Key points

Chronic rhinosinusitis (CRS) describes the family of disease processes that result in inflammation of the paranasal sinuses. The causes of these processes vary, but they all share an identical common endpoint—inflammation. CRS affects nearly 31 million Americans annually and is responsible for approximately 20 million annual office visits and 200,000 sinus surgeries a year. Treatment for CRS is also responsible for approximately 6 billion dollars in annual direct and indirect health care costs. The disease process has a significant functional and emotional impact on those who suffer from it. Patients with CRS have demonstrated quality-of-life scores lower than patients with congestive heart failure, angina, chronic obstructive pulmonary disease, and low back pain. CRS can be divided into 2 categories: chronic rhinosinusitis with nasal polyposis (CRSwNP) and chronic rhinosinusitis without nasal polyposis (CRSsNP). This article discusses various forms of CRSwNP that are refractory to medical and surgical therapy.

Chronic rhinosinusitis with nasal polyposis

CRSwNP represents a unique set of disease processes. It is less common than CRSsNP, as demonstrated by a prevalence ranging from 0.5% to 4.3% in national population surveys. However, it commonly results in the need for revision surgery, as demonstrated by the observation that 38% to 69% of cases requiring revision endoscopic sinus surgery are due to CRSwNP. Patients with CRSwNP commonly describe olfactory impairment and are also likely to endorse nasal obstruction. CRSwNP appears to be a more refractory and aggressive form of CRS ( Fig. 1 ). The presence of nasal polyposis is statistically associated with the presence of asthma, inhalant allergy, and aspirin sensitivity. Patients with CRSwNP have been observed to have worse subjective symptoms (as evidenced by higher Sino-Nasal Outcome Test-20 scores), objective symptoms (demonstrated by Lund-McKay computed tomography [CT] scores), and more frequently require revision surgery than patients with CRSsNP. Patients with CRSwNP have also been observed to have greater disease severity on preoperative nasal endoscopy and to demonstrate more improvement after surgery than nonpolyp patients based on endoscopic scores. However, the final postoperative endoscopic scores were still higher for patients with CRSwNP. These observations corroborate the observation that CRSwNP is associated with a greater burden of disease.

( A ) CRSwNP. ( B ) CRSsNP.

The development of CRSwNP is multifactorial. It is a complex disease with suspected contributions from multiple genetic and environmental factors. A family history of nasal polyposis has been reported in 14% of patients with CRSwNP. Certain forms of CRSwNP, like allergic fungal sinusitis (AFS), have been shown to be more common in specific parts of the United States, although the intrinsic mechanism behind AFS remains to be clarified.

Nasal polyp tissue itself has been examined to elucidate histopathologic and immunohistochemical clues to the cause of CRS. Polyp tissue has demonstrated a significantly greater spontaneous release of inflammatory cytokines than control mucosa, suggesting the polyps actively promote inflammation, rather than simply resulting from it. In Western countries, more than 70% of polyp tissue have shown tissue eosinophilia, suggesting association with allergy and Th-2 processes. Neutrophilic inflammation has been more commonly observed in polyps from patients with cystic fibrosis (CF) and in patients in Asian countries. Eosinophilic polyps demonstrate less glandularity, more edema, and minimal collagen deposition except at the basement membrane, as opposed to their noneosinophilic counterparts, which display glandular hypertrophy, more fibrosis, denser collagen deposition, and a mononuclear cellular infiltrate. Grossly eosinophilic polyps are friable and readily disintegrate, whereas noneosinophilic polyps have been described as rubbery. Noneosinophilic polyps have also been shown to have an increase in transcripts for vascular endothelial growth factor, suggesting that hypoxia due to obstruction of sinus ostia may be a driving force. These histologic and immunohistochemical observations have augmented the understanding of the processes driving CRSwNP.

