10.14639/0392-100X-N2422
Objective. We conducted a national survey to understand how rhinology practice has changed with the advent of biologics and how this affected patients with uncontrolled, severe chronic rhinosinusitis with nasal polyps (CRSwNP). We aimed to analyse the results of the survey and infer practical recommendations for clinical practice. Methods. A group of ear, nose, and throat specialists (ENTs) experienced in the management of CRSwNP developed a 74‑question survey. ENTs from rhinology centres authorised to prescribe biologics in the context of the national health system were invited to answer it between 01/05/2022 and 31/07/2022. The responses underwent descriptive analyses, and the authors discussed the results and derived practical recommendations for clinical practice. Results. ENTs working in rhinology centres changed their practices coinciding with the advent of biologics. CRSwNP evaluations have become more complex because they involve diagnostic confirmation, determining the patients’ immunologic profile, and other factors. We observed heterogenous behaviours in practice that may be conditioned by the novelty of the topic. The results of the survey were used to develop practical recommendations for ENTs and are summarised herein. Conclusions. Clinical practice in rhinology outpatient clinics has changed profoundly in the era of biologics. Our practical recommendations for clinicians working in rhinology centres are expected to help standardise practice and improve care.
text/xml
1827-675X
2422
en
Fabio Pagella
http://creativecommons.org/licenses/by-nc-nd/4.0
ACTA Otorhinolaryngologica Italica
Type 2 inflammation
Practical recommendations for managing severe chronic rhinosinusitis with nasal polyps in the era  of biologics
Text.Serial.Journal
https://www.actaitalica.it/
43
Rhinology
2023-05-23
2022-12-12
2023-09-29
2023-10-02
324-340
1
Fabio Pagella
2023/05/23
10.14639/0392-100X-N2422
324
Department of Clinical, Surgical, Diagnostic, and Pediatric Sciences, University of Pavia, Pavia, Italy; Otorhinolaryngology Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; D. Passali, J. Galli and F. Pagella shared the seniorship of the article.
1827-675X
Type 2 inflammation
en
340
Practical recommendations for managing severe chronic rhinosinusitis with nasal polyps in the era  of biologics
https://www.actaitalica.it/article/download/2422/1007
43
ACTA OTORHINOLARYNGOLOGICA ITALICA 2023;43:324-340; doi: 10.14639/0392-100X-N2422




Rhinology


Practical recommendations for managing severe
chronic rhinosinusitis with nasal polyps in the era
of biologics
Raccomandazioni pratiche nella gestione ambulatoriale della rinosinusite cronica
con poliposi nasale severa, nell’era dei biologici
Eugenio De Corso1, Carlotta Pipolo2, Elena Cantone3, Giancarlo Ottaviano4, Stefania Gallo5, Matteo Trimarchi6,
Sara Torretta7, Carlo Cavaliere8, Daniela Lucidi9, Veronica Seccia10, Stefano Settimi11, Frank Rikki Mauritz Canevari12,
Ernesto Pasquini13, Ignazio La Mantia14, Massimiliano Garzaro15, Gianluca Bellocchi16, Michele De Benedetto17,
Nicola Lombardo18, Alberto Macchi19, Luca Malvezzi20, Gaetano Motta21, Claudio Vicini22, Alessandro Maselli23,
Valeria Dell’Era15, Alberto Dragonetti24, Francesco Asprea25, Valentina Lupato26, Angelo Ghidini27, Simonetta Masieri8,
Davide Mattavelli28, Francesco Antonio Salzano29, Desiderio Passali30*, Jacopo Galli1,11*, Fabio Pagella31,32*


1
  Otorhinolaryngology Unit, Head and Neck Department, A. Gemelli Universitary
Hospital Foundation IRCCS, Rome, Italy; 2 Otorhinolaryngology Unit, Head and Neck
Department, Dipartimento di Scienze della Salute, Università degli Studi di Milano,
ASST Santi Paolo e Carlo Hospital, Milan, Italy; 3 Department of Neurosciences,
Reproductive and Odontostomatologic Sciences, Unit of Ear, Nose and Throat,
“Federico II” University, Naples, Italy; 4 Department of Neuroscience DNS,
Otolaryngology Section, University of Padua, Padua, Italy; 5 Otorhinolaryngology
Unit, Head and Neck Department, ASST Sette Laghi and UPLOAD Research
Center, University of Insubria, Varese, Italy; 6 Division of Head and Neck Department,
Otorhinolaryngology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy;
7
  Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy;
                                                                                            Received: December 9, 2022
8
  Dipartimento di scienze odontostomatologiche e maxillo facciali. Sapienza
                                                                                            Accepted: March 9, 2023
University of Rome, Rome, Italy; 9 Department of Otolaryngology – Head and Neck
                                                                                            Published online: May 23, 2023
Surgery, University Hospital of Modena, Modena, Italy; 10 Otolaryngology, Audiology,
and Phoniatric Operative Unit, Department of Surgical, Medical, Molecular                   Correspondence
Pathology, and Critical Care Medicine, Pisa University Hospital, Pisa, Italy; 11 Catholic   Eugenio de Corso
University of The Sacred Heart, Rome, Italy; 12 UOC di Otorinolaringoiatria IRCCS           Otorhinolaryngology – Head and Neck Surgery, “A.
Policlinico San Martino Genova, Dipartimento DISC Università di Genova, Genoa,              Gemelli” Universitary Hospital Foundation IRCCS,
Italy; 13 ENT Unit “Bellaria” Hospital – Specialized Dep AUSL Bologna, Italy; 14 ENT        largo A. Gemelli 8, 00168 Rome, Italy
                                                                                            Tel +39 06 30154439. Fax +39 06 30156665
Unit Department “G.F. Ingrassia” – Catania University, Italy; 15 ENT Division, Maggiore
                                                                                            E-mail: eugenio.decorso@policlinicogemelli.it
Hospital, Eastern Piedmont University – Novara, Italy; 16 ENT Department, San
Camillo‑Forlanini Hospital, Rome, Italy; 17 ENT Unit, Vito Fazzi Hospital, ASL Lecce,
Italy; 18 ENT Unit Department of Medical and Surgical Sciences, University Magna              How to cite this article: De Corso E, Pipolo C,
                                                                                              Cantone E, et al. Practical recommendations for
Græcia Catanzaro, Italy; 19 ENT University of Insubria, ASST Settelaghi, Varese,
                                                                                              managing severe chronic rhinosinusitis with na-
Italy; 20 IRCCS Humanitas Research Hospital, Department of Otorhinolaryngology                sal polyps in the era of biologics. Acta Otorhi-
and Head and Neck Surgery, Rozzano (MI), Italy; 21 Otorhinolaryngology – Head and             nolaryngol Ital 2023;43:324-340. https://doi.
Neck Surgery, University of Campania “L. Vanvitelli”, Naples, Italy; 22 Department of         org/10.14639/0392-100X-N2422
Head‑Neck Surgery, Otolaryngology, Head‑Neck and Oral Surgery Unit, Morgagni
                                                                                            © Società Italiana di Otorinolaringoiatria
Pierantoni Hospital, Forlì, Italy; 23 Department Otorhinolaryngology, Hospital of           e Chirurgia Cervico-Facciale
Barletta, Barletta (BT), Italy; 24 Department of Otolaryngology, Ospedale Niguarda,
Milan, Italy; 25 Otorinolaringoiatria e audiologia. Università degli studi di Messina,                     OPEN ACCESS
Messina, Italy; 26 Division of Otolaryngology, Ospedale Civile di Pordenone, Azienda
                                                                                            This is an open access article distributed in accordance with
Sanitaria Friuli Occidentale (ASFO), Pordenone, Italy; 27 Otorinolaringoiatria Azienda      the CC-BY-NC-ND (Creative Commons Attribution-Non-
USL di Reggio Emilia/IRCCS, Italy; 28 Unit of Otorhinolaryngology – Head and Neck           Commercial-NoDerivatives 4.0 International) license. The
Surgery, Department of Medical and Surgical Specialties, Radiological Sciences,             article can be used by giving appropriate credit and mentio-
                                                                                            ning the license, but only for non-commercial purposes and
and Public Health, ASST Spedali Civili di Brescia – University of Brescia, Brescia,         only in the original version. For further information: https://
Italy; 29 Department of Medicine, Surgery and Dentistry, University of Salerno,             creativecommons.org/licenses/by-nc-nd/4.0/deed.en




