Most episodes of sinonasal symptoms are caused by viral infections, which are a precipitator of ARS. A classic history for ARS is a week of nasal congestion and rhinorrhea that improves slightly and then returns with worsening symptoms several days later. This transition from viral rhinosinusitis to bacterial rhinosinusitis is variable and has been estimated to occur in only 0.5–2 % of cases [25]. Common bacterial pathogens associated with ARS have been identified as Streptococcus pneumonia, Haemophilus influenzae, Moraxella catarrhalis, and Staphylococcus aureus [26] (see Fig. 5.1). Most patients with ARS are successfully treated with broad-spectrum antibiotics and nasal care, although Rosenfeld et al. observed spontaneous resolution in 62–69 % of patients [24]. By definition, ARS manifests fewer than 4 weeks of clinical symptoms [9], after which the disease process is classified as subacute rhinosinusitis.

Symptoms that persist beyond 12 weeks despite maximum medical therapy are defined as CRS [20, 24]. Culture data from patients meeting the diagnostic criteria for CRS demonstrate a preponderance of Staphylococcus aureus, gram-negative species, as well as anaerobes [27]. All cases of rhinosinusitis (acute, subacute, and chronic) were initially believed to be infectious in nature, which has led to the prominent use of antibiotics and surgical drainage procedures as therapeutic modalities [2, 3]. However, it is likely that CRS is a chronic mucosal inflammatory process complicated by chronic infection.

The diagnosis of CRS requires careful consideration and integration of the details of the history, nasal endoscopy, and imaging data. The clinical history should elucidate the specific symptoms described by the patient and identify a pattern of symptoms, as well as precipitating or avoidable factors. Additionally, the previous response to medical therapy, coexisting conditions, a detailed environmental history, and home and occupational exposures constitute important pieces of information [9]. The clinical history can also be very powerful. Benninger showed that the history may be more indicative of CRS than nasal endoscopy and recommended giving it more consideration if the diagnosis is unclear or if limited anterior rhinoscopy is all that is available to the treating physician [28].

Nasal endoscopy is an important part of the physical exam and is typically performed with a rigid nasal endoscope. For patients meeting clinical symptom criteria for CRS, nasal endoscopy has been shown to significantly improve diagnostic accuracy [29]. Typical endoscopic findings of CRS are pus or polyps [24]. One study reported that pus was only present in patients with CRS and never present in patients with negative radiographic computed tomography (CT) findings [30]. Rosbe and Jones found that 91 % of patients with positive endoscopic findings of CRS had CT scans consistent with CRS [23]. Dykewicz and Hamilos found nasal endoscopy was sufficient to establish the diagnosis of CRS but not sufficient to establish the extent of the disease unless the patient had undergone a previous sinus surgery [9]. In a study by Stankiewicz and Chow, positive endoscopic findings did not often correlate with positive CT findings, but the absence of endoscopic findings showed 78 % correlation with negative CT findings [31]. Despite some discrepancies, nasal endoscopy is an important part of the clinical exam and gives the practitioner the opportunity to culture or biopsy suspicious findings [32]. It can confirm CRS but by itself cannot rule out a diagnosis of CRS.

The imaging modality of choice for the diagnosis of CRS is a non-contrast CT scan. The most commonly used sinonasal grading metric for the evaluation of sinonasal CT scans with a high degree of interobserver reliability is the Lund–Mackay score [33]. Radiographic evidence of CRS is important to the practitioner because it identifies the diseased sinuses and can help identify other contributing factors. For example, CT scans have been shown to be more accurate in diagnosing dental disease as the cause of maxillary sinusitis than a panorex, and more than 80 % of CT scans with a maxillary sinus fluid level greater than two thirds the height of the sinus with mucosal thickening have been shown to harbor dental pathology [34]. CT scans can also reveal other precipitating processes like benign sinonasal masses. They are not, however, recommended for the diagnosis of ARS unless a patient manifests with extra-sinus involvement [24]. Some discrepancies between the radiographic findings and patients’ reported symptoms have been reported. Specifically, CT scan findings do not always correlate with the severity of nasal symptoms [35, 36], and Zheng et al. found that radiologic severity assessed by the Lund–Mackay score is weakly correlated by CRS severity as measured by patients’ symptoms [37]. Despite these discrepancies, CT findings are still useful in that they are objective [38] and provide an important road map for surgical planning. Still, it is necessary when considering a diagnosis of CRS to consider the composite of patient’s history, nasal endoscopic findings, and radiographic data to make an accurate diagnosis.