CRSwNP can be refractory to medical and surgical therapy for many different reasons. Recalcitrant forms have been associated with eosinophilia, asthma, and allergy and have also been associated with deficiencies in mucociliary dysfunction, as in CF. Some have proposed that variations in innate immunity may predict and modify more aggressive disease. Superantigens have also been implicated in recalcitrant CRSwNP. This article discusses each of these in more detail. Aspirin-exacerbated respiratory disorder, a well-known aggressive form of CRSwNP, is discussed elsewhere.

Chronic rhinosinusitis with nasal polyposis

CRSwNP represents a unique set of disease processes. It is less common than CRSsNP, as demonstrated by a prevalence ranging from 0.5% to 4.3% in national population surveys. However, it commonly results in the need for revision surgery, as demonstrated by the observation that 38% to 69% of cases requiring revision endoscopic sinus surgery are due to CRSwNP. Patients with CRSwNP commonly describe olfactory impairment and are also likely to endorse nasal obstruction. CRSwNP appears to be a more refractory and aggressive form of CRS ( Fig. 1 ). The presence of nasal polyposis is statistically associated with the presence of asthma, inhalant allergy, and aspirin sensitivity. Patients with CRSwNP have been observed to have worse subjective symptoms (as evidenced by higher Sino-Nasal Outcome Test-20 scores), objective symptoms (demonstrated by Lund-McKay computed tomography [CT] scores), and more frequently require revision surgery than patients with CRSsNP. Patients with CRSwNP have also been observed to have greater disease severity on preoperative nasal endoscopy and to demonstrate more improvement after surgery than nonpolyp patients based on endoscopic scores. However, the final postoperative endoscopic scores were still higher for patients with CRSwNP. These observations corroborate the observation that CRSwNP is associated with a greater burden of disease.

( A ) CRSwNP. ( B ) CRSsNP.

The development of CRSwNP is multifactorial. It is a complex disease with suspected contributions from multiple genetic and environmental factors. A family history of nasal polyposis has been reported in 14% of patients with CRSwNP. Certain forms of CRSwNP, like allergic fungal sinusitis (AFS), have been shown to be more common in specific parts of the United States, although the intrinsic mechanism behind AFS remains to be clarified.

Nasal polyp tissue itself has been examined to elucidate histopathologic and immunohistochemical clues to the cause of CRS. Polyp tissue has demonstrated a significantly greater spontaneous release of inflammatory cytokines than control mucosa, suggesting the polyps actively promote inflammation, rather than simply resulting from it. In Western countries, more than 70% of polyp tissue have shown tissue eosinophilia, suggesting association with allergy and Th-2 processes. Neutrophilic inflammation has been more commonly observed in polyps from patients with cystic fibrosis (CF) and in patients in Asian countries. Eosinophilic polyps demonstrate less glandularity, more edema, and minimal collagen deposition except at the basement membrane, as opposed to their noneosinophilic counterparts, which display glandular hypertrophy, more fibrosis, denser collagen deposition, and a mononuclear cellular infiltrate. Grossly eosinophilic polyps are friable and readily disintegrate, whereas noneosinophilic polyps have been described as rubbery. Noneosinophilic polyps have also been shown to have an increase in transcripts for vascular endothelial growth factor, suggesting that hypoxia due to obstruction of sinus ostia may be a driving force. These histologic and immunohistochemical observations have augmented the understanding of the processes driving CRSwNP.

CRSwNP can be refractory to medical and surgical therapy for many different reasons. Recalcitrant forms have been associated with eosinophilia, asthma, and allergy and have also been associated with deficiencies in mucociliary dysfunction, as in CF. Some have proposed that variations in innate immunity may predict and modify more aggressive disease. Superantigens have also been implicated in recalcitrant CRSwNP. This article discusses each of these in more detail. Aspirin-exacerbated respiratory disorder, a well-known aggressive form of CRSwNP, is discussed elsewhere.