324
                                             Practical recommendations for managing severe chronic rhinosinusitis with nasal polyps in the era of biologics




Salerno, Italy; 30 IFOS Former President and Executive Board member, Rome, Italy; 31 Department of Clinical, Surgical, Diagnostic,
and Pediatric Sciences, University of Pavia, Pavia, Italy; 32 Otorhinolaryngology Unit, Fondazione IRCCS Policlinico San Matteo,
Pavia, Italy

Document supported by the Joint Committee on Biologics in Rhinology and by the Italian Rhinology Committee of the Italian Society
of Otorhinolaryngology.

*D. Passali, J. Galli and F. Pagella shared the seniorship of the article.



SUMMARY
Objective. We conducted a national survey to understand how rhinology practice has changed with the advent of biologics and how this affected
patients with uncontrolled, severe chronic rhinosinusitis with nasal polyps (CRSwNP). We aimed to analyse the results of the survey and infer
practical recommendations for clinical practice.
Methods. A group of ear, nose, and throat specialists (ENTs) experienced in the management of CRSwNP developed a 74‑question survey.
ENTs from rhinology centres authorised to prescribe biologics in the context of the national health system were invited to answer it between
01/05/2022 and 31/07/2022. The responses underwent descriptive analyses, and the authors discussed the results and derived practical recom-
mendations for clinical practice.
Results. ENTs working in rhinology centres changed their practices coinciding with the advent of biologics. CRSwNP evaluations have be-
come more complex because they involve diagnostic confirmation, determining the patients’ immunologic profile, and other factors. We ob-
served heterogenous behaviours in practice that may be conditioned by the novelty of the topic. The results of the survey were used to develop
practical recommendations for ENTs and are summarised herein.
Conclusions. Clinical practice in rhinology outpatient clinics has changed profoundly in the era of biologics. Our practical recommendations
for clinicians working in rhinology centres are expected to help standardise practice and improve care.
KEY WORDS: biologics, practical recommendation, chronic rhinosinusitis, nasal polyps, Type 2 inflammation

RIASSUNTO
Obiettivo. Abbiamo condotto un’indagine nazionale per capire come la pratica rinologica sia cambiata con l’avvento dei biologici e come que-
sto abbia influenzato i pazienti con rinosinusite cronica grave non controllata con polipi nasali (CRSwNP). L’obiettivo è analizzare i risultati
dell’indagine e dedurre raccomandazioni pratiche per la pratica clinica.
Metodi. Un gruppo di otorinolaringoiatri esperti nella gestione della CRSwNP ha sviluppato un sondaggio di 74 domande. Gli otorinolarin-
goiatri dei centri di rinologia autorizzati a prescrivere biologici nel contesto del sistema sanitario nazionale sono stati invitati a rispondere
tra il 01/05/2022 e il 31/07/2022. Le risposte sono state sottoposte ad analisi descrittiva e gli autori hanno discusso i risultati e definito alcune
raccomandazioni applicabili alla pratica clinica.
Risultati. Gli otorinolaringoiatri che lavorano nei centri di rinologia hanno modificato la loro routine diagnostica con l’avvento dei biologici.
La valutazione della CRSwNP è diventata più complessa, perché implica la conferma diagnostica, la determinazione del profilo immunologico
del paziente e non solo. Abbiamo osservato comportamenti eterogenei nella pratica che possono essere condizionati dalla novità dell’argo-
mento. I risultati dell’indagine sono stati utilizzati per sviluppare raccomandazioni pratiche per gli otorinolaringoiatri e sono qui riassunti.
Conclusioni. La pratica clinica negli ambulatori di rinologia è profondamente cambiata nell’era dei biologici. Le nostre raccomandazioni
pratiche per i medici che lavorano nei centri di rinologia dovrebbero contribuire a standardizzare le pratiche e a migliorare l’assistenza.
PAROLE CHIAVE: raccomandazioni pratiche, terapie biologiche, rinosinusite cronica, polipi nasali, infiammazione di tipo 2



Introduction                                                                  available for prescription and that Italian Medicines Agen-
                                                                              cy (AIFA) has approved the anti‑IL‑5 agent mepolizumab
The advent of biologics has caused a rapid and widespread
                                                                              for CRSwNP. However, the real‑world utilisation of dif-
change in the treatment of chronic rhinosinusitis with na-
                                                                              ferent diagnostics and their impact on the management of
sal polyps (CRSwNP) 1,2. Consequently, the management
of this condition, especially severe cases, has evolved in                    CRSwNP remain the object of discussion. Another aspect
clinical practice 3. The evaluation of CRSwNP is usually                      that should be investigated is the role of multidisciplinary
performed by collecting information via medical history                       referrals for this condition 5.
and scoring tools to determine disease severity and level                     Although disease-specific consensus and protocols are
of control4. Notably, endo‑phenotyping is particularly rel-                   widespread 5-11 to guide treatment with biologics, it is de-
evant prior to the initiation of biologics 5. This will be even               sirable to reach a national consensus on baseline and fol-
more important in the future, given that, in addition to the                  low-up examinations to determine eligibility and assess
anti‑IL‑4/13 dupilumab, the anti‑IgE omalizumab is now                        response to biologic treatments. The use of biologics in



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E. De Corso et al.




