Nasal polyps (NPs) represent a common clinical end point for a myriad of inflammatory disease processes involving the paranasal sinuses. Chronic rhinosinusitis is the most common cause for NPs, but not all NPs are created equally. This article outlines the current understanding of pathogenesis in nasal polyposis and discusses the implications on therapy.
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Nasal polyp (NP) is the end product of chronic rhinosinusitis (CRS).
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NPs are created through multiple inflammatory or infectious pathways.
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All types of CRS have the potential to develop NPs, given enough time and insult.
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Medical treatment depends on the pathogenesis of NPs.
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Surgical removal of inflammatory cell and mediators followed by medical treatment is likely to have the best success in patients with severe nasal polyposis.
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Evaluation of allergy, whether it is negative or positive, is important in the management of patients with nasal polyposis.
NPs represent a common clinical end point for a myriad of inflammatory disease processes involving the paranasal sinuses. NP is common, with 1% to 4% of the general population having evidence of an NP on autopsy. However, not everyone with NP develops clinical symptoms because only a portion of population becomes symptomatic, with a yearly incidence of 0.627 per 1000 people. Men seem to outnumber women (2:1), with the overall incidence increasing in both sexes with age. Even though these numbers of individuals with NP are small compared with that of other more common chronic illnesses, such as hypertension, the overall effect of NP should not be underestimated. In fact, NPs have been shown to have a significant detrimental effect on the quality of life, which is similar in severity to chronic obstructive pulmonary disease.
Clinical presentation and diagnosis
When discussing trends in clinical presentation, the diversity of patients with NPs must always be respected, and broad generalizations should be avoided. Nevertheless, trends in clinical complaints have been shown when comparing patients with CRS with polyps with those without evidence of polyps. Patients with NPs are more likely to complain of a constellation of symptoms, including diminished olfaction, headache, and postnasal drip. In addition, symptoms are more likely to be described as bilateral in 80% to 90% of patients. Although a thorough clinical history taking is invaluable, the gold standard for diagnosis of NPs remains endoscopy. In an effort to quantify endoscopic findings, multiple staging systems have been proposed. The utility of these systems lie primarily in their ability to allow for preinterventional and postinterventional comparison. Lund and Mackay used a 3-tier system with scoring as follows: 0, no polyps; 1, confined to middle meatus; and 2, beyond middle meatus. Lildholdt and colleagues used a slightly varied system to assess the effect of multiple treatment methods. The 4-point system developed used the upper and lower edges of the inferior turbinate as a landmark to describe polyp extension. The highest score available extended to the inferior edge of the inferior turbinate, essentially contacting the floor and filling the nasal cavity. To assess these systems and several new methods, Johansson and colleagues evaluated interobserver and intraobserver variability in a well-designed clinical study. The Lildholdt system was found to provide good repeatability and less interexaminer variability in comparison with the Lund-Mackay scoring system. Of note, researchers have shown poor reliability or correlation between patients’ recorded visual analog scores for nasal obstruction and the objective polyp burden regardless of the scoring system. Although objective measures are needed for treatment studies, this lack of correlation with symptoms highlights the weakness of using staging systems in clinical practice.
Imaging for Nasal Polyps
It is undeniable that computed tomographic (CT) imaging has become an essential tool for the diagnosis and surgical management of sinusitis. Classically, CT scans of sinuses in patients with NP are described as possessing polypoid masses associated with partial or complete opacification of paranasal sinuses with infundibulum widening. With respect to its use as a diagnostic tool, CT imaging’s major weakness lies in its inability to differentiate polyps from mucous and other soft tissue masses. However, many patients with CRS eventually require operative intervention, and therefore, a major benefit of CT imaging remains in its ability to provide a road map for surgical planning. For patients with nasal polyposis, this information can be invaluable because the deforming nature of the disease can lead to intraoperative disorientation, making knowledge of anatomic variations crucial.
Imaging for Nasal Polyps
It is undeniable that computed tomographic (CT) imaging has become an essential tool for the diagnosis and surgical management of sinusitis. Classically, CT scans of sinuses in patients with NP are described as possessing polypoid masses associated with partial or complete opacification of paranasal sinuses with infundibulum widening. With respect to its use as a diagnostic tool, CT imaging’s major weakness lies in its inability to differentiate polyps from mucous and other soft tissue masses. However, many patients with CRS eventually require operative intervention, and therefore, a major benefit of CT imaging remains in its ability to provide a road map for surgical planning. For patients with nasal polyposis, this information can be invaluable because the deforming nature of the disease can lead to intraoperative disorientation, making knowledge of anatomic variations crucial.