Asthma, allergy, and eosinophilia

Asthma and allergy are 2 common conditions that are associated with CRSwNP. Both disease processes are directed by helper T cells and are characterized by an abundance of eosinophils. Eosinophils are the primary effector cell in the pathophysiology of both upper airway sinusitis and allergy, and lower airway asthma. Although asthma and allergy are associated with each other, for reasons not entirely clear, they do not always coexist. Higher levels of eosinophilia, immunoglobulin E (IgE), and interleukin-5 (IL-5; an eosinophil survival and differentiation factor ) have been observed in CRSwNP compared with CRSsNP, and greater levels of eosinophilia have been observed in patients with more aggressive CRSwNP. In fact, total IgE level is considered by some as a marker for upper and lower airway inflammatory disease and has been implicated in CRS.

Eosinophilia has been observed peripherally and in tissue specimens from patients with CRSwNP. The amount of eosinophilia in nasal polyp tissue was found to relate to eosinophilia in peripheral blood, but not to elevated serum IgE. Patients with elevated peripheral eosinophil counts have also been observed to be more likely to experience postoperative sinus infections, experience recurrence of polyps, and need revision sinus surgery. In addition, increased peripheral eosinophilia has been shown to correlate with more severe radiographic sinus disease. Tissue eosinophilia has also been associated with more advanced CRS by radiographic, endoscopic, and smell identification metrics. Patients with elevated mucosal eosinophilia also demonstrated fewer improvements in quality of life after endoscopic sinus surgery than noneosinophilic patients. Tissue eosinophilia also appears to correlate with histologic findings; basement membrane thickness was found to correlate with epithelial and subepithelial infiltration of eosinophils in nasal polyp tissue. These findings all support the conclusion that eosinophilia is intimately involved in CRSwNP.

Allergy is an exaggerated immune-mediated response with objective and reproducible symptoms or signs initiated by exposure to a defined stimulus at a dose tolerated by normal subjects. Allergy is common in CRS and is observed in 25% to 70% of cases. One study found that 39% of patients who required revision sinus surgery demonstrated inhalant allergy. Tan and colleagues reported that although allergy was common to CRSwNP and CRWsNP, patients with polyps had more positive skin tests, and patients with medically refractory sinusitis were more likely to have multiple positive skin tests and asthma. Although allergy has not been shown to predict polyposis, it does worsen the impact of nasal polyposis on quality of life. The identification and appropriate management of allergy are important to effective treatment of CRSwNP.

CRS is common in asthmatics, as evidenced by the observation that up to 80% of asthmatics have some form of radiologic evidence of sinusitis. More severe asthma is often associated with more severe radiographic disease, although radiologic severity is weakly associated with patient-reported symptom scores. Staikuniene and colleagues observed that 40% of patients with CRS had asthma, and Batra and colleagues observed that 48% of patients who required revision sinus surgery had asthma. Asthma is also associated with CRSwNP ; it was observed in approximately 15% of CRS patients with polyps and only 3.5% of patients with CRSsNP. The prevalence of asthma in patients with CRSwNP may in fact be somewhat higher; Klossek and colleagues observed wheezing and respiratory discomfort in 31% and 42% of CRSwNP patients, respectively, but the formal diagnosis of asthma was reported in only 26% of those patients. Furthermore, Batra and colleagues reported that asthma was the only comorbidity that predicted the presence of polyposis in CRS, reinforcing the strength of this association. This interrelationship is not surprising, because asthma and nasal polyps both manifest an inflammatory response with characteristic predominance of eosinophils, goblet cell hyperplasia, and Th-2 cell immune response. Aggressive medical and surgical management of CRS has been shown to reduce the frequency of asthma attacks, usage of inhalers, and steroid requirement, thereby decreasing the severity of a patient’s asthma. Effective management of CRSwNP requires looking for the coexistence of asthma and treating it appropriately when present. A multimodality approach is often required.