clinical rhinology practice, in fact, raises new issues such    (Tabs. I, II). Practical recommendations were written and
as the immunotyping and monitoring of specific param-           submitted for review and approval by all the members of
eters during treatment.                                         the committees. All the changes made were discussed and
Therefore, we conducted a national survey to better under-      refined until unanimous approval was obtained.
stand how rhinology practice has changed with the advent
of biologics and how this has affected the diagnostic and       Results and practical recommendations
therapeutic journeys of patients with uncontrolled, severe
CRSwNP in real‑life. We then analysed the survey results        Epidemiological data of the respondents
and derived practical recommendations that can be useful        A total of 61 ENTs working in rhinology centres authorised
in the management of these patients.                            to prescribe biologics responded to the survey. Most were
                                                                endoscopic sinus surgeons (92%), 57% worked in university
                                                                hospitals and 43% in public hospitals. Before the inclusion of
Materials and methods                                           biologics in clinical practice, a second‑level rhinology clinic
We conducted a survey involving a representative sample         was present in almost half of the facilities and within a multi-
of Italian ear, nose, and throat specialists (ENTs) manag-      disciplinary network (46%), whereas in 28% it existed without
ing severe uncontrolled CRSwNP working in rhinology             a multidisciplinary network; in the remaining, the clinic and
centres authorised to prescribe biologics by the national       multidisciplinary network were created after the approval of
health service. The survey was developed by a group of          biologics for CRSwNP; currently, it is well structured in 70%
ENTs experienced in the management of CRSwNP that               of cases as shown by Q1‑9 in the supplementary file (s.f.).
met remotely to discuss the aspects that should be included
in the questionnaire. The authors were divided into groups      Defining type 2 inflammation in biologic therapy
and proposed questions for specific survey topics related       candidates (Q10‑31 s.f.)
to routine practical management of CRSwNP. Next, a se-          From the results of this section, some discrepancies be-
lection process with critical appraisal of all questions took   tween theory and practice are evident. Respondents ap-
place (by EDC, EC, CP). Finally, a remote approval by all       pear aware of how and what to answer, but clinical practice
authors produced a total of 74 questions that were format-      questions remain challenging. Although ENTs know the
ted for style and answer possibilities to ensure direct and     theoretical concepts, in practice many things are difficult
standardised responses that reflect the respondents’ experi-    to implement from a management point of view. Complete
ence. The full questionnaire and the complete responses are     blood counts (CBCs), for example, are considered useful
available in the supplementary file.                            by survey respondents to define the inflammatory profile
Thanks to the collaboration of the members of the Italian       of CRSwNP patients (88% agree) (Q10 s.f.). Nevertheless,
Committee for the use of Biologics in Rhinology centres         77% of participants “always” check CBCs prior to consid-
authorised to prescribe biologics for severe uncontrolled       ering biologics (Q11 s.f.). Unfortunately, this means that
CRwNP were identified in each region. The survey was set        23% of respondents do not routinely check CBCs to define
up on Survey Monkey® and was sent by email to one of the        the inflammatory profile of CRSwNP patients prior to ini-
prescribing doctors at the centre. No information about the     tiating a biologic, indicating that education in this aspect
participants was collected in order to keep the results of      may be needed since CBCs are affordable and useful when
the questionnaire anonymous. We received questionnaires         they are put in the patient’s clinical context 12‑14.
from throughout Italy without a significant discrepancy         Regarding the use of follow‑up CBCs during biologic treat-
between the north, center and south. The survey distribu-       ment for CRSwNP, almost half (45%) of the respondents
tion started on May 1st, 2022 and was closed on July 31st,      perform these tests every 3 months, over a third perform
2022. All answers were considered appropriate and were          them bi‑monthly or monthly (15% and 22%), and fewer
included in the analysis.                                       (15%) perform them every 6 months (Q12 s.f.).
We performed a descriptive analysis and presented some          Similarly, most respondents are aware of the importance of
of the most significant results as histograms. The members      IgE in defining type 2 inflammation as suggested by the litera-
of the Joint Committee on Biologics in Rhinology and of         ture 15,16, even if less than half of patients have total blood IgE
the Italian Rhinology Committee of the Italian Society of       routinely measured. In fact, most respondents (82%) agree
Otorhinolaryngology discussed the results of the survey         that measuring total IgE is useful to define type 2 inflamma-
and compared them with current guidelines, and especially       tion (Q14 s.f.), although only 47% request total blood IgE in
EPOS 2020. For this purpose, we compared what was re-           practice (Q15 s.f.). Likewise specific IgE levels are not rou-
ported in the EPOS 2020 with what was found in practice         tinely measured in practice (Q16 s.f.).



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                                       Practical recommendations for managing severe chronic rhinosinusitis with nasal polyps in the era of biologics




Other notable discrepancies between theory and practice                 Only 12% reported they perform nasal polyp biopsies to
include histopathological analysis. For instance, 58% of re-            define type 2 inflammation (Q27 s.f.). Respondents, in fact,
spondents believe that definitive histological analysis of the          declared that in practice the information that they can get
polyp may be useful (Q25 s.f.), but the vast majority (75%,             from histopathological examinations may largely vary. In
Q27 s.f.) never or only rarely perform a biopsy to define               35% of the centres the type of inflammation is not speci-
the endotype.                                                           fied and the presence of eosinophils is neither reported nor
Regarding the cut‑offs indicative of type 2 CRSwNP, there               quantified (Q26 s.f.).
is no agreement in practice about blood eosinophil (Q13                 Finally, 59% of respondents agreed that fractional exhaled
s.f), IgE levels (Q17 s.f.), or eosinophil count at histologic          nitric oxide (FeNO) may be helpful to define inflamma-
findings (Q28 s.f.). Therefore, we propose referring to lev-            tory profile of CRSwNP, but only 25% requested it in daily
els suggested by international guidelines (total IgE ≥ 100              practice (Q30 s.f.). Our data demonstrated that most re-
U.I./ml; blood eosinophil count ≥ 250 cell/µl, local eosino-            spondents had no experience with FeNO, did not request it,
phil count > 10/hpf) 2,17.                                              or did not know about it (Q31 s.f.).
From the results of survey, it emerged that clinicians do not
consider other biomarkers to be clinically useful (Q18 s.f.)            Measuring disease severity in CRSwNP candidates for a
with the purpose to define type 2 inflammation. Even though             biologic (questions 32‑37 s.f.)
biomarkers have been widely discussed in the literature 18‑21,          The survey shows that tools to measure disease severity are
there was no agreement among the respondents about those                used in routine practice and specifically the surveyed ENTs
that can be useful in practice and most focus their attention           consider Quality of Life (QOL) questionnaires, CRSwNP
on interleukin‑5 and interleukin‑4, probably due to the new             extent measured by Nasal Polyp Score (NPS) or Computed
treatment possibilities that biologics provide 22.                      Tomography (CT) scan and comorbidity assessment. Fig-
Another notable point is that there is no agreement about               ure 1 (Q32 s.f.) shows the most used tools to determine dis-
when to request CBCs during biologic treatment. Currently,              ease severity in CRSwNP candidates for biologics. In terms
the majority of respondents request CBCs every 3 months,                of symptoms evaluation and the burden on QOL, almost
while others do it every 6 months thereby risking to bypass             all respondents (98%) use the sino‑nasal outcome test 22
the phase of transient increase in eosinophils that some pa-            (SNOT‑22) (Q34 s.f.) confirming its validity as demonstrated
tients may experience with certain biologics. Additional lit-           in the literature 6,24,25. Notably, over 70% of respondents use
erature is needed to establish the importance of performing             the visual analogue scale (VAS) (including nasal obstruction,
CBCs during biologic treatment and if the timing can be                 rhinorrhoea, smell, and craniofacial pain). This scale allows
influenced by the type of biologic used (Q12 s.f.).                     investigating specific rhinology symptoms, giving more
Through the survey, we also sought to understand whether                weight to the nasal domain than to the entire SNOT‑22. This
other modalities are used in practice to define type 2 in-              scale is probably frequently used due to its simplicity and
flammation. Interestingly most respondents (87%) agreed                 speed of execution as suggested in guidelines 26. In compari-
that allergy evaluation and related immune‑allergology                  son, the nasal congestion score (NCS) and total composite
tests are important to define CRSwNP endotypes (Q19 s.f.)               symptoms score (TCSS) are rarely used (25% and 11%),
and almost 73% of them request immune‑allergology tests                 even though most monoclonal antibody studies and some
all the time or often in practice (Q20 s.f.). On the other              guideline recommendations are based on this score 6.
hand, although studies 5,23 show that the definition of local           Furthermore, analysing clinical history of the patient, ENTs
inflammation may be useful in definition of the endotype,               consider previous surgery (86%) more relevant than the need
it is not always characterised in clinical practice. Almost             for previous oral corticosteroid (OCS) cycles (66%) (Q33
70% of respondents agreed that cytologic examinations via               s.f.). Only a minority of respondents considered the total
nasal scraping (standard lower turbinate method) may be                 dose of OCS (41%) and the total days of OCS (30%) used
useful to define the local inflammatory profile (Q21 s.f.),             in the previous year. We believe that the importance of cor-
although only 50% perform nasal cytology routinely (Q22                 ticosteroids during disease control should be emphasised as
s.f.) and there was no agreement about the level of local               suggested in our previous experience 14,32. The evaluation of
eosinophil counts indicative of type 2 inflammation; only               disease control should be performed as well including surgi-
32% indicated a count > 10 cells/field (Q23 s.f.). Almost               cal and medical treatments, especially steroids.
two‑thirds of respondents were uncertain or disagreed                   In terms of instrumental scores, the NPS seems to play a
when asked if nasal cytology should be performed via oth-               prominent role in assessing disease severity via endoscopy
er methods (middle turbinate or lateral nasal wall), while              in practice, and is the most widely used (98%) endoscopic
a third thought those options were acceptable (Q24 s.f.).               score (Q35 s.f.).



