Acta Oto-Laryngologica

ISSN: (Print) (Online) Journal homepage: www.tandfonline.com/journals/ioto20

Impact of single versus multiple surgeries in CRSwNP

patients undergoing treatment with dupilumab

Matteo Alicandri-Ciufelli, Carla Cantaffa, Costanza Galloni, Ignazio Javier

Fernandez, Daniele Marchioni, Carlotta Pipolo, Massimiliano Garzaro, Letizia
Nitro, Valeria Dell’Era, Francesco Ferella, Massimo Campagnoli, Paolo Russo,
Angelo Ghidini, Eugenio De Corso & Daniela Lucidi

To cite this article: Matteo Alicandri-Ciufelli, Carla Cantaffa, Costanza Galloni, Ignazio Javier
Fernandez, Daniele Marchioni, Carlotta Pipolo, Massimiliano Garzaro, Letizia Nitro, Valeria
Dell’Era, Francesco Ferella, Massimo Campagnoli, Paolo Russo, Angelo Ghidini, Eugenio
De Corso & Daniela Lucidi (23 Mar 2025): Impact of single versus multiple surgeries in
CRSwNP patients undergoing treatment with dupilumab, Acta Oto-Laryngologica, DOI:
10.1080/00016489.2025.2481233

To link to this article: https://doi.org/10.1080/00016489.2025.2481233

Published online: 23 Mar 2025.

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Acta Oto-Laryngologica
https://doi.org/10.1080/00016489.2025.2481233

Research Article

Impact of single versus multiple surgeries in CRSwNP patients undergoing

treatment with dupilumab
Matteo Alicandri-Ciufellia , Carla Cantaffaa , Costanza Gallonia, Ignazio Javier Fernandezb,
Daniele Marchionia, Carlotta Pipoloc, Massimiliano Garzarod, Letizia Nitroc, Valeria Dell’Erad, Francesco
Ferellac, Massimo Campagnolid, Paolo Russoe, Angelo Ghidinie, Eugenio De Corsof and Daniela Lucidib
a
Department of Otolaryngology-Head and Neck Surgery, Azienda Ospedaliero-Universitaria di Modena, Modena, Italy; bDepartment of
Otolaryngology, Ospedale Santa Maria delle Croci di Ravenna - Bologna University, Ravenna, Italy; cOtolaryngology Unit, Department of Health
Sciences, Santi Paolo e Carlo Hospital, Università degli Studi di Milano, Milan, Italy; dENT Division, Eastern Piedmont University Hospital of
Novara, Novara, Italy; eENT Department, Azienda USL Reggio Emilia - IRCCS, Reggio Emilia, Italy; fDepartment of Head, Neck and Sensory Organs,
A. Gemelli University Hospital IRCCS, Rome, Italy

ABSTRACT ARTICLE HISTORY

Background: Prior to the introduction of biologic drugs, the natural history of Chronic Rhinosinusitis Received 30 January 2025
with Nasal Polyps (CRSwNP) was characterized by multiple recurrences, thus necessitating multiple Revised 11 March 2025
surgical interventions. Accepted 12 March 2025
Aims/Objectives: To understand whether Dupilumab efficacy in recurrent CRSwNP varies based on KEYWORDS
number of previous surgeries. CRSwNP; dupilumab;
Materials and Methods: This is a multicentric retrospective study on patients with CRSwNP under endoscopic sinus surgery
Dupilumab, who underwent at least one previous surgery. Correlations between number of previous
surgeries and clinical outcomes at baseline and during treatment were investigated.
Results: 141 patients were included. Mean number of prior surgeries was 2.19 (median 2; range 1-13).
For all patients, significant improvements were observed across all time points. Poorer results were
observed in patients subjected to more than one prior surgery in terms of NPS at T2 (p .04), SNOT-22
at T4 (p .03), VAS for olfactory dysfunction at T3 (p .01) and T5 (p .009), VAS for nasal obstruction at T4
(p .047), VAS for rhinorrhea at T4 (p .02), VAS for craniofacial pain at T1 (p .02) and T2 (p .04) and of
VAS for sleep disturbances at T1 (p .04).
Conclusions and significance: Patients subjected to multiple surgeries have worse outcomes during
treatment with Dupilumab, particularly for what concerns craniofacial pain and olfactory dysfunction.

