosinusitis. In patients with allergic rhinitis, specific
allergens induce a Gell and Coombs type I immunologic reaction in the nasal cavities.
Allergens are bound by IgE affixed to the mast cell membrane, which leads to
degranulation and release of inflammatory mediators. These mediators cause increased
vascular permeability and hypersecretion from serous and mucus glands. Cytokines,
formed from lymphocytes and mast cells, attract eosinophils, macrophages, lymphocytes
and mast cells, which cause the late-phase allergic response.
Allergen hypersensitivity has also been shown to directly cause inflammation in the
paranasal sinuses. Slavin studied patients with ragweed sensitivity. During the ragweed
season, these patients had increased hyperemia in the sinuses as well as increased
metabolic activity in the bone around the sinuses using single photon emission
computerized tomography.(A3)
T-helper cells type 2 (Th2) lymphocytes play a commanding role in allergic inflammation
and they are also important in the development of nasal polyps and most CRS. This
commonality speaks to the relationship between AR and CRS.(A4)
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Immunity
Proper host immunity is necessary for sinus health. Low levels of immunoglobulin or
selective IgG subclass deficiency are known causes or contributors to the development of
CRS.(A5,A6) Atopic patients may also be slightly more susceptible to immune
deficiencies.(A7,A8,A9)
MCC
Impaired mucociliary clearance (MCC) in allergic rhinitis also seems to be very
important in the development of chronic sinusitis. MCC is a vital defense mechanism
against infection; it serves to trap foreign particles, including bacteria, and eliminate them
from the body. In patients with allergic rhinitis, saccharin clearance times are
significantly prolonged.(A10,A11,A12) The mechanism is not clearly defined. The slow
flow may be attributed to a change in the rheologic properties of mucus.(A13) Damage
to nasal cilia in patients with allergic and chronic rhinitis may produce a prolongation in
MCC.(A14) The delay in clearance adds to mucus stagnation and consequent bacterial
overgrowth.
Disease states which directly impair MCC will predispose a patient to CRS. Two
examples of such diseases are cystic fibrosis, with overly thickened secretions, and
primary ciliary dyskinesia, with deranged ciliary function.
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Particulate matter
The role of the nasal mucus is to trap and expel foreign material, but the system can be
overtaxed and come to a standstill in the face of an overwhelming insult. Tobacco use
deserves special consideration. Acute, recurrent acute, and chronic rhinosinusitis are
more prevalent among subjects who smoke, or expose themselves directly to
tobacco.(A15,A16) Tobacco use has been associated with poorer outcomes after sinus
surgery among adults with direct exposure and children with indirect or passive
exposure.(A17,A18,A19) Indirect tobacco exposure is a notable respiratory irritant.
Those that complain of rhinitis associated with indirect tobacco exposure have been
shown to have a reduction in MCC.(A20) Tobacco may exert its derogatory effects
through reducing MCC by changing cilia or nasal secretions.(A15) Saccharin clearance
times are significantly increased in smokers.(A11) A significant decrease in ciliary beat
frequency is noted to be tied to cotinine levels which rise with tobacco exposure. (A21)
Other models to help explain chronic rhinosinusitis that do not involve allergy
Bone involvement
Kennedy has suggested possible pathophysiologic changes in the bone morphology in
CRS may explain the persistence of the infection. Ethmoidal bone from patients with
CRS expressed marked activity not seen in controls. These patients expressed increased
fibrosis, remodeling, and woven bone formation; the changes approximate osteomyelitis.
Also, inflammation within the bone may be present even when overlying mucosa is
normal.(A22) Although, the evidence is not conclusive of an osteomylelitic process, it
may contribute to the increased susceptibility for the chronicity of the sinusitis in these
10
patients. Intravenous antibiotics may have improved efficacy in these patients because of
increased concentration and duration of antibiotics present in the blood stream.
Biofilms
In otitis media, a disease analogous to CRS, research has shown the presence of
pathogens attached to inner ear mucosa of animal models as a bacterial biofilm, rather
than as free-floating organisms.(A23) Correlation of biofilm studies in otitis media led to
further investigation in CRS.
A hallmark of biofilms is the chronic nature of the disease. Biofilms have a unique
mechanism of resistance to conventional bacterial therapy. They survive within a
polysaccharide matrix in a metabolically slowed state. In vivo, antibiotics may suppress
symptoms of infection by killing free-floating bacteria shed from the bacterial biofilm,
but fail to eradicate those bacterial cells still embedded in the biofilm. When the course of
antibacterial therapy ends, the biofilm can act as a nidus for a renewed infection as
bacteria again spread out of the biofilm. Intravenous antibiotics may be necessary to
penetrate the sessile biofilm. Biofilms may also explain the relative inability to culture
out bacteria from CRS patients; the low density of organisms recovered in cultures
contributes to the notion that microbial agents are not significant in CRS.
Biofilms have been detected in the mucosal specimens of patients undergoing surgery for
CRS. Biofilms may develop as rapidly as five days after the initiation of bacterial
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sinusitis.(A24)
Biofilms have been detected in the mucosal specimens of patients
undergoing surgery for CRS.(A24,A25)
Fungal hypothesis
Ponikau believes fungi within the nose and sinuses may engender an abnormal immune
response resulting in CRS. Eosinophils are recruited to fight of fungi in the nose and
sinuses of some patients, while healthy controls do not respond to fungi within their nose.
