Chronic rhinosinusitis (CRS) is a condition characterized by persistent inflammation due to intrinsic mucosal hypersensitivity or persistent infection. Proper medical treatment with antibiotic, leukotriene modifiers, oral corticosteroids, or even aspirin desensitization for the sinus inflammation can prevent the need for surgical intervention. The key to delineating the specific medical application is to determine the cause of the sinus mucosa dysfunction and its specific inflammatory pathway. Such targeted antiinflammatory medical therapy will lead to improved efficacy in the management of CRS. Even if surgical intervention is required, postoperative medical treatment is essential to minimizing the intrinsic mucosal inflammation and therefore preventing revision endoscopic procedures.
Despite affecting approximately 20 million Americans, chronic rhinosinusitis (CRS) remains a frustrating and controversial disease entity. Traditional theories on the pathogenesis of CRS have centered on anatomic obstruction, resulting in bacterial infection. This convention has guided antimicrobial and surgical therapies for decades. Although this approach has yielded some success, many patients continue to suffer from CRS despite surgical and medical therapy. Such frustrations have resulted in a shift in focus toward further elucidating the pathogenesis and developing directed therapies. The cornerstone of this approach is the acknowledgment that allergy and inflammation may not only simply exacerbate CRS but also may play a role in its development. Such a paradigm shift allows researchers and clinicians to pursue systemic therapies that target mucosal inflammation and the allergic response as a new means of treating CRS.
CRS is a heterogeneous spectrum disorder that is constantly being further categorized and classified. Classically, patients with CRS can be divided by the presence or lack of polyps. Such a distinction between CRS with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP) demonstrates not only a clinical but also a pathologic difference. Although a poignant inflammatory response is seen in each subset of CRS, the features of each subset vary greatly. Nasal polyp inflammation is predominantly mediated by eosinophils, which constitute 60% of the mucosal cell population. This presence of a large proportion of eosinophils points toward a mast cell– and histamine-associated response. This proposition is further supported by the demonstration of not only high levels of eosinophils in polypoid tissue but also of increased levels of histamine, interleukin (IL) 5, and IL-13. Most of the systemic therapies currently in use seek to treat CRS by disruption of these cytokines and their associated inflammatory cascade.
CRSsNP at first glance seems to be a more straightforward process. Much like acute sinusitis, neutrophils dominate mucosal inflammation in CRSsNP. However, this distinction proves an oversimplification. All CRSsNP are not created equal. Those affected by allergy or asthma may in fact have extensive infiltration by eosinophils, much like CRSwNP. It is therefore possible to see mucosal hypereosinophilia separate from polypoid disease. Such a complex subset indicates the possibility for further categorization of CRS, which may allow for more patient-specific targeted therapy.
The diversity of CRS demands varied and new treatment approaches. Although the final role of systemic therapies remains unsettled, their development combined with the better understanding for the cause of CRS should present a new avenue for CRS therapy.
Antileukotrienes
Leukotrienes are produced by the lipoxygenase pathway from the initial substrate of arachidonic acid. The pathway eventually results in 3 clinically significant leukotrienes: LTC4, LTD4, and LTE4. These products all contain cysteine and are therefore collectively known as cysteinyl leukotrienes, or cys-LTs. Cysteinyl leukotrienes are stored in many different cells, including mast cells. Mast cell release of leukotrienes seems to spur on inflammation and act as early- and late-phase mediators to the allergic response.
As with most systemic therapies, mostof the research involving CRS and antileukotrienes centers on patients with nasal polyposis. As early as 1987, Jung and colleagues had identified elevated levels of leukotrienes in patients with Samter triad. In further research, by challenging aspirin-sensitive patients, researchers observed mast cell activation. The resultant nasal tryptase, histamine, and leukotriene levels were deemed essential for the nasal symptoms experienced in these patients.
