10.14639/0392-100X-N2156
Objective. Treatment for chronic rhinosinusitis with nasal polyps (CRSwNP) includes endoscopic sinus surgery and topic and/or systemic corticosteroids, which have only temporary effects. The development of biologic therapies has provided a new treatment paradigm for CRSwNP. Dupilumab is the only biological approved in Italy for CRSwNP, but its efficacy in a real-life context is still scarce.Methods. We carried out a monocentric prospective study at our institution with a 6-month follow-up on patients administered biweekly 300 mg dupilumab therapy for CRSwNP, prescribed according to EPOS 2020 criteria. Patients were evaluated at baseline and every 2 months.Results. Median values at baseline and 6 months were, respectively, 3/12 and 8/12 for the Brief Smell Identification Test (p = 0.005), 5/8 and 2/8 for the Nasal Polyp Score (p &lt; 0.001), 10/20 and 6/20 for the Lund-Kennedy score (p &lt; 0.001), 65/110 and 14/110 for the Sinonasal Outcome Test (p &lt; 0.001), and 15/25 and 23/25 for the Asthma Control Test score (p = 0.009). Adverse events were mild, consisting mainly in discomfort at the site of injection. Four patients developed asymptomatic hypereosinophilia. The treatment was not discontinued in any patient.Conclusions. Dupilumab was confirmed to be an effective and safe treatment for CRSwNP, as previously seen in registrational studies.
text/xml
1827-675X
2156
en
Mario Bussi
http://creativecommons.org/licenses/by-nc-nd/4.0
ACTA Otorhinolaryngologica Italica
monoclonal antibody
A prospective study on the efficacy of dupilumab in chronic rhinosinusitis with type 2 inflammation
Text.Serial.Journal
https://www.actaitalica.it/
42
Rhinology
2022-12-29
2022-05-13
2022-12-29
2023-01-16
538-544
1
Mario Bussi
2022/12/29
10.14639/0392-100X-N2156
538
Division of Head and Neck department, Otorhinolaryngology unit, IRCCS San Raffaele Scientific Institute, Milan, Italy; School of Medicine, Vita-Salute San Raffaele University, Milan, Italy
1827-675X
monoclonal antibody
en
544
A prospective study on the efficacy of dupilumab in chronic rhinosinusitis with type 2 inflammation
https://www.actaitalica.it/article/download/2156/893
42
ACTA OTORHINOLARYNGOLOGICA ITALICA 2022;42:538-544; doi: 10.14639/0392-100X-N2156




Rhinology


A prospective study on the efficacy of dupilumab
in chronic rhinosinusitis with type 2 inflammation
Studio prospettico sull’efficacia di dupilumab per rinosinusite cronica
con infiammazione di tipo 2
Matteo Trimarchi1,2, Alessandro Vinciguerra3, Andrea Rampi1,2, Umberto Tanzini1,2, Alessandro Nonis4,
Mona Rita Yacoub2,5, Mario Bussi1,2
1
  Division of Head and Neck department, Otorhinolaryngology unit, IRCCS San Raffaele Scientific Institute, Milan, Italy; 2 School of
Medicine, Vita-Salute San Raffaele University, Milan, Italy; 3 Otorhinolaryngology and Skull Base Center, AP-HP, Hospital Lariboisière,
Paris, France; 4 CUSSB, University Centre for Statistics in the Biomedical Sciences, Vita-Salute San Raffaele University, Milan, Italy;
5
  Unit of Immunology, Rheumatology, Allergy and Rare Diseases, IRCCS Ospedale San Raffaele, Milan, Italy


