Chronic Rhinosinusitis with and without Nasal Polyps
Chronic rhinosinusitis (CRS) with and without nasal polyps is mostly referred to as a multifactorial disease, which has been variously defined. It seems justified to use the term rhinosinusitis, as rhinitis and sinusitis usually coexist as a disorder of one continuous mucosal system. The heterogeneity of various definitions is based on the use of different criteria and on the still incomplete understanding of the immunologic mechanisms underlying this disorder.
A well-accepted definition was proposed in the 2007 and reestablished in the 2012 European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS).1 The concept of a unified upper and lower airway is becoming more obvious with the increasing understanding of pathophysiologic aspects. Although major clinical symptoms such as nasal obstruction, nasal discharge, loss of the sense of smell, and facial pain are widely homogeneous in the population of our patients, the inflammatory mechanisms appear rather variable. It still remains unclear whether recurrent acute rhinosinusitis (ARS), CRS, and CRS with nasal polyps (CRSwNP) are to be seen as a cascade of one underlying disease or whether these entities develop independently, but the chances that they are separate diseases are increasing. Several cell types, cytokines, chemokines, and other mediators such as eicosanoids have been described in CRS, as well as various microorganisms, including bacteria and fungi, both potentially acting as biofilm formers. Eosinophilia appears to be of special interest in the etiology of nasal polyps and therefore has stimulated a great amount of research on several aspects involving (1) superantigen effects of microorganisms and their toxins, (2) immunologic disorders imposing a pathologic reaction to fungal proteins, and (3) genetic polymorphisms and variations leading to alterations of metabolisms in, for example, aspirin-sensitive patients. However, the role of allergic sensitization in CRS has not been clearly defined yet.
This chapter reviews the evidence that has been accumulated regarding different clinical manifestations of CRS with and without nasal polyps, highlighting facts on classification, epidemiology, pathophysiology, and clinical characteristics, as well as therapeutic strategies to prevent recurrence.
Chronic Rhinosinusitis: Epidemiological Burden
Epidemiologically, CRS both with and without nasal polyps is of increasing worldwide relevance.1,2 A high prevalence of CRS was found in a recent pan-European survey based on the EP3OS criteria, suggesting that 11% (range 7–27%) of adult Europeans suffer from the disease.3 Undoubtedly, both ARS and CRS result in a considerable burden on individuals in terms of diminished quality of life and on health care systems in terms of resources and costs.4 Indirect costs and socioeconomic impact due to restricted activity days and work abilities are enormous.5
Due to a high heterogeneity of the disease and different diagnostic methods used in published studies, an exact valuation of the prevalence of CRS remains vague.1
In a survey by Collins, the prevalence of CRS without polyps (CRSsNP) was described as higher in women than men by a ratio of 6:4.6 Also, there are data suggesting that the prevalence varies with age, with rates increasing from 2.7% in the third decade to 6.6% in the sixth decade. Thereafter, the prevalence has been shown not to increase after age 60.7
The prevalence of CRSwNP is apparently more difficult to define, as nasal endoscopy is a prerequisite for an accurate judgment of nasal polyps.8 However, in a French survey by Klossek et al using a disease- specific questionnaire, the prevalence of CRSwNP was determined to be 2.1%.9 In a Swedish study analyzing a distinct urban population, the prevalence was confirmed as a comparable level of 2.7%.10
In a Danish prospective study, a gender-related difference in the incidence of nasal polyps was found, with 0.86 male and 0.39 female patients per 1000 per year.11 CRSwNP is uncommon in the age under 20 years and most common in the 5th decade of life.12,13
A well-accepted definition of CRS was proposed in the EPOS position statement.1 CRS with or without polyps is defined as an inflammatory process of the nose or the paranasal sinuses characterized clinically by two or more symptoms, one of which should be either nasal obstruction or nasal discharge. Further symptoms include facial pain/pressure and reduction or loss of smell. Moreover, the position paper defines CRS by symptoms persisting more than 12 weeks without complete resolution.1