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E. De Corso et al.




Figure 1. Scores or elements used in clinical practice to establish disease severity (Q32 s.f.).
SNOT-22: sino-nasal outcome test 22; NSAIDS: Nonsteroidal anti-inflammatory drugs; VAS: visual analogue scale; UPSIT: University of Pennsylvania Smell Identi-
fication Test; NCS: nasal congestion score; TNSS: total nasal symptom score; TSS: total symptoms scores; S: staphylococcus.


The reason for this probably lies in its use in registration                     in practice to assess disease severity. Indeed, only a quarter
trials, biologic therapy guidelines, and regional therapeutic                    of ENTs (26%) perform an active anterior rhinomanometry
plans 27‑29. Regarding CT scans, we observed that partici-                       and only 11% perform peak nasal inspiratory flow (PNIF)
pants use them for diagnostic purposes, differential diag-                       at the first visit (Q37 s.f.). This is probably because rhi-
nosis, and for surgical planning (Q36 s.f.). However, only                       nomanometry is costly and time-consuming, while PNIF
56% of ENTs use the Lund‑Mackay score to assess the ex-                          is not a widely spread tool due to limited experience, even
tent and severity of disease even if high values indicate a                      though it is a quick, affordable option, and could easily and
greater risk of future relapse 30. Other reasons to perform                      satisfactorily be used in clinical practice 31. Nasal obstruc-
CT scans were to confirm CRSwNP diagnoses (localised or                          tion is one of the major symptoms of CRSwNP, and based
diffuse), for surgical planning, and differential diagnoses.                     on our results its evaluation is probably underestimated in
Interestingly, participants also consider haematologic                           practice. We believe that its assessment is important to ob-
markers such as eosinophilia (87%) and total serum IgE                           tain an idea of severity of the disease. For this reason, not
(89%); in addition, type 2 comorbidities are considered                          only VAS nasal obstruction but also NCS and PNIF, due to
predictive of severity by 89% of ENTs. Local eosinophilia                        their simplicity, may be helpful to enhance its evaluation in
is considered only by 48% of respondents by cytology or                          practice 31.
histology. The role of blood eosinophilia and the presence
of type 2 comorbidities is noteworthy and in full compli-                        Measuring the sense of smell in biologic therapy
ance with the literature 33,34. Surprisingly, less than half                     candidates (questions 38‑41)
of the respondents assess local eosinophilia, although the                       Even though olfactory assessments prior to biologic treat-
scientific evidence confirms its correlation with disease                        ment initiation seem to be very important as suggested by
severity 16,18,21,35‑37 and even more compared with blood eo-                    several guidelines 2,5,17,25, the survey clearly shows (Q38
sinophilia. Further studies are necessary to better define                       s.f.) that olfactory function measurement is less common
how the evaluation of local inflammation with the avail-                         in practice 38. Indeed, only 53% of respondents agreed that
able methods may impact definitions of disease severity.                         performing olfactory tests is essential before initiating bio-
The current literature is probably not sufficient to strongly                    logic treatments in CRSwNP patients, and 13% stated that
influence clinical practice.                                                     testing is necessary only if patients report anosmia or hy-
Lastly, there is a final aspect that we would like to high-                      posmia. Moreover, to the same question, 24% declared they
light, namely nasal flow is not often objectively evaluated                      did not perform olfactory tests because they are not avail-



328
                                                     Practical recommendations for managing severe chronic rhinosinusitis with nasal polyps in the era of biologics




able in their outpatient clinic, and 7% considered it was not                             Interestingly, over a third of the respondents (38%) report-
necessary (Q38 s.f.). When asked about the method used                                    ed that they use a VAS for smell dysfunction to determine
to measure olfaction, most reported they use an olfactory                                 olfaction in CRSwNP patients. However, although VAS for
test (Q39 s.f.), and in particular an olfactory identification                            smell is a validated quantitative method, self‑evaluation of
test, but a large proportion also use VAS smell (Tab. I). Not                             olfactory function does not correlate with measured olfac-
surprisingly, the 16 odours Sniffin’ Sticks identification                                tory function 40. This is because patients and their physi-
test is the method of choice to evaluate olfaction. This test                             cians can be completely unaware of their impaired sense of
is in fact simple, fast, and an easy method to measure the                                smell unless it is measured 4. Furthermore, in patients com-
sense of smell 39. Thus, considering the usual distribution                               plaining of hyposmia, the extent of dysfunction can be mis-
of people with normal olfaction and anosmia, an identifica-                               evaluated if only questionnaires are used. The inability of
tion test with 16 odours allows appropriate discrimination                                patients to self‑rate their olfaction is well‑known (30‑40%
between anosmia and normosmia and the interpretation of                                   of CRS patients with impaired olfactory function rate them-
intermediate results (hyposmia) is acceptable 4.                                          selves as unimpaired, and only 27% can accurately report


Table I. Comparison of EPOS guideline indications and those adopted in real‑life regarding definition and measurement of CRS severity and features.
                                           EPOS2020 guidelines 25                                              Italian real‑life practice
                                                                                                                  (% of responders)
 Definition of type 2       The EPOS2020 steering group was unclear as to whether it was              Most respondents (82%) agree that measuring total IgE is useful
 inflammation               essential to measure total IgE either at initial presentation of CRS       to define type 2 inflammation although only 47% request total
                             (10% agreed) or after failure of appropriate medical or surgical                                blood IgE in practice
                                              treatment in ENT (48% agreed)
                               EPOS2020 suggested as serum IgE cut off to define type 2                   Only 37% consider IgE > 100 U.I./ml indicative of type 2
                                          inflammation: Total IgE > 100 U.I./ml                                            inflammation in practice
                               The EPOS2020 steering group was unclear as to whether it                In practice, 88% agree that complete blood counts (CBCs) are
                               was essential to evaluate blood eosinophilia either at initial         useful to define type 2 and 77% of participants check CBCs prior
                             presentation of CRS (17% agreed) or after failure of appropriate                               to considering biologics
                                       medical or surgical treatment (59% agreed)
                                    EPOS2020 suggested as cut off (EOS > 250/ul)                      In practice only 45% of respondents consider EOS > 250 /ul as
                                                                                                                       indicative of type 2 inflammation
                            The EPOS2020 steering group did not consider it is essential to           58% of respondents believe that biopsy may give information on
                             do histopathology / biopsy at initial presentation of CRS (13%)           inflammatory profile of CRS patients but only 12% perform it in
                            and responses were unclear after failure of appropriate medical                                         practice
                                                 or surgical treatment (31%)
                            EPOS 2020 suggested the cut off (EOS > 250/ul) 10 cell /hpf as   42% believe that tissue eosinophilic count value: > 10 cells/hpf is
                                              indicative of type 2 inflammation                                indicative of type 2 inflammation
 Measurement of               Expert committee proposed to combine severity of symptoms,        Parameters used in practice to establish non‑disease control:
 disease severity/           aspect of mucosa and medical intake as parameters of control.                                    (Q33)
 control                       CRS control test takes into account presence and severity of               No. short cortisone cycles in last year 66%
                            four major sinonasal symptoms (VAS > 5), sleep and/or fatigue,
                                  endoscopic evaluation and need for oral medication.                    Total dose of cortisone in the last year 41%
                              Core outcomes set: Need for systemic medication (steroid or             Total days of cortisone intake in the last year 29%
                                 antibiotic); Progression to surgery; Lund‑Kennedy score                         No. previous surgeries 87%
                                                                                                           Recurrence time since last surgery 77%
                                EPOS2020 steering group proposed as important issue to              Scores used in measuring disease severity in practice:
                               be considered for indication to biologics assuming that they   NPS 97%, SNOT-22 98%, total VAS 70%, NCS 25%, smell tests
                            suggest a severe disease: SNOT-22 > 40, Anosmia at smell test,                   61%, presence of comorbidities 89%
                              presence of comorbidities. The authors also suggested that a
                                           VAS > 7 was indicative of severity
 Measurement of             EPOS2020 steering group unclear if essential to do smell test in     58% believe is essential to use olfactory test before starting
 smell                                       CRS after failure of treatment                   treatment with biologicals but in 23% depends on the availability
                                                                                                                    of the olfactometric test
                             EPOS2020 steering group suggested to assess smell through         Tools used to evaluate olfaction in practice: (Q39), VAS olfaction
                                                     testing, not VAS                                        38%, Sniffin’ Sticks 35% UPSIT 10%
EPOS2020: European Position Paper on Rhinosinusitis and Nasal Polyps 2020; CRS: Chronic rhinosinusitis;SNOT-22: sino-nasal outcome test 22; EOS: eosinophilia; VAS: visual ana-
logue scale; UPSIT: University of Pennsylvania Smell Identification Test; NCS: nasal congestion score; NPS: nasal polyp score; VAS: Visual: visual analogue scale.