SUMMARY
Objective. Treatment for chronic rhinosinusitis with nasal polyps (CRSwNP) includes en-
doscopic sinus surgery and topic and/or systemic corticosteroids, which have only tempo-
rary effects. The development of biologic therapies has provided a new treatment paradigm
for CRSwNP. Dupilumab is the only biological approved in Italy for CRSwNP, but its
efficacy in a real-life context is still scarce.
Methods. We carried out a monocentric prospective study at our institution with a 6-month
follow-up on patients administered biweekly 300 mg dupilumab therapy for CRSwNP, pre-
scribed according to EPOS 2020 criteria. Patients were evaluated at baseline and every 2
months.
Results. Median values at baseline and 6 months were, respectively, 3/12 and 8/12
for the Brief Smell Identification Test (p = 0.005), 5/8 and 2/8 for the Nasal Polyp Score
(p < 0.001), 10/20 and 6/20 for the Lund-Kennedy score (p < 0.001), 65/110 and 14/110 for
the Sinonasal Outcome Test (p < 0.001), and 15/25 and 23/25 for the Asthma Control Test
score (p = 0.009). Adverse events were mild, consisting mainly in discomfort at the site of
                                                                                                 Received: May 16, 2022
injection. Four patients developed asymptomatic hypereosinophilia. The treatment was not
                                                                                                 Accepted: August 16, 2022
discontinued in any patient.
Conclusions. Dupilumab was confirmed to be an effective and safe treatment for
                                                                                                 Correspondence
CRSwNP, as previously seen in registrational studies.                                            Matteo Trimarchi
KEY WORDS: chronic rhinosinusitis with nasal polyps, biological therapy, monoclonal              Otolaryngology Department, San Raffaele Hospital,
antibody                                                                                         via Olgettina 68, 20132 Milan, Italy
                                                                                                 Tel. +39 02 26438442
                                                                                                 E-mail: trimarchi.matteo@hsr.it
RIASSUNTO
Obiettivi. Il trattamento della rinosinusite cronica include la chirurgia nasosinusale             How to cite this article: Trimarchi M, Vin-
endoscopica e la terapia steroidea locale e sistemica. I nuovi farmaci biologici hanno for-        ciguerra A, Rampi A, et al. A prospective study
nito un efficace strumento contro i sintomi della malattia. Dupilumab è l’unico biologico          on the efficacy of dupilumab in chronic rhinosi-
approvato in Italia, ma l’evidenza circa la sua efficacia nella pratica clinica è limitata.        nusitis with type 2 inflammation. Acta Otorhi-
Metodi. Questo articolo riporta uno studio prospettico monocentrico su pazienti in fol-            nolaryngol Ital 2022;42:538-544. https://doi.
low up per 6 mesi durante la terapia bisettimanale con dupilumab, secondo i criteri propo-         org/10.14639/0392-100X-N2156
sti da EPOS2020. I pazienti sono stati valutati prima della terapia e ogni due mesi.
Risultati. I valori mediani prima della terapia e a 6 mesi mostrano un miglioramento             © Società Italiana di Otorinolaringoiatria
                                                                                                 e Chirurgia Cervico-Facciale
nell’olfatto, misurato mediante un test oggettivo (Brief Smell Identification Test), nella
dimensione dei polipi, nell’infiammazione della mucosa nasale, nella qualità di vita dei
                                                                                                                OPEN ACCESS
pazienti e nel controllo dell’asma. Gli effetti collaterali sono stati di lieve entità: il più
comune è stato il dolore in sede di iniezione. 4 pazienti hanno sviluppato un’ipereosinofilia    This is an open access article distributed in accordance with
                                                                                                 the CC-BY-NC-ND (Creative Commons Attribution-Non-
asintomatica. Il trattamento non è stato interrotto in nessuno di questi casi.                   Commercial-NoDerivatives 4.0 International) license. The
Conclusioni. Nella nostra esperienza, il trattamento con dupilumab è stato efficace e sicuro     article can be used by giving appropriate credit and mentio-
in linea con i risultati degli studi di registrazione.                                           ning the license, but only for non-commercial purposes and
                                                                                                 only in the original version. For further information: https://
PAROLE CHIAVE: rinosinusite cronica polipoide, terapia biologica, anticorpi monoclonali          creativecommons.org/licenses/by-nc-nd/4.0/deed.en