Rhinosinusitis in adults is defined as:
Inflammation of the nose and the paranasal sinuses characterized by two or more symptoms, one of which should be either nasal blockage/obstruction/congestion or nasal discharge (anterior/posterior nasal drip)
± Facial pain/pressure
± Reduction or loss of smell
Endoscopic signs of:
Nasal polyps, and/or
Mucopurulent discharge primarily from middle meatus, and/or
Edema/mucosal obstruction primarily in middle meatus and/or
− Mucosal changes within the ostiomeatal complex and/or sinuses
Clinical Characteristics and Associated Factors
Ciliary Impairment and Anatomical Variations
It has been shown by Messerklinger that complex ciliary transport is essential for proper ventilation and drainage of the paranasal sinuses.14 Ciliary dysfunction and most likely impaired coordination of ciliary arrays consequently play a causative role in such inflammatory diseases as CRS. Also, chronic mucosal inflammation may lead to secondary ciliary dyskinesia, which may be reversible after successful treatment of the underlying disease.15 Most prominently, in a subgroup of patients with CRS and primary ciliary dyskinesia, the ciliary dyskinesia was found to be causal for the course of the disease.16
Anatomical variations in the drainage pathways exist for different sinuses and may have a significant impact on the efficacy of the mucociliary clearance. This is most frequently seen in the maxillary sinus in cases of accessory ostia in the posterior aspect of the fontanelle ( Fig. 16.1 ). Anatomical abnormalities, however, are not found more often in patients with CRS than in normal controls.
Allergies and Chronic Rhinosinusitis
Allergic rhinitis (AR) is a chronic disease that has been seen with increasing prevalence in the last few decades.17 Several studies have suggested that atopic diseases such as AR predispose to the development of CRS.18 AR affects the osteomeatal area and results in swollen and therefore obstructed sinus ostia, reduced ventilation of the paranasal sinuses, and mucus retention.1 Thus, these pathophysiologic mechanisms may promote the development of sinus diseases.1,2,19,20 However, the number of studies focusing on the occurrence of AR in patients with CRSwNP and CRSsNP are still limited and to some extent controversial.1,20 Some studies reported that 0.5 to 4.5% of patients with AR also reveal polyps, which is comparable to the estimated incidence in the population.21 In contrast, Kern and Schenck reported a prevalence of nasal polyps of 25.6% in patients with allergies compared with 3.9% in a control population.22 Other studies indicated that allergies predispose inflammation in patients with CRS and may worsen clinical outcomes following treatment.23–25
In contrast, a recent study by Robinson et al found no significant increase in the prevalence of atopy in CRS patients who had been scheduled for endoscopic sinus surgery (ESS) in comparison to the general population.26 Moreover, in the postoperative follow-up, no significant difference in the rate of revision surgery was found between atopic and nonatopic patients. The authors concluded that the atopic status only minimally impacts the severity of CRS.
The initial report on intolerance reactions to acetylsalicylic acid (ASA; e.g., in aspirin) and other nonsteroidal antiinflammatory drugs (NSAIDs) was published in the 1920s by Widal et al.27 This disease is characterized by a classic triad of symptoms (Samter triad): (1) sensitivity to NSAIDs, (2) chronic bronchial asthma exacerbating after intake of NSAIDs, and (3) (sinu-) nasal polyps.28–30
Incidence rates between 0.6 and 2.5% were reported for the general population whereas in asthmatic patients these are even higher, between 4.4 and 11%.28,31 In a multicenter European survey by the European Network on Aspirin-Induced Asthma (AIANE Investigators) of 500 patients with ASA intolerance, CRS was described as an early sign of the disease often provoked by recurrent viral infections, showing persistent rhinorrhea and hyposmia as typical symptoms.28 However, second-line hyperresponsiveness of the lower airways typically evolved after some years in ASA-intolerant patients.