The eosinophils migrate through the nasal mucosa and into the mucus. Eosinophils
degranulate to kill off the fungi that selected individuals perceive as a threat. The nasal
mucosa itself is accidentally damaged by the release of toxic products.
Mucosal
destruction allows the bacteria which normally reside harmlessly within the nose to
secondarily invade the patient's mucosa and cause an acute exacerbation of chronic
sinusitis. Applying these concepts into a treatment scheme with amphotericin B nasal
lavage produced modest benefit.(A26) Other researchers have found little benefit with
the use of topical amphotericin B.(A27)
Superantigen hypothesis
One of the possible early events in the development of inflammation in chronic
hyperplastic sinusitis with nasal polyposis is the production of exotoxins from
Staphylococcus aureus. The exotoxins may act as superantigens and cause activation and
clonal expansion of lymphocytes, resulting in massive cytokine production.(A28) The
vigorous inflammatory reaction may be responsible for polyp development.
12
Independent treatment of AR and CRS
It is important to understand that both AR and CRS are treated as distinct diseases
entities. The otolaryngologist combines their treatment protocols to treat both conditions
simultaneously, as they so often co-exist.
AR treatment
Allergic rhinitis is classically treated through a three tiered approach:
1. avoidance/environmental control
2. pharmacotherapy
3. immunotherapy
Seasonal allergens can often be deduced by the timing of symptoms; this allows the
treating physician to discuss what actions, and when, the patient needs to employ to
minimize their pollen exposure. Minimizing outdoor activities during the height of a
pollen season may be wise. Following the pollen counts published in print, television,
and the internet is often useful to guide activities. Advising removing clothes, showering,
and lavaging the nose with saline after prolonged outdoor exposure during an active
season is often helpful. Keeping windows closed and using air conditioning can
minimize pollen entry into buildings.
Avoidance measures for perennial allergens are also possible. The dust mite burden can
be reduced by minimizing dust mite reservoirs (e.g., carpeting, wrapping the mattress)
and maintaining an environment less conducive to mite growth (e.g., cool, dry air). Cat
and dog dander, and cockroach antigen, will fade with removal of the agent. Short of
13
removal, keeping the bedroom free from pets is useful. Allergy testing is often helpful
for counseling a patient as to what they need to avoid. If they appear to have perennial
allergies it may be very helpful to differentiate a sensitivity to dog from a sensitivity to
dust.
Pharmacotherapy is a “shotgun” treatment method for allergy – no matter what the
patient is allergic to, these medications should provide some benefit. Hence, allergy
testing is not an essential feature for prescribing medications for allergic rhinitis.
Steroids reduce inflammation by decreasing inflammatory cell infiltration, especially that
of mast cells and eosinophils. They also diminish the hyperreactivity and vascular
permeability of the nasal mucosa and may reduce the release of mediators from mast
cells.(A29) Steroids may be given orally, parenterally, topically, intramuscularly, and
intra-turbinal. For the nose, topical intranasal steroids are often preferred because they
enhance the therapeutic value while minimizing systemic effects. Intranasal steroid
sprays are effective in alleviating nasal congestion, rhinorrhea, and itching. The various
sprays on the market seem to vary more in issues such as smell, presence of alcohol, and
delivery method rather than efficacy.
H1 antihistamines have been one of the basic treatment options for allergic rhinitis. Their
primary activity is dose-related competitive binding of the H1 receptors on target cells.
They are divided into the classic or first-generation and the second-generation
antihistamines. They primarily treat the itching, sneezing, and rhinorrhea symptoms of
allergic rhinitis. First generation antihistamines are available OTC; they are often
14
slighted for their sedative side effect. The second generation antihistamine loratadine is
also available OTC and it is non-sedating. Other second generation antihistamines are
less or non-sedating, but may be more expensive that their older counterparts.
Leukotriene inhibitors have demonstrated efficacy in treating allergy symptoms after
originally finding a niche treating asthma. These medications also may have efficacy
against rhinosinusitis, supporting the assertion that allergic rhinitis and rhinosinusitis
have similar processes.
Decongestants are available for both topical and oral treatment. The former can cause
rhinitis medicamentosa, or rebound rhinitis, if used for a prolonged period. Oral
decongestants can also cause problems by elevating blood pressure, disturbing sleep,
urinary difficulty, etc.
Other medications exist in the allergy armamentarium. Mast cell stabilizers prevent the
dissolution of the mast cell wall and prevent degranulation. The mechanism is one of
inhibition of calcium-dependent degranulation with accumulation of cyclic AMP. With
this action, these agents reduce nasal itching, sneezing, rhinorrhea, and nasal obstruction
in allergic rhinitis. Mast cell stabilizers are used topically with minimal side effects;
however, the duration of the effect is quite short and thus they must be given several
times a day. (A30)
15
Anticholinergics will decrease nasal rhinorrhea. Anticholinergics decrease the amount of
nasal secretions, but they have no effect on nasal obstruction. Anticholinergics, such as
ipratropium bromide and oxitropium bromide, inhibit muscarinic cholinergic receptors.