538
                                                             A prospective study on the efficacy of dupilumab in CRS with type 2 inflammation




Introduction                                                      ing the first year after approval of dupilumab in Italy. This
                                                                  represents an early description of its use in real-life experi-
Chronic rhinosinusitis (CRS) is a common condition which          ence, also depicting our approach to preliminary screen-
has a serious impact on healthcare systems 1. Tradition-          ing and evaluation, as well as subsequent monitoring of the
ally it has been divided, depending on its phenotype, into        disease.
chronic rhinosinusitis without nasal polyps (CRSsNP) and
chronic rhinosinusitis with nasal polyps (CRSwNP). This
latter condition, representing around 25-30% of cases, is         Materials and methods
associated with significantly higher morbidity and worse          Study design and endpoints
quality of life 2,3. More recently, the increasing evidence on    This is a prospective, observational, cohort, monocentric
the aetiopathogenetic mechanisms underlying CRS has led           study assessing the effectiveness and safety of dupilumab
to a shift of paradigm towards a classification based on the      in patients with CRSwNP. All patients who were prescribed
endotype of the CRS, as reflected by the European Posi-           dupilumab for CRSwNP and who were followed for at least
tion Paper on Rhinosinusitis and Nasal Polyps (EPOS) in           6 months in our hospital were included. All patients were
2020 4. Studies relating endo- and phenotype have shown           prescribed dupilumab according to EPOS 2020 criteria, i.e.
that CRSwNP is more commonly associated, especially               presented bilateral polyposis, underwent at least one previ-
in European and North American patients, with a pattern           ous endoscopic sinus surgery (ESS) and presented at least
of type 2 inflammation; this type of inflammation, whose          3 of the following 5 criteria: evidence of Th2 inflammation
major markers are interleukin (IL)-4, IL-5 and IL-13, is de-      (tissue eosinophilia > 10/hpf OR blood eosinophilia ≥ 250
termined by a complex cooperation between eosinophils,            OR total IgE ≥ 100), need for systemic corticosteroids (≥ 2
mast cells and innate lymphoid cells 5. Unfortunately, the        courses per year OR ≥ 3 months of low dose systemic cor-
therapeutic armamentarium against CRSwNP has long                 ticosteroids) or contraindication to steroids, significantly
been completely unsatisfying: traditionally, corticosteroids      impaired quality of life (SNOT-22 ≥ 40), significant loss
are the only molecules that can halt the type 2 inflammatory      of smell (anosmic on smell test), diagnosis of comorbid
cascade and intranasal corticosteroids (INCS) are sufficient      asthma (asthma needing inhaling corticosteroids) 4.
