Staphylococcus aureus is well recognized for its production of superantigens,

synthesizing more than a dozen exotoxins associated with superantigen effects.

Investigators have shown that patients with an elevated specific IgE to staph-
ylococcal enterotoxins A and B had a higher incidence of asthma (12). Other
investigators have expanded on these findings by identifying antibodies to other
bacterial superantigens in CRS patients and by demonstrating altered steroid
sensitivity in the presence of these superantigens (13,14).
Odontogenic infections are important to note as a potential etiology of CRS due
to potential differences in microbial flora. The most common isolates in these cases
are anaerobic streptococci, gram-negative bacilli, and enterobacteriaceae (15).
A biofilm is an organized community of bacteria adherent to an inert or living
surface, embedded in a self-produced extracellular polymeric matrix. Biofilms
appear to be the preferred form of bacterial existence, with only approximately 1%
of bacteria existing in the free-floating planktonic form (16). The Center for Disease
Control (CDC) estimates that around 65% of all human infections are caused or
persist due to biofilms. Within the field of otolaryngology, biofilms have been
implicated in varied diseases, including otitis media, chronic tonsillitis, adenoiditis,
and device infections (such as in cochlear implants, tympanostomy tubes, and
tracheostomy tubes) (17).
The extracellular matrix which constitutes biofilms is thought to protect against
multiple defense systems such as antibodies, immune-system phagocytosis, and
complement binding, making it up to 1,000 times more resistant to treatment when
compared with the planktonic form (18). In addition, biofilms facilitate
intermicrobial communication and exchange. Through quorum sensing, bacterial
populations can redistribute densities to optimize utilization of nutrient resources.
Biofilms also enable the interbacterial transfer of genetic information via plasmids
to promote variability and adaptive mutations, such as antibiotic resistance. These
factors, in addition to intrinsic nutrient gradients that are integral to the biofilm
matrix, minimize the impact of environmental stressors and promote bacterial
viability that can contribute to the persistence of infection in spite of prolonged
therapy with antibiotics (19). Multiple studies have now shown the presence of both
bacterial and fungal biofilms in patients with CRS, although the exact contribution
of the biofilm to the pathogenesis of CRS remains to be clarified (20-22).
The pathogenicity of fungus in the paranasal sinuses has been well documented
in cases of fungal ball, invasive fungal sinusitis, and allergic fungal sinusitis.
However, the extent to which fungus may play a role in CRS at large remains a
point of much debate (23).
In much the same way that bacteria can be found in the sinuses of both patients
with CRS and healthy controls, fungus has also been found to be widely prevalent in
the nose and sinuses of both CRS and normal populations (24). Thus the mere
detection of fungus in the nose or sinuses of a patient with CRS does not indicate
the pathogenicity of the fungus. The host response to fungus appears to be the
differentiating factor between states of sinonasal disease and health. Shin et al.
showed that by exposing peripheral blood mononuclear cells to fungal antigens in
vitro, 89% of CRS patients showed increase in IL-5 and IL-13, but there was no such
increase in controls. Interestingly, these results correlated with fungal-specific IgG,
not IgE, implicating a nonallergic mechanism (25). However, Orlandi et al. found
contradicting results when replicating the Shin study using CRS patients and
controls from multiple geographic regions. Orlandi et al. (26) demonstrated
elevated IL-5 and IL-13 production in both CRS patients as well as controls, and the
IL-5 levels correlated to IgE response instead of IgG, directly contradicting the find-
ings of the Shin study. It appears that more data is needed to make any conclusions
about the extent of the association between fungus and CRS (27).

Environmental Factors
Smoking and exposure to secondhand smoke have been identified as morbid
cofactors in CRS. Senior et al. found that the most significant risk factor for
requiring revision sinus surgery was continued smoking. This was especially tme for
patients with more advanced disease. Briggs et al. (28) also demonstrated that
persistent smoking is significantly associated with worse symptom outcomes after
endoscopic sinus surgery. Cohen et al. (29) recently demonstrated decreased ciliary
beat frequency as well as impaired transepithelial chloride secretion in both murine
septal and human sinonasal epithelial cell (SNEC) cultures when exposed to
cigarette smoke condensate. Two case-control studies have now documented a
significant independent association between secondhand smoke and CRS (30,31).