The differential diagnosis for CRS is broad. A patient’s age is an important stratifier because some disease processes with similar symptoms are more common in children than adults (i.e., adenoid hypertrophy) [1, 9]. Children are also more likely to have nasal foreign bodies that may mimic CRS [1, 9]. Sinonasal tumors [1] like inverted papilloma, juvenile angiofibroma, antrochoanal polyps [9] and odontogenic sinus disease [34], and nasal carcinoma can present with similar symptoms as CRS. Anatomic abnormalities that predispose to recurrent sinus infections like nasal septal deviation may coexist with CRS and can mimic the symptoms of CRS [9].

Embryologic remnants like Thornwaldt cysts can also present similarly to CRS [1]. Furthermore, there is considerable overlap between sinus headaches and migraine or midfacial pain syndrome that can present with nasal congestion and rhinorrhea [39, 40]. Finally, systemic diseases like granulomatosis with polyangiitis (Wegener’s), sarcoidosis, and Churg–Strauss disease can have prominent sinonasal manifestations. Thus, a comprehensive differential diagnosis with appropriate workup is paramount to accurately diagnose CRS.

The etiology of CRS is the subject of much current research. Because different forms of CRS have different pathophysiology, no single process or pathogen has been identified as the trigger for CRS [4]. Still, some of the immunologic factors involved in CRS are well understood. Histologic findings have furthered the immunologic understanding of disease processes. Other contributing factors like superantigens and nitric oxide have been suggested. More recent data demonstrates that pulmonary physiology in asthma has substantial similarities to sinonasal physiology in CRS [41]. All processes result in inflammatory changes that lead to decreased sinonasal mucociliary clearance and perpetuate the disease process. Instead of a coordinated beating action by millions of cilia that line the surface of the sinus epithelium and move particles toward the natural ostia, swelling and inflammation compromise this process and result in a decreased ciliary beat frequency. This in turn leads to stagnation of sinus secretions, lack of oxygen in the sinus, and further reduction of mucociliary clearance and nitric oxide production [27].

Because all forms of CRS manifest varying degrees of inflammation, an understanding of the immunologic processes driving them is critical to treating the disease. Allergy is a well-known risk factor for CRS. Consequently, patients with CRS and allergic rhinitis have been shown to have elevated levels of interleukin-5 (IL-5) [42]. Elevated levels of IL-5 have been discovered in the serum and secretions of patients with allergic rhinitis as well as that of non-allergic nasal polyps [43]. Aurora et al. showed that peripheral blood leukocytes isolated from patients with CRS responded to control lavage samples to produce IL-5. The same lavage samples when applied to leukocytes from healthy controls showed no production of IL-5 [44]. Interleukin-1 (IL-1), a cytokine responsible for increasing the presence of adhesion molecules that assist in neutrophil recruitment, has also been shown to be elevated in CRS [45–48]. CRS has also been associated with increased bone marrow eosinopoesis [42] leading to increased serum IgE, particularly in allergic forms of the disease [43]. Interleukin-8 (IL-8), another powerful cytokine whose expression has been elevated in CRS that is generated by neutrophils, has been found elevated in non-allergic forms of CRS [49]. It functions as a chemoattractant for other inflammatory mediators [45–48], and levels fivefold higher than healthy controls have been documented in nasal polyps and turbinates of patients with CRS [50]. The complex inflammatory milieu of CRS has received much attention and may hold the key to fully understanding the disease process.

Histologic findings of CRS have demonstrated that the epithelium and basement membrane of patients with CRS are thicker than that of healthy epithelium [51, 52], and one study reported that this finding was more pronounced in children [53]. Saitoh et al. reported that in patients with CRS and nasal polyps, the thickness of the basement membrane and epithelium correlated with the number of infiltrated eosinophils [52]. Other studies have also demonstrated increased tissue eosinophils in CRS [51, 54, 55]. These histologic sinonasal findings are similar to those found in pulmonary tissue of asthmatics [56–58], and they have been found to be unaffected histologically based solely on a patient’s asthma status [52]. Additionally, tissue eosinophils have been found to be markedly increased in the sinonasal mucosa of asthmatics [59]. In asthmatics, eosinophilic infiltration was identified inside the subepithelial layer, and the amount of infiltration was related to the amount of epithelial damage and basement membrane thickness [59]. The amount of neutrophils was also increased in the subepithelial layer of the CRS sinonasal mucosa of these patients [59]. The histologic findings of the CRS mucosa suggest a link between upper and lower airway pathophysiology.

