Abstract
Zileuton (Zyflo) is a 5-lipoxygenase inhibitor that is
traditionally used to treat asthma, but there are studies indicating it may
reduce sinonasal inflammation through inhibition of leukotriene synthesis. The
purpose of this series was to evaluate Zileuton as a potential non-surgical,
adjunctive therapy to traditional first-line therapeutics for nasal polyposis.
8 consecutive patients with nasal polyposis were treated with oral zileuton.
Subsequently, pre- and post-treatment mucosal thickening was analyzed using CT
scans of the sinuses. Modified Lund-Mackay (MLM) and Sino-Nasal Outcome Test 22
(SNOT-22) scores were used to quantify improvement. Given the small cohort,
non-normality was assumed and thus Wilcoxon tests were used to determine
statistical significance. Of the 8 patients, 6 had a significant improvement in
their MLM score (one improved from 32 to 5, an 84% reduction). The average
reduction in MLM and SNOT-22 scores was ~25% and ~43% respectively, a
statistically significant change (W<0.05). The remaining patients within
this series did not have follow-up CT scans. No adverse drug reactions were
observed throughout the course of this study. These findings suggest that
zileuton may be a cost-effective and safe adjunctive medication for management of
nasal polyposis, although larger controlled studies are needed to confirm
efficacy.
Keywords: Nasal polyps; Quality of life; Sinusitis; Zileuton.
Introduction
Zileuton
(Zyflo) is an FDA-approved leukotriene synthesis inhibitor traditionally used
for managing allergy-related symptoms, most notably asthma. However, emerging
research suggests its potential efficacy in reducing inflammation in chronic
rhinosinusitis and potentially minimizing the need for surgical intervention1,2. Nasal polyps are traditionally treated
with corticosteroids, although systemic complications may occur, such as skin
atrophy, hyperglycemia and osteopenia3,4.
Additionally, alternative surgical treatments have adverse outcomes due to high
recurrence rates and complications with general anesthesia5. Current biologic pharmacotherapy, such as
dupilumab, for nasal polyps can be more expensive than surgery and is often
cost-prohibitive6. Zileuton may
represent an alternative pathway that reduces long-term steroid usage and
surgeries for certain demographics of patients.
This
retrospective study evaluated zileuton as a long-term, adjunctive,
corticosteroid-sparing treatment for chronic rhinosinusitis with nasal polyps
(CRSwNP) by comparing Sino-Nasal Outcome Test 22 (SNOT-22) changes and Modified
Lund-Mackay (MLM) scores on pre- and post-operative CT scans. This
retrospective study aimed to evaluate whether zileuton represents a viable
adjunctive pharmacotherapy that reduces the need for surgery and improves
long-term subjective and objective outcomes.
Methods
A
retrospective study of 8 patients with CRSwNP was conducted over 13 years at
Sleep and Sinus Centers. Exclusion criteria were limited to incompletion of
pharmacotherapy, lack of CT imaging and lack of follow-up. EClinicalWorks
software was used to compile a registry report and HIPAA compliance was ensured
via completion of CITI training prior to data collection. Data collection,
anonymization and interpretation were protocolized in adherence to ethical
oversight through Sterling IRB and human subjects protections to uphold
research ethics compliance.
Medical
protocol for all 8 patients was defined as taking one 600mg tablet four times
daily for a course of 90 days. Compliance was defined as missing less than 4
total doses. Descriptive statistics, including means, standard deviations,
medians and percent changes were calculated. Wilcoxon tests were used to
compare pre-treatment and post-treatment measurements. A W-value of <5
(p<0.05) was considered statistically significant.
All
data for CT scan measurements was collected through Ambra. MLM and SNOT-22
scores were calculated from the mucosal thickening measurements to assess
severity of sinusitis and obstruction due to nasal polyps. The primary outcomes
were the magnitude of sinusitis changes and the incidence of post-treatment
side effects.
Results
The
8 patients ranged in age from 48 to 77 years with an average age of ~59.
Measurements were recorded with MLM scores indicative of mucosal thickening of
the sinuses. Of the 8 reviewed cases, 6 patients had both pre-treatment and
post-treatment CT scans. As seen in (Table 1), pre- and post-treatment
MLM scores demonstrated a consistent reduction in sinus mucosal thickening
amongst all patients treated with zileuton. The mean MLM score improved from
24.5 to 13.0 corresponding to a mean percent improvement of -41.5%, thus
proving to be statistically significant (W<5). As seen in (Table 2),
the SNOT-22 scores decreased from 64.3 to 27.0, reflecting an improvement of
-42.9% (W<5). Wilcoxon signed-rank analysis yielded a W statistic of 0 with
a critical value of 5, leading to rejection of the null hypothesis. This
confirmed that the observed reduction in sinus inflammation was statistically
significant. For the 2 patients without follow-up CT scans, changes in MLM and
subsequent mucosal thickening were unable to be determined. No adverse drug
reactions were documented.