Allergic fungal sinusitis

AFS is a distinct disease process with an aggressive form of CRSwNP. Its discovery began in 1976 when Safirstein ⁴⁷ described a patient suffering from allergic bronchopulmonary aspergillosis (ABPA) with nasal obstruction, hard and blood-tinged nasal casts, nasal polyposis, and cultures positive for Aspergillus fumigatus . In 1981, Millar and colleagues recognized a histologic resemblance between specimens of patients with chronic fungal sinusitis and expectorated plugs from patients with ABPA. Katzenstein and colleagues noted fungal hyphae in ABPA and this variant of CRS and coined the term allergic Aspergillus sinusitis. In 1994, Bent and Kuhn were credited with defining the disease with 5 criteria ( Box 1 ).

AFS has been reported to account for up to 8% of CRS requiring surgery, although this is significantly affected by geography. It is much more prevalent in the humid river basins and coastal regions of the southeastern United States. The mean age at presentation ranges from 20 to 35 years old, and men and women appear to be equally affected. Most patients present with nasal obstruction (often unilateral), olfactory dysfunction, and expulsion of nasal casts, and some patients present with extrasinus complications. Aspirin sensitivity is rarely observed in AFS, and there are mixed reports suggesting a relationship with asthma. The pathophysiology of the disease remains largely unknown. It has been suggested that patients with ostiomeatal complex disease without the propensity to develop AFS in whom fungus becomes trapped develop a mycetoma, whereas those who are atopic are more likely to develop AFS. Much remains to be discovered about the exact pathophysiologic mechanism driving AFS.

Patients with AFS demonstrate evidence of type 1 hypersensitivity. Allergy to fungus is present, although it is not necessarily to the same species detected in the eosinophilic mucin. Interestingly, a significant portion of CRS patients have fungal allergy but do not have the syndrome of AFS, suggesting additional factors must be driving this process. Bent and Kuhn observed that AFS patients have either a strong history of allergy (inhalant or fungal), increased total IgE, and positive skin-prick testing or radioallergosorbent testing, and nonfungal allergy is common. Peripheral eosinophilia has also been observed, as has increased expression of fungal and nonfungal IgE in sinus tissues of patients with AFS. Nasal polyposis is universal to AFS and is characterized by tissue eosinophilia. Furthermore, AFS tissue specimens show the presence of fungus without tissue invasion. Some reports suggest that Bipolaris is more common than other species, although Aspergillus, Alternaria, Cladosporidium, Curvularia, Drechslera, and Helminthosporidium have also been identified.

Imaging studies for AFS are characteristic, as are the eosinophilic mucin associated with them. CT scans demonstrate serpiginous areas of increased attenuation ( Fig. 2 ), which is thought to be due to ferromagnetic elements produced by fungi and inspissated secretions. Most CT scans demonstrate some degree of bone erosion, and extension of sinus disease into adjacent sites is also not uncommon. One series reported that 98% of patients had expansion of sinuses, and 93% had erosion of a sinus wall. Eosinophilic mucin of AFS is a thick, tenacious, highly viscous substance that has been described as the consistency of peanut butter or axle grease. It contains Charcot-Leyden crystals, made up of the breakdown products of necrotic eosinophils. Although eosinophilic mucin is not specific to AFS, it does represent a hallmark characteristic of the disease.

AFS; notice the double densities.

The goal of treatment of AFS is to provide relief from the extensive polyposis of the disease and to prevent recurrences. Surgical removal of all the disease is necessary, and special attention is required to remove all of the fungal mucin driving the local tissue response. Large surgical outflow tracts should be created to improve drainage and ventilation of the sinuses and to facilitate improved delivery of topical therapies. Cultures are routinely obtained as well as both tissue and mucin abnormality to definitively confirm the diagnosis. Oral and topical corticosteroids have proven effective at retarding recurrences, although recurrence of polyps and eosinophilic mucin is high and patients should be counseled accordingly. Oral corticosteroids should be administered in the immediate postoperative period, and the patient should be transitioned to topical corticosteroids to control the inflammation long term. Immunotherapy has been shown to demonstrate variable efficacy, although it is recommended when possible. A recent review of topical and systemic antifungal therapies for AFS showed no benefit, and side effects (particularly in systemic antifungals) can be significant.