 Other environmental pollutants can also have adverse effects on the upper
respiratory tract predisposing to CRS. Longitudinal studies of clean-up workers at
the World Trade Center disaster site show a clear correlation between
environmental pollution exposure and disease in the upper respiratory tract,
especially in patients with preexisting atopy (32).
Although there does appear to be a subset of patients with ABRS who have
classic IgE-mediated allergic triggers, the association between allergy and CRS, in
spite of the strong eosinophilic induction in both processes, is much less defined
(33). While allergic rhinitis is a common comorbidity with CRS, the presence of
allergy has not consistently been shown to affect the extent of radiographic
disease, symptom severity, or the need for surgery (34).

Structural Factors
Structural and anatomic factors were traditionally the main etiologic focus during
the early years of endoscopic sinus surgery. Although multiple structural anomalies
have been identified and associated with rhinosinusitis, we now know that the
anatomic basis of the disease is only one of the categories of inciting factors, and
these must be examined in light of other factors as described in this chapter. The
term ostiomeatal complex (OMC) has been widely described and incorporated into
our literature. It should be stressed that the OMC is a functional unit rather than an
anatomic structure. It refers to the physiologic arrangement of structures into which
the frontal, maxillary, and anterior ethmoid sinuses drain. Anatomically, this
corresponds to the area of the ethmoid infundibulum, the middle meatus and its
surrounding structures. Classic teaching suggested a pivotal role for the OMC in the
establishment of CRS, and a recent study sought to test that hypothesis. Chandra
et al. performed a retrospective review in which they found that more than 35% of
patients meeting the definition of CRS did not manifest OMC obstruction
radiologically. When present, however, OMC obstruction was associated with
increased disease burden (35).
Patency of the pathways through which the sinuses drain is crucial for adequate
mucociliary function and subsequent sinus drainage. The nasal and sinus mucosa
produces approximately 1 L of mucus per day, which is cleared by mucociliary
transport. Ostial obstruction may lead to fluid accumulation and stagnation, creat-
ing a moist, hypoxemic environment ideal for growth of pathogens.
Sinus obstruction may be caused by multiple anatomic variants, including septal
deviation, concha bullosa, paradoxical middle turbinates, and infraorbital (Haller)
cells (Fig. 35.3). Scarring from previous surgery or trauma can also anatomically
impair sinus drainage. Craniofacial anomalies in which the anatomy of the sinuses
is altered may predispose patients to rhinosinusitis. In children, foreign bodies
should always be considered as another possible obstructive cause of sinusitis.
The underlying bone within the sinuses may itself also contribute to persistent
inflammation or infection. Kennedy et al. demonstrated histologic changes in the
ethmoid bone of CRS patients consistent with bony inflammation.
Histomorphometry showed increased numbers of inflammatory cells and
significantly increased bone turnover, comparable to the rate seen in osteomyelitis.
Subsequently, Khalid et al. (36) found evidence of chronic osteomyelitis in the
contralateral maxillary sinus of 52% of rabbits that had undergone induced
unilateral maxillary rhinosinusitis. With these findings, the authors suggested that
inflammation and possibly infectious agents may spread to distant sites through the
bony Haversian system. Additional research is needed to determine whether these
observed bony changes represent a primary causative phenomenon or a secondary
reaction to the overlying inflammatory milieu.

Genetic Factors
The increased prevalence of CRS in patients with certain inherited disorders such as
cystic fibrosis (CF) has led to the investigation of possible genetic mutations
predisposing to CRS. A landmark study in 2000 showed that mutations in CF genes,
in non-CF patients, were significantly more common in CRS patients than in controls
(37). In confirmation, a recent genome-wide screen for CRS susceptibility identified
a locus on 7q31.1-7q32.1, with the largest linkage signal near the CFTR gene (38).
Polymorphisms in the TNF-a, MMP-9, IL-13, IL-33, and ILIA genes have been
associated with increased susceptibility to CRS. Furthermore, alterations in the
6p22, 22ql3, and lq23 chromosomal regions have been demonstrated in both CRS
and aspirin-sensitive asthma phenotypes, reinforcing concepts of a unified airway
pathophysiology (39).

