Keywords

FormalPara Key Take-Home Points

  • Thorough understanding of the microbiology of chronic rhinosinusitis is a requisite in the management of CRS patients.

  • The most common cultured organisms in chronic rhinosinusitis are Staphylococcus aureus, coagulase-negative Staphylococcus, and gram-negative rods.

  • S. aureus is the most common organism seen in chronic rhinosinusitis. Its presence at the time of endoscopic sinus surgery has been demonstrated to be a strong predictor of postoperative S. aureus infection and impaired mucosal healing.

  • Pseudomonas aeruginosa is the most commonly cultured gram-negative rod and can be associated with biofilm formation.

  • Stenotrophomonas maltophilia is a multidrug-resistant gram-negative bacteria seen in patients with previous FESS and prior antimicrobial treatment.

Introduction

Chronic rhinosinusitis (CRS) represents one of the most common healthcare problems in the United States, afflicting approximately 31 million Americans [1]. CRS is a clinical syndrome associated with persistent inflammation of the mucosa of the nose and paranasal sinuses for 12 weeks or longer [2, 3]. It is known to cause significant physical impairment, adversely impacting patient quality of life and psychosocial well-being. Despite its prevalence, CRS remains a challenging and, at times, controversial disease entity. The etiologic mechanisms of CRS continue to be a source of much debate, and as such, different schools of thought exist on the optimal management strategy. The purpose of this chapter is to describe the different proposed pathophysiologic mechanisms of CRS, with a focus on the microbiology associated with CRS.

Accurate diagnosis of CRS rests on the ability to identify signs and symptoms associated with the disease process, such as nasal obstruction, purulent discharge, and/or facial pain, as well as objective evidence of mucosal inflammation, either by nasal endoscopy and/or computerized tomography [4]. However, it is also important to recognize that this is a heterogeneous disease spectrum, subject to further subclassifications. Patients with CRS may be divided into CRS with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP). This distinction leads to both clinical and pathologic differences. CRSwNP is predominantly mediated by eosinophils, as well as increased levels of histamine, interleukin (IL)-5, and IL-13 [5]. In contrast, CRSsNP seems, at first glance, to be predominantly mediated by neutrophilic inflammation [6]. However, some CRSsNP cases may also exhibit extensive eosinophilic infiltration. Therefore, the distinction between CRS with and without polyps is not as clear as originally thought. In addition, CRS must be clearly differentiated from systemic processes that lead to sinonasal mucosal inflammation. Clinical entities, such as cystic fibrosis, sarcoidosis, Wegener’s granulomatosis, and primary immunodeficiency (PID), may present with sinus involvement as a component of the multisystem process. Some cases of PID can be relatively mild and manifest primarily as sinusitis without pneumonia or other more serious systemic infections. The prevalence of PID in patients with recalcitrant CRS varies widely in the literature, from 0 to 19 %. Furthermore, secondary CRS may arise as a result of local, discrete processes such as tumor, mycetoma, and foreign-body reaction. A recent study even suggests a potential causal relationship between tobacco smoke exposure and the development of CRS [7]. The primary focus of this review is to discuss CRS as a primary disease process in the absence of systemic or local predisposing factors.

Etiology of CRS

Bacteria likely represent the main underlying cause of acute rhinosinusitis (ARS), with the most commonly identified bacteria being Streptococcus pneumoniae, Moraxella catarrhalis, and Haemophilus influenzae [8]. In contrast, the central pathophysiology of CRS remains elusive to date. A variety of possible etiologic mechanisms have been proposed, including microbes (viruses, bacteria, fungi), allergy, osteitis, biofilm formation, staphylococcal superantigen, and derangements in innate and adaptive immunity. Though the exact role of bacteria in the disease process remains to be fully elucidated, it is likely that bacterial infection plays an important role in CRS, either as a causative or an exacerbating factor [9].

Bacteria

The microbiology of CRS varies greatly from ARS. Nadel et al. evaluated 507 endoscopically guided cultures in 265 patients [10]. The predominant organisms identified include Staphylococcus aureus (31.3 %), coagulase-negative Staphylococcus (SCN) (44.2 %), and gram-negative rods (34.3 %). A multitude of gram-negative organisms were cultured, with the most common being Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Escherichia coli, and Serratia marcescens. Kingdom and Swain analyzed 182 total cultures with 257 isolates in 101 patients at the time of sinus surgery. The microbiologic yield was similar; the most common isolates were SCN (45 %), gram-negative rods (25 %), and Staphylococcus aureus (24 %) [11]. Comparative analysis between primary and revision sinus surgery cases demonstrated no differences in the bacterial yield or types. Bhattacharyya and Gopal have demonstrated that while approximately half of the bacteria cultured in CRS are found in isolation, the rest exhibit polymicrobial growth, with two or more bacterial species present [12]. See Table 2.1 for key bacteria and fungi identified in CRS.

