Nonpolypoid Rhinosinusitis: Pathogenesis, Diagnosis, Staging, and Treatment
Zara M. Patel
Peter H. Hwang
Rhinosinusitis is one of the most common diseases diagnosed in the United States. Approximately 20 million cases of acute bacterial rhinosinusitis (ABRS) are diagnosed annually (1). In addition, more than 30 million people suffer from chronic rhinosinusitis (CRS). This corresponds to an annual prevalence of 13% to 16%, which has been increasing (2). CRS, therefore, is one the most common chronic conditions reported in the United States, more prevalent than asthma, heart disease, diabetes, or headache.
The costs associated with rhinosinusitis are substantial and are also increasing. Direct health care expenditures associated with acute rhinosinusitis are estimated at $3.5 billion annually, while those of CRS total $4.3 billion (1,3). These figures do not take into account indirect costs such as lost or restricted workdays or decreased productivity. For the individual CRS patient, this represents an approximate annual cost of $1,539 (4).
CRS can significantly worsen patients’ quality of life. When compared to the general population, CRS patients report more pain, less vitality, and decreased social functioning. Outcomes studies have shown that patients with CRS have worse scores in several quality of life domains compared to patients with chronic obstructive pulmonary disease, diabetes, and congestive heart failure (5).
Our understanding of the pathophysiology of CRS has improved dramatically over the last decade, although these findings have inevitably led to even more questions about CRS etiologies. Progress in basic science coupled with technologic improvements in endoscopy, imaging, and surgical technique have progressively enhanced our ability to diagnose and treat rhinosinusitis.
PATHOPHYSIOLOGY
Acute Rhinosinusitis
The etiology of acute rhinosinusitis is thought to be more straightforward than that of CRS. In acute rhinosinusitis, the role of viral and bacterial pathogens has been well established (1,2). Acute viral rhinosinusitis is by far more common than acute bacterial rhinosinusitis (ABRS). Adults, on an average, have two to three acute viral upper respiratory tract infections annually, many of which involve the paranasal sinuses. Specific incidence rates are not known, but it is estimated that 39% to 87% of acute viral upper respiratory tract infections result in acute viral rhinosinusitis. Rhinovirus is responsible for approximately half of the cases, with other viruses such as coronavirus, influenza, parainfluenza, respiratory syncytial virus, adenovirus, and enterovirus accounting for the rest. Of all viral upper respiratory tract infections, approximately 0.5% to 2% will become complicated by a secondary ABRS (6).
During the acute viral infection, multiple inflammatory mediators are upregulated. Acute inflammation of the sinus mucosa, manifested by mucosal hypersecretion and edema, may cause obstruction of the sinus outflow tracts. The resulting mucus stasis may provide a rich environment for bacterial proliferation. Viruses may also damage or disrupt the nasal epithelium and impair mucociliary clearance, further predisposing the patient to a secondary bacterial infection. While acute viral infection is a primary etiology of ABRS, host factors such as odontogenic infection, atopy, systemic immunodeficiency, dysfunctional innate immunity, or anatomic obstruction may be secondary predisposing factors.
The most common pathogens associated with ABRS are Streptococcus pneumoniae (33%), Haemophilus influenzae
(32%), Staphylococcus aureus (10%), and Moraxella catarrhalis (9%) (7). Since the introduction of the 7-valent pneumococcal vaccine for children, there has been a trend toward decreasing prevalence of S. pneumoniae isolates and increasing prevalence of H. influenzae isolates derived from adults with acute maxillary sinusitis (8).
(32%), Staphylococcus aureus (10%), and Moraxella catarrhalis (9%) (7). Since the introduction of the 7-valent pneumococcal vaccine for children, there has been a trend toward decreasing prevalence of S. pneumoniae isolates and increasing prevalence of H. influenzae isolates derived from adults with acute maxillary sinusitis (8).
Chronic Rhinosinusitis
The pathophysiology of CRS has revealed itself to be much more complex than previously assumed, and the paradigm of treating rhinosinusitis simply as a prolonged infection is long past. The contribution of inflammation to CRS pathogenesis is increasingly appreciated, with multiple varied pathways potentially leading to a common endpoint of mucosal inflammation.
The categorization of CRS subtypes has evolved to reflect an improved understanding of varied pathophysiologies in CRS. Indeed, CRS subtypes may demonstrate differential clinical responses to treatment, likely due to differing pathophysiologies. The first branching point of classification is polypoid versus nonpolypoid rhinosinusitis; as another chapter in this book covers the polypoid type, we do not concentrate on it here. Further subcategories include eosinophilic versus noneosinophilic, and finally allergic fungal versus nonallergic fungal (Fig. 35.1). As another chapter in this text covers fungal rhinosinusitis, we only discuss fungus as it may relate to other forms of CRS (9).
Our understanding of underlying mechanisms of CRS has evolved beyond the local milieu of the nose and paranasal sinuses towards a greater appreciation of systemic pathophysiology. For example, the emerging concept of unified airway disease emphasizes the mutual influence and interplay between the upper and lower respiratory tracts, with shared inflammatory mediators such as T-cell cytokines IL-4, IL-5, and IL-13 and similar leukocytic profiles, especially eosinophils (10).
 Figure 35.1 Classification for CRS. |
Paranasal sinus inflammation can be incited by the interaction of multiple etiologies, including microbial factors, environmental factors, and host factors such as abnormalities in structure, genetics, physiology, and innate immunity (Fig. 35.2).