Currently, 2 therapeutic approaches exist to control the inflammatory effect of cysteinyl leukotrienes. Medications named with the suffix -lukast, such as montelukast or zafirlukast, bind to cysteinyl leukotriene receptors, whereas the drug zileuton works in a different fashion by inhibiting the action of the enzyme 5-lipoxygenase. Initially, the ability of these medications to reduce nasal symptoms was observed anecdotally in asthmatic patients with nasal polyps undergoing therapy. In 1999, Parnes and Chuma examined the acute effects of antileukotrienes in patients with CRSwNP. These patients were treated in a prospective manner with zafirlukast initially with crossover to zileuton for failure to respond to zafirlukast. Overall, the therapy resulted in reduction of polyps which was observed by endoscopy, decreased steroid use, and improvement in patient-reported symptoms. This study, however, was limited by open trial design and short follow-up. There have been other studies that have also demonstrated the benefit of the use of leukotriene modifiers in reducing polyp size and subjective improvement of patients with CRSwNP, but there remains a paucity of well-designed randomized controlled trials examining the effectiveness of antileukotrienes in patients with CRS.
Although there is a scarcity of robust data to demonstrate that leukotriene modifiers may be beneficial for patients with CRS, this does not translate to lack of benefit. Cysteinyl leukotriene receptor antagonists are most likely to be helpful in patients with allergic rhinitis and asthma that have sinusitis because leukotrienes are responsible for the chronic inflammation in these patients. Patients with extremely elevated levels of cysteinyl leukotrienes such as in aspirin triad, also known as aspirin exacerbated respiratory disease (AERD), are less likely to benefit from cysteinyl leukotriene receptors antagonists and more likely to benefit from lipoxygenase inhibitors such as zileuton, which decrease cysteinyl leukotriene production higher upstream. However, the use of zileuton requires careful monitoring of the liver enzymes to monitor liver toxicity. Although patients with severe polyposis may benefit from this group of medications, further rigid investigation is necessary.
Corticosteroids
The use of oral corticosteroids such as prednisone in CRS, particularly in patients with nasal polyps (CRSwNP), has been advocated for decades. Initial anecdotal evidence has been supported by years of successful clinical implementation. With further understanding of the role of eosinophils in CRS comes a possible explanation for the effect of corticosteroids. It is proposed that the benefit observed might stem from the ability of corticosteroids to limit the availability of IL-1, IL-3, and IL-5, all of which are necessary for eosinophil survival. Effects of steroids on inflammatory cytokines were further examined by Lennard and colleagues in 2000. This small study evaluated cytokine profiles in patients with CRS by nasal biopsy before and after a short course of systemic steroids. They noted a significant decrease in IL-6 levels with other cytokines, including tumor necrosis factor α trending toward significance. This research did not attempt to correlate their findings with symptom relief.
In an attempt to evaluate symptomatic relief, several open label trials have examined corticosteroid use in CRS. These studies have often combined oral with topical treatment and have demonstrated improvements in nasal symptoms including congestion and olfaction. Despite the widespread use of this treatment modality, few randomized trials exist. A randomized, controlled, double-blind study demonstrated improved nasal symptom scores when comparing placebo with a 14-day treatment with 50 mg prednisolone. In the same study, patients were found to have reduction of nasal polyp size on magnetic resonance imaging and endoscopy.
Years of clinical practice and some focused research have shown the possible benefits of systemic corticosteroids in CRS, particularly in patients with polyposis. With the available data it seems reasonable to recommend the use of corticosteroids in a multifaceted treatment plan including other systemic therapies and topical agents. Although further investigation into the mechanisms and extent of efficacy of corticosteroids in CRS is needed, their success, particularly in the treatment of nasal polyposis, is apparent. Less clear is the role, if any, of corticosteroids in patients with CRSsNP. There is currently no evidence to support the use of oral or topical steroids despite anecdotal clinical success.
Oral steroids should be used judiciously, understanding the potential complications associated with the long-term use of corticosteroid, such as adrenal suppression and bone density loss. In children, the risk for inhibition of the hypothalamic pituitary adrenal axis should be strongly considered, and therefore oral steroid use should be minimized as much as possible.