Cystic fibrosis

CF is the most common life-shortening autosomal-recessive disease process, with a prevalence of 1:3500 live births and a carrier frequency of 1:25 people. The pathogenesis of CF is due to the mutation of the gene on chromosome 7 that results in a defect in the CF transmembrane conductance regulator protein (CFTR) associated with this chloride-ion channel. This defect results in viscous secretions with decreased water content, and therefore, impairs the function of the mucociliary apparatus. A broad spectrum of phenotypes has been associated with different CFTR gene mutations. In the United States, approximately half of CF is due to mutational homozygosity at codon 508, termed the ΔF508 mutation. This mutation has been correlated with clinical disease severity and nasal polyposis on endoscopy.

The diagnosis of CF relies on the sweat chloride test and genotyping. Diagnosis requires clinical symptoms in at least one affected organ system as well as evidence of CFTR dysfunction (via sweat chloride or genotype analysis). CRS, with or without nasal polyps, is universal to patients with CF by either clinical or radiographic evaluation. Patients typically present with olfactory dysfunction. Nasal obstruction is commonly described if polyps are present, and headaches are more common when mucoceles are present. Often these symptoms arise in childhood. Up to two-thirds of CF patients will develop nasal polyps, many of which present in childhood. Polyps in CF tend to be more neutrophilic and less eosinophilic, which reflects the excessive inspissated mucous and stasis of secretions produced in this disorder that drives the sinonasal inflammation. This phenomenon results in colonization of the sinuses with noncommensal bacteria and biofilm formation. For example, Pseudomonas aeruginosa is a commonly cultured bacterium from CF patients’ sinuses. Furthermore, the inflammatory sinonasal process associated with CF results in a cycle of infection, remodeling, glandular hyperplasia, and recurrent infection. In addition, radiographic evaluation commonly demonstrates underdeveloped sinuses ( Fig. 3 ). Interestingly, Steinke and colleagues described increased levels of extracellular DNA in CF tissue specimens. DNA has been shown to make secretions more viscous, and CF patients who underwent revision sinus surgery demonstrated improved quality of life in association with the administration of dornase alpha, a synthetic protein that degrades DNA present in secretions. Although strides have been made in treating CRS due to CF, it still often remains a challenge for both the physician and the patient.

CT scan of 14-year-old CF patient before surgery; notice the underdeveloped sinuses.

( Courtesy of Frank Virgin, MD, Nashville, TN.)

Some evidence has been suggestive that the CF carrier state is related to the development of CRS in the general population. In 2000, Wang and colleagues discovered that adult CRS patients were more likely to harbor a mutation associated with CF than a control group. In 2002, Raman and colleagues found the same to be true in children with CRS. In 2005, Wang and colleagues demonstrated that known CF carriers had a higher prevalence of CRS than the general population. Although this does not explain all forms of CRS, it may explain some forms given the high prevalence of CF carrier status. Furthermore, the phenotypic variability of CF may correspond with a tendency for carriers of the same genes to develop CRS. Further investigation is warranted.

Although controversial, treatment of the sinuses in CF patients may benefit pulmonary function. In 1990, it was noticed that aggressive sinonasal management decreased the frequency of pulmonary exacerbations. It has been suggested that the paranasal sinuses may act as a reservoir for pathogens that are responsible for acute exacerbations of sinusitis as well as seeding the lungs. The findings of Holzmann and colleagues demonstrated a significant correlation in lung transplant patients between the sinus aspirates and bronchoalveolar lavage specimens, lending support to this proposed mechanism. Furthermore, they found that successful management of the sinuses led to fewer pneumonias and episodes of tracheobronchitis. Surgical treatment of the sinuses has also been shown to significantly improve nasal obstruction, rhinorrhea, olfactory dysfunction, cough, and congestion, and to improve quality of life. Virgin and colleagues demonstrated that CF patients who underwent surgical therapy with modified endoscopic medial maxillectomies had improved symptoms scores, endoscopic scores, and fewer hospital admissions due to pulmonary exacerbations, although the forced expiratory volume in 1 second did not change. Although surgery does not offer a cure, it does facilitate better medical management of the sinuses. Still, many CF patients will require revision surgery with some estimates ranging from 37% to 58%. Medical management for CF includes frequent sinonasal irrigations to help facilitate the mucociliary apparatus. Topical steroids have been shown to improve endoscopic findings, but have not altered symptoms. However, they are still often recommended. Topical dornase alfa has been shown to improve symptoms and endoscopic findings. One of the largest breakthroughs in CF treatment is the use of ivacaftor and lumacaftor, a potentiator and corrector of the CFTR channels, respectively. They are only approved for 10 mutations carried by approximately 7% of the CF population, but preliminary results are promising. To date, no large studies exist focusing specifically on their effect on CRS associated with CF.

