Association of Sinonasal Symptoms and Disease With Immune Checkpoint Inhibitor Therapy

ABSTRACT

Background

Immune checkpoint inhibitors (ICIs) are widely used for cancer therapy and are associated with immune‐related adverse events (irAEs) in various organ systems. However, data on sinonasal irAEs remain limited. This study investigates the association between ICI therapy and sinonasal conditions, including chronic rhinosinusitis (CRS) and nasal polyps, using a national health database.

Methods

This retrospective cohort study utilized the TriNetX US Network to analyze adults diagnosed with malignant neoplasms for which ICIs are an accepted treatment option. Patients treated with FDA‐approved ICIs (pembrolizumab, nivolumab, cemiplimab, atezolizumab, durvalumab, avelumab, or ipilimumab) were compared to those not receiving ICIs. Exclusion criteria included sinonasal neoplasms and prior sinus surgery. Propensity score matching on age, race, sex, and asthma diagnosis was performed. Outcomes included first‐time diagnoses of CRS, nasal polyps, and cardinal symptoms of CRS. Subgroup analyses by ICI mechanism of action and a post hoc analysis of all‐cause mortality were conducted.

Results

ICI therapy was associated with a decreased likelihood of CRS diagnosis (OR 0.90, 95% CI 0.85–0.96), nasal polyp diagnosis (OR 0.65, 95% CI 0.51–0.83), and facial pain (OR 0.74, 95% CI 0.56–0.99). Conversely, patients receiving ICIs had an increased likelihood of anosmia/parosmia or parageusia (OR 1.86, 95% CI 1.68–2.07), and rhinorrhea (OR 1.16, 95% CI 1.10–1.22). Subgroup analyses supported these findings across different ICI categories. Risk of mortality was higher among ICI‐treated patients (HR 4.09, 95% CI 4.02–4.16).

Conclusion

This is the first propensity‐matched study to evaluate the relationship between ICI therapy and sinonasal conditions, revealing a decreased risk of CRS and nasal polyps in patients undergoing ICI therapy. Future studies are needed to explore the clinical significance and mechanism of ICI‐related sinonasal symptoms.

Level of Evidence

3.

1. Introduction

Immune checkpoint inhibitors (ICIs), which suppress immune checkpoint receptor‐ligand binding to promote T‐cell activation and antitumor immunity [1], have been increasingly utilized in recent years, becoming the standard of care for approximately 8% of head and neck cancers in 2020 [1, 2, 3]. However, ICIs have been associated with immune‐related adverse events (irAEs)—including rash, arthritis, colitis, hepatitis, and endocrine disturbances—which are thought to involve abnormalities in the downstream propagation of inflammatory cascades [4, 5, 6]. This off‐target immune activation has been demonstrated in multiple organ systems, but there is a paucity of data pertaining to sinonasal irAEs [7, 8, 9, 10]. To date, there have been numerous case reports of sinusitis and nasal polyps associated with ICI therapy [9, 11, 12, 13, 14, 15]. This study aims to investigate the association of sinonasal symptoms with ICI therapy utilizing a national health database.

2. Methods/Results

This retrospective cohort study utilized the TriNetX US Network to analyze adults with a malignant neoplasm for which an ICI is an accepted treatment option, including cancers of the breast, respiratory tract, head and neck, urinary tract, genital organs, digestive organs, skin, and hematopoietic tissue. Patients treated with any of seven FDA‐approved ICIs for cancer therapy (pembrolizumab, nivolumab, cemiplimab, atezolizumab, durvalumab, avelumab, or ipilimumab) were compared to those without ICI therapy. Patients were included if they met inclusion criteria within 20 years of the date of analysis (December 6, 2024). Exclusion criteria included sinonasal neoplasms or prior sinus surgery. Patients were matched on age, race, sex, and asthma diagnosis. Outcomes included first‐time diagnosis of chronic rhinosinusitis (CRS), nasal polyps, and cardinal symptoms of CRS (including parageusia, given its association with smell perception) and were assessed using all available follow‐up data through the date of analysis. Subgroup analyses were conducted to explore associations by ICI mechanism of action, and an exploratory post hoc analysis evaluated all‐cause mortality. A sensitivity analysis adjusting for prior COVID‐19 infection and use of sinonasal medications (fluticasone, budesonide, mometasone) was also conducted. The Institutional Review Board of the University of Southern California determined this study to be exempt from approval requirements, as only de‐identified population‐level data were utilized.

Patients treated with ICI therapy had a significantly lower likelihood of CRS diagnosis (OR 0.90, 95% CI 0.85–0.96), nasal polyp diagnosis (OR 0.65, 95% CI 0.51–0.83), and facial pain (OR 0.74, 95% CI 0.56–0.99) compared to patients without ICI therapy. However, ICI therapy was associated with an increased likelihood of anosmia, parosmia, or parageusia (OR 1.86, 95% CI 1.68–2.07) and rhinorrhea (OR 1.16, 95% CI 1.10–1.22) (Table 1). These findings remained consistent across different ICI categories (Table 1) and in the sensitivity analysis adjusting for COVID‐19 and sinonasal medication use (Table S1). There was a higher risk of mortality among patients treated with ICIs (HR 4.09, 95% CI 4.02–4.16, p < 0.0001).