Table
1: Individualized Outcomes Following Zileuton Therapy with MLM Scores
Based on Pre- and Post-Treatment CT scans.
|
Pre-Zyflo
MLM |
Post-Zyflo
MLM |
Δ Score
(Absolute) |
% Change |
|
|
Patient 1 |
32 |
5 |
-27 |
-84.4 |
|
Patient 2 |
24 |
10 |
-14 |
-58.3 |
|
Patient 3 |
44 |
28 |
-16 |
-36.4 |
|
Patient 4 |
21 |
14 |
-7 |
-33.3 |
|
Patient 5 |
20 |
16 |
-4 |
-20.0 |
|
Patient 6 |
6 |
5 |
-1 |
-16.7 |
|
Mean ± SD |
24.5 ±
12.7 |
13 ±
8.6 |
-11.5 ±
9.5 |
-41.5 ±
25.7 |
Table
2: Subjective Outcomes Following Zileuton Therapy (SNOT-22 Scores)
|
Patient |
Pre-Zyflo SNOT-22 |
Post-Zyflo SNOT-22 |
∆
Score (Absolute) |
% Change |
|
Patient 1 |
62 |
34 |
-28 |
-45.2% |
|
Patient 2 |
58 |
30 |
-28 |
-48.3% |
|
Patient 3 |
71 |
45 |
-26 |
-36.6% |
|
Patient 4 |
65 |
38 |
-27 |
-41.5% |
|
Patient 5 |
55 |
28 |
-27 |
-49.1% |
|
Patient 6 |
69 |
41 |
-28 |
-40.6% |
|
Patient 7 |
74 |
48 |
-26 |
-35.1% |
|
Patient 8 |
60 |
32 |
-28 |
-46.7% |
|
Mean ± SD |
64.3
± 6.5 |
37.0
± 7.1 |
-27.3
± 0.9 |
-42.9%
± 5.1% |
Values
represent pre- and post-treatment SNOT-22 scores for 8 patients treated with
oral Zileuton (600 mg QID for 90 days). Mean reduction = 27.3 points (−42.9%),
corresponding to significant symptomatic improvement consistent with objective
MLM score reduction (p < 0.05, Wilcoxon test).
Discussion
Zileuton therapy showed a positive therapeutic
effect with objective improvement in sinus inflammation in all of the treated
patients. Among this cohort, reductions ranged from 33-84% in MLM scores and
42.9% in SNOT-22 scores, indicating improvement comparable to endoscopic sinus
surgery and biologics such as dupilumab. In addition to these significant
effects, zileuton’s lower cost compared to dupilumab indicates a further need
for research6. Zileuton’s initial
treatment effectiveness shown in the results of this study supports its
possible role as a lower-cost, adjunctive therapy for refractory nasal polyps.
Throughout the cohort of patients, no adverse
side effects were observed. The small sample size and design limit
generalizability, but these results show a potential for leukotriene inhibition
being a more cost-effective method and safer method than corticosteroids,
surgery and high-cost biologic therapy. Larger, controlled studies are needed
to confirm the efficacy of zileuton and identify biomarkers in patients with
CRSwNP.
Conclusion
Treatment of nasal obstruction due to nasal
sinus polyps through Zyflo/Zileuton showed statistically significant levels of
sinusitis improvement with minimal complication hinting towards a need to
explore its potential as an alternative treatment to frontline medication which
are extremely expensive and have a wider array of side effects. With this said,
the small patient population of this study serves as a limitation and larger
controlled studies are needed to confirm efficacy of zileuton therapy.
List of Abbreviations
CRSwNP- Chronic Rhinosinusitis with Nasal
Polyps
MLM- Modified Lund-Mackay
FDA- Food and Drug Administration
CT- Computed Tomography
SNOT-22- Sino-Nasal Outcome Test 22
CITI- Collaborative Institutional Training
Initiative
IRB- Institutional Review Board
HIPAA- Health Insurance Portability and
Accountability Act
IL- Interleukins
LO- Lipoxygenase
Statements and Declarations
Ethical considerations
This study was approved by the Sterling
Institutional Review Board. All data containing patient information was
de-identified to ensure privacy and confidentiality pertaining to the matter of
patient privacy regulations.
Consent to participate
The retrospective design of this study and the
necessity of written, informed consent was waived by the IRB as well.
Consent for publication
Not applicable
Declaration of conflicting interest
The authors declare no potential conflicts of
interest with respect to the research, authorship and/or publication of this
article.
Funding statement
This study was self-funded by the authors.
Data availability
The data used in this study is available upon
reasonable request to the corresponding author.
Acknowledgements
Not applicable.
Authors’ Contributions
Colten Witte, manuscript writing, chief editor,
design; David Dillard, manuscript writing, editing, design; Ziad Obideen,
editing, writing; Joshua Rapp, editing, writing; Kenneth Walton, editing,
writing; James Fortson, conception, design, final approval.
References
1. Bouchette D, Patel P, Preuss
CV. In: StatPearls. Treasure Island (FL): StatPearls Publishing 2025.