Pathogenesis of Chronic Rhinosinusitis

Fungi

The role of fungi in the etiology of CRS remains controversial. Using sensitive techniques, fungi can be detected in the nasal cavity of all patients—those with CRS and controls—without a clear increase of fungal biomass in disease. Nevertheless, the demonstration of fungi, as well as eosinophilic mucin, in all patients with CRS formed the initial basis of the fungal hypothesis of CRS. This theory proposed an exaggerated inflammatory response to the common airborne fungus Alternaria as the underlying cause of both CRSsNP and CRSwNP, thought to be forms of a single disease varying primarily in intensity. Further in vitro studies supported this hypothesis by showing that supraphysiologic levels of Alternaria triggered a cytokine response from the peripheral blood mononuclear cells of patients with CRS but not of control patients. Nasal mucus or tissue from CRS patients triggered eosinophil migration, and a 60-kDa component of the Alternaria fungus was later shown to trigger eosinophil degranulation in vitro. These data were interpreted to suggest that Alternaria served a dual role: first, Alternaria proteins are presented to sensitized T cells, which induces a cytokine response that serves to attract and activate eosinophils; second, Alternaria serves as the target of the eosinophils, triggering degranulation and mucosal damage. Attempts to replicate the fungal-induced cytokine responses from peripheral blood mononuclear cells by other investigators failed, however, which indicates the absence of a universal hyperresponsiveness to fungal antigens in CRS patients. Even more significant, a multicenter randomized controlled trial from 2009 that involved intranasal amphotericin B lavages failed to show any significant anti-inflammatory effect in CRS. Overall, the literature does not support the routine use of topical antifungals for CRS, and support for the fungal hypothesis as originally proposed is scant. While the view of fungi as the universal or even primary antigenic stimulus in CRS has largely faded, this does not eliminate fungi as a factor in CRS etiology or pathogenesis for several reasons. First, fungi likely play a role in allergic fungal rhinosinusitis (AFRS), a subset of CRS classically distinguished by a type 1 hypersensitivity response to fungi, type 2 cytokine expression, nasal polyps, and by a characteristic eosinophilic mucin. Still unclear is whether fungus is the true initiator of the inflammatory response, however, even in AFRS. Second, fungi exhibit intrinsic protease activity, and in combination with the upregulation of protease-activated receptors (PARs) in nasal epithelial cells (ECs) of CRS patients, this may provide a potential pathogenic mechanism for the exacerbation of the primary inflammatory processes seen in CRS. Third, the cell walls of fungi contain the polysaccharide polymer chitin, which has been proposed as an etiologic driver of eosinophilic responses in some mouse and human studies, although the clinical significance of this finding remains uncertain. Lastly, paranasal sinus fungal balls occur in patients with a normal immunologic status and may cause symptoms indistinguishable from CRS or may be asymptomatic and discovered incidentally. Pathology reveals tangled hyphae of a variety of fungal species, and while the pathophysiologic relationship to AFS or typical CRS remains unclear, symptoms resolve with removal of the lesion.

In summary, with the possible exception of AFRS, consistent in vitro or in vivo evidence is lacking to demonstrate that fungal antigens are the primary targets of the mucosal immune responses observed in CRS. Fungi are, however, capable of inciting epithelial immune responses, which suggests a possible secondary role as disease modifiers in some CRS subtypes.

Bacteria

The role of bacteria in acute rhinosinusitis (ARS) is well established, but involvement in CRS pathogenesis has been more presumptive. Although now disproven, the sinus cavities were believed to be sterile and conventional culture studies revealed that organisms were initially interpreted as evidence of pathology. More recent culture-independent molecular techniques have demonstrated that microbial communities colonize the mucosa of the nose and sinuses from an early age, definitively proving that the nose and sinuses are not sterile, even in normal patients. The techniques are evolving in power and are now being applied to study the composition of these communities in both health and CRS. The results indicate some differences between patients with CRS and controls, and this gave rise to the microbiome hypothesis of CRS . This initial study, using human subjects, as well as an animal model, suggested that the absence of commensals permitted the emergence of Corynebacterium tuberculostearicum , which was proposed to be a key organism in CRS pathogenesis. While later studies failed to confirm the significance of this specific organism, the collective microbiome data from this study and others supported the hypothesis that dysbiosis of the community as a whole may be associated with the presence of sinonasal mucosal inflammation. From this perspective, the resident microbiota embedded in the respiratory mucus effectively provide the first line of defense, in that commensal organisms would prevent colonization of pathogens and also likely provide certain local metabolites that enhance mucosal health. The results of various studies on the CRS microbiome vary greatly, however, depending on number of subjects, sampling methodology, techniques used, depth of sequencing, phenotype, and prior treatments. As a result, any firm conclusions about the precise nature of that dysbiosis remain limited, but these newer techniques are only now being applied to large numbers of patients using standardized protocols. The largest study to date did not indicate any key role for a specific organism but did indicate that the depletion of two genera ( Corynebacterium and Peptonophilus ) was associated with CRS. It is possible that studies using narrow CRS patient groups may reveal associations with characteristic microbiomes or even the presence of specific organisms. Nevertheless, this would only be the first step toward validating the microbiome hypothesis, as the association of a more specific microbial signature with a specific endotype may not be causative.