Corticosteroids
The use of oral corticosteroids such as prednisone in CRS, particularly in patients with nasal polyps (CRSwNP), has been advocated for decades. Initial anecdotal evidence has been supported by years of successful clinical implementation. With further understanding of the role of eosinophils in CRS comes a possible explanation for the effect of corticosteroids. It is proposed that the benefit observed might stem from the ability of corticosteroids to limit the availability of IL-1, IL-3, and IL-5, all of which are necessary for eosinophil survival. Effects of steroids on inflammatory cytokines were further examined by Lennard and colleagues in 2000. This small study evaluated cytokine profiles in patients with CRS by nasal biopsy before and after a short course of systemic steroids. They noted a significant decrease in IL-6 levels with other cytokines, including tumor necrosis factor α trending toward significance. This research did not attempt to correlate their findings with symptom relief.
In an attempt to evaluate symptomatic relief, several open label trials have examined corticosteroid use in CRS. These studies have often combined oral with topical treatment and have demonstrated improvements in nasal symptoms including congestion and olfaction. Despite the widespread use of this treatment modality, few randomized trials exist. A randomized, controlled, double-blind study demonstrated improved nasal symptom scores when comparing placebo with a 14-day treatment with 50 mg prednisolone. In the same study, patients were found to have reduction of nasal polyp size on magnetic resonance imaging and endoscopy.
Years of clinical practice and some focused research have shown the possible benefits of systemic corticosteroids in CRS, particularly in patients with polyposis. With the available data it seems reasonable to recommend the use of corticosteroids in a multifaceted treatment plan including other systemic therapies and topical agents. Although further investigation into the mechanisms and extent of efficacy of corticosteroids in CRS is needed, their success, particularly in the treatment of nasal polyposis, is apparent. Less clear is the role, if any, of corticosteroids in patients with CRSsNP. There is currently no evidence to support the use of oral or topical steroids despite anecdotal clinical success.
Oral steroids should be used judiciously, understanding the potential complications associated with the long-term use of corticosteroid, such as adrenal suppression and bone density loss. In children, the risk for inhibition of the hypothalamic pituitary adrenal axis should be strongly considered, and therefore oral steroid use should be minimized as much as possible.
Immunotherapy
The pathogenesis of CRS has been influenced by the unified airway theory. This theory represents a movement to view allergic rhinitis, CRS, and asthma as similar entities resulting from generalized inflammation. These previously separate conditions could variably affect the development of, or alter the course of, one another. Researchers and clinicians have noticed that therapies directed at one disease process often have benefits on other aspects of symptomatology. Such interplay was demonstrated when management of sinusitis resulted in improvement of asthma symptoms. In keeping with this trend, if one could prevent the inflammation associated with allergic rhinitis caused by seasonal allergies, perhaps patients would also experience improvement in their CRS symptoms.
Immunotherapy achieves its effects by modulating the immunoglobulin and T lymphocyte responses. After several months of immunotherapy, a shift in the circulating allergy-specific immunoglobulin occurs with an increase in IgG4 level, which may serve to block IgE-mediated release of histamine. The response of T lymphocytes to allergens is also altered with a shift from T H 2 to T H 1 predominance. This alters the cytokines produced from T H 2 (IL-4, IL-5, and IL-13) to T H 1 cytokines (interferon gamma and IL-2). Such a transition away from the T H 2-driven inflammatory process involved in CRS could have therapeutic effects. One study compared the nasal eosinophil and cytokine profiles of patients treated with ragweed immunotherapy with placebo. After a course of therapy, nasal biopsies were performed on treatment and control groups after allergen challenge. Biopsy specimens demonstrated significantly decreased level of eosinophils and IL-4–mRNA positive cells in the treatment group. Such findings support a shift from T H 2 to T H 1 cytokine production. In addition, after prolonged follow-up, treatment group patients experienced a significant reduction in chest symptoms and a trend toward improved nasal symptoms. This research points to the profound effect that treatment with immunotherapy can have a local tissue response to allergen. At least in theory some patients with CRS should benefit from the decreased inflammatory response offered by immunotherapy. Even though the cause-and-effect relationship between allergic rhinitis, asthma, and sinusitis is not completely clear, it is reasonable to evaluate patients with CRS for allergy in an attempt to remove an additional insulting inflammatory process.