There are many similarities between asthma and CRS. The cytokine profile of CRS is similar to that of the lungs in asthma [57]. In fact, the inflammatory changes with epithelial shedding and thickening of the basement membrane identified in CRS are similar to the findings in asthmatic pulmonary tissue [51]. The discovery of neutrophils in CRS mirrors their discovery in asthma [4]. There are also clinical correlations between the lungs and sinuses indicating a link between the two. It has long been known that upper respiratory tract infections can precipitate asthma attacks [60]. Some have suggested that nasal obstruction, stasis of nasal secretions, and infections of the sinonasal mucosa may be a trigger for lower airway pathology in susceptible individuals [61].

Grünberg et al. demonstrated that after nebulization of a rhinovirus-16 suspension, asthma patients develop rhinitis symptoms with worsening of the asthma state [62]. Additionally, most patients with CRS who did not carry a diagnosis of asthma showed bronchial hyperreactivity when given a methacholine challenge [51]. Furthermore, the frequency of asthma in nasal polyp patients ranges from 17 to 31 % [63, 64], and the incidence of nasal polyps in asthmatics over age 40 years is 10–15 % [65]. Surgical treatment of CRS has been shown to have beneficial effects on asthma. Senior et al. demonstrated that after a mean of 6.5 years of follow-up, 90 % of asthmatics who underwent endoscopic sinus surgery (ESS) reported improvement in asthma, a lower number of asthma attacks, and less asthma medication usage [66]. Asthmatic children who underwent ESS reported fewer asthma-related hospitalizations and school days missed [67]. Finally, patients with CRS, nasal polyps, and asthma who underwent ESS had improvement in pulmonary function tests and required fewer systemic steroids for asthma control [65]. These studies have led to the conclusion that ESS in asthmatics is most often successful for sinonasal symptoms and may improve bronchial asthma symptoms as well as decrease medication use [68].

Nitric oxide (NO) has also been under investigation as a contributor to CRS [60]. NO is produced by the sinuses and functions as an innate immune mediator capable of killing bacteria, fungi, and viruses [27]. In cases of severe nasal obstruction, NO levels have been shown to be low, whereas inflammatory conditions are associated with a higher level of NO [69]. The clinical utility of NO has yet to be defined, but it has been proposed that it may be useful in assessing the response to treatment in CRS by gauging ostiomeatal complex (OMC) patency [70].

Biofilms have also been implicated as a cause of CRS [71], particularly refractory CRS. Biofilms are an organized community of bacteria adherent to a mucosal surface or foreign body and are situated in an extensive extracellular polymeric substance that is composed primarily of polysaccharides forming a glycocalyx [72]. This glycocalyx is a mixture of bacterial colonies of various phenotypes and serves as protection for its bacterial inhabitants while also modulating the microenvironment of the colonies through its numerous water channels via a process of interbacterial signaling called quorum sensing [72]. When in the form of a biofilm, infectious bacteria are difficult to detect and culture using conventional methods and are largely resistant to current antimicrobial therapy [73]. Antibiotics freely penetrate the bacterial biofilm, but the resistance is probably related to the slow growth conditions within the biofilm and sharing of multiple resistance genes within the members of the biofilm community [73]. Unfortunately, there is currently no simple, noninvasive clinical test for detecting biofilms; their identification relies on electron or confocal scanning laser microscopy or indirectly by identification of a DNA signature for presence of biofilm-forming genes [73]. In fact, in 2004, they were first discovered in sinonasal mucosa by using a scanning electron microscope to look at the mucosa from clinical nonresponders with CRS [71]. Since then, biofilms have been implicated in recurrent adenotonsillar infections, otitis media, and cholesteatoma [74, 75] and are thought by some to be present and likely contributors to all forms of CRS [76]. They have been identified in at least one third of CRS patients [73] and act as a source of bacteria which can be sources of antigens, superantigens, toxins, and other proinflammatory factors [76]. The most common bacteria identified in sinonasal biofilms is Staphylococcus aureus, but Pseudomonas aeruginosa and Haemophilus influenzae have also been identified [77–80]. Unfortunately, the presence of biofilms prognosticates a poor outcome after surgery [81, 82]. The presence of a biofilm does not determine the clinical course of the disease, but the persistence of the pathogenic organism via biofilm-forming capacity can impact the disease course [73]. Treatment for biofilms involves mechanical pressure irrigation [83] and different topical therapies [73]. Surfactant solutions have been tried with some success [84], and some data suggests that sinus rinses that contain baby shampoo have some effect [85]. Mupirocin irrigations have also been found to be effective for staphylococcal-cultured positive biofilms [86]. Treatment often requires prolonged courses of topical modalities after shorter courses of other medical and surgical therapies.