TABLE 1.

Sinonasal outcomes in patients treated with versus without immune checkpoint inhibitor (ICI) Therapy.

	Any ICI (N = 105,507)		Pembrolizumab only (N = 51,080)		PD‐1 inhibitors (N = 73,673)		PDL‐1 inhibitors (N = 16,070)		CTLA‐4 inhibitor (N = 1468)
	OR	95% CI	OR	95% CI	OR	95% CI	OR	95% CI	OR	95% CI
Chronic rhinosinusitis	0.90	(0.85, 0.96)	0.82	(0.75, 0.89)	0.86	(0.80, 0.92)	0.68	(0.59, 0.79)	1.31	(0.86, 1.99)
Nasal polyps	0.65	(0.51, 0.83)	0.42	(0.29, 0.62)	0.52	(0.39, 0.70)	0.44	(0.23, 0.88)	—	—
Nasal congestion	0.99	(0.93, 1.05)	0.97	(0.89, 1.06)	1.02	(0.95, 1.10)	0.99	(0.85, 1.16)	0.61	(0.35, 1.06)
Anosmia/parosmia or parageusia	1.86	(1.68, 2.07)	2.47	(2.13, 2.86)	2.47	(2.18, 2.80)	2.22	(1.72, 2.87)	1.00	(0.42, 2.41)
Rhinorrhea	1.16	(1.10, 1.22)	1.07	(0.99, 1.16)	1.10	(1.03, 1.17)	0.88	(0.76, 1.02)	2.63	(1.71, 4.04)
Facial pain	0.74	(0.56, 0.99)	0.71	(0.48, 1.04)	0.87	(0.64, 1.19)	0.46	(0.22, 0.94)	1.00	(0.42, 2.41)

Note: Bold values indicate statistically significant results.

Abbreviations: CTLA‐4: cytotoxic T‐lymphocyte‐associated antigen‐4; PD‐1: programmed cell death‐1; PDL‐1: programmed death‐ligand 1.

3. Discussion

Our findings revealed that patients receiving ICI therapy had a lower likelihood of CRS and nasal polyps, a trend that persisted across multiple sub‐analyses. The observed prevalence aligns with a recent FAERS study reporting sinonasal irAEs at 0.62% [10].

Of note, the higher mortality rates among the ICI cohort may limit the development of chronic conditions and diagnostic opportunities, with lower CRS and nasal polyp rates potentially reflecting differences in disease severity, competing risks, and surveillance biases. However, this is the first propensity‐matched study to evaluate the relationship between ICI therapy and sinonasal conditions, revealing a novel negative association that suggests that CRS and nasal polyps involve distinct immunological mechanisms from other irAEs and that ICI therapy may even have a protective effect.

CRS and nasal polyps have been characterized by robust localized immune responses within the sinonasal environment, which may be impacted by the systemic T‐cell modulation elicited by ICIs. For instance, disruptions in the sinonasal epithelial barrier in patients with CRSwNP increase susceptibility to antigen exposure that exacerbates the chronic inflammation characteristic of nasal polyposis [16, 17]. Other studies have shown elevated levels of B cells and plasma cells in nasal polyp tissue that produce immunoglobulins without corresponding increases in systemic levels [18, 19]. It is possible that these tissue‐specific immune processes may remain unaffected—or indirectly suppressed—by ICI‐induced systemic immune modulation, potentially reducing sinonasal inflammation through enhanced surveillance or local immune modulation.

Patients treated with ICIs also had a higher likelihood of rhinorrhea and anosmia/parosmia or parageusia. Rhinorrhea and olfactory dysfunction are recognized symptoms of CRS, and their increased prevalence in the ICI cohort may reflect undiagnosed sinus disease, possibly due to a focus on the underlying malignancy or an overlap of these symptoms with other comorbidities. The study by Pak et al. also noted that sinonasal irAEs may have been underreported in FAERS due to voluntary reporting and potential misattribution of sinonasal symptoms.

Study limitations include reliance on electronic health records, which may incompletely capture sinonasal conditions. Further, although rhinorrhea was included as a representative symptom of nasal drainage, post‐nasal drainage was not specifically examined and may represent a distinct presentation not captured in our analysis. Residual or unmeasured confounders—such as disease severity or differences in comorbidities and treatment—may have influenced the observed associations.

4. Conclusions

In this cohort of adult patients with malignant neoplasms, ICI therapy was associated with decreased risk of CRS and nasal polyps. Patients receiving ICIs also had a higher likelihood of rhinorrhea and anosmia/parosmia, or parageusia. Future research should consider prospective studies to explore the underlying mechanisms of ICI‐related sinonasal symptoms to better characterize their clinical significance.

Conflicts of Interest

Kevin Hur, MD is a consultant for Sanofi. All other authors declare no conflicts of interest.

Supporting information

Table S1.