in only a proportion of cases, while systemic therapy is bur-     All patients underwent preliminary blood tests, measur-
dened by serious side effects and therefore limited in time.      ing basal cell blood count (CBC), levels of serum IgG,
As a consequence, for patients whose disease status was           IgA, IgM, IgE, C-reactive protein (CPR), and anti-nucleus
not controlled by nasal sprays, the ENT surgeon is often          (ANA) and anti-neutrophil cytoplasmic antibodies (cAN-
challenged to find a difficult balance between frequent revi-     CA and pANCA) to rule out immunodeficient or autoim-
sion surgeries, courses of systemic corticosteroids and the       mune conditions, such as eosinophilic granulomatosis with
need to prevent short- and long-term risks 1.                     polyangiitis. Patients suffering from asthma were evaluated
In this context, the recent introduction of monoclonal an-        by an allergist or pneumologist, and none of the patients
tibodies, also known as biological therapies, represents a        met the requirements for the prescription of a doubled pri-
turning point for the treatment of CRSwNP. These drugs            mary dose.
specifically target inflammatory mediators or immune              If the abovementioned screening was permissive, a multi-
cells, and have been shown to be effective not only in severe     disciplinary team of ENT surgeons and allergists met and
asthma and atopic dermatitis (AD), but also in CRSwNP.            eventually prescribed dupilumab 300 mg subcutaneously
Even though additional molecules are expected to be ap-           every two weeks for CRSwNP. The baseline visit investi-
proved soon, dupilumab is the only biologic therapy that          gated the following parameters:
can be currently prescribed in Italy for CRSwNP, since            • past medical history: a) presence of comorbidity, with
January 2021. This molecule is a fully human, VelocIm-               particular attention to asthma and AD; b) presence of al-
mune-derived IgG-4 monoclonal antibody, that inhibits the            lergies or intolerance to acetylsalicylic acid (ASA) or to
activity of the shared receptor subunit of IL-4 and IL-13,           other non-steroidal anti-inflammatory drugs (NSAIDs);
thus blocking signalling from both. Although its efficacy            c) number of EPOS 2020 criteria met (ranging from 3 to
and safety have been extensively investigated in two major           5) 4; d) date of previous surgery/ies;
multicentre, randomised, double-blind, placebo-controlled,        • quality of life assessment: a) Sino-Nasal Outcome
phase 3 trials (SINUS24 and SINUS52), reports of its use             Test-22 (SNOT-22), (range 0-110) 8; b) Brief-Smell
outside the framework of a clinical trial are scarce 6,7.            Identification Test (B-SIT), (range 0-12): olfactory func-
The current study investigated the experience of our centre          tion was considered normal if ≥ 9, hyposmia corresponds
in the treatment of patients suffering from CRSwNP dur-              to 5-8 and anosmia to ≤ 4 9; c) Olfaction Visual Analogue