Chronic Rhinosinusitis and Nasal Polyp
The largest proportion of patients with NP has a diagnosis of CRS. CRS affects about 30 million Americans, imparting an annual medical cost of $2.4 billion. Societal effects are further compounded by sick days, lost work hours, and other indirect costs. To standardize a formerly amorphous clinical diagnosis, CRS criteria have been set forth. A diagnosis of CRS requires a symptom duration longer than 12 weeks with 2 of the following symptoms: facial pain/pressure, hyposmia/anosmia, nasal obstruction, or anterior/posterior nasal drip. Even though all types of CRS have the potential to develop NPs, given enough time and insult, the presence of NPs has been used as a way to subdivide CRS into 2 groups: CRS with NPs (CRSwNP) and CRS without NPs (CRSsNP). CRSwNP represents 20% to 33% of overall CRS cases, although this can vary depending on the geographic location. Although only a portion of patients with CRS have nasal polyposis, these patients likely represent a disproportionate number of recalcitrant patients.
A diverse collection of chronic sinusitis can present with NPs, which include allergic fungal sinusitis, aspirin-exacerbated respiratory disease (AERD), and cystic fibrosis (CF). Despite having similar macroscopic findings, each of these disorders represents a complex pathology and varying treatment strategy. This article outlines the current understanding of pathogenesis in nasal polyposis and discusses the implications on therapy.
Pathogenesis
In attempting to understand pathogenesis in nasal polyposis, it must be remembered that this subject represents a topic in flux. To date, there exists no delineated pathway that can clearly explain the journey from insult to tissue change. The current understanding is instead limited to comprehending and elucidating differing inflammatory promoters and pathways. Much as in the mastery of any sport, it is essential to understand the roles of the key players before tackling overall strategy. It is hoped that by understanding the various inflammatory pathways and their effects eventually, detailed classification will allow for prediction of clinical course and tailoring of intervention.
Cytokines
The division of CRSwNP and CRSsNP has long centered on the separation of the inflammatory pathways that drive them. Classically, CRSsNP is a helper T cell (T H ) subtype 1–dominant and neutrophil-dominant process, whereas CRSwNP represents an eosinophilic T H 2 process. This paradigm has been supported by the finding that 60% to 90% of the cell population in NPs is composed of eosinophils. It is presumed that through degranulation and release of cytotoxic compounds, such as eosinophilic cationic protein (ECP), these invading cells propagate inflammation and cell damage. High levels of the T H 2 cytokines interleukin (IL)-5 and IL-4 have long been confirmed in NP tissues. Research in reactive airway diseases has also demonstrated a clear link between these cytokines and both tissue and blood eosinophilia. IL-4 in particular seems to promote not only eosinophil migration and activation but also T-cell differentiation from T H 0 to T H 2. The resultant cyclical T H 2 upregulation further spurs on eosinophilic inflammation. IL-5 arguably plays the most important role in eosinophilic-driven processes. Like IL-4, this cytokine has a dual action and influence, prompting propagation and activation while simultaneously preventing apoptosis.
CRSsNP can be characterized by the presence of the T H 1 cytokine interferon γ (INF-γ). INF-γ plays an essential role in both innate immunity and acute inflammation. In contrast to IL-4 and IL-5, INF-γ has been shown to prevent airway eosinophilia and allergic response. As would be expected, the INF-γ level is found to be decreased in NPs. The role of another T H 1 cytokine, IL-8, is not completely discerned. IL-8 represents a neutrophil chemoattractant that is frequently associated with acute sinus infections. In patients with CRSwNP, Chen and colleagues demonstrated that IL-8 was diffusely upregulated throughout mucosa but without specific association with polyp tissue.
The real goal of delineating the cytokine profile is to allow for the differentiation of CRS subtypes. Van Zele and colleagues, in an attempt to realize this goal, evaluated inflammatory cells and mediators in those with CRSsNP, CRSwNP, and CF and in controls. This group confirmed statistically significant IL-5 and eosinophil levels in individuals with CRSwNP compared with abundant INF-γ in those with CRSsNP. In contrast, individuals with CF nasal polyps (CF-NP) displayed neutrophil-dominant markers with increases in IL-8 and myeloperoxidase (MPO) levels. The inflammatory process responsible for CF-NP formation is not driven by the T H 2 process or eosinophils as most typical CRSwNP but rather by the T H 1 process. In addition, using receiver operating characteristic analysis, the best cytokine profiles to differentiate each group were identified. Of note, a sensitivity and specificity rate of 75% was observed using IL-5, ECP, and IgE levels to differentiate CRSwNP from CRSsNP. INF-γ was found to offer a similar rate of successful differentiation. IL-8 and MPO were found to provide a sensitivity and specificity of 75% for differentiation between other forms of CRS. Such research offers a window into the future of CRS management in which inflammatory cells and mediators may be used in combination with history taking and examination to classify patients with CRS.