Table 2.1 Key microbes cultured in chronic rhinosinusitis [8]
Full size table

Staphylococcus aureus

S. aureus is a ubiquitous microorganism, occupying the nasal vestibule of nearly one-third of the human population at any given time. S. aureus has emerged as an important pathogen in community- and hospital-acquired infections, resulting in sepsis, bacteremia, endocarditis, and soft tissue infections. S. aureus is commonly assayed in cultures performed for CRS [10, 11, 13, 14]. Nadel et al. and Kingdom and Swain reported its presence in 23.1 and 25 % of sinus cultures, respectively [10, 11]. Though the exact role in pathogenesis is a matter of debate, the presence of S. aureus infection at the time of sinus surgery has been demonstrated to be a strong predictor of postoperative S. aureus infection and impaired mucosal healing.

A variety of novel mechanisms of pathogenicity have also been implicated, including biofilm formation and intracellular residency [15]. Foreman et al. characterized bacterial biofilm by fluorescence in situ hybridization in 50 CRS patients. Biofilms were detected in 36 of 50 patients, with S. aureus being the most common biofilm-forming organism [16]. The capacity to form biofilms may confer the ability to create a recalcitrant infectious state unresponsive to conventional antimicrobial therapies. An increase in the recovery of methicillin-resistant Staphylococcus aureus (MRSA) has recently been noted in acute and chronic rhinosinusitis and anterior nares of normal individuals [17]. Brook et al. compared MRSA rates in chronic maxillary sinusitis between two time periods. S. aureus was found in 15 (15 %) of the patients between 2001 and 2003, four (27 %) of which were MRSA. S. aureus was cultured in 23 (20 %) of the patients between 2004 and 2006, with 14 (61 %) being MRSA. Indeed, MRSA represents a treatment challenge in the setting of CRS, given paucity of optimal treatment options. Oral antibiotics that may be effective include doxycycline, trimethoprim/sulfamethoxazole, and clindamycin. Topical mupirocin irrigations may also serve as an important adjunct in the postoperative CRS patient [18].

Staphylococcal Superantigens

The superantigen hypothesis proposes that S. aureus secretes high molecular weight proteins known as enterotoxins. These enterotoxins have significant stimulatory activity that can foster the characteristic tissue response seen in patients with nasal polyps. Approximately 50 % of CRSwNP patients show lymphocyte responses consistent with superantigen exposure [19]. In addition, staphylococcal toxin-specific IgE antibodies have been detected in 18 of 23 patients with nasal polyps [20]. It is unclear, however, whether S. aureus superantigens represent an etiologic agent or a disease modifier. The link between superantigens and CRSsNP has not yet been established.

Coagulase-Negative Staphylococcus

The exact role of SCN in CRS remains to be determined, as its reported incidence varies widely [11]. It has been posited to be a contaminant, supported by previous work that found CNS in the middle meatus of 56 % of healthy patients and in only 20 % of patients with CRS [21]. Moreover, the microbe is ubiquitous on human skin; thus, contamination may occur readily without proper sterile precautions during culture technique. However, different strains of CNS may have differing abilities to cause disease. Recent studies evaluating CNS in indwelling devices have shown that bacterial pathogenicity is dependent on genes associated with biofilm formation, which are only found in certain strains [22]. The mere presence of SCN may not indicate infection, as a specific strain may be necessary for such an infection to develop. Nonetheless, endoscopically acquired cultures have consistently identified SCN in multiple studies in CRS. Bolger found SCN in 17 %, Hsu et al. in 42 %, and Nadel et al. in 35 % of cultures [10, 13, 14]. One possible method to ascertain significance of SCN culture is based on the quantitative growth on culture, along with presence of leukocytosis on the gram stain result. Scant or light growth, especially with a paucity of gram-positive rods or white blood cells (WBCs) on gram stain, likely represents contamination. In contrast, moderate to heavy growth, with large number of WBCs on gram stain, should alert the clinician of the possibility of a true infection.