                                                                                                                                       539
M. Trimarchi et al.




   Scale (VAS), (range 0-10); d) in asthmatic patients, the     scopic surgical procedures (range 1-7); in the 19 cases in
   Asthma Control Test (ACT) was used (range 5-25) 10;          which a CT scan was performed after the last surgery and
• endoscopic findings, obtained with a 0°/30° rigid nasal       the subsequent recurrence of symptoms was available, the
   endoscope: a) NPS (Nasal Polyp Score) (range 0-8); b)        median values of the Lund-Mackay and ACCESS scores
   Lund-Kennedy score (LKS) (range 0-20) 11. We used            were 21 (18-23) and 10 (4-15), respectively. Altogether,
   two different endoscopic scores because NPS mainly fo-       15/21 (71%) patients in the cohort suffered from asthma.
   cuses on the dimension of polyps, while LKS provides         In 9 cases, asthma was associated with ASA sensitivity,
   additional information on mucosal oedema and nasal           with the subsequent presence of the triad for diagnosis of
   secretion and, in general, on the grade of inflammation;     NSAIDs-exacerbated respiratory disease (N-ERD). The re-
• radiological findings on the last CT: a) Lund-Mackay          sults are reported in Table I.
   score (LMS) 12; b) ACCESS score 13. Both scores vary         The blood tests did not result in any first diagnosis of latent
   from 0 to 24. CT scans were obtained after the last sur-     rheumatologic disease or any abnormality determining a
   gery and as close to the first administration as possible,   contraindication to biologic treatment. Subcutaneous self-
   with a median of 2 months between the CT scan and the        administration was considered easy to perform by all pa-
   first dose.                                                  tients; only in a single administration was loss of the drug
Patients were advised not to discontinue nasal douches          reported.
and intranasal corticosteroids (INCS) (as their therapy for     All examinations, tests and questionnaires showed pro-
asthma, if any) and, immediately after the baseline visit,      gressive and significant improvement compared to
the first injection was administered subcutaneously in the      baseline (p-values are shown in Table II). The median
presence of the ENT surgeon to instruct the patient on self-    SNOT-22 at baseline and at 2, 4 and 6 months was 65,
administration and recognise possible side effects related to   23, 24 and 14, respectively (Fig. 1); in the same time in-
the first dose. Subsequent injections were performed by the     tervals, endoscopic examinations revealed a median for
patients themselves at home.                                    NPS of 5, 3, 2 and 2 and for Lund-Kennedy of 10, 8, 6
The scheduled follow-up included a visit every two months       and 6 (Fig. 2). Olfactory performance evaluated with B-sit
for six months. During these visits, the ENT surgeon            was poor at baseline with a median of 3/12, but reached
reevaluated the abovementioned parameters at endoscop-          8/12 at the end of follow-up (interim values of 6/12 and
ic examination, and the questionnaires on quality of life       8/12 at 2 and 4 months), (Fig. 1); these results were com-
and the olfactory tests were submitted again. In addition,      parable with the subjective data obtained with olfactory
patients were asked to undergo new blood tests, including
                                                                VAS, showing a median of 0, 6, 7 and 8 at the consecu-
CBC, total IgE, and CPR, every two months from baseline.
                                                                tive intervals. Analogously, the ACT score displayed a
Side effects and compliance with therapy were recorded.
                                                                progressive increase (15/25, 21/25, 22/25, 23/25), thereby
At 4 and 6 months response to biological treatment was
                                                                depicting improvement in asthma control. The abovemen-
evaluated according to EPOS 2020 criteria, counting how
many of the following five criteria were met: reduced na-
sal polyps size, reduced need for systemic corticosteroids,     Table I. Variables at baseline. Age, eosinophil absolute count, total IgE, Lund-
increased quality of life, improved sense of smell and re-      Mackay score, ACCESS score and number of previous surgeries are indicated
duced impact of comorbidities 4.                                as median values and in parentheses the minimum and maximum value. For
                                                                sex, the number of male (M) and female (F) patients is indicated. For asthma
                                                                and N-ERD, the total of patients of the 21 included with specific comorbidity
Statistical analysis                                            are listed.
Data are reported as median and interquartile range (IQR).       Variable (n = 21)                                      Values
Comparison between times was evaluated by Wilcoxon               Age                                                   47 (29-84)
signed rank test with Bonferroni Correction and statistical      Sex                                                   16 M, 5 F
significance was considered for p < 0.05. Computations
                                                                 Presence of asthma                                      15/21
was done with R 4.1.3.
                                                                 NSAIDs-exacerbated respiratory                           9/21
                                                                 disease (N-ERD)
Results                                                          Eosinophil absolute count (EAC)                      0,54 (0-1,1)
                                                                 Total IgE                                            69 (31-643)
A total of 21 patients with a median age of 47 years
                                                                 Lund-Mackay score                                    21 (18-23)
(range 29-84) completed the 6-month follow-up (FU) (16
M, 5 F). All patients had undergone previous endoscopic          ACCESS score                                          10 (4-15)
sinus surgery (ESS) with a median of 2 previous endo-            Number of previous surgeries                           2 (1-7)




540
                                                                                     A prospective study on the efficacy of dupilumab in CRS with type 2 inflammation