Introduction count and increased IL-5 and IgE levels in the nasal or
sinus tissues. These patients show higher rates of polyp
Chronic rhinosinusitis with nasal polyps (CRSwNP) is a recurrence and earlier post-surgical recurrence [3].
chronic inflammatory condition affecting millions of people The introduction of biologic drugs has revolutionized
worldwide, with significant patient morbidity and healthcare CRSwNP management. Dupilumab was the first monoclonal
costs [1]. Treatment of CRSwNP is based first of all on antibody approved for the treatment of CRSwNP in 2019
medical therapy, namely nasal saline irrigation and topical [4]. It inhibits the signaling of both IL-4 and IL-13 by bind-
intranasal corticosteroids, with possible short courses of oral ing to their shared receptor component.
systemic corticosteroids in case of uncontrolled severe dis- Efficacy of Dupilumab has been largely demonstrated [5].
ease [2]. When the pathology is not controlled by medical As of today, Dupilumab can be prescribed to selected
therapy, endoscopic sinus surgery (ESS) can be performed. patients as early as after the first surgery [6]. However, there
Historically, despite optimal treatment, patients affected by is a considerable group of patients who have only gained
CRSwNP frequently experienced plenty of recurrences, thus access to the treatment after multiple prior surgeries.
necessitating several surgical interventions. In these patients, It has been previously demonstrated that Dupilumab
severity is mostly driven by a type 2 inflammatory pathway, maintains superiority over placebo and intranasal corticoste-
with the involvement of IL-4, IL-13, and IL-5 [2]. In patients roids in patients with recurrent CRSwNP irrespective of the
with a type 2 inflammatory signature CRSwNP often clus- number of previous sinus surgeries [7,8]. However, there is
ters with asthma and nonsteroidal anti-inflammatory drug- no clear understanding on how its efficacy varies based on
exacerbated respiratory tract disease or elevated eosinophil the number of previous surgeries.

CONTACT Carla Cantaffa [email protected] Department of Otolaryngology - Head and Neck Surgery, University Hospital of Modena, Largo del
Pozzo, 71, Modena, 41124 Italy.
© 2025 Acta Oto-Laryngologica AB (Ltd)
2 M. ALICANDRI-CIUFELLI ET AL.