Physiologic Factors
Mucociliary dysfunction has often been dted as a precursor to CRS. Inherited
disorders such as CF are associated with abnormal mucociliary clearance from the
sinuses. The increased viscosity of nasal secretions in CF patients impedes
adequate clearance and leads to ciliary injury, local mucosal edema, and further
inflammation. Ciliary dysfunction is the hallmark of a group of disorders known as
Primary Ciliary Dyskinesia. Morphologic ciliary defects, such as absent ATPase-
containing dynein arms, result in ciliary dysmotility that predisposes patients to
both acute and chronic rhinosinusitis. Kartagener syndrome, the most common
form of Primary Ciliary Dyskinesia, is associated with a triad of chronic sinusitis,
bronchiectasis, and situs inversus. The former term "immotile cilia syndrome" is no
longer used in recognition of the fact that true ciliary immo- tility is far less
common than motile but dyskinetic cilia.
Cytokines and other inflammatory mediators, along with respiratory pathogens
and particulates released in patients with CRS, have been shown to impact ciliary
function and propagate a cyclic loop of inflammation and ciliary dysfunction
(40,41).
Acid reflux disease has long been noted by physicians in patients with CRS, but
until recently, good data to support a correlation, let alone a causative association,
have been lacking. DelGaudio et al. performed a prospective study looking at
postsurgical patients with persistent CRS, looking for a possible role for
nasopharyngeal reflux. The patients with persistent CRS had more reflux at the
nasopharynx, the upper esophageal sphincter, and at the distal esophagus than
controls, with the greatest difference at the nasopharynx (42). Wong et al. actively
instilled acid into the esophagus of healthy volunteers, looking for a possible reflex
arc to the nose. An increase in nasal mucus production occurred with instillation of
both saline and hydrochloric acid into the esophagus. Although there was no dear
difference between the test groups, the authors still conduded this may have
demonstrated a reflex arc via the vagus nerve (43). A provocative study recently
published in the gastroenterology literature was a placebo-controlled, double-blind
trial in which 75 participants with symptoms of chronic postnasal drainage were
randomized to treatment with 30 mg of lansoprazole twice daily or placebo (44).
Patients did not have sinusitis or allergy, and they underwent ambulatory
esophageal pH monitoring. After 16 weeks, the lansoprazole-treated group was 3.5
times more likely to have symptomatic improvement versus placebo, with absolute
symptom improvements of 50% in the lansoprazole group versus 5% in the placebo
group. Notably, the presence of heartburn symptoms or abnormal esophageal pH
was not predidive of symptom improvement. While this study exduded patients
with CRS, the demonstration of a therapeutic effed of proton pump inhibitors on the
function of the nasal mucosa opens the door for further investigation.
CRS is a common finding in granulomatous disorders such as sarcoidosis and
Wegener granulomatosis, but these are discussed elsewhere in this textbook so will
not be expounded upon in this chapter. Briefly, in Wegener granulomatosis, nasal
symptoms can be a presenting manifestation and often one of the most common
complaints. Autoimmune disorders such as systemic lupus erythematosus, Sjogren
syndrome, and relapsing polychondritis can also present with signs and symptoms
of rhinosinusitis.
Immune deficiencies, whether inherited or acquired, can also contribute to
sinusitis. In a retrospective review, Chee et al. (45) demonstrated immune
deficiencies, which induded low immunoglobulin levels and deficient T-cdl function,
in up to half of their patients with medically refractory sinusitis. Although IgG
subdass deficiency is the most common deficiency identified, multiple entities
induding seledive IgA deficiency, common variable immunodeficiency, and X-linked
agammaglobulinemia can present with ABRS or CRS. In human immunodeficiency
vims (HIV)-infected individuals, rhinosinusitis is one of the most common infections
and can be more severe and treatment-resistant than in HIV-negative individuals.
Hyperimmune states such as is seen in Churg-Strauss and lob syndromes can also
predispose to rhinosinusitis. Even though most patients with rhinosinusitis are not
immu- nodeficient, a history of persistent or recurrent infections despite adequate
antimicrobial therapy should raise the suspicion of immune deficiency as a
contributing fador.