The most common bacterial isolates from CRS patients using conventional culture techniques were Staphylococcus aureus and anaerobes, markedly different from culture results taken in cases of ARS. The potential significance of S. aureus , in particular, was suggested for other reasons in addition to culture data. First, this bacterium has the capability to reside within nasal ECs, the presence of which in CRS appears to confer a poor prognosis. Secondly, S. aureus can form biofilms on the mucosal surfaces of the nose and paranasal sinuses; these are highly organized structures with encasement of the bacteria in an extracellular matrix (ECM) that allows for protection against host defenses and antibiotics. Multiple other species have been implicated in biofilm production in CRS patients as well, including Haemophilus influenzae , Streptococcus pneumoniae , Pseudomonas aeruginosa , and Moraxella catarrhalis , although P. aeruginosa and S. aureus appear to convey a worse prognosis. In addition to conferring resistance, the intermittent release of bacteria by biofilms may be a key mechanism that underlies exacerbations of CRS, further suggesting a role for biofilms in pathogenesis. Although never formally articulated as such, a biofilm hypothesis for CRS etiology and pathogenesis has been implied in what are, to date, largely descriptive studies. The presence of biofilms within sinonasal passages of CRS and normal patients varies widely in the literature, however, and as yet it remains unclear whether biofilms play a significant role in CRS beyond explaining resistance to conventional therapy. Specifically, the presence of large amounts of bacteria in a biofilm format may simply reflect host susceptibility or the secondary effects of chronic inflammation as opposed to any role as a primary etiologic driver. The third factor implicating S. aureus in CRS pathogenesis is the capacity to secrete superantigenic toxins that can directly alter the immune response of the host. This has given rise to the superantigen hypothesis of CRSwNP , which proposes that exotoxins released from staphylococci incite a characteristic inflammatory response with type 2 cytokines, eosinophil recruitment, local polyclonal immunoglobulin E (IgE) production, and polyp formation. Studies on select populations of Western polyp patients have demonstrated B- and T-cell responses consistent with superantigen exposure in a significant percentage of CRSwNP. A recent large, multi-institutional European study, however, revealed the presence of a staphylococcal superantigen effect in only a minority of CRSwNP patients. CF polyps, known to be colonized with staphylococci, also show little evidence of superantigen effects. Furthermore, despite the not infrequent presence of S. aureus in CRSsNP by culture, no evidence of a superantigenic response has been reported in this phenotype. Lastly, Asian CRSwNP patients, who have much less type 2 inflammatory skewing than Western polyps, show little evidence of superantigen effects. Viewed conservatively, these findings would suggest that superantigens act as disease-modifiers in only a subgroup of severe type 2 skewed CRSwNP, worsening the degree of inflammation in that subgroup rather than causing it.

The normal physiologic defense mechanism against bacteria typically involves type 1 or type 3 inflammatory responses and not the type 2 response often seen in Western CRS in general and Western CRSwNP in particular. The pathomechanism for this type 2 inflammatory skewing in CRS is unclear, but would appear to be critical for understanding the etiology and pathogenesis. Superantigenic toxins, for instance, may accentuate type 2 responses that are already present, but it is not clear that they are capable of initiating the primary type 2 response. Although thus far limited, there is some very recent evidence to suggest that S. aureus may be capable of initiating a type 2 response via toll-like receptor 2 (TLR2), even in strains that do not express the superantigenic toxins.