Other contributors to CRS have been proposed. Superantigens have been described in the literature, and enterotoxins from Staphylococcus aureus, a well-known pathogen in CRS, have been hypothesized to cause some forms of CRS [87]. Bachert et al. demonstrated that the presence of Staphylococcus aureus enterotoxin was associated with the upregulation of the production of polyclonal IgE antibodies [88]. Some suggest that hypoxia may be the etiology of CRS [89, 90]. Recently, it was hypothesized that fungi were responsible for CRS. It was thought that toxic mediators secreted by eosinophils that play an essential role in the elimination of sinonasal fungal infections also have an unwanted side effect of causing local tissue destruction and CRS-related symptoms [91, 92]. Later, a placebo-controlled study did not show any relevant effectiveness of antifungal treatment in the alleviation of CRS symptoms or on relevant mediators [93–96].

Many factors contribute to the development of CRS. There is a tendency for CRS to run in families [97]. Cohen et al. reported that the severity of the disease process is proportional to the penetrance of an underlying genetic component [97]. Aspirin intolerance [98] and diseases that cause decreased mucociliary clearance [99] predispose to the development of CRS. Some forms of CRS are precipitated by anatomic deformities, specifically nasal septal deviation, concha bullosa, paradoxical middle turbinates, or Haller cells [9]. However, these anatomic variants are also seen in patients without CRS [100–103]. Smoking [104] and gastroesophageal reflux (GER) [1] have been associated with CRS. Smoke has been shown to inhibit the mucociliary clearance and epithelial regeneration of sinonasal mucosa [105], and GER has been associated with CRS, but direct causality has not been demonstrated [106].

Atopy has long been associated with CRS [104]. Although it is not causal in its relationship, there is a correlation between allergy and CRS. Newman et al. demonstrated that an increased serum total IgE level was associated with severe CRS [107]. Rachelefsky et al. reported that 53 % of people with allergic rhinitis had sinusitis [108], and other reports estimate that 25–58 % of people with sinusitis had allergic rhinitis [109, 110]. Allergic rhinitis without CRS has been shown to negatively impact a patient’s quality of life compared to the general level of the US population [111]. Atopy with CRS is also a predictive factor for decreased quality of life and poorer surgical outcome for CRS patients [1]. CT scans in atopic CRS patients are also more likely to show increased inflammatory changes [107, 112, 113]. Steinke and Borish reported that more than 50 % of people with perennial allergic rhinitis have been shown to have abnormal CT scans [108, 114]. Berrettini et al. compared CT scans from adults with perennial allergic rhinitis with controls and found that 67.5 % of the atopic group had evidence of CRS compared with 33.4 % of controls [115]. CRS patients who required ESS were also more likely to be atopic. Tan et al. reported that 82 % of patients with CRS requiring ESS had positive skin tests which was similar to patients with allergic rhinitis (72 %) [116]. Emanuel and Shah showed that 84 % of patients who failed maximal medical therapy and required ESS tested positive for allergy [117]. Interestingly, more than 60 % of them had house dust mite allergy. It has also been reported that the most prevalent positive skin test in CRS and allergic rhinitis was to dust mites and that sensitivity to multiple allergens and perennial allergies put patients at a higher risk for chronic hyperplastic eosinophilic sinusitis [116]. Therefore, some have suggested that perennial allergy may be one of the underlying inflammatory factors for CRS [118]. Although some data suggests that atopic status is weakly associated with the severity of CRS [119–121], there is general consensus that management of allergy in CRS is important for proper disease control [1].