Abnormalities in innate immunity are being increasingly wdl charaderized and
appreciated for their potential causative role in CRS. Early on in this past decade,
CRS was thought to be mediated primarily by the adaptive immune system, with
Thl cells mediating neutrophilic nonpolypoid subtypes of CRS and Th2 cells driving
the eosinophilic inflammatory response typified by polyposis. Recently, the
interaction between innate immune functions within the SNEC and the adaptive
immune system has come to light. The innate system recognizes certain pathogen-
associated molecular patterns via transmembrane glycoproteins known as Toll-like
receptors, which in turn switch on a signaling cascade, activating Thl, Th2 or type I
interferon profile (46). Multiple antimicrobial peptides, such as lacto- ferrin,
lysozyme, cathelecidins, defensins, SP-A and SP-D, and secretory leukocyte
proteinase inhibitor are produced by the SNEC and are a major part of the innate
immune system. Mucociliary dearance also plays a key role within the innate
immune system, being the first defense against all inhaled partides (47).

TREATMENT

Antimicrobial Therapy
The 2007 guidelines actually offered no specific treatment recommendations for
CRS, instead focusing on minimizing symptoms with preventive strategies such as
normal saline irrigation, good hand-washing habits, and treatment of underlying
exacerbating factors. They also recommended evaluating refractory patients with
CRS for contributory factors or disease states such as CF, ciliary dyskinesia, or
anatomic variations (48). In keeping with the multifactorial pathophysiology of CRS,
the treatment options are equally varied; as in ABRS, the relative lack of published
trials comparing treatments in CRS is a barrier to providing truly validated
evidence-based care. As discussed above, the role for a microbial effect on
inflammation is more likely mediated through superantigens and biofilm formation
rather than solely a planktonic infection. Nevertheless, oral antibiotics are the most
commonly prescribed agents for CRS. Because of increased prevalence of
Staphylococcus species, gram-negative bacilli, and anaerobes in CRS (especially
after sinus surgery), broader spectrum antibiotics may be necessary if given
empirically (68). Antibiotic selection should be guided by appropriately obtained
cultures whenever possible, especially in postoperative patients and those who
have failed an initial trial of first-line antimicrobials. Culture-directed therapy may
reduce drift toward highly resistant organisms over time, and sinus cultures have
been shown to direct a change in therapy in 51.4% patients with CRS (69,70).
Parenteral antibiotics have a limited role in the treatment of CRS and are not
indicated for routine treatment. Intravenous antibiotics may be indicated in unusual
cases of severe or complicated infections, highly resistant organisms, or patient
intolerance of other therapies.
The optimal duration of antibiotic therapy for CRS has not been clearly
established. Most authors recommend a prolonged course of 4 to 6 weeks of
antibiotics; however, the only randomized controlled clinical trial looking at
antibiotic therapy in CRS compared macrolide treatment (roxithromycin) to placebo
for 3 months (71). The authors found statistically significant improvements in SNOT-
20 score, nasal endoscopy, saccharine transit time, and IL-8 levels in lavage fluid in
the macrolide group. This study was published in 2006, and by the time a Cochrane
review was performed in 2011, it was still the only randomized clinical trial
evaluating an antibiotic versus placebo in the literature (72).
Interestingly, it is not the antibiotic effect of macrolides that led to this study, but
rather the anti-inflammatory effects of macrolides. Studies have shown that 14- and
15-membered ring macrolides inhibit multiple aspects of neutrophilic inflammation.
Not only do they interfere with neutrophil migration and adherence to sites of
inflammation, but they also reduce the neutrophil oxidative burst and increase the
rate of programmed cell death. They also inhibit IL-lb, IL-8, nuclear factor kB,
transforming growth factor B, and granulocyte-macrophage colony stimulating
factor, all inflammatory cytokines (73). Multiple studies have demonstrated that
macrolides may also inhibit formation of Pseudomonal biofilms, reduce the
thickness of airway mucus secretions, and even have a reparative effect on
inflamed upper and lower airway mucosa (74).