Subcutaneous Immunotherapy and Sublingual Immunotherapy
There are no clinical trials examining the efficacy of subcutaneous (SCIT) or sublingual immunotherapy (SLIT) in CRS. Nevertheless, to successfully treat patients with CRS with coinciding atopy, an understanding of the practice of immunotherapy is crucial. Although not one article or review is likely to settle the debate between SCIT and SLIT, it is reasonable to delineate the efficacy, safety, and practical considerations associated with both. With the increasing involvement of otolaryngologists in allergy and immunotherapy, these basic tenets are important to understand even though one may perform either SCIT or SLIT.
The efficacy of SCIT has been evaluated in multiple trials over the past several decades with typically positive results. A Cochrane review was undertaken by Calderon and colleagues to assess the available randomized data. This review included a total of 2871 patients. Although the studies included were found to be somewhat heterogeneous, meta-analysis did reveal significant improvements in symptom scores and medication use.
It has long been accepted that there is a small but real risk associated with SCIT. In surveys of allergy practitioners, fatal reactions are estimated to occur in 1 in every 2 to 2.8 million injections. Until recently there was little quantification of nonfatal but severe reactions. Near-fatal reactions are defined as severe respiratory compromise, hypotension, or both, requiring emergency epinephrine treatment. A large survey by Amin and colleagues determined that serious near-fatal reactions were 2.5 times more likely than fatal reactions, with 1 event per million doses. This rate would result in 5 such reactions per year in the United States. Asthma was found to be an important risk factor for a reaction. Eighty-eight percent of fatal reactions and 46% of near-fatal reactions were found in asthmatic patients. With regard to severity of reaction, 88% of reported incidents involved hypotension, whereas only 10% of patients developed severe respiratory distress. All of those patients experiencing severe respiratory symptoms were known to have asthma. It must also be realized that dosing error was found to be at fault in 25% of cases in which cause could be determined. These results should give some guidance toward identifying those rare patients who may have a serious or fatal reaction to SCIT, allowing for refinement and improvement of practice.
With the limited availability of SLIT in the United States most clinical trials have taken place in Europe or Asia. In 2005, Wilson and colleagues sought to review the available research in a large meta-analysis study. As in the review by Calderon and colleagues a significant improvement and reduction in the need for medication was once again demonstrated. In general, the safety profile of SLIT is considered to be better than that of SCIT. To date there have been no reported deaths and only 3 case reports of anaphylaxis. However, as the use of SLIT increases over the next few decades, these numbers may change.
At this time in the United States, immunotherapy is an underused tool. Although there are approximately 55 million Americans with allergy in the United States, only 2 to 3 million patients are currently receiving immunotherapy. The benefits of SLIT including home dosing and decreased risk of systemic reactions seem to offer practical means to increase the number of patients treated. However, more investigation is needed to fully understand the exact dosing and potential amount of extract required in determining evidence-based approach for the guideline of SLIT antigen or extract. It is even possible that the doses required may be too high to practically treat millions of patients with SLIT. Clearly, more research is needed. The effect of allergy on CRS is indisputable, but how they are exactly related remains unclear. The heterogeneous nature of CRS still requires further delineation because it relates to atopy; however, early identification and treatment of patients in whom allergic rhinitis effects CRS may minimize further disease progression of CRS and provide an early-preventative and cost-effective intervention.