They have no known current role in the treatment of vascular congestion/decongestion of
the nose.(A31)
Anti-IgE therapy has proven efficacy in treating both seasonal and perennial allergic
rhinitis.(A32)
Immunotherapy is considered by many allergists to be the most powerful tool to treat
allergy. Immunotherapy or “desensitization” is not a necessity for all allergic patients. It
is usually considered if there is insufficient control with the use of pharmacotherapy and
avoidance for patients with moderate to severe symptoms. The exact mechanism(s) of
immunotherapy is unknown, but includes the development of IgG blocking antibody, and
the alteration of T-cell interactions.(A33) Patients are given extracts containing the
allergens that they are sensitive to; over time they lose their sensitivity to these exact
items. Immunotherapy can be given orally or sublingually, although it is most often
delivered by subcutaneous injection in the United States. The benefits of immunotherapy
can last long after discontinuing therapy.
CRS treatment
Treatment for CRS revolves around identifying and treating any underlying causes and
attempting to break the inflammatory cycle as depicted earlier. Infectious contribution
16
must be considered. Conservative measures to treat CRS include nasal saline lavage,
decongestants, and mucolytic agents. Multiple prescription agents to combat CRS are
available as well.
Broad-spectrum antibiotics are useful in CRS and if they do not cure the disease state,
they tend to provide at least a temporary reprieve from symptoms. Antibiotics should be
used for 3 or more weeks. Culture-directed therapy may be more effective than empiric
treatment. Antibiotics can be delivered orally, intravenously, or topically; the later is
controversial as to whether the agent actually reaches the target tissue.
Steroids are potent agents to diminish inflammation, regardless of the type of
inflammation. Steroids can reduce polyp tissue as well as shrinking inflamed tissue back
to a normal appearance. Topical, injection, and oral steroids all serve roles in managing
chronic rhinosinusitis. The relative banality of topical steroids leads a physician to
prescribe these medications to most patients with chronic rhinosinusitis. Oral steroids,
and even local steroid injection, are used by physicians to shrink polyp tissue.
Leukotriene inhibitors also work to modify the inflammatory response, and may play a
role in treating chronic rhinosinusitis. Macrolide antibiotics appear to also have antiinflammatory effects and, while not convincingly inhibiting the typical pathogens
involved in CRS, they may be a useful adjunctive therapy when used for longer than 4
weeks.(A34) Macrolides may also inhibit biofilm formation.(A24) Aspirin
17
desensitization can help to limit the recurrence of polyposis in Samters triad
patients.(A35)
Conjoint Treatment of Allergic Rhinitis and Chronic Rhinosinusitis
Considering allergic rhinitis in all rhinosinusitis patients, and treating allergies
accordingly, is an important way to combat rhinosinusitis. Atopic disease is considered a
strong cofactor in rhinosinusitis, so its contribution to the disease process cannot be
overstated; treatment of atopic disease may help to resolve rhinosinusitis symptoms.
Several studies have suggested allergic patients with rhinosinusitis may benefit from
immunotherapy.(20,21) Improvement in MCC from immunotherapy may be a factor in
this therapy’s effectiveness.(A36)
18
Appendix II: Supplementary Results
Table AI. Allergy prevalences among CRS cases tested by RAST or IDT.
Allergy
Percentage Prevalence (SE)
59.9 (3.2)
Any
40.5 (3.2)
Seasonal
27.2 (2.9)
Trees
Cottonwood
12.9 (2.2)
White Birch
12.9 (2.2)
White Ash
11.6 (2.1)
American Elm
11.2 (2.1)
Sycamore
10.8 (2.0)
White Mulberry
8.6 (1.8)
30.6 (3.0)
Grasses
Brome or Bermuda
27.2 (2.9)
Redtop
11.2 (2.1)
31.9 (3.1)
Weeds
Lamb’s Quarters
17.2 (2.5)
English Plantain
16.4 (2.4)
Sheep’s Sorrell
11.2 (2.1)
56.9 (3.3)
Perennial
38.4 (3.2)
Dust mites
Dermatophagoides farinae
35.8 (3.1)
Dermatophagoides pteronnysius
33.6 (3.1)
39.2 (3.2)
Epidermals
Cat
29.7 (3.0)
Dog
22.0 (2.7)
Cockroach
22.0 (2.7)
29.3 (3.0)
Molds
Candida
19.8 (2.6)
Alternaria
15.5 (2.4)
Aspergillus fumigatus
11.6 (2.1)
Helminthosporium
10.3 (2.0)
Hormodendrum
9.5 (1.9)
Phoma
9.5 (1.9)
Pullularia
8.2 (1.8)
Penicillium
7.3 (1.7)
Curvularia
6.0 (1.6)
Trichoderma
3.9 (1.3)
Trichophyton
2.6 (1.0)
Rhizopus
2.2 (1.0)
Epidermophyton
1.7 (0.9)
Fusarium
1.7 (0.9)
19
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