The mechanism by which allergy contributes to CRS is complex. Bacterial ARS can be due to allergic rhinitis, especially as mucosal inflammation causes occlusion of the sinus ostia with stagnation of secretions within the sinus cavities [109]. Moreover, the mucosal changes due to allergic rhinitis can alter mucociliary clearance, which can further predispose to CRS [1]. But this mechanism appears too simplistic to describe the relationship between CRS and allergy. Nasal allergen challenges in allergic patients have been shown to yield increased eosinophils and histamine in nasal and maxillary sinus specimens [122]. Furthermore, nasal allergen challenges in sensitive patients have demonstrated radiographic opacification in the maxillary sinus [123]. In 2004, Steinke and Borish described a potential mechanism between atopy and CRS that explains many of the observed relationships [124]. Environmental peptides are loaded onto dendritic cells associated with sinonasal cavities and migrate to nasal-associated lymphatic tissue. T-helper cells migrate from the nasal airway to the nasal lymphatic tissue and bone marrow. Some of the cells newly activated in the nasal airway may include locally produced eosinophil precursors. Once delivered to the bone marrow, these Th2-like cells stimulate the production of inflammatory cells, including basophils, eosinophils, and mast cell precursors. These inflammatory cells infiltrate susceptible tissues like sinuses and lungs. A process of selective recruitment takes place whereby tissues are induced to express appropriate adhesion molecules for inflammatory mediators. This process only occurs in the presence of preexisting disease. Subjects without preexisting sinusitis (or non-asthmatics) do not have adhesion molecules in their airways so their exacerbations of rhinitis do not spread to the sinuses (or lungs). Therefore, allergen-induced rhinitis or non-allergic rhinitis can cause increased systemic inflammation that may contribute to exacerbations of asthma frequently seen in individuals with these underlying conditions.

Leukotrienes have also been implicated in the pathology of allergy. Cysteinyl leukotrienes (cysLTs) have proinflammatory capabilities. Specifically, they induce chemotaxis, increase eosinophilic inflammation of the airways, increase smooth muscle hyperreactivity as well as vascular permeability, and increase mucous secretion, thereby reducing mucociliary clearance [125]. They have been found in elevated levels in the nasal polyps of patients with chronic hyperplastic eosinophilic sinusitis compared to tissue from patients with chronic inflammatory sinusitis and healthy sinus tissue [125].

Asthma is a well-known risk factor for CRS [41]. The incidence of asthma in CRS patients is 23 % compared with 5 % in the general population [126], and CRS has been estimated to coexist with asthma in 30–50 % of patients [127, 128]. Ponikau et al. demonstrated that up to 91 % of patients with CRS had asthma or bronchial hyperreactivity [51]. Many patients with asthma have also been shown to have radiographic findings suggestive of CRS. In adult asthmatics, 74–90 % had CT evidence of some degree of mucosal hyperplasia [107, 129, 130], and in patients with CRS and asthma, a higher Lund–Mackay score was associated with more severe asthma [38, 113, 131, 132]. Two forms of asthma have been described: a Th2 eosinophilic form and a Th2 non-eosinophilic form [59]. Similarly, asthma has been associated with an increase in eosinophils [59] that often correlates with the severity of asthma [133, 134] and a neutrophilic pulmonary infiltrate (rather than eosinophilic) [59]. Similar histologic observations have been made with CRS. Asthma with CRS is also associated with severe nasal polyposis [134].

