10.14639/0392-100X-N1699
Objective. This study compared three severity measures for chronic rhinosinusitis with nasal polyps (CRSwNP). The outcome was to identify patients who are eligible for biological therapy.Methods. 330 adult patients with CRSwNP were examined. Nasal polyp score (NPS), sinonasal outcome test (SNOT-22) and clinical-cytological grading (CCG) were compared. Clinical history, past surgery and asthma control test were also considered.Results. Only 45 (13.6%) patients had a contextual positivity to the three severity measures. The concordance among tests was slight/fair. Patients with severe disease (all tests positive) had more impaired parameters. The mixed cytotype (OR = 4.07), nasal obstruction (OR = 10.06), post-nasal drip (OR = 1.98), embarrassment (OR = 2.53) and difficulty falling asleep (OR = 1.92) were significantly associated with severe CRSwNP.Conclusions. To identify candidates for biological therapy, the contextual use of NPS, SNOT-22 and CCG is preferable. In this way, global assessment of CRSwNP, including morphology, inflammation, comorbidity, symptoms and quality of life is possible.
text/xml
1827-675X
1699
en
Collaborators - Italian Study Group on Nasal Polyps
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ACTA Otorhinolaryngologica Italica
biological therapy
Chronic rhinosinusitis with nasal polyps: how to identify eligible patients for biologics in clinical practice
Text.Serial.Journal
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42
Rhinology
2022-03-07
2021-05-11
2022-03-07
2022-03-07
75-81
1
Collaborators - Italian Study Group on Nasal Polyps
2022/03/07
10.14639/0392-100X-N1699
75
Luca Amorosa, Flavio Arnone, Paolo Luperto, Pasqua Irene Sciancalepore, Luigi Alonzi, Marilena Tomaiuolo, Alessandro Maselli Del Giudice, Anna Miglietta, Veronica Seccia, Giovanni Giulio Sulis, Cristiano Caruso, Valentina Rossi, Andrea Ciofalo, Consagra Calogera, Antonio Palma, Michela Mancini
1827-675X
biological therapy
81
Chronic rhinosinusitis with nasal polyps: how to identify eligible patients for biologics in clinical practice
https://www.actaitalica.it/article/download/1699/741
42
ACTA OTORHINOLARYNGOLOGICA ITALICA 2022;42:75-81; doi: 10.14639/0392-100X-N1699




Rhinology


Chronic rhinosinusitis with nasal polyps: how to identify
eligible patients for biologics in clinical practice
Rinosinusite cronica con poliposi nasale: come individuare i candidati alla terapia
biologica nella pratica clinica
Matteo Gelardi1, Corso Bocciolini2, Mario Notargiacomo3, Irene Schiavetti4, Cristiano Lingua5, Pietro Pecoraro6,
Lucia Iannuzzi7, Vitaliano Antonio Quaranta8, Rossana Giancaspro1, Gianluca Ronca1, Michele Cassano1,
Giorgio Ciprandi9
Italian Study Group on Nasal Polyps
1
  Department of Otolaryngology, University of Foggia, Italy; 2 UOC of Otolaryngology Hospital Maggiore of Bologna, Italy;
3
  Otorhinolaryngology Unit, Melzo Hospital, Milan, Italy; 4 Epidemiology, Biostatistics and Committe, Department of Direction, Istituto
Giannina Gaslini, Genoa, Italy; 5 Otorhinolaryngology SC, ASO S, Croce and Carle, Cuneo, Italy; 6 ORL - Asp 6, Palermo, Italy,
7
  ENT Clinic, Department of Biomedical Sciences, Neurosciences and Sense Organs, University of Bari, Bari, Italy;
8
  Pneumology Unity, Di Venere Hospital, Bari, Italy; 9 Allergy Clinic, Casa di Cura Villa Montallegro, Genoa, Italy