A more in-depth discussion of CF can be found elsewhere in this issue.

Innate immunity and cytokines

The innate immune system is evolutionarily old. In the sinonasal cavity, it is made up of epithelial cells, pattern recognition receptors, and other cytokines that work in concert as a nonspecific defense mechanism. It does not function independently of the adaptive immune system, but the innate immune system serves as the body’s initial defense. Lane and colleagues suggested that “the ultimate common pathway of immune activation that characterizes CRS is an abnormal response to a trigger at the mucosal surface.” Impairment of the innate immune system renders the mucosal surface vulnerable to insult, that stimulates the adaptive changes observed in CRS. Sinonasal epithelial cells serve several functions in host defense. They form a mechanical barrier and facilitate mucociliary clearance, which has been suggested to be the primary mechanism of sinonasal innate immunity. Epithelial cells also express pattern recognition receptors to allow for identification of pathogens in the form of toll-like receptors (TLR), transmembrane receptors that interact with pathogen ligands and are involved in signal transduction. Recent studies investigating the relationship of certain TLRs to CRSwNP provided evidence linking innate immunity with CRS. Patients with surgically recalcitrant CRSwNP have been shown to have lower levels of TLR-9 activity, contributing to the hypothesis that the underactivity of the innate immune system in sinonasal mucosa may play a role in the perpetuation of Th2 inflammation and failure to restore the Th1-Th2 balance in CRSwNP. It has also been shown that patients with CRSwNP who develop early recurrence of polyps after surgery had a lower level of TLR-2 (recognizes peptidoglycan) and TLR-9 (recognizes bacterial/viral DNA) than surgically responsive counterparts. Furthermore, Ramanathan and colleagues demonstrated that exposure of sinonasal epithelial cells from non-CRS patients to IL-4 or IL-13, 2 cytokines associated with Th2-inflammatory disease, resulted in decreased expression of TLR-9 genes, suggesting a link between Th2-inflammation and genes associated with innate immunity. It has been suggested that the downregulation of TLR-9 in recalcitrant CRSwNP may contribute to colonization of the sinuses with noncommensal organisms, because there is evidence to suggest increased colonization with bacteria and fungi. TLRs appear to be an important link between innate immunity and CRSwNP and represent an exciting newer area of research.

In addition to TLRs, cytokines and cell signaling molecules play a large role in mediating innate and adaptive immunity. Interleukins have been shown to mediate CRS—specifically, IL-3, IL-5, IL-6, IL-8, and IL-13 are involved in the activation of eosinophils in nasal polyps. Staikuniene and colleagues suggested that eotaxin-3, a known indicator of eosinophil chemotaxis and activation, may be a driver of CRSwNP via recruitment of eosinophils, IL-25 and IL-33 have also been identified in CRSwNP. IL-33 is a cytokine that is normally retained in the nucleus of basal epithelial cells. When tissue damage occurs, various intracellular molecules are released that broadly elicit an innate immune response. Tissue damage has been shown to be a nonspecific trigger of epithelial IL-33 in recalcitrant nasal polyps. IL-16 is a cytokine that functions as a potent chemoattractant for eosinophils. Elevated serum and tissue levels of IL-16 have been found to be associated with CRSwNP. IL-22 is a T-helper cell-derived cytokine that has been speculated to play a role in innate immunity. Polarization of T cells toward a Th2 phenotype has been shown to lower IL-22 production. Stimulation of IL-22 receptor-1 (IL-22R1) has been shown to nonspecifically increase the innate immune response in skin and bowel inflammatory diseases, and CRSwNP tissue demonstrated decreased expression of the IL-22R1 compared with CRSsNP. Interestingly, in the same study, IL-22 levels of recalcitrant CRSwNP were elevated compared with those of controls and medically responsive CRSwNP, although without statistical significance. This observation suggests another link between innate immunity and the Th2 phenotype commonly observed in CRSwNP. Further discussion of various cytokines can be found in this issue.