The aim of our study is to assess the effect of the num- time points: baseline (T0), 1 month (T1), 3 months (T2),
ber of prior surgeries on Dupilumab efficacy, evaluating the 6 months (T3), 9 months (T4) and 12 months (T5). Outcomes
main objective and subjective outcomes at different follow-up parameters are the following: SNOT-22 score, NPS score,
timepoints. VAS score related to loss of smell, nasal obstruction, rhinor-
rhea, craniofacial pain, and sleeping disorders. VAS (Visual
Analogue Scale) score is a validated measurement for
Methods self-reporting the severity of a symptoms, ranging from 0
Study design (no symptom) to 10 (the most intense symptom imagin-
able). VAS sleeping disorders refers to sleep disruption
This is a multicentric retrospective study performed in the related to nocturnal exacerbation of CRSwNP symptoms.
Rhinology units of the Modena University Hospital, Reggio To assess the effect of the number of prior surgeries on
Emilia Santa Maria Nuova Hospital, Novara University Dupilumab efficacy, patients have been divided into two
Hospital and Milano Santi Paolo e Carlo Hospital. groups: Group 1 included patients who underwent just one
The participating centers were chosen for having a similar previous ESS before starting Dupilumab, while Group 2
Rhinology unit, with analogous follow-up schedule, as follows: patients with history of two or more sinus surgeries.
baseline (T0), 1 month (T1), 3 months (T2), 6 months (T3),
9 months (T4) and 12 months (T5). All the patients who com-
pleted the T5 follow-up have values for all the prior timepoints. Statistical analysis
The study protocol and informed consent forms were
Statistical analysis was performed with GraphPad Prism ver-
approved by the Institutional Ethics Committee and con-
sion 7.0a (GraphPad Software, San Diego CA). Patients were
ducted in accordance with the World Medical Association
subdivided into two groups based on the number of previ-
Declaration of Helsinki. Each patient signed informed con-
ous surgeries. Since the frequency distribution of the num-
sent to participate in the study.
ber of previous surgeries was uneven, group 1 included
patients with only 1 prior surgery, while group 2 consisted
Study population of patients with ≥ 2 previous surgeries. Continuous variables
were expressed as mean ± standard deviation (SD); median;
Patients treated in the previously mentioned centers between range. Frequency distribution of the study sample was
November 2020 and October 2022 were considered for assessed by means of the D’Agostino and Pearson omnibus
inclusion in the study and their clinical charts were retro- normality test and determined to be not Gaussian. Therefore,
spectively reviewed. Mann–Whitney U test was adopted as a nonparametric test
Patients ≥18 years old affected by severe uncontrolled to compare ranks between the 2 groups under study.
CRSwNP, whose clinical data were available, who underwent Chi-square test was used for discrete variables. ANOVA was
at least one sinonasal surgical procedure (FESS or ESS) prior performed to evaluate response to treatment across different
to Dupilumab initiation and who were subjected to subcuta- time points. Results were considered significant for p values
neous 300 mg Dupilumab home self-administered every <.05 with a confidence interval of 95%. Choen’s d was cal-
2 weeks prescribed accordingly to the plan provided by Italian culated to assess the effect size of the difference between
Agency of Drugs [9] have been included in the study. groups. Effect sizes were interpreted as small (d = 0.2),
Exclusion criteria were as follows: pregnancy, immuno- medium (d = 0.5), and large (d = 0.8), according to Cohen’s
suppressive therapy, radio-chemotherapy in the 12 months guidelines.
before starting therapy, and concomitant long-term cortico-
steroid therapy for chronic autoimmune disorders, intended
as a daily low-dose systemic steroid administration.
The criteria observed for biological therapy candidacy Results
were the following: severe disease stage (NPS ≥5 and/or General characteristics
SNOT-22 ≥ 50); inadequate symptoms control with intranasal
corticosteroids; failure of (or intolerance to) previous medi- A total of 141 consecutive patients (86 males and 55 females;
cal treatments (at least 2 cycles of oral corticosteroid over mean age: 55.1 years, range: 27–86) were included in the
the last year); and/or previous ESS. study. Although an NPS cutoff of 5 is indicated by the
All patients undergoing Dupilumab were indicated not to national prescription plan, four patients with NPS = 4 were
discontinue their previous intranasal corticosteroids during included in the analysis, due to severe clinical condition and
treatment. All the participating institutions routinely prescribe high personal motivation to undertake therapy. All included
mometasone furoate nasal spray 200 μg/day for 12 to 24 con- patients were responders to Dupilumab [6].
secutive weeks. A course of oral corticosteroid has a duration Mean number of prior surgeries in the whole cohort was
of 7 to 21 days according to EPOS 2020 guidelines [2]. 2.19 ± 1.8 (median 2; range 1-13).
Patients in Group 2 had a mean number of prior surger-
ies of 3.15 ± 1.92 (median 3). Among them, 38 were sub-
Outcomes
jected to 2 previous surgeries (47.5%), 25 to 3 (31.3%), 6 to
An anonymous database was created, retrospectively enter- 4 (7.5%), 5 to 5 (6.3%), 2 to 6 (2.5%), 1 to 9 (1.3%), 1 to
ing patients’ data and outcome parameters at the following 10 (1.3%), and 1 to 13 previous surgeries (1.3%). The
 Acta Oto-Laryngologica 3

frequency distribution of the number of surgeries in the

<.0001*
<.0001*
<.0001*

<.0001*

<.0001*

<.0001*

<.0001*
study sample is shown in Figure 1.

p-value
General characteristics of patients in the 2 groups are
reported in Table 1. Age and disease duration were found to
be higher in Group 2 patients, while distribution was compa-