SUMMARY
Objective. This study compared three severity measures for chronic rhinosinusitis with nasal
polyps (CRSwNP). The outcome was to identify patients who are eligible for biological therapy.
Methods. 330 adult patients with CRSwNP were examined. Nasal polyp score (NPS),
sinonasal outcome test (SNOT-22) and clinical-cytological grading (CCG) were compared.
Clinical history, past surgery and asthma control test were also considered.
Results. Only 45 (13.6%) patients had a contextual positivity to the three severity measures.
The concordance among tests was slight/fair. Patients with severe disease (all tests posi-
tive) had more impaired parameters. The mixed cytotype (OR = 4.07), nasal obstruction
(OR = 10.06), post-nasal drip (OR = 1.98), embarrassment (OR = 2.53) and difficulty fall-
ing asleep (OR = 1.92) were significantly associated with severe CRSwNP.
                                                                                                 Received: May 11, 2021
Conclusions. To identify candidates for biological therapy, the contextual use of NPS,
                                                                                                 Accepted: November 7, 2021
SNOT-22 and CCG is preferable. In this way, global assessment of CRSwNP, including
morphology, inflammation, comorbidity, symptoms and quality of life is possible.
                                                                                                 Correspondence
KEY WORDS: chronic rhinosinusitis with nasal polyps, nasal polyp score, SNOT-22,                 Giorgio Ciprandi
CCG, biological therapy                                                                          Outpatients Clinics Department, Casa di Cura Villa
                                                                                                 Montallegro, via Montezovetto 27, 16132 Genoa,
                                                                                                 Italy
RIASSUNTO                                                                                        Tel. +39 010 3531284
Obiettivo. Questo studio confrontava 3 differenti indici di gravità della rinosinusite cronica   E-mail: gio.cip@libero.it
con poliposi nasale (RSCcPN). L’obbiettivo era individuare i pazienti eleggibili al tratta-
mento con farmaci biologici.                                                                       How to cite this article: Gelardi M, Bocciolini
Metodi. 330 pazienti adulti con RSCcPN erano arruolati. Tutti i pazienti venivano valutati         C, Notargiacomo M, et al. Chronic rhinosinusi-
mediante nasal polyp score (NPS), sinonasal outcome test (SNOT-22) e clinical-cytological          tis with nasal polyps: how to identify eligible
grading (CCG). Inoltre erano considerati la storia clinica, i pregressi interventi chirurgici      patients for biologics in clinical practice. Acta
ed il controllo dell’asma.                                                                         Otorhinolaryngol Ital 2022;42:75-81. https://
Risultati. Solamente 45 (13,6%) pazienti avevano i 3 indici positivi. La concordanza tra i         doi.org/10.14639/0392-100X-N1699
3 indici era bassa/modesta. I pazienti con la malattia grave (contestuale positività a tut-
ti i test) avevano peggiori parametri. Il citotipo misto (OR = 4,07), l’ostruzione nasale        © Società Italiana di Otorinolaringoiatria
                                                                                                 e Chirurgia Cervico-Facciale
(OR = 10,06), il post-nasal drip (OR = 1,98), il disagio (OR = 2,53), e la difficoltà ad
addormentarsi (OR = 1,92) erano significativamente associati con la malattia grave.
                                                                                                                OPEN ACCESS
Conclusioni. È preferibile utilizzare contemporaneamente i 3 test per individuare i pazienti
candidati alla terapia biologica. In questo modo si può avere un quadro generale della           This is an open access article distributed in accordance with
                                                                                                 the CC-BY-NC-ND (Creative Commons Attribution-Non-
malattia, comprendente la morfologia dei polipi, lo stato di infiammazione, le comorbidità,      Commercial-NoDerivatives 4.0 International) license. The
i sintomi e la qualità della vita.                                                               article can be used by giving appropriate credit and mentio-
                                                                                                 ning the license, but only for non-commercial purposes and
PAROLE CHIAVE: rinosinusite cronica con poliposi nasale, NPS, SNOT-22, CCG, terapia              only in the original version. For further information: https://
biologica                                                                                        creativecommons.org/licenses/by-nc-nd/4.0/deed.en




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M. Gelardi et al.