Table II. Median value and interquartile range of the main variables at baseline and at 2, 4 and 6 months. The p-value refers to the comparison versus baseline
with Wilcoxon signed rank test and Bonferroni correction. Data are reported as median and interquartile range. ACT was applicable in 15/21 patients.
 Variable (n = 21)                                 Baseline                    2 months                      4 months                     6 months
 SNOT-22 median [IQR] (0-120)                          65 [48, 74]              23 [19, 42] (p < 0.001)    24 [9, 33] (p < 0.001)                  14 [5, 28] (p < 0.001)
 NPS median [IQR] (0-8)                                  5 [5, 6]                 3 [2, 4] (p < 0.001)      2 [2, 4] (p < 0.001)                    2 [0, 3] (p < 0.001)
 Lund-Kennedy score median [IQR] (0-20)                 10 [8, 10]                8 [6, 8] (p = 0.016)      6 [6, 8] (p = 0.009)                    6 [4, 6] (p < 0.001)
 B-SIT median [IQR] (0-12)                               3 [3, 5]                 6 [4, 8] (p = 0.030)     8 [5.50, 9] (p = 0.009)               8 [6.75, 9.25] (p = 0.005)
 VAS olfaction median [IQR] (0-10)                          0                     6 [3, 7] (p < 0.001)      7 [5, 8] (p < 0.001)                    8 [7, 9] (p < 0.001)
 ACT score median [IQR] (5-25)                      15 [10.75, 19.25]        21 [19.75, 22.25] (p = 0.003) 22 [20, 24] (p = 0.007)               23 [21.50, 24] (p = 0.009)
SNOT-22: SinoNasal Outcome Test-22; NPS: Nasal Polyp Score; B-SIT: Brief-Smell Identification Test; VAS: Visual Analog Scale; ACT: Asthma control Tes; IQR: InterQuartile Range.




Figure 1. Median values of Sino-Nasal Outcome Test-22 (SNOT 22) and                         Figure 2. Median values of endoscopic findings for Nasal Polyp Score (NPS)
Brief Smell Identification Test (BSIT) during the study.                                    and Lund-Kennedy score during the study.


tioned results and the corresponding IQRs are shown in                                      nose; one patient reported the development of wheals after
Table II. Despite being instructed to continue their pre-                                   drug administration at 3-4 months of therapy, with sponta-
vious therapy, 8 patients admitted to having suspended                                      neous resolution.
mometasone spray and 4 suspended asthma therapy for a                                       As already known from the registration studies, an increase
period during follow-up, mainly due to the perceived lack
                                                                                            in eosinophil absolute count (EAC) was observed. EAC
of need consequent to their improved condition. There
                                                                                            at baseline, 2, 4 and 6 months had a median of, respec-
were no acute exacerbations of symptoms requiring oral
corticosteroids.                                                                            tively, 0.50, 0.90, 0.85 and 0.80. Similarly, total IgE had a
The EPOS 2020 criteria met for the prescription of therapy                                  median of 128.00, 77.60, 63.90 and 57.75 [22.58, 93.85].
had a median of 4/5, while the median at 4 and 6 months                                     In four cases, EAC reached values for hypereosinophilia
of the criteria met for defining response to biological treat-                              (> 1.5 x 10^9/L): in those cases, we repeated blood tests
ment was 5/5. Only one patient had a poor response, i.e.                                    every month instead of every two months. None showed
≤ 2 criteria of 5, with stable NPS and LMS, no improve-                                     any symptoms related to hypereosinophilia, but in two
ment in olfaction, no impact on its comorbidities (the pa-                                  cases patients were preventively treated with a short-term
tient was not affected by asthma), and a 9-point reduction
                                                                                            course of corticosteroids as EAC reached values > 3 x 109.
in SNOT-22.
The adverse events seen were mainly mild, consisting of                                     In those two cases, we performed routine blood tests to as-
discomfort or burning at the site of injection or transient                                 sess liver, heart and renal function, which showed no signs
weakness/headache. One patient reported conjunctivitis                                      of organ involvement. The management of dupilumab-
treated with topical therapy, while another underwent a                                     induced hypereosinophilia is thoroughly described in our
course of antibiotics due to a purulent discharge from the                                  previous publication 14.



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M. Trimarchi et al.