Pseudomonas aeruginosa

Gram-negative rods are often identified in CRS cultures, more commonly in patients who have undergone endoscopic sinus surgery [10, 13, 14]. However, their role in patients with CRS without previous surgery should also not be underestimated. Kingdom and Swain found GNRs in 31 % of cultures in a group of patients at the time of primary sinus surgery [11]. Nadel et al. found GNRs in 9.5 % of cultures taken from patients without previous sinus surgery [10]. P. aeruginosa has long been recognized as an important pathogen in the upper and lower airway in cystic fibrosis patients. It also represents a common and problematic organism in CRS. Rates of assay in CRS cultures have been reported between 9 and 16 % [10, 11]. Nadel et al. noted that P. aeruginosa was most commonly cultured in patients with previous FESS and irrigation usage [10]. P. aeruginosa also has the capability of biofilm formation which may in part contribute to its refractory nature in CRS patients. Further, the presence of P. aeruginosa biofilm has been associated with poor evolution after FESS [23]. Fluoroquinolones are the only orally administered antibiotic group with efficacy against P. aeruginosa. Quinolone resistance has become more problematic, with limited alternate proven oral antimicrobial therapies for Pseudomonas rhinosinusitis.

Stenotrophomonas maltophilia

Stenotrophomonas maltophilia is a multidrug-resistant gram-negative bacillus most often encountered as a nosocomial pathogen in immunocompromised and intensive care unit patients. Infection with S. maltophilia most frequently involves the respiratory tract, bloodstream, wounds, and genitourinary tract. S. maltophilia has also been cultured from the paranasal sinuses, often in the setting of prior antimicrobial treatment and sinus surgery. The exact implication of S. maltophilia cultures in the paranasal sinuses is unclear. Whether this represents a true infection by an atypical microorganism or colonization that surfaces after eradication of other microbes by antimicrobial therapy merits additional research. Despite its multidrug-resistant nature, trimethoprim/sulfamethoxazole and fluoroquinolone monotherapy has been employed with improvement of symptoms and endoscopic findings in CRS patients [24].

Viruses

Patients with CRS frequently report that their symptoms initially started after an acute viral event [25]. Furthermore, viruses can cause multiple changes on a cellular level, facilitating an infectious and inflammatory milieu of CRS, such as increase in bacterial adhesion and production of inflammatory mediators by nasal epithelial cells [26, 27]. Multiple studies have evaluated the presence of respiratory viruses in samples taken from patients with CRS. Ramadan and colleagues found RSV present in 20 % of samples collected from patients with CRS [28]. However, this study did not report a control group or the timing of the specimen collection, as the presence of RSV is much greater in the winter months in the general population. Jang et al. reported a similar study with a control group and collected specimens during the summer months [29]. Rhinovirus was identified in 21 % of samples from CRS patients and 0 % in the control group. However, these samples were taken from the inferior turbinates and not the paranasal sinus mucosa. In contrast to the above studies, Wood et al. collected sinus mucosa samples from 13 CRS patients and 2 controls [25]. No respiratory viruses, including RSV and rhinovirus, were identified in any of the samples. While viruses may be implicated in the initial or ongoing stimulus of inflammation, their exact role in CRS is not clearly defined.

Fungus

It is clear that fungus is responsible for some forms of sinusitis, in both invasive and noninvasive forms. Though a wide variety of fungi have been identified in the sinuses of CRS patients, the central etiologic role of fungus in CRS has not been clearly demonstrated. In 1999, positive fungal cultures from nasal mucus were used as the basis to posit that eosinophilic infiltration and fungal presence provided the main inciting event for CRS [30]. However, further studies found a similar percentage of positive cultures in normal control patients [31]. In addition, a double-blind, placebo-controlled randomized multicenter trial has failed to identify any benefit of topical antifungal therapy in objective and subjective outcome measures in patients with CRS [32]. A subset of CRS, allergic fungal rhinosinusitis (AFRS), is characterized by type I hypersensitivity to fungi, nasal polyposis, eosinophilic mucin, hyperdensities on CT imaging, and positive fungal stain or culture with the absence of diabetes, immunodeficiency, or an invasive fungal process [33]. Furthermore, patients with AFRS have been shown to have elevated levels of total serum IgE and IgG anti-Alternaria antibodies when compared to patients with CRS [34]. While fungus does play a role in specific subtypes of CRS, its role as a central pathophysiologic mechanism of CRS is not corroborated in the literature.