Introduction                                                     useful clinical information that can also be collected over
                                                                 time 12. The GCC is also associated with the sense of smell
Chronic rhinosinusitis with nasal polyps (CRSwNP) is
                                                                 impairment 13. In particular, CCG evaluates the presence of
an inflammatory disease characterised by different ana-          comorbidity, including asthma, allergy and aspirin hyper-
tomic distributions, endotypes and phenotypes 1. In West-        sensitivity, and the pattern of the cellular infiltrate, includ-
ern countries, type 2 immunity predominates, and conse-          ing eosinophils, neutrophils and mast cells.
quently, abundant eosinophils infiltrate mucosal tissues 2.      Based on this background, we tested the hypothesis that
Persistent inflammation drives and maintains polyp forma-        the contextual use of three tools, namely NPS, SNOT-22
tion and proliferation. In addition, patients with CRSwNP        and CCG, can be helpful to identify eligible candidates for
frequently have comorbidities, including asthma, allergy         biologic therapy. Therefore, the present nationwide study
and aspirin hypersensitivity 3. From a clinical perspective,     evaluated a large group of patients with CRSwNP in a clini-
patients with CRSwNP experience bothersome symptoms              cal setting.
that significantly affect the quality of life.
CRSwNP management includes medical treatments, main-
ly corticosteroids (CS). CS are usually prescribed topically     Materials and methods
(intranasal CS), but an oral CS course may be required to        Study population
achieve adequate reduction of polyp size 4. However, medi-       This cross-sectional study enrolled patients who were con-
cal treatment may be unsatisfactory; as a result, surgery        secutively visited in 23 Italian ENT Clinics.
represents an additional therapeutic option. Polyp surgery       Inclusion criteria were: i) age ≥ 18 years; ii) male or fe-
can be effective, but many patients, unfortunately, relapse      male; iii) suffering from CRSwNP; and iv) informed writ-
and may require multiple operations 5.                           ten consent.
The therapeutic scenario has changed after the launch of         Exclusion criteria were: CRSsNP, severe anatomic defects
biologics, such as monoclonal antibodies antagonising pro-       of the nasal cavity and/or the nasal pyramid.
inflammatory mediators 6. In this regard, dupilumab is an
anti-IL-4 monoclonal antibody that targets the alpha chain       Study design
of IL-4Ra, a common receptor for IL-4 and IL-13. There           All patients were evaluated by: clinical history, objective
is evidence that dupilumab is effective in patients with         examination, fibre-optic endoscopy, nasal cytology, skin
CRSwNP with and without asthma 7.                                prick test, and allergological and pulmonology visits. Di-
Recently, dupilumab has been approved in Italy by the Ital-      agnosis of CRSwNP was performed according to validated
ian Agency for the Drugs (AIFA). Dupilumab prescription          criteria according to European and International guide-
requires the compilation of an individual therapeutic plan       lines 1,2.
by authorised specialists (hospital otorhinolaryngologists
and allergists). The inclusion criteria for dupilumab eligi-     Outcomes
bility include: i) adulthood; ii) documented diagnosis of        Outcomes of the current study evaluated concordance
severe CRSwNP; iii) severe CRSwNP defined by a nasal             among prognostic tests and identified factors associated
polyp score (NPS) ≥ 5 or a 22-item sinonasal outcome test        with positive contextual scores for severe CRSwNP, such
(SNOT-22) score ≥ 50; and iv) failure of previous treat-         as NPS ≥ 5, SNOT-22 ≥ 50 and CCG ≥ 7.
ment 8. Regarding the latter requirement, two options are        Nasal cytology includes sampling, processing and micro-
considered: i) at least two oral CS courses (in the past year)   scope reading. Sampling requires collecting cells from the
discontinued due to intolerance/adverse events or lack of        surface of the middle portion of the inferior turbinate with
efficacy; or ii) endoscopic sinus surgery followed by unsuc-     a sterile disposable curette. The procedure was performed
cessful/inadequate response or complications.                    under anterior rhinoscopy, with an appropriate light source,
These requirements may identify many eligible patients,          and is painless. The sample obtained is immediately
but without pheno/endotyping them. NPS is an endoscopic          smeared on a glass slide, air-dried and stained with May-
score that assesses the polyp size and anatomy, but has not      Grünwald-Giemsa (MGG) for 30 minutes. The stained
been completely validated 9. SNOT-22 mainly investigates         sample was read by optical microscopy, with a 1,000x ob-
symptom severity and quality of life (QoL) as perceived          jective under oil immersion. Fifty fields were considered
by the patient 10. Therefore, neither prognostic measure as-     the minimum number to identify a sufficient number of
sesses inflammatory pattern or comorbidity. In this regard,      cells. The count of each cell type was expressed by a semi-
a clinical-cytological grading (CCG) has been proposed to        quantitative grading as previously described 14. Cytology
assess patients with CRSwNP 11. This tool allows obtaining       also permits the detection of bacteria, spores and biofilm.