30
30
30

30

30

25

25
N
rable between the 2 groups in terms of sex; concomitant
asthma and nonsteroidal anti-inflammatory drugs-exacerbated

11.5 ± 7.7; 10; 1-38

1.6 ± 1.7; 1.5; 0-6

1.4 ± 1,9; 1; 0-9

1.2 ± 1.3; 1; 0-4

0.8 ± 1.3; 0; 0-5

0.8 ± 1.8; 0; 0-7

respiratory disease; and time from prior surgery to the begin-

1.2 ± 1.1; 1; 0.3

ning of treatment with Dupilumab. Comparing allergologic

T5
profiles, no significant differences emerged between inhalant
allergies prevalence in Group 1 vs. Group 2 (54% versus 58%
respectively; p > .05), whereas a significant difference was
found comparing mean hematic total IgE in the two groups

23
24
23

23

23

25

25
N
(280 IU/ml in Group 1 versus 448 IU/ml in Group 2; p < .05).

12.4 ± 10.2; 10; 1-40

2.4 ± 2.9; 1; 0-10

0.9 ± 1.4; 0; 0-5

0.7 ± 1.1; 0; 0-4

1 ± 1.1; 1; 0-5

0.5 ± 1; 0; 0-4

1 ± 1.6; 0; 0-5
Efficacy of Dupilumab

T4
Tables 2 and 3 depict baseline and in-treatment parameters
registered over time for Group 1 and 2 patients, respectively.
For both groups, significant improvements in all analyzed
parameters were observed across all time points. Eighteen

46
47
47

46

46

45

45
N
patients out of 141 (12%) had some sort of adverse event, all
of them were minor (mainly arthralgia and myalgia) and did

13.7 ± 10.7; 10; 0-51

1.1 ± 1.6; 0.5; 0-8

1.8 ± 2.5; 1; 0-10

1.1 ± 1.9; 0; 0-10

1.4 ± 1.9; 1; 0-9

0.4 ± 0.8; 0; 0-3

2 ± 1.8; 2; 0-7
not lead to discontinuation of therapy. No differences were
detected comparing adverse events rate between groups (p > .05).

T3
46
47
49

45

45

46

46
N

16.8 ± 11.4; 16; 0-56

1.2 ± 1.5; 0.5; 0-6

2.8 ± 2.8; 2; 0-10

1.8 ± 2.2; 1; 0-10

1.7 ± 1.4; 2; 0-7

0.9 ± 1.7; 0; 0-8

2 ± 2.2; 1; 0-10

T0 = baseline, T1 = 1 mo, T2 = 3 mo, T3 = 6 mo, T4 = 9 mo, T5 = 12 mo, N: number of evaluable participants.

T2
48
49
52

49

49

49

49
N

27.6 ± 16; 25; 0-67

2.5 ± 1.5; 2; 0-6

3.9 ± 2.6; 4; 0-9

2.7 ± 2.1; 2; 0-8

2.6 ± 2.4; 2; 0-8

1.3 ± 1.9; 0; 0-8

1.6 ± 1.8; 1; 0-6

T1

Figure 1. Frequency distribution of number of previous surgeries.

Table 2. Group 1 baseline and in-treatment parameters.

60
61
59

59

59

59

59
N

Table 1. General characteristics of the study group.

55.8 ± 18.7; 59; 8-86

Differences
7.5 ± 3.1; 9, 0-10

6.4 ± 2.3; 7; 1-10

2.7 ± 2.8; 2; 0-10

5.7 ± 2.5; 6; 0-10

5.6 ± 1.9; 6; 4-8

7.4 ± 2; 8; 2-10

between groups
Group 1 Group 2 (p-value)
T0

Total n° of patients 61 80
Males 36 50 .6744
Females 25 30
statistically significant results.