A dual diagnosis of asthma and CRS has many clinical implications. While asthma alone was not shown to negatively impact a patient’s quality of life, asthma with nasal polyps has been demonstrated to severely affect one’s quality of life [12, 135]. In 2008, Staikuniene et al. reported that patients with CRS, asthma, and nasal polyps were more likely to be of older age, have a greater duration of nasal symptoms, undergone more previous sinus surgeries, present with worse CT scans, have a higher blood leukocyte and eosinophil count, have higher total IgE level, have increased bronchial obstruction, and have a higher incidence of allergic rhinitis [118]. Many studies also suggest that treatment of CRS in asthmatics improves asthma severity [38, 136–138]. In a study of 30 patients who had undergone FESS, 90 % reported asthma improvement, 74.1 % had fewer asthma attacks, 46 % described less inhaler usage, and 65 % reported decreased steroid requirement [66]. While the physiologic mechanism linking asthma to CRS is still debated, some potential mechanisms have been suggested [139]. Some have suggested that inflamed sinus secretions that are aspirated into the lower airways could precipitate an asthma attack. Others have proposed that enhanced vagal stimulation in the infected sinus could lead to bronchospasm. Finally, inflamed sinuses may produce cytokines that act as bronchoconstrictive mediators in the lower airways. As the mechanism is more completely defined, the treatment modalities for both CRS and asthma will hopefully improve. For now, it is clear that optimal treatment of CRS requires addressing a patient’s asthma as well.

A common manifestation of immunodeficient patients is CRS. Some estimates report that 8–20 % of cases of persistent or recurrent ARS are due to immunodeficiency [1]. Similarly, deficient antibody production in response to vaccination or hypogammaglobulinemia was found in 12 % of adults with CRS with nasal polyps [140]. Therefore, chronic recalcitrant sinusitis should raise suspicion about the possibility of immunodeficiency [27]. Typically, these patients present with sinonasal symptoms that are responsive to antibiotic therapy but recur after their withdrawal [141]. This presentation is also common to other forms of CRS, so low index of suspicion is required. The most common primary immunodeficiency in adults is common variable immunodeficiency. It occurs in up to 10 % of patients with refractory CRS. General immunoglobulin deficiencies are seen in as many as 22 % of refractory CRS patients [142, 143]. Table 5.2 demonstrates appropriate lab tests to begin a workup for immunodeficiency. A multidisciplinary approach should be undertaken for these patients.

The classification systems of CRS have mirrored our understanding of the disease processes that cause sinonasal inflammation. Much effort has been spent developing and refining different schema with a goal to improve patient outcomes. This is due in part to the difficulty associated with managing refractory CRS. Initial classification systems stratified CRS based on the presence or absence of nasal polyps [56, 144–147], and significant differences were discovered. CRS without nasal polyps demonstrated elevated levels of Th1 and Th2 mediators [145, 148, 149], with higher levels of neutrophils, IL-1, and IL-8 [45–48]. Furthermore, no difference was observed in epithelial IgE levels between CRS patients without nasal polyps and healthy controls [150]. On the other hand, CRS with nasal polyps demonstrates an immune profile with a Th2 skew with elevated levels of mast cells [151], IL-4 and IL-13 [152], and typically a preponderance of eosinophils [145, 148, 149, 153] with fewer observed neutrophils [153]. The prevalence of CRS with nasal polyps is estimated to be approximately 30 % in patients with CRS [38]. Approximately 80–90 % of all cases of nasal polyposis are characterized by eosinophilic infiltrates [154], particularly in Western cultures [155]. Curiously, Asian nasal polyps tend to be more neutrophilic [156] although they are macroscopically indistinguishable from their Caucasian counterparts [4]. Even in non-Asians, some nasal polyps do not contain elevated levels of eosinophils [157, 158]. Patients with CRS with nasal polyposis are also more likely to be associated with asthma [41, 159, 160]. Up to 7 % of asthmatics have nasal polyps [68], and CRS patients with nasal polyps are more likely to have aspirin sensitivity or asthma than the general population [1]. Although this classification provided some clinical value, it was still viewed by many as overly simplistic and incomplete.

Additional subclassification schemas have been introduced. Steinke and Borish [124] divided CRS into four subsets: CRS due to immunodeficiency, inflammatory CRS without prominent hyperplasia of immune cells, chronic hyperplastic eosinophilic sinusitis (CHES), and allergic fungal sinusitis (AFS). Two more categories were added later—aspirin-exacerbated respiratory disorder (AERD) and non-eosinophilic CRS [27]. CRS associated with immunodeficiency, AFS, and AERD are discussed later in this chapter. CHES is similar to most forms of CRS with nasal polyposis. CHES is often characterized by nasal polyposis [57, 161–165], activated eosinophils, fibroblasts, mast cells, and goblet cells [19, 161, 166]. The cytokine profile is also similar in that IL-3, IL-4, IL-5, IL-13, eotaxin, and GM-CSF levels are elevated [125].