Microbial Factors
Although antimicrobial agents are ubiquitously used to treat CRS, the actual role that infectious organisms play in CRS has been a controversial topic over the last decade. Bacteria have been cultured from the sinuses of patients with CRS but also from those of healthy normals. With the identification of bacterial superantigens and bacterial biofilms associated with CRS, it appears that bacteria may have a much more complex role in the etiology of CRS beyond the classic pathway of infection as is seen in ABRS.
Superantigens are exotoxins produced by a wide array of infectious microorganisms that have the ability to activate a much larger subpopulation of the T-lymphocyte pool (5% to 30% as opposed to less than 0.01% activated by traditional antigens). The activation of the T cell is able to occur without antigen-peptide receptor specificity due to crosslinking of both the outside portion of the major histocompatability class II complex on antigen presenting cells as well as the T-cell receptor in its variable beta portion.
Without requiring antigen specificity, T-cell-mediated inflammation may be propagated and magnified by the presence of bacterial exotoxins. Superantigens are not only linked to a dramatic upregulation in T-cell response, but have also been associated with increased eosinophils, increase in IL-5 and upregulation of PGE2 (11).
Without requiring antigen specificity, T-cell-mediated inflammation may be propagated and magnified by the presence of bacterial exotoxins. Superantigens are not only linked to a dramatic upregulation in T-cell response, but have also been associated with increased eosinophils, increase in IL-5 and upregulation of PGE2 (11).
 Figure 35.2 Underlying factors contributing to the pathophysiology of CRS. |
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 staphylococcal 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 (20,21,22).
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 findings 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 true 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).
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, creating 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.
 Figure 35.3 Coronal CT scan showing bilateral concha bullosa. |
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 IL1A genes have been associated with increased susceptibility to CRS. Furthermore, alterations in the 6p22, 22q13, and 1q23 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 cited 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 immotility 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 clear difference between the test groups, the authors still concluded 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 predictive of symptom improvement. While this study excluded patients with CRS, the demonstration of a therapeutic effect 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 included low immunoglobulin levels and deficient T-cell function, in up to half of their patients with medically refractory sinusitis. Although IgG subclass deficiency is the most common deficiency identified, multiple entities including selective IgA deficiency, common variable immunodeficiency, and X-linked agammaglobulinemia can present with ABRS or CRS. In human immunodeficiency virus (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 Job syndromes can also predispose to rhinosinusitis. Even though most patients with rhinosinusitis are not immunodeficient, a history of persistent or recurrent infections despite adequate antimicrobial therapy should raise the suspicion of immune deficiency as a contributing factor.
Abnormalities in innate immunity are being increasingly well characterized 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 Th1 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 Th1, Th2 or type I interferon profile (46). Multiple antimicrobial peptides, such as lactoferrin, 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 clearance also plays a key role within the innate immune system, being the first defense against all inhaled particles (47).
DIAGNOSIS
In order to foster effective communication among physicians and researchers and to standardize the reporting of rhinosinusitis, the Task Force on Rhinosinusitis was created in 1996, sponsored by the American Academy of
Otolaryngology-Head and Neck Surgery (AAO-HNS). Their work resulted in the publishing of “working definitions” for rhinosinusitis in 1997 (48). The Task Force proposed a symptom-based format for the diagnosis of rhinosinusitis, with major and minor symptom categories (Table 35.1). According to the duration of the symptoms, rhinosinusitis was defined as acute when symptoms lasted 4 weeks or less, subacute when symptoms were present for 4 to 12 weeks, or chronic for symptoms lasting longer than 12 weeks. The term recurrent acute rhinosinusitis was reserved for patients with four or more episodes per year with disease-free intervals in between. An acute exacerbation of CRS was defined as a sudden worsening of symptoms in a patient already diagnosed with CRS, with return to baseline symptoms after treatment. A strong history consistent with rhinosinusitis would require the presence of either two major factors, or one major and two minor factors. When only one major factor or two or more minor factors were present, this constituted a suggestive history in which rhinosinusitis should be included in the differential diagnosis.
Otolaryngology-Head and Neck Surgery (AAO-HNS). Their work resulted in the publishing of “working definitions” for rhinosinusitis in 1997 (48). The Task Force proposed a symptom-based format for the diagnosis of rhinosinusitis, with major and minor symptom categories (Table 35.1). According to the duration of the symptoms, rhinosinusitis was defined as acute when symptoms lasted 4 weeks or less, subacute when symptoms were present for 4 to 12 weeks, or chronic for symptoms lasting longer than 12 weeks. The term recurrent acute rhinosinusitis was reserved for patients with four or more episodes per year with disease-free intervals in between. An acute exacerbation of CRS was defined as a sudden worsening of symptoms in a patient already diagnosed with CRS, with return to baseline symptoms after treatment. A strong history consistent with rhinosinusitis would require the presence of either two major factors, or one major and two minor factors. When only one major factor or two or more minor factors were present, this constituted a suggestive history in which rhinosinusitis should be included in the differential diagnosis.
TABLE 35.1 SIGNS AND SYMPTOMS ASSOCIATED WITH DIAGNOSIS OF RHINOSINUSITIS (1996 RHINOSINUSITIS TASK FORCE) | ||||||||||||||||
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TABLE 35.2 DIAGNOSTIC CRITERIA FOR SINUSITIS FROM 2007 TASKFORCE | ||||||||||
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