Viruses

Evidence that latent or chronic viral infections can be a source of sinonasal inflammation that mediates CRS is, thus, far relatively scant. It is possible, however, that viral infections at any early age may predispose to the subsequent development of CRS as has been proposed in early onset asthma. Conversely, the presence of allergic rhinitis (AR) may predispose to viral upper respiratory infections by reducing the immune response of the nasal mucosa. Recurrent viral infections secondary to AR may lead to acquired ostiomeatal obstruction, mucociliary stasis, and CRSsNP. Regardless of any role in CRS etiology, viral infections exacerbate both upper and lower respiratory symptoms. In summary, while the relationship between viral infection and CRS remains understudied, the ability of viral upper respiratory infections to disrupt the epithelial barrier suggests the potential for some role in pathogenesis if not etiology.

Toxins and Allergens

Environmental toxins have been proposed as etiologic agents for CRS, presumably through damage to the sinonasal epithelial barrier, but evidence is generally weak. Tobacco smoke exposure has the strongest epidemiologic association, presumably acting through the production of reactive oxygen and nitrogen species, with secondary mucociliary dysfunction, biofilm production, and proinflammatory cytokine induction. Overall, data suggest that cigarette smoke likely can contribute to the inflammation in CRS in exposed individuals, worsening symptoms and prognosis, but evidence for a role in the initial establishment of the disorder is uncertain.

The relationship between AR and rhinosinusitis has been studied for decades; while many large studies have demonstrated an association, the significance is unclear. The symptoms of AR overlap with rhinosinusitis to a substantial degree, but are generally less severe than those present in most forms of CRS. Untreated AR increases mucosal edema of the nasal cavity and sinus outflow tracts, which leads to poor ventilation and some degree of secondary sinus obstruction, thereby exacerbating CRS symptoms. AR likely also reduces anti-viral immunity of the sinonasal mucosa, increasing the frequency of acute viral rhinosinusitis and secondary bacterial ARS, with possible scarring of sinus outflow tracts leading to CRS. However, the contribution of AR to the total inflammatory picture in CRS is typically relatively mild. Furthermore, allergy-specific treatment, avoidance, and immunotherapy relieve some associated rhinitis symptoms but do not reverse sinonasal disease.

AR occurs through host sensitization to foreign protein across a mucosal barrier via dendritic cells (DCs) and naive CD4-positive lymphocytes, with the generation of antigen-specific Th2 lymphocytes and IgE-secreting plasma cells. Subsequent antigenic challenge across the mucosa results in cross-linking of IgE bound to the surface of mast cells with subsequent degranulation with release of additional type 2 cytokines, leading to recruitment of inflammatory cells that include eosinophils. The pathogenesis of CRS is much less clear, but at least some of these mechanisms are operative. This begs the question as to whether perennial AR, at least in some cases, is simply a well understood but mild form of CRS. Historically, it was assumed that allergens had minimal direct access to the sinus cavities, as mucociliary outflow was believed to restrict exposure of the sinus mucosa to environmental agents. Molecular techniques have indicated that the sinus cavities are not sterile, suggesting that allergens also have at least some access. Studies have also indicated that nasal challenge with allergen leads to both sinus and nasal mucosal eosinophilic inflammation that is also detected on computed tomography scans. Hence, severe perennial AR can fulfill the definition of chronic rhinosinusitis : inflammation of the nasal and sinus mucosa of over 12 weeks’ duration confirmed by computed tomography. In support of this concept, a recent study utilizing a birth cohort has suggested a phenotype of early onset CRS that is closely linked to AR and asthma. This phenotype could at least in theory be considered the extension of the atopic march into the sinus cavities. Although not clearly associated with early age of onset, an “allergic phenotype of CRS” has been proposed by a separate group of investigators, with primarily central intense nasal inflammation and milder signs of inflammation in the dependent sinuses. Further study is necessary to validate whether an allergic phenotype of CRS is a significant discrete entity.

In summary, AR is generally considered to be a superimposed problem that contributes in a variable but relatively mild way to the sinonasal inflammation seen in most severe CRS patients. Notable potential exceptions may be the patients with (1) severe CRSwNP associated with AFS and (2) local polyclonal IgE in the absence of systemic atopy. It has been suggested that at least a proportion of this latter group of patients manifests a superantigen-driven local polyclonal IgE response to a diffuse array of environmental agents with resultant massive chronic mast cell stimulation.