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                                                                                          Chronic rhinosinusitis with nasal polyps and biologics




The skin prick test was performed as stated by the Euro-         was diagnosed if the sensitised allergen caused symptoms
pean Academy of Allergy and Clinical Immunology 15.              after its exposure 19. Aspirin hypersensitivity was diagnosed
The allergen panel consisted of the following: house-dust        according to international guidelines 20.
mites (Dermatophagoides farinae and Dermatophagoides             Asthma control test (ACT) questionnaire consisted of 5
pteronyssinus), cats, dogs, grasses mix, Compositae mix,         questions with five possible responses, exploring the pa-
Parietaria judaica, birch, hazel trees, olive trees, cypress,    tient’s perception of his/her asthma control 21. The result
Alternaria tenuis, Cladosporium and Aspergilli mix. The          ranged between 0 and 25, where 25 was the optimal asthma
concentration of allergen extracts was 100 immune reac-          control and < 20 was poor asthma control.
tivity/mL (Stallergenes-Greer Italia, Milan, Italy). A hista-    Statistical analysis. No statistical sample size calculation
mine solution in distilled water (10 mg/mL) was used as the      was done a priori due to the exploratory nature of this
positive control, and the glycerol-buffer diluent of the al-     study. Descriptive data were reported as mean with stand-
lergen preparations was used as the negative control. Each       ard deviation, median with interquartile ranges, or count
patient was skin tested on the volar surface of the forearm      and percentage, as appropriate. Cohen’s kappa was used
using 1-mm prick lancets. The skin reaction was recorded         to assess the agreement between scores and has to be in-
after 15 minutes by evaluating the skin response compared        terpreted as follows: ≤ 0 no agreement; 0.01-0.20 none to
to the wheal given by the positive and the negative controls.    slight; 0.21-0.40 fair; 0.41-0.60 moderate; 0.61-0.80 sub-
A wheal diameter of at least 3 mm was considered as a            stantial; 0.81-1.00 almost perfect agreement (McHugh,
positive reaction.                                               2012).
Nasal Polyp Score. Polyps were evaluated on each side            Univariable and multivariate stepwise logistic regression
through nasal endoscopy at each visit and graded based on        analyses were performed to evaluate all possible factors
polyp size, resulting in scores of 0 to 4 9. Zero is no polyp,   predicting a severe condition confirmed by all three scores
1 = small polyps in the middle meatus not reaching be-           (SNOT22; CCG and NPS). Variables with P < 0.20 in the
low the inferior border of the middle turbinate, 2 = polyps      univariate models were candidates for subsequent multi-
reaching below the lower border of the middle turbinate,         variate analysis. Results were expressed with odds ratio
3 = large polyps reaching the lower border of the inferior       (OR) and related 95% confidence intervals (CI); two-sided
turbinate or polyps medial to the middle turbinate, and 4 =      p-values ≤ 0.05 were considered statistically significant.
large polyps causing complete obstruction of the inferior        The analyses were performed using SPSS Statistics version
nasal cavity. The sum of the left and right nostril scores is    24.0 (IBM Corp., Armonk, NY, USA).
the NPS. Values ≥ 5 define severe CRSwNP.
Sinonasal Outcome Test. SNOT-22 is a 22-items disease-
                                                                 Results
specific, validated, patient-rated outcome measure 10. It is
also considered the most suitable tool in terms of ease of       Three-hundred thirty patients (202 males, 128 females,
use 16. It contains the key diagnostic symptoms included         mean age 52.1 years) participated in the study. Table I
in the EPOS definition for CRS, as well as other items of        shows the stratification for the different severity scores: 99
importance to patients with CRS. It is increasingly used to      (30%) patients were negative for all tests, 122 (37%) posi-
measure the disease-specific quality of life in clinical prac-   tive to one test, 64 (19.4%) to two and 45 (13.6%) to three.
tice routinely. Values ≥ 50 identify a severe score 17.          The concordance between tests was slight to fair, as report-
Clinical-Cytological Grading has been previously de-             ed in Table II. In particular, Cohen’s Kappa coefficient was
scribed in detail elsewhere 11,12. Briefly, CCG is a score       0.09 between NPS and SNOT-22, 0.28 between NPS and
based on both nasal cytology findings and comorbidities,         CCG, and 0.30 between SNOT-22 and CCG.
including asthma, allergy and ASA hypersensitivity. For          Patients with all three tests positive were defined as severe,
each variable, a score value was assigned: neutrophilic in-      and subdivided into two subgroups: not-severe and severe.
filtrate was scored as 1, mast cell infiltrate was scored 1,
eosinophilic infiltrate was scored 2 and eosinophilic + mast
cell was scored 4; similarly, ASA hypersensitivity scored        Table I. Severity from different scores.
1, asthma 2, allergy 2 and ASA sensitivity + asthma 3. The                                                         N (%)
CCG was composed as the sum of these individual scores.           Severity confirmed for:                          No score        99 (30.0)
CCG global score is classified as low-grade (score 1-3),                                                          One score       122 (37.0)
medium-grade (4-6) and high-grade (≥ 7).                                                                         Two scores        64 (19.4)
Comorbidities. Asthma was diagnosed according to with                                                          All three scores    45 (13.6)
global initiative for asthma (GINA) guidelines 18. Allergy       Data are reported as count with percentage.




