Similar to other airway irritants, tobacco smoke causes inflammation and increased mucus production. Patients that are chronic smokers have been found to have markedly increased mucociliary transport times. Increased clearance time leads to mucostasis, which allows for increased inflammation in the nasal cavity and paranasal sinuses [26]. Heavy smokers (i.e., those who smoke more than 5 packs per week) are believed to have even greater mucociliary clearance times than less avid smokers [27]. In addition to the changes in mucus viscosity and volume, ciliary beat frequency significantly decreases in these patients [28]. These findings have led to the identification of tobacco smoke and second-hand smoke as independent risk factors for CRS [29].

Several alterations in the immune response have been implicated in the development of sinonasal polyposis. While sinonasal polyposis is estimated to affect approximately 4 % of the general population, its prevalence is 2–4 times greater in patients with asthma [30–32]. Moreover, sinonasal polyposis has been noted to be associated with an increased incidence in patients with aspirin intolerance, conjunctivitis, urticaria, eczema, food and other allergies, and current smokers. These disorders share a common pathophysiologic mechanism, namely, a predominance of a type 2 helper T-cell-mediated (or Th2-mediated) response. Certain studies have demonstrated an upregulation in Th2-mediated immunity, downregulation of Th1-mediated immunity, and reduction (up to 50 %) in toll-like receptor (TLR) 9 gene expression [33]. The decrease of this TLR (which helps recognize bacterial DNA) has been directly correlated with severity of CRSwNP [34]. An upregulation of B-cell activating factor of the TNF family (BAFF) has been recognized in CRSwNP. It is this upregulation that is believed to upregulate B-cell production of IgA which may also contribute to the eosinophilia of nasal polyps [34]. Ongoing basic and translational research will continue to elucidate our understanding of nasal polyposis.

Asthma is caused by lower airway inflammation, immune dysregulation, and airway wall remodeling. The pathophysiologic changes in asthma mirror those of CRS and allergic rhinitis. The high degree of coexistence and shared causative mechanisms has led to the postulation of the concept termed the unified airway (and, consequently, unified airway disease). In unified airway disease, the Th2-mediated immune response produces local hypereosinophilia and elevated levels of immunoglobulin E (IgE), as well as elevated Th2-type cytokines, including TGF-ß [35]. This eosinophil-dominated response leads to airway remodeling. TGF-ß1 activation and regulation has been found to play important physiologic role in CRS and differ in its subtypes [35, 36]. Although exact mechanisms are still under investigation, the difference in activity of plasminogen activator inhibitor 1 (PAI-1) and fibrinolytic pathways may help differentiate either CRSwNP or CRSsNP [37].

The clinical triad of nasal polyposis, asthma, and aspirin intolerance was first described by Samter and Beers in 1968 [38]. Aspirin hypersensitivity is believed to be related to the inhibition of cyclooxygenase enzyme and increases in lipoxygenase, leading to an elevation of leukotriene synthesis. The leukotrienes then induce increased nasal mucosal edema, mucus secretion, bronchoconstriction, and eosinophilic migration [39]. Symptomatically, these patients have more severe clinical presentation of CRS and asthma [40]. They are at high risk for treatment failure and recurrence of polyps following endoscopic sinus surgery (ESS) and often require multiple subsequent procedures. While only 4.6 % of patients undergoing ESS have ASA triad, Kim and Kountakis noted that these patients had undergone ten times as many surgeries as the non-ASA triad counterparts [40].

Bacterial biofilms have been theorized to play a role in both CRSwNP and CRSsNP. A biofilm is an organized aggregation of bacteria that adheres to mucosal surfaces and expresses a molecular profile unique from that expressed by the individual planktonic bacteria. Biofilm is associated with an extracellular matrix material that facilitates genetic alterations, increases resistance to antibiotics, and enhances capabilities to resist host immunity [13, 43]. One mechanism attributed to biofilms is quorum sensing [44, 45]. This encompasses the responsiveness of these bacterial aggregates to produce hormone-like molecules that are controlled by water channels found in the biofilm and function in an autocrine fashion [44]. Patients with biofilm formation exhibit a clinical course characterized by chronic infections with periods of marked worsening of symptoms [46].

Multiple studies have noted mucosal biofilms in the majority of samples among the CRS patient population [43, 47–49]. Further supporting the role of biofilms in the development of CRS is the fact that numerous analyses have noted a relative absence of biofilms in healthy controls not affected by sinus disease [43, 50–52].

Singhal et al. evaluated the role of biofilms in patients undergoing ESS for CRS [50]. Consistent with prior reports, 71 % of their 51 CRS patients had bacterial biofilms. Following surgery, this cohort of patients had significantly worse sinus symptoms and nasal endoscopy findings than individuals without biofilms, supporting the concept that biofilms may be an important contributor to treatment-resistant CRS [34, 53].

The relationship between S. aureus and biofilms has been studied in the context of CRS, as certain strains of S. aureus have a propensity for biofilm formation through increased expression of immunosuppressive proteins (relative to non-biofilm-forming S. aureus strains) [54, 55]. However, it should be noted that even in the biofilm state, S. aureus can differentiate into free-living bacteria that are thought to be responsible for acute exacerbations [44].

Recent studies also illustrate that S. aureus may survive intracellularly within nasal epithelial cells, mucus-producing cells, and antigen-presenting cells [56, 57]. One theory of CRS pathogenesis posits that intracellular S. aureus releases toxins that activate lymphocytes and thus drives inflammation [58].