Age (mean ± SD) 51.9 ± 12.6 57.5 ± 11.7 .0081*

Concomitant asthma 48 60 .6083
Concomitant NSAID-ERD 14 17 .8397
Parameter (mean ± SD;

VAS nasal obstruction

VAS craniofacial pain

Months from last prior ESS/FESS 66.4 ± 68.3 72.5 ± 66.6 .6261
VAS sleep disorders

(mean ± SD)
VAS loss of smell
SNOT-22 (0–120)
median; range)

VAS rhinorrhea

Years from diagnosis to 17.8 ± 17.4 30.7 ± 18.3 <.0001*

(0–10 cm)

(0–10 cm)

(0–10 cm)

(0–10 cm)

(0–10 cm)

Dupilumab (mean ± SD)

NPS (0–8)

ESS: endoscopic sinus surgery; FESS: functional endoscopic sinus surgery;

NSAID-ERD: nonsteroidal anti-inflammatory drugs-exacerbated respiratory
disease.
*
 4

Table 3. Group 2 baseline and in-treatment parameters.

Parameter (mean ± SD;
median; range) T0 N T1 N T2 N T3 N T4 N T5 N p-value
NPS (0–8) 5.7 ± 1.5; 6; 79 3 ± 1.9;3 60 2.5 ± 2; 2 62 2.4 ± 1.7; 2 62 1.4 ± 1.2; 1; 28 1.6 ± 2; 1; 35 <.0001*
SNOT-22 (0–120) 56.4 ± 18.4; 56 79 26.7 ± 15.6; 22 61 20.9 ± 15; 18 59 14.7 ± 9.8; 12 63 16.5 ± 11; 12.5 28 13.5 ± 10.9; 10 34 <.0001*
VAS loss of smell 1.6 ± 2.9; 8 79 4.2 ± 2.4; 4 62 3.5 ± 2.8; 3 60 3 ± 3; 2 64 2.8 ± 2.5; 2 28 3.3 ± 3.1; 2 33 <.0001*
(0–10 cm)
M. ALICANDRI-CIUFELLI ET AL.

VAS nasal obstruction 7.9 ± 2.3; 8 79 3.3 ± 2.2; 3 62 2.4 ± 2; 1 60 1.6 ± 1.7; 1 65 1.6 ± 2; 1.5 28 1.2 ± 1.8; 0 33 <.0001*
(0–10 cm)
VAS rhinorrhea 7 ± 2.2; 7 79 3 ± 2.2; 3 62 2.1 ± 2.1; 2 60 1.6 ± 1.8; 1 65 1.4 ± 1.3; 1 28 1.5 ± 1.9; 1 33 <.0001*
(0–10 cm)
VAS craniofacial pain 3.2 ± 3.4; 2 79 2.1 ± 2.1; 2 62 1.4 ± 1.9; 1 61 1 ± 1.7; 0 64 0.8 ± 1; 0 31 0.8 ± 1.3; 0 30 <.0001*
(0–10 cm)
VAS sleep disorders 5.7 ± 3.2; 6 78 2.5 ± 2.2; 2 62 1.4 ± 1.9; 0 61 0.9 ± 1.5; 0 63 1 ± 1.2; 0 31 1.2 ± 1.6; 0 29 <.0001*
(0–10 cm)
T0 = baseline, T1 = 1 mo, T2 = 3 mo, T3 = 6 mo, T4 = 9 mo, T5 = 12 mo, N: number of evaluable participants.
*
statistically significant results.