Most other published data on antimicrobials in the setting of CRS surrounds their
use in topical application (Table 35.5). As discussed above, biofilms are thought to
be an important causative factor in CRS, and high concentrations of antibiotic are
known to be necessary for eradication. The appeal of topical antibiotic therapy is
the ability to achieve high concentrations at the level of the sinonasal mucosa with
minimal systemic absorption and adverse side effects. Ha et al. (75) evaluated
topical mupirocin, ciprofloxacin, and vancomycin for the treatment of S. aureus bio-
films in vitro, and determined that mupirocin was the only suitable choice for
intranasal delivery because of its efficacy and lack of potential side effects.
Ciprofloxacin was ineffective even at high concentrations, and vancomycin was only
effective at concentrations so high that any absorption would lead to serum levels
in the toxic range. Chiu et al. (76) found disappointing results when trying to apply
topical tobramycin to eradicate Pseudomonas biofilms in the sinuses of rabbits,
eradicating only planktonic bacteria with increasing concentrations, but not the
biofilms themselves.
Topical therapies are less likely to be beneficial in treating unoperated sinuses,
and the efficacy of distribution (nebulizer vs. irrigation) should be considered when
assessing antimicrobial efficacy (77). Although early non- randomized and
uncontrolled clinical studies examining nebulized antibiotic therapy suggested it
was safe and effective, the only study with a placebo comparison group showed no
difference in outcomes between nebulized tobramycin versus nebulized saline
alone (78-80). Studies of medicated irrigations have shown greater promise, per-
haps related to better efficacy of large volume rinses in reaching the sinuses. Uren
et al. (81) studied twice-daily irrigations of mupirocin at 500 /ig/mL in sixteen
patients with surgically recalcitrant CRS and endoscopic cultures positive for S.
aureus. Fifteen of the sixteen patients had improved endoscopic findings, 12 of 16
noted improvement in overall symptoms, and 15 of 16 had negative posttreatment
cultures for S. aureus. Although the current level of evidence is low for the use of
topical antimicrobial therapy, promising results from pilot studies will hopefully be
validated by larger scale controlled clinical trials.
Research interest in potential fungal etiologies of CRS has led to multiple studies
examining topical antifungal therapy as a possible treatment option for CRS.
Ponikau et al. (82) first published a prospective open-label trial using topical
amphotericin B twice a day for 3 months and found it to be safe and effective.
Criticisms of this study included lack of placebo control and randomization. This
study was then followed by prospective randomized placebo- controlled studies
using topical amphotericin B which failed to show any benefit, although notably
these studies used nasal spray as the delivery method in lieu of irrigation (83,84).
Ponikau et al. published a follow up randomized, blinded placebo-controlled study of
amphotericin nasal lavage. Although the authors claimed beneficial effects of
amphotericin B, there was no significant difference in quality of life improvement
between the treatment and control groups, and the study suffered from small
sample size. Improvement in the endoscopic exam and a slight radiologic
improvement were observed in the treatment group versus control (85). Finally, a
definitive multicenter, placebo-controlled, double-blinded study was conducted,
using multiple subjective and objective outcome measures, and no difference was
demonstrated between the treatment and control arms (86). Recently this same
group published a follow up "part two" to the multicenter trial, again examining
topical amphotericin B compared with placebo; there was no significant effect on
the levels of multiple pro- inflammatory cytokines, chemokines, and growth factors
in CRS nasal lavage samples (87). It appears there is not sufficient evidence at this
time to recommend topical antifungal therapy.
Multiple studies have been performed on adjunctive topical therapies targeting
biofilms. Naturopathic treatments including tea tree oil and manuka honey have
proven effective against biofilms through in vitro testing, but have yet to show their
efficacy in clinical trials (88,89). Surfactants have recently held the most focus in
the literature, with the goal of disruption of the biofilm matrix itself. Although
neither 1% baby shampoo in saline irrigation or citric acid zwitterionic surfactant
(CAZS) have been evaluated in randomized trials, both have shown clinical efficacy
in disruption of biofilms on the paranasal sinus mucosa. Studies evaluating baby
shampoo have shown symptomatic improvement in greater than half the patient
population, but approximately 10% were forced to stop using it due to side effects
(90). CAZS dismpted biofilms but at the same time caused ciliary dysfunction, with
almost 85% of the cilia denuded compared to the saline controls (91).