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E. De Corso et al.




their olfactory ability) 40. Accordingly, in a recent study of   rhinology follow‑ups during biologic therapy are not rou-
the olfactory performance of CRSwNP patients before and          tinely planned for asthmatic patients (88%) (Q43 s.f.). In-
after biologics, the authors 41 observed that patients report-   stead, they are requested on demand depending on nasal
ed a higher degree of improvement of smell dysfunction on        symptoms (22%), previous history of rhinology patholo-
the VAS than on tests for smell identification, demonstrat-      gies (51%), or for patients with a diagnosis of CRSwNP
ing that the patients were not aware of the degree of their      (15%) (Q43 s.f.).
olfactory dysfunction. This observation would demonstrate        On the other hand, respondents carefully evaluate their pa-
the partial unreliability of VAS alone and the need to al-       tients with severe asthma and CRSwNP from a pneumolog-
ways perform an olfactory test, at least for smell identifica-   ical point of view, especially to obtain information about
tion. For this reason, we suggest that olfactory tests should    duration of biologic therapy, asthma control, and endotype
be used in association to subjective methods 42.                 (Q44 s.f., 60‑94% of respondents). Notably, 60% consider
Regarding how to measure olfaction during biologic treat-        it is essential to share information with pulmonologists
ment (Q40 s.f.), over two‑thirds of respondents (68%) use        about asthma control prior to biologic therapy initiation
semi‑objective olfactometry tests, 47% use VAS for olfac-        (Q47 s.f.), although only 35% of ENTs are aware of spe-
tion, and only 13% do not see the need for olfactometric         cific assessment tools for asthma control (Q45 s.f.).
testing. Close to a third evaluate sense of smell every three    Regarding OCS (Q46 s.f.), ENTs often (81%) evaluate the
months or at every follow‑up (35% and 32%)(Q41 s.f.).            amount of OCS their patients take for asthma. They recog-
The fact that some of respondents consider olfactory dys-        nise that this is useful to make in‑depth evaluations with
function evaluation not necessary before starting biolog-        relevant indicators (54%), to record systemic OCS doses
ics (11%) and during the therapy (13%) is not acceptable.        relative to their condition (19%) and to assess endocrine
This is noteworthy because smell impairment is one of            side effects (9%). Only 19% reported that OCS intake is
the key factors in determining disease severity and sever-       difficult to quantify or that it is unnecessary (Q46 s.f.).
ity of olfactory loss is known to be parallel to the severity    Asking for specific information about multidisciplinary
of inflammation in CRS patients. Therefore, using simple         team meetings (MDT), structured multidisciplinary meet-
methods to measure olfaction during follow‑up can help to        ings before patients initiate biologics take place in only
assess response to treatment.                                    25% of rhinology centres (Q47 s.f.). We suggest that rhi-
In conclusion, although olfactory threshold tests are            nology centres where patients with uncontrolled, severe
more precise than suprathreshold olfactory identification        CRSwNP are followed should establish direct collabora-
tests 40,42, we believe that since quick and affordable tests    tive networks with pulmonologists to facilitate pathways
are needed, smell evaluation prior to biologics in CRSwNP        and to jointly discuss candidates for biologics. Structured
patients and during follow‑up can be assessed with tests for     multidisciplinary boards may be helpful in clinical practice
smell identification (16 or 12 odours Sniffin’ Sticks iden-      to discuss and quickly share information about candidates
tification test) together with subjective methods (VAS for       for biologics 23,43‑45.
smell) that provide important information about olfaction        Interestingly, our data demonstrate that ENTs concen-
and inflammation status 4,42.                                    trate more on correct asthma diagnosis, level of control,
                                                                 and previous and ongoing treatments (including systemic
Practical management of asthma patients with CRSwNP              corticosteroids) than on comorbidities. This overlaps with
(Q42‑47 s.f.)                                                    the findings of our recent national survey 32, where ENTs
Our data show high levels of multidisciplinary collabora-        reported that they pay more attention to previous need of
tion between pulmonologists and ENTs in these complex            systemic steroids for CRSwNP and where we suggested
comorbid patients (Q47 s.f.). Our data shows that 92% re-        that the dosage of systemic steroids used for asthma should
spondents have a good experience in evaluating comorbid          also be considered.
patients because they work in centres where there is al-
ready an established medical pathway for severe asthmatic        Practical management of severe CRSwNP patients naïve to
patients (Q42 s.f.). A minority not working in centres with      surgical treatment (Q48‑53 s.f.)
specialised asthma clinics may have less experience with         Our data suggest that the baseline clinical evaluations of
biologics, since they have not worked previously with these      severe CRSwNP patients naïve to surgery become more
therapies in direct contact with pulmonologists.                 complex to perform compared to the past because an ad-
Although baseline rhinology assessments of severe asthma         ditional work up is now suggested by international guide-
patients prior to initiating biologics are common accord-        lines. Figure 2 (Q48 s.f.) shows the tests that respondents
ing to most respondents (Q42 s.f., 92%), pre‑established         consider necessary prior to surgical referral or biologic ini-



330
                                              Practical recommendations for managing severe chronic rhinosinusitis with nasal polyps in the era of biologics




Figure 2. Tests and evaluations considered necessary for a patient with moderately/severe CRSwNP who has never been operated on and has never taken bio-
logical therapy (Q48 s.f.). SNOT-22: sino-nasal outcome test 22.