Table 4. Results of comparisons between the two groups at different time points.
T0 T1 T2 T3 T4 T5
p-value 95% CI Choen’s d p-value 95% CI Choen’s d p-value 95% CI Choen’s d p-value 95% CI Choen’s d p-value 95% CI Choen’s d p-value 95% CI Choen’s d
NPS (0–8) .29 0 to 1 0.1 .2 0 to 1 0.3 .04* 0 to 1 0.5 .15 0 to 1 0.3 .17 0 to 1 0.4 .84 −1 to 1 0.3
SNOT-22 (0–120) .8 −7 to 5 0.03 .75 −7 to 5 0.06 .18 −1 to 8 0.3 .37 −2 to 5 0.02 .03* 0 to 8 0.4 .71 −3 to 4 0.2
VAS loss of smell .96 0 to 0 0.02 .51 −1 to 1 0.1 .13 0 to 2 0.2 .01* 0 to 2 0.5 .15 0 to 2 0.1 .009* 0 to 2 0.7
(0–10 cm)
VAS nasal obstruction .06 0 to 1 0.2 .15 0 to 1 0.3 .15 0 to 1 0.2 .3 0 to 1 0.1 .047* 0 to 1 0.4 .32 −1 to 0 0.07
(0–10 cm)
VAS rhinorrhea (0–10 cm) .09 0 to 1 0.3 .21 0 to 2 0.2 .28 0 to 1 0.1 .14 0 to 1 0.3 .02* 0 to 1 0.6 .69 −1 to 0 0.05
VAS craniofacial pain .47 0 to 1 0.2 .02* 0 to 1 0.4 .04* 0 to 1 0.3 .06 0 to 0 0.5 .31 0 to 0 0.2 .89 0 to 0 0.01
(0–10 cm)
VAS sleep disorders .79 −1 to 1 0.006 .04* 0 to 2 0.4 .71 0 to 0 0.2 .74 0 to 0 0.1 .6 0 to 0 0.01 .15 0 to 1 0.2
(0–10 cm)
T0 = baseline, T1 = 1 mo, T2 = 3 mo, T3 = 6 mo, T4 = 9 mo, T5 = 12 mo, 95% CI: 95% Confidence Intervals. *statistically significant results.
 Acta Oto-Laryngologica 5

Figure 2. Bar plots showing the comparison between groups 1 and two in terms of olfactory dysfunction (A) and craniofacial pain (B). * statistically significant
at Mann-Whitney test.

Effect of multiple surgeries on treatment with have higher VAS scores at various in-treatment time points,
dupilumab particularly for what concerns craniofacial pain and olfac-
tory function, with respect to patients with only one prior
Comparing results at different time points between the two sinus surgery.
groups, we observed significantly poorer results for Group 2 It is known that surgical manipulation of the nose and
patients in terms of NPS at T2 (p .04), SNOT-22 at T4 (p paranasal sinuses could lead to changes in the anatomy and
.03), VAS for olfactory dysfunction at T3 (p .01) and T5 (p physiology of these structures, mainly through the processes
.009), VAS for nasal obstruction at T4 (p .047), VAS for of new bone formation and mucosal thickening, either due
rhinorrhea at T4 (p .02), VAS for craniofacial pain at T1 (p to scarring or edema. As one might easily deduce, these
.02) and T2 (p .04) and of VAS for sleep disturbances at T1 changes are the more frequent the higher the number of
(p .04). Results of all comparisons are summarized in surgeries patients have been subjected to [11–13]. Excessive
Table 4. bone growth and mucosal scarring, which are
Figure 2 shows a graphic representation of results from well-documented possible consequences of sinus surgery,
comparison analysis on VAS for olfactory dysfunction (2a) especially when extensive, could potentially lead to irritation
and craniofacial pain (2b). of surrounding structures, leading to neuralgic-type
discomfort.
Thus, it may be hypothesized that they could be the
Discussion
cause of persistent nasal symptoms, mainly in the form of
Current guidelines recommend candidacy to biologic drugs facial pain or pressure and subjective nasal obstruction, in
in patients affected by type-2 CRSwNP after failure of sur- patients treated with Dupilumab after multiple previous
gical treatment [6]. However, before the advent of biologic sinus surgeries, even in the absence of nasal polyps.
drugs, the natural history of CRSwNP was characterized by However, another possible explanation is that patients
a high likelihood of undergoing multiple sinus surgeries undergoing multiple surgeries were affected by an intrinsi-
[10], as exemplified by this study’s cohort, where more than cally more severe pattern of disease characterized by a
half (56.7%) of the total number of patients underwent higher disease burden and a more refractory immunologic
more than one sinus surgery. and biologic profile and that might partially justify worse
The results of this study confirm that patients benefit dupilumab-related outcomes.
from treatment with Dupilumab regardless of the number of Similarly, persistent olfactory dysfunction after multiple
previous surgeries, as previously demonstrated elsewhere ESS could be explained both by iatrogenic damage to the
[7,8]. However, we also observed that patients subjected to olfactory mucosa and pre-existent sensorineural loss due to
more than one sinus surgery prior to Dupilumab initiation reiterated inflammatory insult.
6 M. ALICANDRI-CIUFELLI ET AL.