To the current understanding, the pathophysiological mechanisms underlying ASA-intolerance mainly include abnormalities in arachidonic acid metabolism resulting in an overexpression of proinflammatory leukotriens as initially described by Szczeklik ( Fig. 16.3 ).32
The Role of Fungal Antigens in the Etiology of Chronic Rhinosinusitis and Nasal Polyposis
In the late 1990s, Ponikau proposed his hypothesis that fungi, capable of inducing the eosinophilic inflammation of the upper airway in CRS, are present on endonasal surfaces of all patients and all healthy controls.33
Recent studies show that, although there are several potential deficits in the innate and potentially also in the acquired immunity of patients with CRS that may reduce or change their ability to react to fungi, there are not many arguments to suggest a causative role for fungi in CRSwNP or CRSsNP. However, due to the intrinsic or induced change in immunity of patients with CRS, fungi may have a disease-modifying role.
Over a decade after the presentation of respective immulogic data, a causative role of fungi in the etiology of CRS has not been demonstrated.
Staphylococcus aureus Superantigens and New Considerations in the Medical Management of Nasal Polyposis
Enterotoxins derived from Staphylococcus aureus have been implicated in the pathophysiology of nasal polyps as disease-modifying factors; recent findings using therapeutic proof-of-concept approaches support this hypothesis. These findings imply new therapeutic approaches apart from the currently used topical and systemic steroid therapy for nasal polyposis.34 In double-blind, placebo-controlled studies, it was shown that (1) oral corticosteroids led only to a short-term reduction of polyp size, (2) a low dose of doxycycline treatment for 20 days had a very small but sustained clinically relevant effect on polyp size for more than 3 months, and (3) a significant effect on polyp size was seen with a selective interleukin-5 (IL-5) antagonizing monoclonal antibody.35 From this new understanding of CRSwNP, new therapeutic approaches could emerge, such as anti-IL-5, anti- immunoglobulin E, and antibiotic treatment.
Depending on the results of pending larger clinical studies, these may enlarge the nonsurgical armamentarium for CRS, especially with polyps.
Therapeutic Options Deriving from Different Clinical Parameters
Specific Immunotherapy in Patients with Concomitant Allergies
In a study by Nishioka et al, 72 allergic CRS patients and 211 nonatopic CRS patients were followed postoperatively for middle meatal antrostomy patency, middle meatal synechia formation, and polyp recurrence.36 In 66 of the 72 allergic CRS patients, an allergen-specific immunotherapy was initiated before or after surgery. In general, the rate of polyp recurrence was found to be higher for allergic patients than for nonallergic patients. However, the authors concluded that allergic patients benefit from combination therapy of surgery and specific immunotherapy, whereas allergic patients treated with surgery alone (only six patients in this study) revealed a poorer outcome for all three parameters measured.
In another prospective study of 141 children with CRS, specific immunotherapy and antiallergic pharmacotherapy in the subgroup of allergic children demonstrated significant improvement in the surgical success rate from 62% (no allergy treatment) to 84% at 12-month postoperative follow-up. This rate was comparable to the outcome in children without allergies.37 The study lacked a control group, however, making a conclusion impossible.
In a retrospective analysis, 65 patients with CRS (31 with concomitant allergies) were observed after sinus surgery over the course of 2 to 22 years.38 Fifteen patients of the allergic subgroup also received concomitant specific immunotherapy. Interestingly, surgical outcome was demonstrated equally in both nonallergic and allergic patients after allergen-specific immunotherapy. However, in allergic patients treated with pharmacotherapy only significantly diminished results were observed.
Taken together, these data indicate that allergenspecific immunotherapy may have a role in improving sinus surgery results in allergic CRS patients; however, the data are far from clear, and adequate controlled studies are needed. At the moment, data are not strong enough to advocate immunotherapy in the treatment of CRS, although it can be used in the treatment of concomitant AR.1