It has been postulated that S. aureus exotoxins may function as superantigens. A superantigen is a substance that can activate T cells nonspecifically, resulting in polyclonal (rather than monoclonal) activation of T cells, as well as eosinophilic activation, leading to a vigorous immune response. Activation of immune cells in this manner within the sinonasal tract stimulates the release of IL-4, IL-5, and IL-13, which skew the response toward a Th2 phenotype seen in CRSwNP. This is consistent with the fact that S. aureus may be found in greater numbers in CRSwNP than CRSsNP. Krysko et al. noted that phagocytosis of S. aureus by antigen-presenting cells, specifically macrophages, may be impaired in CRSwNP, promoting chronic inflammation [59]. Definitive evidence for the superantigen hypothesis is still lacking as approximately 50 % of patients will express superantigen-specific IgE and approximately one third will demonstrate superantigen-specific T-cell changes [34].

The role of inflammation of the bone (i.e., osteitis) in the development of CRS has been extensively studied. Proponents of osteitis as a pathogenic factor in CRS cite computed tomography (CT) findings of bony thickening with neo-osteogenesis in refractory disease as potential evidence [60]. Histologic sections demonstrate thickened bone with neo-osteogenesis, further perpetuating mucosal fibrosis. It is important to differentiate osteitis from osteomyelitis, as the latter signifies infection of bone marrow, while the former specifically refers to inflammation of the bone. As sinuses are devoid of marrow, osteitis is the correct nomenclature [61]. Kennedy et al. analyzed ethmoid bone samples which were found to histologically resemble lesions seen in patients suffering from osteomyelitis; further, debridement of this inflamed bone led to resolution of overlying mucosal inflammation [62]. Animal models support this hypothesis and suggest that inflammation in the bone disseminates through the Haversian canal system [60, 63]. Turning to more clinical evaluations of the role of the bone in CRS, greater disease burden has been demonstrated on the CT scans of those with neo-osteogenesis compared to controls [60, 64, 65], as well as worse endoscopically documented disease severity and increased rates of dysosmia [60, 66].

Primary ciliary dyskinesia (PCD), also referred to as immotile cilia syndrome, is a primarily autosomal recessive genetic condition which affects the structure or function of cilia, thereby resulting in impaired mucociliary clearance. Patients with PCD are usually afflicted by chronic, recurrent lower respiratory tract infections. Early descriptions of PCD identified a clinical picture of sinusitis, bronchiectasis, and situs inversus that eventually came to be known as the Kartagener triad [67]. In a report of 78 subjects diagnosed with PCD, Noone et al. identified a 100 % frequency of chronic rhinitis/sinusitis. These patients were also noted to have very low levels of nasal nitric oxide production relative to normal subjects [68]. The mechanism for this alteration in nitric oxide is unknown, but proposed theories include altered ciliary activity, altered expression of nitric oxide synthase, or another aspect of chronic sinonasal inflammation itself [69].

Cystic fibrosis (CF) is an autosomal recessive genetic disorder which disrupts the transport of chloride ions across cell membranes (via the CF transmembrane conductance regulator, or CFTR), leading to an abnormally low level of water in mucous secretions. Mucous secretions become abnormally viscous, and, as a consequence, mucociliary transport is severely altered [70]. Patients with classic CF have an incidence of CRS that approaches 100 %. In these patients, the incidence of sinonasal polyposis can be as high as 48 % [71]. CF is often associated with decreased pneumatization or frank hypoplasia of the paranasal sinuses, as well as mucocele formation. Active CRS may also impact the frequency of serious lower respiratory tract infections. Traditionally, patients have been treated with a combination of systemic antibiotics, corticosteroids, and ESS. However, the precise roles of these treatment modalities remain the subject of controversy. Several novel therapeutic agents aimed at rescuing CFTR function at the molecular level are currently in clinical trials.

Granulomatosis with polyangiitis (GPA) is an autoimmune disorder characterized by a necrotizing vasculitis of small- to medium-sized vessels. Sinonasal complaints are quite common. In a retrospective analysis of 120 patients with GPA referred for otolaryngologic evaluation, Cannady et al. found that 89 % of patients exhibited sinonasal involvement, including nasal crusting (69 %), CRS (61 %), nasal obstruction (58 %), bloody rhinorrhea (52 %), and septal perforation (33 %) [72]. The inflammatory reaction characteristic of this disease typically arises from the nasal septum and inferior turbinates and then spreads bilaterally to the rest of the nasal cavity and sinuses. If left untreated, this disease can lead to erosion of the sinonasal architecture, leading to a common cavity [73, 74]. The mainstay of therapy for GPA is to induce and then maintain remission using immunosuppressive agents. Many of the regimens include methotrexate, cyclophosphamide, azathioprine, corticosteroids, TNF-alpha blockers (including infliximab), and rituximab [75].

Sarcoidosis is an idiopathic disorder that can affect multiple organ systems. It exhibits a broad range of severity, ranging from an essentially asymptomatic radiographic abnormality to a life-threatening condition. Unlike GPA, the granulomatosis seen in sarcoidosis is non-necrotizing. The precise incidence of CRS in sarcoidosis is unclear. However, it is thought to be low, on the order of <1 % [76]. A retrospective analysis of 36 patients with sarcoid rhinosinusitis identified nasal obstruction as the most frequent symptom (86 %), followed by nasal crusting (47 %), anosmia (44 %), epistaxis (28 %), and nasal polyposis (25 %) [77].

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare disorder characterized by a necrotizing, eosinophilic vasculitis of small- to medium-sized vessels. “Paranasal sinusitis” is among the six diagnostic criteria established by the American College of Rheumatology in 1990; approximately 61 % of patients exhibit this complaint at the time of diagnosis [78

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