As for the former cause, it has been demonstrated that operated on multiple times until biologic drugs became
postoperative nasal adhesions create local airflow disruption available are necessarily those who are older and have longer
and deflect the airstream away from the olfactory epithelium disease duration. Moreover the two Groups did not show
[14,15]. any significant clinical differences at baseline assessment.
The effect of sinus surgery on olfactory function recovery In conclusion, our results support early Dupilumab initi-
is known to be highly variable and difficult to predict. ation in patients with recurrent nasal polyposis after a single
Different studies assess that olfactory dysfunction improved sinus surgery.
in patients affected by CRSwNP with anosmia after ESS, Results on olfactory function could not be confirmed by
while in hyposmic patients smell did not improve after sur- objective measurement, and this constitutes a limitation of
gery [16,17]. Prior sinus surgery itself has been hypothe- this study. Moreover, due to its retrospective nature, there
sized to be among the negative predictive factors for might be some missing data. However, we consider the risk
olfactory function recovery after ESS [10]. In addition, more of having missing data to be comparable to all real-life stud-
extensive surgeries (as determined by the ACCESS score ies. In addition, at present, novel biologic drugs have been
[18]) have been shown to correlate with poorer subjective approved for the treatment of severe uncontrolled recurrent
olfactory function recovery after treatment with Dupilumab CRSwNP, but our experience with these drugs is still lim-
in a previous study [19]. In the authors’ opinion, with ited, therefore we could not include them in the analysis.
increasingly higher number of surgeries, the risk of mucosal Finally, in light of the relatively low sample size, we ought
stripping is progressively greater, to the point that not to employ a mathematical model whereby patients were
enough basal cells are left to provide a recovery of the olfac- divided in a first group composed of patients with only one
tory epithelium, which gets progressively replaced with prior surgery and a second group of patients subjected to
respiratory-type epithelium that lacks an olfactory function. more than one sinus surgery, we could not explore potential
Along with previous sinus surgery, longer olfactory dys- differences related to the effect of two versus more than two
function duration has been proposed as a negative predic- surgeries.
tive factor for olfactory function recovery after ESS [20].
Thus, another reason behind poorer olfactory function
scores in patients subjected to multiple sinus surgeries with Compliance with ethical standards
respect to those subjected to a single sinus surgery could be
All the procedures performed in this study were in accor-
that these patients usually have a longer-standing olfactory
dance with ethical standards of the Institution at which the
dysfunction, as it was observed in this study’s cohort. Still,
study was conducted.
it is widely recognized that Dupilumab treatment leads to
an improvement in olfactory function scores even in patients
subjected to multiple prior surgeries [21], therefore it is
likely that loss of smell in patients with recurrent CRSwNP Disclosure statement
after multiple sinus surgeries is multifactorial, and that only No potential conflict of interest was reported by the author(s).
a partial recovery could be expected after treatment with
Dupilumab.
Interestingly, there were no differences in baseline olfac- Funding
tory function between the two groups, which might be
No funding is reported for the present study.
explained by the fact that nasal polyps and rhinorrhea may
mask the effect of multiple surgeries on olfactory function.
Consistent with our findings, previous reports have demon-
ORCID
strated a significantly lower improvement in olfactory func-
tion in patients subjected to ≥ 2 prior sinus surgeries [22,23]. Matteo Alicandri-Ciufelli http://orcid.org/0000-0002-3479-297X
Similarly, Ottaviano et al. [24] found out that previous sur- Carla Cantaffa http://orcid.org/0000-0001-8484-4961
gery had a negative impact on Sniffin’ Sticks Identification
Test (SSIT) scores. On the other hand, in a study by Bertlich
et al. [25], authors did not observe significant differences at References
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 Acta Oto-Laryngologica 7

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