tiation. Most (> 90%) confirm diagnosis with maxillofacial                     categorical refusal of surgery by the patient and in the pres-
CT scans, nasal endoscopies, and also administer QOL ques-                     ence of poor prognostic indicators (Q53 s.f.).
tionnaires. If local corticosteroids had never been prescribed                 Basing on current evidence, we believe that a first surgery
(Q49 s.f.), ENTs usually suggest a course of these drugs with                  should be skipped only if there is a real contraindication
reassessment to evaluate efficacy over time. Blood tests dur-                  to it. It is still controversial if there could be a small win-
ing the first evaluation are frequently required, especially                   dow for drugs in naïve patients with clear risk factors for
blood counts (86%) and total IgE (80%) (Q48 s.f.). Aller-                      post‑surgical recurrence 5. Clinician attitudes may evolve in
gology and pneumology evaluations are also considered if                       the future regarding first‑line treatments for a specific sub-
never performed before (Q52 s.f.). Our results demonstrate                     set of non‑operated patients, but the current evidence does
that Italian ENTs are well‑trained in diagnosing patients                      not support this strategy 47.
with nasal polyps and use additional evaluations. Most seek
to confirm the diagnosis and assess type 2 inflammation by                     Practical management of CRSwNP patients that have under-
ordering eosinophils and total IgE levels at first evaluation.                 gone surgery but are naïve to biologics (Q54‑57 s.f.)
This may be due to the educational initiatives on biologics                    Regarding CRSwNP patients who have undergone func-
promoted by the Italian Society of Otolaryngology over                         tional endoscopic sinus surgery (FESS) and are being
the past two years 2,5,32,46. Respondents are inclined to refer                considered for biologics, only 36% are routinely assessed
CRSwNP patients to allergology and pneumology specialists                      with CT scans, and 51% only if needed for specific reasons
for further evaluation. However, more than half refer them to                  (Q54 s.f.). From these results, it emerged that ENTs re-
a pneumologist only when asthma is already diagnosed or                        spondent to this survey do not routinely use CT scans when
strongly suspected. We believe that a practical compromise                     re‑evaluating patients after surgery, especially if relapsing.
could be to routinely perform multidisciplinary evaluation                     Furthermore, they seldomly consider quantifying the ex-
in severe cases and in the presence of suggestive pulmonary                    tent of previous surgery (23%) (Q54 s.f.). Notably, our data
symptoms in moderate or mild cases 2.                                          show that respondents do not use specific scores to evaluate
Regarding the indication of biologics to treat naïve patients,                 the adequacy of previous surgeries 48. For example, 63%
most respondents (Q53 s.f.) would prescribe first‑line bio-                    of respondents do not use the Amsterdam Classification of
logics only if there is a real contraindication to surgery                     Completeness of Endoscopic Sinus Surgery (ACCESS) 48
(68%) as suggested in guidelines 25. Notably, 15% of re-                       score to evaluate the extent of the surgery (Q55 s.f.). Fi-
spondents always recommend surgery in naïve patients and                       nally, our data suggest that the majority of the respondents
a minority referred that it could be considered in case of                     do not know how to use ACCESS to decide between surgi-



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E. De Corso et al.




cal revision over medical/biologic therapy (Q56 s.f.). There                      respondents mostly answered that early recurrence (with-
may be several reasons for this reluctance: Italian ENTs                          in one year) suggests biologics over surgical treatment 51
may not know this score since it has recently been intro-                         (92%) (Q57 s.f.).
duced and since most ENTs have personally operated on
their patients, they may not see the need for routine CT                          Practical management of CRSwNP patients initiating
assessments. It is hard to interpret the answers for cases                        and during biologic therapy (Q 58‑62 s.f.)
when ACCESS is used (Q56 s.f.) because of the paucity of                          The responses demonstrate a relatively homogenous ap-
responses 49.                                                                     proach for rhinology assessment of these patients. As shown
When CRSwNP recurs post‑endoscopic surgery (Q57 s.f.),                            in Figure 3 (Q58 s.f.), all the ENTs surveyed perform nasal
the choice of biologics rather than surgical re‑intervention                      endoscopies (rhinofibroscopies) prior to initiating biolog-
may be challenging, especially if the previous surgery was                        ics. Other tests commonly performed are eosinophil count
insufficient (i.e., simple polypectomy without ethmoidec-                         (95%), total IgE (85%), maxillofacial CT scans (71%), and
tomy). In this situation, different factors (inflammation lev-                    olfactometries (64%). Almost half (47%) of respondents
el, endotype) may be influential, and it may be difficult to                      also evaluate nasal cytology and only a few (15%) assess
establish how much the technical aspects of the surgery are                       PNIF. Other blood tests are used by a minority of clini-
involved. In this context, we encourage the use of specific                       cians. Similarly, pulmonary inflammation assessments via
assessment tools such as the ACCESS score, which may be                           FeNO are performed only by 10% of ENTs.
useful to determine the completeness of the previous sur-                         For evaluation of response, the parameters used during
gery (Q55 s.f.) 50. The fact that the respondents seldomly                        the first year of follow‑up include QOL assessments via
use ACCESS indicates a need to provide education about                            SNOT‑22 by 100% of respondents, while only one‑third
the usefulness of this score.                                                     (34%) use the NCS. Over half of respondents (53%) per-
The literature provides information on how to determine                           form olfactometric assessments, while a minority of ENTs
in which patients surgery may not guarantee control of the                        perform pneumology tests (FeNO, 5%; spirometry, 17%).
condition based on timing of recurrence. When considering                         Eosinophilia is evaluated through blood count by 80% of
another surgery, the data indicates that patients recurring                       ENTs and blood chemistry tests by 39%(Fig. 4) (Q61 s.f.).
within 3 years have poorer prognoses. Coincidentally, the                         All ENTs assess response to biologic treatment at 12




Figure 3. Evaluations deemed necessary to consider a patient with CRSwNP ready to initiate therapy with a biologic (Q58 s.f.).
CM: contrast medium; ESR: erythrocyte sedimentation rate; CRP: C-reactive protein; PNIF: peak nasal inspiratory flow; C‑ANCA: cytoplasmic anti‑neutrophil cyto-
plasmic antibodies; P‑ANCA: perinuclear anti‑neutrophil cytoplasmic antibodies; FeNO: fractional exhaled nitric oxide.



332
                                                Practical recommendations for managing severe chronic rhinosinusitis with nasal polyps in the era of biologics




Figure 4. Parameters used in clinical practice in the first year of treatment during follow‑up visits (Q61 s.f.).
SNOT-22: sino-nasal outcome test 22; NPS: nasal polyp score; PNIF: peak nasal inspiratory flow; CM: contrast medium; FeNO: fractional exhaled nitric oxide.




Figure 5. Parameters used to establish the response of biological therapy at 12 months (Q62 s.f.).
SNOT-22: sino-nasal outcome test 22; NPS: nasal polyp score; ACT: asthma control test; CM: contrast medium; PNIF: peak nasal inspiratory flow.



months mainly via NPS and SNOT‑22 (Fig. 5, Q62 s.f.).                            NPS as it does not always correlate with improvements in
It is necessary to emphasise that in clinical practice, Ital-                    smell and SNOT‑22 41. Furthermore, more attention should
ian colleagues seem to give equal importance to NPS. Re-                         be given to evaluating the sense of smell, improving co-
al‑world data may help this perception to evolve and change                      morbidities, and reducing corticosteroid intake according
the use of this test towards a more cautious interpretation of                   to EPOS guidelines.



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E. De Corso et al.