T-cell Regulation and Transforming Growth Factor β1
Once the primary cytokines involved in NPs have been described, it becomes essential to examine the intracellular processes upstream that lead to T-cell differentiation and propagation. An interesting avenue of research in this field examines the interplay of forkhead box P3 (FoxP3) and T regulatory (T reg ) cells. T reg cells, also described as suppressor T cells, function to maintain self-tolerance and immune hemostasis. The lack of adequate function can result in rampant and uncontrolled immune activation seen in fatal autoimmune disease. The FoxP3 gene exerts control over immune hemostasis by regulating T reg production. The characterization of this pathway has provided insight into a wide array of allergic and inflammatory pathways. In the realm of CRS, Van Bruaene and colleagues have demonstrated diminished FoxP3 expression and T reg production in those with CRSwNP compared with both those with CRSsNP and controls. It can be suggested that such an environment of diminished immune control may act as the priming pump for excessive inflammation. Levels of transforming growth factor β1 (TGF-β1) were also proportionally decreased in NPs for the CRSwNP group. This association offers a possible link between the upregulation of inflammation and TGF-β1–associated tissue damage. TGF-β1 is a cytokine produced by lymphocytes, macrophages, eosinophils, and fibroblasts and is associated with local deposition of extracellular matrix and eventual cellular damage. TGF-β1 seems to exert an influence on fibroblasts, resulting in the production of fibrous stroma and hypertrophic scar tissue. This propensity for thick fibrous tissue formation offers an additional point of differentiation between CRSwNP and CRSsNP. A cellular disparity could explain the obvious differences in the gross pathology between the edematous polypoid mucosa of CRSwNP and the thickened scarred sinuses of CRSsNP.
The function of TGF-β1, however, does not seem to be 1-dimensional. In in vitro studies of fibroblast activity, TGF-β1 has been shown to be increased 3-fold in patients with NPs when exposed to IL-4. In a follow-up study, Little and colleagues examined the influence of increased TGF-β1 levels on NP-derived fibroblasts. Although proliferation and fibrotic potential were clearly increased, TGF-β1 was also associated with decreased levels of eotaxin and other eosinophilic inflammation promoters. The investigators propose these findings to help define a dual role for TGF-β1 as both an antiinflammatory agent and a promoter of fibrosis. Such a system could explain the transition from acute/chronic inflammation to fibrotic changes.
Eosinophilic and noneosinophilic nasal polyposis
It has been well accepted that not all patients with CRS that form NPs demonstrate T H 2 eosinophilic-dominant pathology. New emphasis on noneosinophilic nasal polyposis has emerged primarily from Asian research groups. It is notable that 80% of Western patients with CRSwNP demonstrate tissue eosinophilia compared with less than 35% of Korean patients. To examine the possible differences in Western and Eastern nasal polyposis, Zhang and colleagues compared Chinese patients with CRSwNP with their Belgian counterparts. These groups were found to have similar symptoms, CT findings, and endoscopic examination results compared with controls. In addition, both groups expressed upregulation of IL-2 levels and downregulation of FoxP3 T reg cells and TGF-β1 levels, confirming previous findings. Differences were, however, noted with regard to inflammatory cells and T-cell dominance. The Belgian contingent confirmed previous findings of T H 2-dominant eosinophilic inflammation. In comparison, the Chinese group displayed a neutrophilic pattern with T H 1/T H 17 T-cell upregulation.
The role of T H 17 in immunology has only recently been elucidated. Over the past 5 years, the basic CD4 differentiation pathway into T H 1 and T H 2 cells has been challenged by the discovery of T H 17 as an alternative end point. The discovery of T H 17 and its associated cytokines IL-23 and IL-17 was prompted by the inability of T H 1/T H 2 subtypes to explain murine autoimmune models. Instead of IL-4 (T H 2) or IL-12 (T H 1), induction of T H 17 differentiation is promoted by IL-1 and IL-6. Such a profile was confirmed by Zhang and colleagues when patients with noneosinophilia displayed an upregulation in IL-1, IL-6, IL-17, and T H 17 levels. This production eventually results in the production of proinflammatory mediators, fibroblasts, and tissue change.
Staphylococcus aureus enterotoxin
S aureus enterotoxin (SAE) has been suggested as a possible instigating and/or modifying factor in nasal polyposis. As in other superantigen reactions, SAE acts to nonspecifically activate T cells by binding the major histocompatibility II complex. The unregulated upregulation results in an increase of T H 2-biased proinflammatory cytokine levels. This outcome is enhanced by S aureus colonization, with 60% of patients with CRSwNP demonstrating colonization compared with 33% in controls. The effect of this colonization as shown by SAE IgE is not universal among patients with CRSwNP. Instead, asthmatic patients are more likely to have colonization of S aureus and detectable IgE levels, therefore resulting in elevated IL-5, eotaxin, and ECP levels. Despite their different clinical and inflammatory phenotypes, Chinese patients with asthma were also more likely to have detectable SAE levels. Although these results are interesting, further work is needed to correlate SAE effects with clinical symptoms and course. Further research should focus on defining the effect that SAE plays, particularly in asthmatic eosinophilic CRSwNP.
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