Immunomodulators
With the recognition that certain cytokines and mediators play a role in allergic rhinitis and CRS, inevitably came the strategy to target and disable these propagators of inflammation. The interrelationship of IL-5 with eosinophils and mast cells made it an ideal initial target for the creation of a monoclonal antibody. Early research focused on treatment of asthma with mepolizumab. Initial in vitro studies showed promising results, demonstrating decreased tissue eosinophilia and apoptosis. Although Leckie and colleagues were able to show an 80% to 90% reduction of circulating eosinophils with a one time dose, their study was underpowered for efficacy. Later, a pilot study examining a competitor’s product SCH55700 failed to effect lung function in controlled clinical trials.
The use of IL-5 monoclonal antibodies in CRS was initially spurred on by the role of IL-5 in the recruitment, maturation, and activation of eosinophils in nasal polyposis. Randomized data for IL-5 therapy in nasal polyposis have thus far been limited to a few small studies. For example, Gevaert and colleagues evaluated patients with CRSwNP who were treated with a one time dose of placebo, 1 mg/kg or 3 mg/kg of anti-IL-5 and monitored for change in blood eosinophil levels as well as levels of serum and nasal eosinophil cationic protein. Although their results pointed toward an improvement in the treatment group, there was no statistical difference among the control and treatment groups. One possible explanation for the lack of statistical significance is that the CRSwNP groups are a mixture of different diseases. When the subjects in the treatment arms were divided into responders and nonresponders, those demonstrating a measurable response were significantly more likely to have a higher baseline IL-5 level. The treatment appeared safe with no increase in adverse events compared with placebo.
In 2009, 2 research groups published randomized controlled studies describing the effective use of mepolizumab in a subset of severe asthmatic patients with sputum eosinophilia. Parameswaran and colleagues worked on 20 patients with prednisone-dependent asthma and were able to show a significant reduction of asthma exacerbations as well as improvement in level of serum eosinophils, asthma control, and forced expiratory volume in the first second of expiration (FEV 1 ). Similarly, Halder and colleagues also demonstrated a reduced number of exacerbations in 61 patients with refractory eosinophilic asthma. However, no significant change was found in FEV 1 , bronchodilator use, airway hyperresponsiveness, or asthma symptoms. These trials are limited by their size and seem to be applicable to a small subset of patients with asthma. However, the successful use of anti-IL-5 in a particular type of asthmatic patient may provide a guiding influence for further research in CRS.
IL-5 has not stood alone as the only target of monoclonal antibody therapy. Omalizumab, a monoclonal antibody against IgE, has received approval for treatment of severe asthma. In particular, patients with severe persistent allergic asthma have been shown to benefit from omalizumab. Most notably, the Investigation of Omalizumab in Severe Asthma Treatment trial showed a 26% reduction in exacerbations compared with placebo when more than 400 such patients were treated in a randomized fashion.
Success in the treatment of allergic asthma has led to several studies investigating the efficacy of anti-IgE therapy in allergic rhinitis. Two such studies have found improvements in symptoms and quality of life. Success in asthma and rhinitis has prompted some limited use of anti-IgE therapy in patients with CRSwNP. A pilot study analyzing the treatment of nasal polyposis with anti-IgE has shown promising, although limited, results. Another small study with 8 patients treated with omalizumab was found to have improvement in nasal polyp scores when compared with a control group of similar untreated patients.
Immunomodulators offer an interesting new frontier in the treatment of CRS. Further research involving well-designed and well-selected randomized trials is necessary. It is important not to ignore the practical issues involved in these therapies. Whereas mepolizumab has yet to become commercially available, omalizumab currently costs $694 for a 150-mg dose. Because of their cost, their use must be rationed to those patients refractory to other treatments in which clinical benefit seems likely. With this possible limitation in mind, focus in immunomodulation should be placed on determining the cytokine characteristics and specific patient populations that will allow for effective targeted therapy. Again a cornerstone to providing the correct medical treatment is to better define the different pathophysiology of CRS with specific cytokine profiles so that the benefit from immunomodulation can be reaped. Studies so far appear to point toward the future of immunomodulator therapy in CRS, but much research and treatment outcomes still need to be addressed.
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