Regarding the timing of follow‑up, most ENTs agree on the                          patients who require further testing, for example with the
importance of frequent follow‑up visits during the first year                      Asthma Control Test (ACT).
of treatment (Q59 s.f.), and 64% of respondents agree on
their timing during the first year (15 days, 1/3/6/9 months,                       Practical management of patients with secondary CRSwNP
and 1 year post‑treatment initiation) (Q59 s.f.). After one                        eosinophilic granulomatosis with polyangitis (EGPA) and
year of biologic treatment, follow‑ups are less frequent                           candidate for biologics (Q63‑66 s.f.)
(every 6 months) (Q60 s.f.). We believe that frequent as-                          Our data (Q63 s.f.) suggest that in practice ENTs screen
sessments, especially within the first 6 months, may be piv-                       only selected patients with severe, uncontrolled CRSwNP
otal to evaluate response to treatment, detect adverse events                      for autoimmune parameters, and especially in case of
(increased eosinophils), monitor adherence, and train pa-                          known autoimmune disease (64%), increased eosinophils
tients to self‑inject the medication 5. On the other hand, af-                     (49%), or concomitant eosinophilic disorders (58%). The
ter one year of treatment, the frequent visits (every 2 or 3                       blood tests used to exclude concomitant autoimmune dis-
months) reported by a third of respondents (Q60 s.f.) may                          eases (Q64 s.f.) are reported in Figure 6 (Q64); the most
not be sustainable in the long term.                                               cited are cytoplasmic anti‑neutrophil cytoplasmic antibod-
Notably, many ENTs do not evaluate CBCs at baseline to                             ies (C‑ANCA) or perinuclear anti‑neutrophil cytoplasmic
characterise inflammation and do not screen for increased                          antibodies (P‑ANCA) (90%), and CBC with differential
eosinophils during the first months of biologic treatment.                         (73%). Regarding other exams used to screen patients sus-
Evaluating eosinophils via CBC and total IgE prior to and                          pected of rheumatologic diseases, most ENTs (95%) refer
during biologic treatment should be considered essential to                        patients to a rheumatologist, and only 12% perform a pre-
the care of these patients. (Q61 s.f.) 15.                                         liminary nasal biopsy prior to referral (Q65 s.f.). There was
Since many ENTs do not consider lung function prior to                             no agreement about eosinophilia levels as thresholds con-
and during biologic therapy (Q58, Q61, and Q62 s.f.), it                           sidered suggestive of concomitant autoimmune disease in
is necessary to focus more on lung function assessments                            CRSwNP patients. Eosinophil levels > 1500/mcL are used
at those points in time. This is essential since response                          by 32% of ENTs, followed by > 600/mcL by 20%. Interest-
to treatment, as stated in EPOS2020 25, is also defined by                         ingly, 17% stated they do not consider eosinophils to guide
reductions in comorbidities such as asthma. ENTs that                              clinical decisions (Q66 s.f.).
aim to work in multidisciplinary settings should perform                           EPOS2020 25 suggests that EGPA should be ruled out in pa-
questionnaire‑based assessments of lung function to screen                         tients with severe CRSwNP not responding to conventional




Figure 6. Blood chemistry tests considered useful for the exclusion of CRSwNP associated with autoimmune disease in the screening of a patient who is can-
didate for biological therapy (Q64 s.f.). C‑ANCA: cytoplasmic anti‑neutrophil cytoplasmic antibodies; P‑ANCA: perinuclear anti‑neutrophil cytoplasmic antibodies;
CRP: C-reactive protein; ESR: erythrocyte sedimentation rate.



334
                                       Practical recommendations for managing severe chronic rhinosinusitis with nasal polyps in the era of biologics




treatment, eosinophils over 1500/mcL, and ANCA positivi-                that protocol of ASA desensitisation could be an option in
ty as these should be considered active EGPA markers. Our               patients that experienced OCS or surgical failure (Q69). Fi-
data shows that this recommendation has not been incorpo-               nally, there is a minority (12%) that believe that ASA desen-
rated universally by our survey respondents. The authors of             sitisation should never be proposed as a therapeutic option
this manuscript agree that CBC with differential, P‑ANCA,               perhaps because it can be a high‑risk procedure 61,62.
and C‑ANCA can be useful to exclude the presence of con-
comitant autoimmune diseases. These conditions should be                Conclusions
always ruled out in candidates for biologic treatment with
severe uncontrolled CRSwNP. This aspect becomes even                    Our survey has shown that clinical practice in rhinology
more important considering that in some cases the admin-                outpatient clinics has changed profoundly. ENTs work-
istration of dupilumab may trigger the onset of EGPA in                 ing in rhinology centres have changed their activities,
predisposed patients 52. Finally, we would like to stress that          coinciding with the new therapeutic possibilities of-
EGPA may become apparent during or after the discontin-                 fered by targeted therapies. CRSwNP evaluations have
uation of biologic treatments for asthma (with or without               become more complex because they involve diagnostic
CRSwNP) 53‑56.                                                          confirmation and determination of the immunologic pro-
                                                                        file (especially endotype). Evaluations of the endonasal
Practical management of exacerbated respiratory disease                 situation in patients on biologics for asthma are also
(ERD) (Q67‑74 s.f.)                                                     required. Finally, special attention must be paid dur-
Our data suggest that ENTs are aware of NSAID‑ERD, es-                  ing assessment of candidates for biologics by carefully
pecially regarding its characteristic correlation with drugs            evaluating past treatments and response to them, and the
and its typical clinical picture. The respondents consider              results of tests performed during multidisciplinary care.
that nasal endoscopy is an important diagnostic tool to di-             Counselling prior to the possible initiation of biologics
agnose NSAID‑ERD (71%). However, for 81% document-                      is also particularly important. Patients have to be part of
ing NSAID intolerance is crucial. Spirometry (69%) is also              clinical decisions and have to be informed of the clinical
considered an important diagnostic tool (Q71 s.f.). ENTs                course they will undergo.
consider bronchospasm (70%) and nasal obstruction (60%)                 The members of the Joint Committee on Biologics in Rhi-
pathognomonic signs for the diagnosis of NSAID‑ERD                      nology and of the Italian Rhinology Committee of the Ital-
(Q72 s.f.). In addition to the classic NSAID‑ERD triad,                 ian Society of Otorhinolaryngology that discussed the re-
respondents consider ocular symptoms (41%) or an itchy                  sults of the survey extrapolated practical recommendations
rash (39%) as characteristic symptoms (Q73 s.f.).                       for clinical practice in rhinology centres as summarised in
Most respondents (85%) are aware of the current definition              Tables III and IV and approved by all the authors.
of NSAID-ERD that emphasises drug‑induced exacerba-                     With this survey, we tried to emphasise the novelties pre-
tion of respiratory symptoms in patients with asthma and                sent in rhinology clinics in terms of practical management
nasal polyps (Q67‑Q68 s.f.) 57. Our survey shows that ENTs              and how closely ENTs adhere to and apply guidelines in
rely predominantly on symptom assessments to diagnose                   clinical practice. We tried to underline how some aspects
NSAID‑ERD. Over half (51%) consider that in‑depth an-                   of the new diagnostic and therapeutic algorithm may be
amnestic evaluation is useful to confirm diagnosis; how-                improved and provided practical suggestions. We believe
ever, most (90%) consider this insufficient and referral to             that some of the practices and heterogenous behaviours
an allergologist or a pulmonologist with additional allergy             reported by respondents may be conditioned by the nov-
testing or bronchial reactivity studies is considered manda-            elty of the topic. It is worth noting that the conclusions
tory to definitively diagnose NSAID‑ERD 58‑60.                          drawn from this survey need to be considered also taking
Concerning ENTs define NSAID‑ERD disease control in                     into account the limited number of respondents involved.
terms of relapse of polyps (85%), asthma exacerbations                  In addition, some challenging topics will unquestionably
(83%), symptom severity (83%), number of surgeries                      be further debated. We need to discuss which tests to per-
(61%), and eosinophil counts (56%, more often in serum                  form at baseline and which to repeat during follow‑up
than tissue) (Q74 s.f.).                                                and at what frequency. We also have to focus on the best
Regarding acetylsalicylic acid (ASA) desensitisation as a               timing of visits during follow‑up. In an era of precision
therapeutic strategy for NSAID‑ERD, almost half of the re-              medicine, diagnostic protocols should align with the po-
spondents (46%) reported that it is not performed in their              tential of targeted therapies such as monoclonal antibod-
centres. When it is practised it happens exclusively after              ies. Another challenge will arise when more biologics are
standard medical therapy failure; indeed respondents believe            approved for CRSwNP. Evidence from the literature and



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E. De Corso et al.