Osteitis

Osteitis is another possible etiologic factor for CRS. Patients with CRS often show areas of irregular bony thickening on CT imaging. It has been proposed that this irregular thickening and increased bone density may be a sign of inflammation in the bone, resulting in persistent inflammation of the overlying mucosa [35]. Osteitis is marked by varying degrees of osteoclast-osteoblast activity, leading to disruption of organized lamellar bone and formation of immature woven bone [36]. Entry of inflammatory infiltrate into the Haversian canal system may act as a potential pathway for spread of inflammation and, as such, mucosal disease. The prevalence of osteitis is estimated between 36 and 53 % in CRS patients, based on CT findings or pathologic evaluation [37]. This concept of osteitis, an inflammation of the bone, should be differentiated from osteomyelitis, as direct bacterial invasion of the bone in CRS has not yet been demonstrated in studies.

Innate and Adaptive Immune Dysfunction

The innate immune system provides the first line of defense against pathogens through both physical barriers, such as ciliated mucosa, and the expression of several antimicrobial molecules, including S100 and surfactant protein A. The data on these antimicrobial molecules has been somewhat inconsistent. Some studies have not shown consistent changes in these antimicrobial molecules in patients with CRS [38, 39]. Other, more recent studies have shown more consistent changes, specifically in the S100 proteins [40]. These have direct antimicrobial effects as well as aid in recruitment of neutrophils and lymphocytes. These proteins are decreased in patients with CRS compared to controls. The dysfunction of the innate immune system remains a strong area of ongoing research to determine its true role in the pathophysiology of CRS.

Dysfunction in the adaptive immune system may also play a role in the development of CRS. The epithelium serves an important role in the adaptive immune system, mediating communication through cell surface molecules that regulate activation of T cells, as well as producing cytokines and chemokines that activate B cells and T cells and enable their migration. Dysregulation of the interaction between epithelial cells and the adaptive immune system may also play an important role in the development of CRS. Moreover, free light chains, which are thought to be involved in mast cell-dependent immune responses, have been found to be increased in nasal secretions and mucosal tissue of patients with CRS [41]. This increase is most prominent in CRSwNP. The increased free light chains suggest a possible role in mediating the local immune dysregulation in CRS.

Allergy

Allergy may represent a confounding factor in the development of CRS. Allergy often manifests as swelling of nasal mucous membranes, leading to sinus ostia narrowing and obstruction. Such obstruction can lead to retained mucus, decreased ventilation, and infection. Furthermore, positive allergy skin prick tests are highly associated with CRS. Benninger reported 54 % of patients with CRS had positive skin prick tests [42]. This is in keeping with multiple other studies, showing rates of positive skin prick tests in 50–84 % of patients with CRS undergoing sinus surgery [43, 44]. However, others studies point toward no increase in CRS in patients with positive allergic responses. Despite the lack of a clear etiologic role for allergy in CRS, it likely represents a contributing factor that should be addressed in the overall treatment strategy.

Anatomic Factors

Anatomic factors have been theorized to play a role in the development of CRS. These include a pneumatized middle turbinate (concha bullosa), septal deviation, and variations in configuration of the uncinate process. Despite the proposed mechanisms of anatomic variability leading to CRS, multiple studies have shown no difference in prevalence of anatomic variations between patients with and without CRS [45, 46]. In contrast, a systematic review on the role of septal deviation in CRS concluded that increasing angles of septal deflection were associated with a small, but significant, increasing prevalence of CRS [47]. Based on current information, the exact role of anatomic variations in CRS is unclear. It would seem that altered sinus ventilation may result from anatomic variants, but this alone is likely insufficient for the development and propagation of CRS.

Conclusion

This snapshot of etiologic information highlights the inherent difficulties in managing the infectious aspects of CRS. Though coagulase-negative Staphylococcus, S. aureus, and P. aeruginosa predominate in microbiologic studies, multitude of gram-negative rods and other atypical organisms may also be cultured in refractory CRS, especially in the setting of previous sinus surgery. Furthermore, other factors including immune derangements, osteitis, fungus, viruses, allergy, and anatomic factors may also play a role in the etiology of CRS. Ongoing research in pathophysiologic mechanisms and treatment schemes is absolute imperatives to continue to enhance patient care.