Anti-Inflammatory Therapy
Topical steroid therapy is generally accepted as part of the treatment regimen for
CRS in the form of nasal spray, with strong evidence supporting its use (92). Topical
steroid irrigation has become a commonplace practice among rhinologists,
particularly in the treatment of CRS with nasal polyposis, but also it can be used in
CRS without polyposis. Uncontrolled case series have been published
demonstrating efficacy in CRS patients refractory to more traditional treatments
(93,94). Although there have not been any randomized trials looking at efficacy,
budesonide irrigation is used frequently enough that studies examining the safety
profile have emerged. Two articles to date have published no significant
suppression of the adrenal axis in patients using budesonide, at 1 month and 2
month endpoints, respectively (95,96).
As with topical antimicrobial therapy, the efficacy of topical steroid therapy is
related to the vehicle of delivery as well as the successful reach of medication to
the target site. Saline irrigation alone has been shown to be beneficial in
management of CRS symptoms, though the magnitude of the symptomatic
improvement was not as large as that observed with topical nasal steroids (97).
High volume irrigation in the head-down position appears to be most effective for
delivery into the paranasal sinuses.
Systemic steroids have proven valuable in a variety of chronic inflammatory
diseases, and their use in CRS is well established, especially in treating CRS
patients with nasal polyposis. Although oral steroids are also commonly used by
otolaryngologists for CRS without polyposis, a recent systematic review has
revealed that the level of published evidence for their use is primarily level 4 and 5
(98). The use of oral steroids may be limited by well known side effects such as
insomnia and weight gain, and may be contraindicated in patients with
osteoporosis, diabetes, glaucoma, or psychiatric illness.
Other immunomodulating agents have been of increasing interest in
management of the inflammatory aspects of CRS. Leukotriene receptor antagonists
such as zafirlukast and montelukast have been anecdotally reported to have
therapeutic effects in patients with nasal polyps who are being treated concurrently
for lower airway disease, but there are no randomized clinical trials supporting its
use in nonpolypoid CRS (99). Zileuton, a 5-lipoxygenase inhibitor, has been shown
to be effective in nasal polyposis associated with aspirin exacerbated respiratory
disease, but no studies have been conducted in nonpolypoid CRS (100).
 That same understanding is what has spurred the study of omalizumab, an anti-
IgE monoclonal antibody, in CRS. This antibody has had success in treating both
asthma and allergic rhinitis (101). Pinto et al. (102) recently published a
randomized, double-blind, placebo-controlled trial of omalizumab for patients with
CRS, and while improvements were seen on the SNOT-20 at 3, 5 and 6 months
compared to controls and reduced inflammation was seen on imaging in these
patients, there were multiple other endpoints which showed no statistical
difference. The authors concluded that IgE may play a small role in CRS, but that
studies with larger enrollment were necessary to determine the clinical significance
of these differences.
A number of other candidate therapeutic agents are being evaluated for their
potential immunomodulatory effects in CRS. Vitamin D is one such agent, and there
appear to be immunomodulatory interactions with the innate and adaptive immune
systems (103). Treatment of CRS with vitamin D analogues remains to be studied.
Statin drugs have also recently shown promise in decreasing inflammation in the
upper and lower airways. Wang et al. recently performed an analysis of sinus
tissues collected from patients with CRS. Suppression of highly expressed
inflammatory mediators CCL5, CCL11, and IL13RA was found in patients who were
on statins, suggesting that statins may induce antiinflammatory effects (104). In
vitro studies of cultured primary human airway epithelial cells exposed to ambient
air pollution confirmed that expression of these mediators was suppressed by
pretreatment with statins. Other compounds being investigated include retinoic
acid, L-ascorbate, resve- ratrol, and bioflavanoids (105-108).
Although medical therapy is always considered first line, endoscopic sinus
surgery is the final treatment pathway for many patients with CRS. There have
been multiple studies showing that endoscopic sinus surgery improves patient
symptoms, quality of life, and nasal endoscopic exam in cases of CRS refractory to
medical therapy (109,110). Surgical indications, perioperative management, and
surgical technique are discussed in another chapter.