Table II Comparison of EPOS guidelines to real‑life practice regarding practical management of CRS.
                                         EPOS2020 guidelines                                                   Italian real‑life practice
                                                                                                                  (% of responders)
 Practical management        A patient’s self‑assessment of their chest symptoms        In the presence of a patient with moderately/severe CRSwNP who has
 of asthma patients       (wheeze, shortness of breath, chest tightness, and cough)      never been operated on and has never taken biological therapy, 76%
 with CRSwNP               and severity is often poor, or they may even be unaware       of respondents believe that evaluation of lower airways with objective
                            that the lower respiratory tract is affected so objective                             testing is required
                                   assessment of lower airways is necessary
 Practical management     The EPOS2020 steering group was unclear as to whether           In practice respondents consider in naïve patients with moderately/
 of severe CRSwNP         nasal cytology, nasal lavage, blood eosinophilia and IgE in    severe CRSwNP blood eosinophil count (86.44%), total IgE (79.66%),
 patients naïve to        CRS patient at presentation of symptoms or after failure of                      local nasal eosinophilia (52.54%)
 surgical treatment                            previous treatment
                          EPOS steering group suggested that QoL instruments are        In practice 98.31% of respondents believe that QOL Questionnaires are
                           important for the management of CRS (100%) and the                                important and use SNOT‑22
                                     SNOT-22 was the most used 84%
                           Nasal endoscopy is an essential part of the rhinological        In practice, 100% of respondents believe that nasal endoscopy is
                                               examination                                                        important and use it
                         EPOS criteria consider this scenario and put the endoscopic      In real‑life practice, the respondents usually take into consideration
                            sinus surgery (ESS) procedure as a given in order to         not only the contraindications to surgery but also factors predictive of
                          access biological therapy. However, EPOS also considers                    failure and even categorical refusal of the patient
                           exceptional circumstances in which treatment can be
                            accessed without prior ESS (e.g., not fit for surgery)
 Practical management      Recommendations regarding the response criteria for         What parameters do you use to establish the response of biological
 of CRSwNP patients        biologicals in the treatment of CRS can be found that                     therapy at 12 months? NPS (93%)
 initiating and during include reduced nasal polyp size, reduced need for systemic              SNOT‑22(100%), NCS (32%), PNIF (18.64%)
 biologic therapy       corticosteroids, improved quality of life, improved sense of Improved comorbidities (ACT 28.81% – spirometry ‑16.95%) improved
                                smell and reduced impact of comorbidities                           sense of smell, olfactometry 55.93%
                            No practical management/timing guidelines are given         What is your timing of follow up for a patient with CRSwNP on biologic
                                                                                                        therapy in the first year of treatment?
                                                                                         15 days, 1 month, 3 months, 6 months, 9 months, 1 year (64.41%)
                                                                                                                Every month (5.08%)
                                                                                                  Every 3 months (25.42%); every 6 months (5.08%)
 Practical management    EGPA should be considered in any patient with severe                 In practice, respondents consider it necessary to screen for
 of patients with       nasal polyposis, not responding to conventional therapy,            autoimmunity patient with severe and uncontrolled CRSwNP in
 secondary CRSwNP     crusting/bleeding and severe symptoms, marked peripheral             the case of very high values of blood hypereosinophilia (49.15%)
 associated to EGPA       eosinophilia (usually > 1500/cells/ul or > 10%) and             without agreement on a specific cut‑off, in case of other associated
                         ANCA‑positivity (not always present). However, Delphi           autoimmune diseases (64.41%). In case of obvious alterations of the
                      consensus is unclear on if it essential to do an objective test        nasal mucosa (e.g., septal perforations, crustiness) (35.59%)
                         for vasculitis in CRS after failure of previous treatment
 Practical management     All patients with CRS should be asked about reactions to          The diagnosis of NSAID‑ERD is mainly based on clinical history
 of NSAID exacerbated      aspirin and NSAIDs. At least one documented reaction          including asthma, nasal polyps, and respiratory reactions to NSAIDs
  respiratory disease     to aspirin or NSAIDs is required to make the diagnosis of                                    (85%)
                           NSAID-ERD though history alone is not always reliable.
                         Aspirin provocation tests are needed when the history is not
                                                     clear




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Table III. Practical recommendations in diagnostic work up of CRSwNP.
 Definition of type 2 inflammation in practice
 CBCs and total IgE are useful blood biomarkers in defining type 2 inflammation in CRS patients
 Definition of local eosinophilia may be useful, especially in cases with negative blood evidence of type 2 inflammation
 Multidisciplinary evaluations that clearly define the presence of asthma or aspirin intolerance are useful in the definition of type 2 inflammation
 It is highly recommended that treatment‑naïve patients are accurately endotyped before initiating any treatment
 Definition of severity of CRSwNP
 Nasal endoscopy must be routinely performed to evaluate severity of disease
 NPS and SNOT-22 scores are useful to define severity of disease
 Lund‑Mackay score applied to CT scan evaluation and endoscopic Lund-Kennedy endoscopic score are useful to evaluate severity of disease
 Evaluating completeness of previous intervention is recommended when assessing CT scans of patients who underwent previous surgery
 Previous need of OCS must be carefully documented
 Previous number and type of surgery performed for CRSwNP must be specifically investigated
 Parameters for nasal obstruction should be taken into consideration in evaluating disease severity. NCS and PNIF can be helpful
 Olfaction evaluation
 It is recommended to routinely assess olfaction impairment in severe CRS patient by subjective and semi‑objective tools
 Olfaction impairment should be taken into account in order to define severity of disease
 Evaluation of olfaction by specific olfactory test (Sniffin’ Sticks; Upsit) at time of diagnosis should be enhanced in Rhinology centres in which severe uncontrolled CRS
 patients are managed and biologics are prescribed
 Multidisciplinary evaluation
 In severe uncontrolled CRSwNP routinely request multidisciplinary assessments
 In mild/moderate cases, multidisciplinary assessment is required if symptoms are suggestive of other comorbidities
 Establish direct collaborative networks with asthma specialists (allergologist and pulmonologist) in order to facilitate the patient journey
 Structured multidisciplinary boards may be useful in practice to discuss indications for a biologic in comorbid patients
 Refer patients to immunologic evaluation in case of eosinophils > 1500/mcL and/or positive autoimmune tests
 Pulmonary function should be assessed in all patients with severe CRSwNP, especially in candidates for a biologic (diagnose asthma, baseline definition of its severity
 and control)
 Pulmonary function must be always performed in CRSwNP patients if pneumological symptoms are present


Table IV. Practical recommendations before starting with biologics and during treatment.
 Recommendations before starting with biologics
 All efforts should be made to define the presence of type 2 inflammation before starting with biologics (CBCs, total IgE, evidence of local eosinophilia etc)
 A careful analysis of disease control must be performed, including response to previous medical and surgical treatment
 CBCs must be performed before starting with biologics not only to define type 2 inflammation, but also to start with a baseline value that could be modified by biologics
 after
 Cytoplasmic and perinuclear anti‑neutrophil cytoplasmic antibodies can be useful to exclude the presence of concomitant autoimmune disease in case of clinical
 suspicion
 Measurement of olfaction with specific cut off (VAS olfaction Sniffin’ Sticks Upsit) may be useful to start with a baseline value
 Adequate counselling of patients is advised trying to involve them in the decision
 Educating patients prior to treatment initiation regarding the possible therapeutic alternatives
 Educating patients on possible adverse events and to provide quick referral if necessary
 Provide logistic details and in hospital training for self‑injection (caregiver involvement if patient is frail or needs support)
 Plan the first injections in hospital and allow for observation time
 Recommendations during treatment with biologics
 Follow‑up visits are highly recommended to monitor efficacy and adverse events (1 month, 3, 6 and 12 months) in the first year of treatment
 After the first year of treatment, follow‑up visits may be carried out every 6 months if there are no red flags (such as hypereosinophilia, etc.)
 Follow‑up visits should be standardised using specific assessment tools
 Evaluation of olfaction by specific olfactory tests (Sniffin’ Sticks; Upsit) during biologic therapy to assess its efficacy is advised
 Perform CBC at follow‑up visits to screen variation of eosinophils. Timing should be chosen based on fluctuation of blood eosinophilia
 Assess pulmonary function and asthma control in patients on biologics for CRSwNP and comorbid asthma during treatment




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E. De Corso et al.




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