                                                                                                                                            77
M. Gelardi et al.




Table II. Agreement between scores.                              significantly impaired QoL, significant loss of smell and
                                         NPS                     diagnosis of comorbid asthma 6. Moreover, this document
                                      Not severe    Severe       defined the response criteria for biological treatment, con-
 SNOT22            Not severe         116 (35.2)   100 (30.3)    sidering five aspects: reduced nasal polyp size, reduced
                    Severe             50 (15.2)    64 (19.4)    need for systemic CS, improved QoL and sense of smell
 κ = 0.09; p = 0.09                                              and reduced impact of comorbidities 6.
                                         NPS
                                                                 On the other hand, the AIFA established less stringent cri-
                                                                 teria for selecting eligible patients for dupilumab. In par-
                                      Not severe    Severe
                                                                 ticular, the documentation of type of inflammation, olfac-
 CCG               Not severe         135 (40.9)   88 (26.7)     tory dysfunction, and comorbidities were surprisingly not
                     Severe            31 (9.4)    76 (23.0)     required. Consequently, the quote of eligible patients may
 κ = 0.28, p < 0.001.                                            become substantially high. These non-strict criteria might
                                       SNOT22                    implicate an inappropriate prescription and potentially
                                      Not severe    Severe       therapeutic failure. For these reasons, we designed a na-
 CCG               Not severe         168 (50.9)   55 (16.7)     tionwide study conducted in a real-world setting.
                     Severe            48 (14.5)   59 (17.9)     Most patients had underwent previous surgery, and 60%
 κ = 0.30, p < 0.001.                                            had recurrent polyps. Moreover, the findings showed that
                                                                 30% of CRSwNP patients had no positive score for severe
                                                                 CRSwNP, but only 45 (13.6%) had reasonably severe dis-
Table III reports the considered variables in all patients,      ease, contextually confirmed by the NPS, SNOT-22 and
not-severe and severe. There was a prevalence of males.          CCG. Interestingly, the three tests were reasonably consist-
Relapse after surgery was reported by 198 (60%) of pa-           ent. This aspect underlined the clinical relevance that they
tients. Using the criteria proposed by AIFA, 215 (65.2%)         are not interchangeable and, consequently, it is convenient
patients were candidates for dupilumab. Patients with se-        to consider them together. In fact, following AIFA criteria,
vere CRSwNP had significant impairment of all considered         two-thirds of these patients could be eligible for dupilumab,
variables, except for asthma control, dog allergy, aspirin       but only 13.6% should more appropriately receive the bio-
hypersensitivity, presence of biofilm and bacteria.              logic using more discerning criteria. The direct consequence
Multivariate analysis (Tab. IV) identified significant factors   of this result could represent a higher probability of thera-
predicting severe CRSwNP. In particular, nasal obstruction       peutic success, prescriptive appropriateness, and lastly, sav-
(OR = 10.06), embarrassment (OR = 2.53), post-nasal drip         ing of financial resources. Consistently, patients with severe
(OR = 1.98) and trouble sleeping (OR = 1.92) were signifi-       CRSwNP, documented by multiple positive tests, had all
cantly associated with severe CRSwNP. Considering cyto-          parameters more impaired than other patients. In particular,
types: mixed type, mast cell and eosinophil, significantly       multivariate analysis identified some factors associated with
predicted (OR = 4.07) severe CRSwNP.                             severe disease. Nasal obstruction is the key symptom able
                                                                 to predict a severe score. This symptom accurately reflects
                                                                 type 2 inflammation as confirmed in patients with allergic
Discussion                                                       rhinitis 23. Another nasal symptom had a predictive role, such
Chronic rhinosinusitis with nasal polyps is an inflamma-         as post-nasal drip that depends on mucus discharge from the
tory disease of the upper airways, commonly sustained by         sinus. Hence, both symptoms are associated with congestion
a type 2 inflammatory response. As a result, anti-inflamma-      and hyperproduction of mucus: expression of upper airway
tory agents, topical or systemic, are the first-line strategy.   inflammation. Embarrassment for symptoms and disturbed
However, this approach may be insufficient. Sinus surgery,       sleep affects the QoL and is a significant predictor of severe
therefore, is a treatment option in patients failing medical     CRSwNP. These variables were derived from SNOT-22,
treatment 22. In addition, sinus surgery may be unsatisfac-      whereas NPS did not generate any predictive outcome. Nasal
tory as many patients have recurrent nasal polyps after sur-     cytotypes provided a relevant predictive factor, such as the
gery. Therefore, biological therapy may be an appropriate        mixed mast cell-eosinophil type. This result was consistent
option in patients with refractory CRSwNP. The European          with a previous study that demonstrated that this cytotype is
Forum for Research and Education in Allergy and Airway           characterised by severe outcomes 14.
Diseases (EUFOREA) defined the indications for biologi-          These results, therefore, seem to suggest that the combined
cal treatment that include evidence of type 2 inflammation,      use of three CRSwNP gradings could be a reasonable
need for systemic CS (2 or more courses in the past year),       means to identify an eligible patient to dupilumab. On the