Discussion                                                        If on the one hand, our study is consistent with the present
                                                                  literature on the efficacy and safety of dupilumab, on the
A new era in the treatment of type 2 inflammation has begun       other hand major concerns about its cost have arisen 17,21.
with the introduction of biological therapy in clinical prac-     A recent article by Scangas et al. took a position against
tice 15. Dupilumab, the first molecule receiving approval for     biologic therapy in comparison to ESS for primary ther-
CRSwNP, showed promising results during registrational            apy when taking into account quality-adjusted life-year
studies with a low number of adverse events 6; evidence           (QALY); but also reported that revision ESS is more cost-
from real-life practice is scarce 7,16,17. To our knowledge,      effective in case of recurrent polyposis 1. However, as the
this is one of the first studies reporting on outcomes of         authors explicitly state in the article, the analysis is biased
dupilumab prescribed for CRSwNP in a real-life context.           by the possible effects of multiple anaesthesias and the in-
The present analysis confirms the efficacy of dupilumab           creasing surgical difficulty in revision ESS, which are not
in reducing NPS and improving quality of life, sense of           easily quantifiable 21. Regarding the economical sustain-
smell and control of asthmatic comorbidity, as well as a          ability of biological therapy, future studies should address
low number of side effects. The time to onset is rapid, with      two main issues: the optimal interval for administration and
a significant reduction at 2 months of 2 and 42 points for        the patients who could benefit most from it. In relation to
median NPS and SNOT-22, respectively; the subsequent              the first point, our results confirm that the improvement in
months show further progressive improvement, although             symptoms and reduction in polyp size is rapid. It might be
less pronounced. Similar considerations apply to olfactory        possible to consider, after reaching an adequate control of
function for both objective (B-SIT) and subjective (olfac-        nasal polyps, to progressively prolong the interval between
tory VAS) assessments: at 4 months, the median B-SIT              doses: registrational studies, in fact, supported a two-week
values rose from anosmia (3/12) to the superior limit of          interval administration (Q2W) for its superior efficacy, but
hyposmia (8/12), as olfactory function is considered nor-         data from SINUS 52 may suggest that a monthly regimen
mal if ≥ 9/12, and the median VAS from 3 to 7. It is worth        might be sufficient as a maintenance dose after adequate
specifying that previous studies have suggested that the ol-      response 6. This option has been already tested in AD 22,23,
factory dysfunction in CRSwNP is not attributable only to         and a pioneering contribution on CRSwNP has been pro-
the conductive obstruction to the olfactory cleft, but also       vided by the study by Van Der Lans et al., who investigated
due to a complex mechanism related to type 2 inflamma-            a stepwise interdose interval prolongation until Q6W in pa-
tion, which alters the concentration of olfactory mucus,          tients with moderate to excellent response with satisfying
inhibits the olfactory neural regeneration and leads to ol-       results 7.
factory bulb atrophy as a consequence of prolonged loss           A second topic worthy of further exploration is identifica-
of stimuli 18. As biologics determine both polyp shrinkage        tion of a subset of patients who may benefit more from bio-
and a reduction in inflammatory neurotoxins, their action         logics, thereby increasing the cost-efficacy ratio 24. In this
on olfactory function is multifactorial 18; further studies are   perspective, it must be considered that dupilumab inhibits
needed to assess the role of therapy in the olfactory epi-        type 2 inflammation, which (in Western countries) is re-
thelium renewal after disuse atrophy and/or surgical harm.        sponsible for a majority – but not all – cases of CRSwNP;
Nevertheless, predisposition to type 2 inflammation is a          nevertheless, the evidence of this kind of inflammation is
systemic condition that implies multidisciplinary evalua-         not strictly mandatory for prescription. In this regard, the
tion to assess type 2 comorbidities 4,19. Among these, par-       patient in the present study who had the poorest response
ticular attention should be paid to the eventual tapering of      to therapy in the 6-month period (only 9-point reduction
corticosteroid (CS) therapy for asthma or AD: previous re-        in SNOT-22, stable NPS and LKS, only 2 criteria for re-
ports suggest that the reduction of topical steroids in AD        sponse according to EPOS2020) had laboratory tests that
may play a role in the transient increase in AEC observed         were not suggestive of type 2 inflammation at baseline. A
during dupilumab treatment, although it has been mainly           similar finding, in fact, has been reported by Van Der Lans
ascribed to the inhibition of eosinophilic chemotaxis 20.         et al. 7, and some guidelines already consider the evidence
Multidisciplinary evaluation may therefore postpone CS            of type 2 inflammation as a mandatory requirement for bio-
tapering in patients with high AEC until normalisation of         logic therapy 19,25.
the blood count. For the same reason, counseling should           Our study has some limitations: first, some data is missing
emphasise the need for adherence to therapy: even if ad-          due to its prospective design; moreover, spirometry was re-
vised differently, a considerable proportion of our patients      quired only in patients suspected for insufficient control of
stopped or tapered their therapy for CRSwNP or asthma as          disease, while other asthmatic subjects were investigated
it was no longer considered necessary.                            through the ACT score. Lastly, we included a relatively low



