There are no established indications for the use of leukotriene-modifying agents in CRS. These agents are FDA approved for use in patients with allergic rhinitis and asthma and have been shown to be of benefit in these patients [1]. They have been used frequently in the treatment of aspirin triad and CRSwNP. As discussed below, limited studies in regard to use in CRS suggest a benefit of leukotriene-modifying agents in specific cases.

The most frequently used leukotriene-modifying agent is montelukast. It is a leukotriene receptor antagonist, specifically against CysLT₁. It is usually prescribed as one 10 mg tablet daily. The other commonly used leukotriene receptor antagonist is zafirlukast. Zileuton is the only 5-lipoxygenase inhibitor currently on the market.

In general, these drugs are fairly well tolerated. The most common side effect of zileuton, montelukast, and zafirlukast is headache (25 %, 18 %, and 13 % of patients, respectively). Montelukast and zafirlukast are class B pregnancy category drugs. These agents have been linked to neuropsychiatric changes, with increased agitation, disorientation, irritability, vivid dreams, depression, and suicidal ideation. Additionally, cases have been described of increased eosinophilia and vasculitis in montelukast. Unlike, zafirlukast and zileuton, liver function tests are not necessary for patients taking montelukast. Zafirlukast has been associated with Churg-Strauss syndrome and hepatitis. Careful surveillance should be undertaken when starting patients on this medication, and baseline liver function tests should be performed. It is contraindicated in patients with existing Churg-Strauss syndrome and patients with cirrhosis or liver disease. Zileuton is a class C pregnancy category drug. This drug, as well, can exacerbate underlying liver disease and is contraindicated in patients with a history of liver disease or heavy alcohol use. Zileuton also can cause similar neuropsychiatric effects. It additionally has a higher incidence of gastrointestinal symptoms.

A few randomized clinical trials exist studying the effects of antileukotrienes in CRS. There are additionally multiple case series documenting the effects of antileukotrienes on patients with CRS, with the majority of these studying aspirin triad patients.

Leukotriene-modifying agents in comparison to placebo have been studied in CRSwNP. Pauli et al. performed a randomized clinical trial comparing montelukast against placebo in CRSwNP patients [15]. The montelukast group had significant improvements in health-related quality of life symptoms, including headaches, sleep, and emotional problems, as well as objective measurement of polyp burden. Schaper et al. [16] performed a crossover study comparing montelukast to placebo in patients with CRSwNP who also had mild to moderate asthma. Overall, patients demonstrated statistically significant improvement in nasal symptoms (nasal obstruction, rhinorrhea, itching), reduction in nasal edema, increased nasal airflow, and decreased local and systemic eosinophil counts while on montelukast in comparison to placebo. A case series by Kutting et al. [17] provided montelukast to patients who had undergone multiple previous endoscopic surgeries for sinonasal polyposis. Seven out of nine patients noted significant improvement in symptoms up to 1 year out. Notably, when two patients discontinued montelukast, they suffered recurrence of their symptoms. These studies do suggest that antileukotriene medications have an overall beneficial effect when compared to placebos.

Other studies have compared leukotriene modifiers to standard nasal corticosteroids. Mostafa et al. performed a randomized controlled study treating CRS patients with sinonasal polyps postoperatively with either montelukast or beclomethasone [18]. Both groups demonstrated symptomatic improvement postoperatively, with the montelukast group showing greater improvement in postnasal drip, headache, and itching and the beclomethasone group having greater improvement in dysosmia and nasal obstruction. There was no difference in nasal polyp recurrence rates. There was no combination group or negative control group postoperatively in this study, however. Another study by Vuralkan et al. compared treatment with montelukast versus mometasone postoperatively in patients with CRSwNP, with both groups showing improvement on SNOT-22 scores and decreased sinonasal disease on CT imaging [19]. Mometasone performed slightly better than montelukast in preventing polyp recurrence. Overall, studies do not support replacement of standard nasal corticosteroid therapy with leukotriene-modifying agents, but do not symptomatic benefits and objective decrease in nasal polyposis with antileukotriene therapy.

Additional studies have focused on adding leukotriene inhibitors to patients already taking nasal corticosteroid regimens. Parnes and Chuma studied the effect of adding zileuton or zafirlukast to standard therapy in patients with CRS with sinonasal polyposis [20]. Seventy-two percent of patients reported symptomatic improvement with added antileukotriene therapy, although there were no control or comparison groups in this study. Nonaka et al. added montelukast to the treatment regimen of 20 CRSwNP patients who were already taking inhaled corticosteroids for over 1 year [21]. After 1 year of combined treatment, significant reductions in nasal polyp size, sinus disease burden, and peripheral eosinophil counts were noted. Similarly, Kieff and Busaba added montelukast to patients with nasal polyposis who had been taking intranasal corticosteroids for greater than 6 months [22]. After addition of montelukast, 71 % of patients noted symptomatic improvement, and biopsies of nasal polyps demonstrated a significant reduction in eosinophil burden. The greatest effect of montelukast, notably, was found in patients with documented allergic rhinitis, indicating that leukotriene-modifying agents may be ideally suited in CRS patients with an allergic component. Stewart et al. [23] tested for additional benefits of adding montelukast to an oral steroid course and nasal steroids for 8 weeks. They identified statistically significant improvement in headache, facial pain, and sneezing in the montelukast group, although these benefits did not last after discontinuing therapy. Ragab et al. [24] also studied the addition of montelukast to patients with CRSwNP and asthma refractory to treatment with intranasal steroids. The researchers subdivided their subjects into those with aspirin sensitivity and those without. Subjective improvement was noted in patients who were aspirin tolerant. However, other measures such as rhinometry and nasal inspiratory peak flow did not improve. Aspirin sensitivity was not associated with improvement on montelukast in this study. Overall, these studies suggest symptomatic improvement with the addition of leukotriene-modifying therapy to standard steroid therapy, although many of the studies reviewed did not have control groups.

Ulualp et al. [25

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