Nitric oxide (NO) is another chemical that aids in innate immunity. The paranasal sinuses have been shown to be a reservoir of NO. Levels of exhaled NO are decreased in patients with CF, CRS (with and without polyposis), and acute rhinosinusitis, and levels have been shown to increase after successful treatment of CRS with surgery. NO functions as a vasodilator, smooth muscle relaxer, and regulator of inflammation and innate immunity. It has been shown to be involved in ciliary motion in that low NO is associated with ciliary dyskinesia. NO has also been shown to be involved in antibacterial defense; it can diffuse inside of cells and change bacterial DNA, enzymes, and lipids on membranes. In vitro studies have also shown that NO is bactericidal against P aeruginosa . NO remains a potential site of intervention to improve sinonasal health in patients with CRS.

Staphylococcal superantigens

The development of CRSwNP has long been suggested to be due to allergy and infection. Some have suggested that there may be a link between the 2, and that the microbes themselves may be amplifying the immune response in unique ways, lending support to the concept of superantigen participation in CRSwNP. Superantigens are molecules that trigger an inordinately large T-cell response and have been implicated in CRSwNP. They have been suggested to participate in the pathophysiology of other chronic disease processes that are characterized by inflammation : rheumatoid arthritis, diabetes mellitus, rheumatic fever, Kawasaki disease, and toxic shock syndrome. They are 10,000 times more potent than conventional antigens. Superantigens do not require processing by antigen-presenting cells, instead binding directly to the MHC complex. Simultaneously, they bind to the T-cell receptor outside the typical antigen-binding site to form a “clamp” between the T cell and the antigen-presenting cell. This action results in a massive release of Th-1 and Th-2 cytokines. Activation of up to 30% of all host T cells can occur in response to superantigens because many superantigens are capable of binding to several T-cell receptor variable beta gene motifs.

S aureus is a ubiquitous bacterium. Reports have suggested that approximately 29% of the population in the United States is colonized with S aureus , and 1.5% is colonized with methicillin-resistant Staphylococcus aureus (MRSA), although they are asymptomatic. Approximately 25% of people have been found to be nasal carriers of S aureus , and up to 60% of patients with CRSwNP have been found to be colonized with S aureus . MRSA has been reported in 2% to 21% of sinonasal culture isolates. It is one of the most common bacteria to colonize the paranasal sinuses in both asymptomatic postoperative and operative patients with CRS. The process of autogenous infection is supported by the observation of 80% concordance between S aureus isolated from the infection site and the anterior nasal cavity. Some have suggested that carriers are genetically asymptomatic, whereas those who develop signs and symptoms of sinusitis are genetically susceptible.