542
                                                             A prospective study on the efficacy of dupilumab in CRS with type 2 inflammation




sample size, due to the monocentric design of the study,          (IRB) of San Raffaele Hospital (Comitato Etico Ospedale
and therefore no sub-analysis was possible. On the other          San Raffaele, 112/INT/2021), and conducted according to
hand, the monocentric design guarantees uniform manage-           the ethical standards established in the 1964 Declaration of
ment of patients, and more consistence in assigning endo-         Helsinki, as revised in 2013.
scopic scores.
Despite these limitations, this paper represents one of the       References
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stimulate discussion for future perspectives. In particular,
                                                                  5
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Conflict of interest statement
                                                                       results from two multicentre, randomised, double-blind, placebo-
The authors declare no conflict of interest.                           controlled, parallel-group phase 3 trials. Lancet 2019;394:1638-1650.
                                                                       https://doi.org/10.1016/S0140-6736(19)31881-1
Funding                                                           7
                                                                       van der Lans RJL, Fokkens WJ, Adriaensen GFJPM, et al. Real-life
This research did not receive any specific grant from fund-            observational cohort verifies high efficacy of dupilumab for chronic
                                                                       rhinosinusitis with nasal polyps. Allergy 2022;77:670-674. https://
ing agencies in the public, commercial, or not-for-profit              doi.org/10.1111/all.15134
sectors.                                                          8
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                                                                       sinonasal outcome test 22 (SNOT-22) in chronic rhinosinusi-
Author contributions                                                   tis. Acta Otorhinolaryngol Ital 2020;40:113-121. https://doi.
                                                                       org/10.14639/0392-100X-N0364
AV, AR, UT and AN made substantial contributions to con-
                                                                  9
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ception, design and acquisition of data, drafted the article           lowing frontal sinus surgery in chronic rhinosinusitis. Laryngoscope
and revised it critically for important intellectual content,          2021;131:2173-2178. https://doi.org/10.1002/lary.29513
gave final approval of the version to be published, and           10
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agreed to be accountable for all aspects of the work in en-            the Asthma Control Test (ACT) and other outcomes: a targeted lit-
suring that questions related to the accuracy or integrity of          erature review. BMC Pulm Med 2020;20:79 https://doi.org/10.1186/
                                                                       s12890-020-1090-5
any part of the work are appropriately investigated and re-       11
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solved; MT, MRY and MB made substantial contributions                  relevant endoscopic grading system for chronic rhinosinusitis using
to conception of the data, revised it critically for important         canonical correlation analysis. Int Forum Allergy Rhinol 2016;6:478-
intellectual content, gave final approval of the version to be         485. https://doi.org/10.1002/alr.21683
published, and agreed to be accountable for all aspects of        12
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tigated and resolved.                                                  tion of Completeness of Endoscopic Sinus Surgery (ACCESS): a new
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Ethical consideration                                                  2020;58:538-543. https://doi.org/10.4193/Rhin20.165
Informed consent was obtained from each patient for treat-
                                                                  14
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                                                                       management in patients with type 2 chronic rhinosinusitis treated
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