Role of Anti-leukotriene Agents in the Management of Chronic Rhinosinusitis with Nasal Polyps

Amber Luong, MD, PhD
Associate Professor

 

As both clinicians and patients will attest, chronic rhinosinusitis with nasal polyposis (CRSwNP) represents a challenging disease to manage. Functional endoscopic sinus surgery is often required and successful for the initial management, but the disease process typically leads to recurrence of the polyps if medical therapy is not initiated. The typical therapy involves a course of systemic steroids, intranasal steroids, and some form of nasal irrigation. Although corticosteroids are the only medications that have shown clear efficacy for CRSwNP, a number of other medications are available and used (sometimes off label) to manage CRSwNP. One such class is leukotriene inhibitors, which include montelukast (Singulair), zafirlukast (Accolate) and zileuton (Zyflo).

Leukotrienes are cytokines that are made from arachidonic acid in the presence of 5-lipoxygenase. This pathway is present in various leukocytes including mast cells, neutrophils, eosinophils and monocytes. When released, the leukotrienes bind to cysteinyl-leukotriene receptors located on the cell surface of target cells. Two receptors, known as CysLT1 and CysLT2, have been identified. These receptors are thought to mediate eosinophil recruitment, bronchospasm, vasoconstriction, mucus secretion and plasma exudation. In allergic rhinitis and allergic asthma, exposure to an allergen incites an inflammatory response which causes release of these leukotrienes, contributing to the inflammatory reaction within the nasal cavity. In addition, it is thought that leukotrienes may play a role in the inflammatory response in CRSwNP.

Leukotriene inhibitors were initially introduced for the treatment of chronic asthma. Montelukast and zafirlukast competitively block leukotriene receptors. In January 2003, montelukast received FDA approval for the use in seasonal allergies and is currently approved for the treatment of perennial allergic rhinitis in patients as young as 6 months of age. It is also used to treat other conditions including chronic idiopathic urticaria and a variety of eosinophilic conditions such as eosinophilic esophagitis and gastroenteritis. What about the role of leukotriene inhibitors in chronic rhinosinusitis?

Histologically, chronic rhinosinusitis with nasal polyps is characterized by an abundance of eosinophils and inflammatory changes. Klapan et al, (1994) analyzed the levels of leukotrienes in the nasal mucosa of patients with sinonasal polyps and compared it non-CRS patients.1 They found statistically higher levels of leukotriene C4 (LTC4) in patients with recurrent sinonasal polyps after surgery as compared to healthy controls. Higher LTC4 levels were associated with risk of recurrence of nasal polyps. Interestingly, CRS patients with aspirin sensitivity had elevated expression of cystinyl leukotriene receptor CysLt1 on inflammatory cells.2 Given the role of leukotrienes in the recruitment of eosinophils and association with recurrence of nasal polyposis, it is reasonable to hypothesize a beneficial effect of the addition of montelukast in the management of CRS with nasal polyps.

In a study evaluating the effect of antileukotriene agents on the outcome of patients with CRSwNP, either a leukotriene receptor antagonist, zafirlukast, or a 5-lipoxygenase inhibitor, zileuton, was added to the patient’s medical regimen.3 The study described improvements in subjective symptoms in 72% of patients and reduction in nasal polyps in 50% of patients. However, there were a number of weaknesses associated with this study; the study did not include a control group, and neither the investigators nor the patients were blinded. In another study evaluating the effects of antileukotriene agents in CRS with nasal polyps, Ragab found that the subset of patients with asthma had significant objective and subjective improvements.4 In addition, other nonrandomized studies have demonstrated a reduced recurrence rate of nasal polyps in patients treated with antileukotrienes.5, 6 Taken together, it would seem beneficial to add an antileukotriene to the medical therapy of patients with CRS with polyps, especially in those patients with concurrent asthma.

Interestingly, no additional clinical studies evaluating the effects of antileukotriene agents in the treatment of CRS has since been published. The latest study published addressing the effect of montelukast on bacterial sinusitis was performed in mice.7 Three different scenarios were investigated: 1) ovalbumin sensitized mice, 2) ovalbumin sensitized mice infected with S. pneumonia, and 3) normal mice infected with S. pneumonia. Montelukast or placebo was initiated prior to the inoculation with the bacteria, but 2 days after sensitization. The researchers reported a higher bacterial count in mice treated with montelukast and concluded that leukotrienes may play a role in the innate response to bacterial infection.

Another caveat associated with the use of montelukast is the possible association of the development of Churg-Strauss syndrome (CSS). The mechanism of this effect has not been elucidated, but there are several reports in the literature of this observation. The leading theory is that there is an underlying eosinophilic disorder which has been masked with the chronic corticosteroid use and only becomes unmasked with the withdrawal of the corticosteroids in lieu of other medications such as an antileukotriene.

Our clinical experience with montelukast has been mixed at best. And when effective, the effect has been mild. It is a medication that we will use in patients with CRS and nasal polyps with either allergic rhinitis and/or asthma. We also utilize antileukotrienes as a steroid sparing medication. In some patients, we have found a synergistic effect of montelukast with zileuton. Given the short half life of montelukast, the effect of montelukast can be determined within a couple of days. In addition, we have observed on a handful of patients a peripheral elevation of eosinophils with the addition of antileukotrienes. Consequently, we follow patients’ peripheral eosinophil counts.

In conclusion, anti-leukotriene agents represent an alternative class of medications that can be utilized in patients with CRS with nasal polyps with allergic rhinitis and/or asthma. Of course, it can be utilized in the management of allergic rhinitis and/or asthma without CRS. The positive effects are generally mild, but can be more dramatic when both a receptor antagonist and leukotriene inhibitor is used concurrently. Care must be taken to monitor peripheral eosinophil levels.

References

  1. Klapan I, Culo F, Culig J, et al.: Arachidonic acid metabolites and sinonasal polyposis. I. Possible prognostic value. Am J. Otolaryngol 1995, 16:396-402.
  2. Sousa AR, Parikh A, Scadding G, et al.: Leukotriene-receptor expression on nasal mucosal inflammatory cells in aspirin-sensitive rhinosinusitis. N Engl J Med 2002, 347:1493–1501.
  3. Parnes SM and Chuma AV. Acute effects of antileukotrienes on sinonasal polyposis and sinusitis. Ear Nose Throat J 2000, 79(1):18-20, 24-5.
  4. Ragab S, Parikh A, Darby YC, Scadding OK: An open audit of montelukast, a leukotriene receptor antagonist, in nasal polyposis associated with asthma. Clin Exp Allergy 2001, 31:1385–1391.
  5. Dirienzo L, Artuso A, Cerqua N: Antileukotrienes in the prevention of postoperative recurrence of nasal polyposis in ASA syndrome. Acta Otorhinolaryngol Ital 2000, 20:336–342.
  6. Grundmann T, Topfner M: Treatment of ASS-associated polyposis (ASSAP) with a cysteinyl leukotriene receptor antagonist—a prospective drug study on its anti-inflammatory effects. Laryngorhinootologie 2001, 80:576–582.
  7. Khoury P, Baroody FM, Kiemens JJ, Thompson K, and Naclerio RM: Effect of montelukast on bacterial sinusitis in allergic mice. Ann Allergy Asthma Immunol 2006, 97(3):329-35.