S aureus superantigens have been implicated in the development of asthma and allergy and have been suggested to participate in the development of CRSwNP. S aureus is known to have 6 groups of enterotoxins (SAEs): Staphylococcal enterotoxin-A (SEA), Staphylococcal enterotoxin-B (SEB), Staphylococcal enterotoxin-C, Staphylococcal enterotoxin-D, Staphylococcal enterotoxin-E, and Toxic Shock Syndrome Toxin-1. SEB has been shown to polarize mucosal inflammation to a Th-2 pattern. This observation has led to the concept that in a genetically susceptible host, superantigen production may drive inflammatory patterns implicated in CRSwNP. Several studies lend support to this possibility. High levels of SEA and SEB have been observed in the nasal secretions of patients with CRS and asthma. Corriveau and colleagues reported a higher rate of intramucosal colonization of S aureus in patients with CRSwNP compared with controls and patients with CRSsNP. A meta-analysis with 340 cases demonstrated a higher culture-positive rate in patients with CRSwNP compared with controls. Immunologic mediators have been used to demonstrate the presence of superantigens in CRSwNP. Staphylococcal IgE antibodies have been detected in 78% of cases of CRSwNP, and Bachert and colleagues found that 50% of sinonasal tissue from patients with CRSwNP demonstrated IgE antibodies directed at SEA and SEB. A meta-analysis in 2014 showed that S aureus superantigens and their specific IgE were detected in higher concentrations in patients with CRSwNP. Some research has focused on specifics in immunology. For example, in vitro studies in mice have shown that S aureus superantigens have been shown to augment isotype switching and synthesis. The immunoglobulin variable beta chain region appears to be involved in enterotoxin stimulation of the immunoglobulin response. Bernstein and colleagues showed that the clonal expansion of the variable beta chain correlated with the observed enterotoxin. Another study demonstrated that T-cell receptor variable beta chain expansion was noted in 58% of patients with CRSwNP. Both findings suggest that T-cell receptors with specific variable beta chains are expanded and activated, whereas those without the T-cell receptor variable beta chain are excluded.

Superantigens have also been observed to directly affect sinonasal mucosa. Min and colleagues demonstrated that in rabbit sinonasal mucosa SEA induces subepithelial edema and inflammatory cell infiltrate and decreases ciliary beat frequency. Another study showed that polyp tissue from patients exhibiting an immune response to SAEs had higher levels of cysteinyl leukotrienes, lipoxin A-4, and leukotriene B-4 compared with enterotoxin IgE-negative nasal polyps. Stimulation of human nasal epithelial cells with SEB has been associated with an increased presence of proinflammatory mediators and prolonged eosinophil survival. The effect of SAEs on sinonasal mucosa in CRS (and nasal polyps) establishes a link between the immune response observed in CRS and the microbiology observed in CRS.

Although most studies investigating S aureus superantigens appear to corroborate their contribution to the development of CRSwNP, some studies do not. Damm and colleagues showed that the nasal Staphylococcal culture rate in patients with CRSwNP were no higher than the control group, and the carrier condition was not a risk factor of disease extent and severity. Furthermore, a relationship between S aureus superantigen genes and the severity of nasal polyposis was not identified.

Most of the evidence suggests that superantigens are involved in CRSwNP, but much still needs to be learned about their treatment. It is crucial for the clinician to obtain a culture and sensitivity because there are differences in community-acquired bacteria compared with hospital-acquired counterparts. Many different regimens have been proposed for the treatment of S aureus (including MRSA). McCoul and colleagues comparatively reviewed systemic antibiotics, topical mupirocin, nebulized solutions, and chlorhexidine baths. No regimen was found to be statistically superior. Steroids have long been a mainstay of management of CRSwNP. Some have suggested that superantigens may participate in steroid insensitivity. Wang and colleagues further expounded on this concept. Tissue samples obtained from patients with CRSwNP and CRSsNP were exposed to Staphylococcus exotoxins and tested for a glucocorticoid receptor. Among polyp patients, 72% of recurrent polyp patients and 55% of primary polyp patients tested positive for the receptor, whereas only 6% of patients with CRSsNP tested positive, and no controls tested positive. These results suggest that more refractory CRSwNP may be related to the presence of a glucocorticoid receptor that is induced by Staphylococcal exotoxins, resulting in steroid insensitivity.

Much still remains to be learned about S aureus superantigen. Although its presence has certainly been associated with CRSwNP, the appropriate management regimens remain to be elucidated.