78
                                                                                                                      Chronic rhinosinusitis with nasal polyps and biologics




Table III. Characteristics by all three severity scores.
                                                               Total (n = 330)            Not severe (n = 285)         Severe (n = 45)               p^
 Sex, males                                                       202 (61.2)                    182 (63.9)                20 (44.4)               0.013*
 Age, years                                                     52.1 ± 14.21                   52.1 ± 14.54             52.1 ± 12.06               0.83
 Number of operations for nasal polyposis                         1.2 ± 1.96                    1.1 ± 2.05               1.6 ± 1.15               0.001*
 Relapse after surgery                                            198 (60.0)                    161 (56.5)                37 (82.2)              < 0.001*
 Eligibility for biologic                                         215 (65.2)                    170 (59.6)               45 (100.0)              < 0.001*
 Asthma                                                           144 (43.6)                    118 (41.4)                26 (57.8)               0.040*
 Asthma Control Test (ACT)                                   Controlled asthma                    11 (3.3)                  9 (3.2)               2 (4.4)             0,19**
                                                         Partially controlled asthma             53 (16.1)                42 (14.8)              11 (24.4)
                                                           Not controlled asthma                 80 (24.3)                67 (23.6)              13 (28.9)
 Aspirin hypersensitivity                                          62 (18.8)                     52 (18.2)                10 (22.2)                0.53
 Aspirin hypersensitivity and asthma                               47 (14.2)                     37 (13.0)                10 (22.2)               0.10**
 Allergy diagnosis                                                180 (54.5)                    138 (48.4)                42 (93.3)              < 0.001*
 Dog allergy (SPT)                                                 34 (10.3)                      28 (9.8)                 6 (13.3)                0.47
 Cat allergy (SPT)                                                 36 (10.9)                      27 (9.5)                 9 (20.0)               0.035*
 Dust allergy (SPT)                                               110 (33.3)                     80 (28.1)                30 (66.7)              < 0.001*
 Inhalant sensitivity                                             147 (44.5)                    111 (38.9)                36 (80.0)              < 0.001*
 Cytotype                                                 Eosinophils + Mast cells              130 (39.9)                97 (34.5)              33 (73.3)          < 0.001*
                                                                  Eosinophils                    95 (29.1)                84 (29.9)              11 (24.4)
                                                                  Mast cells                     76 (23.3)                75 (26.7)               1 (2.2)
                                                                  Neutrophils                     25 (7.7)                 25 (8.9)               0 (0.0)
 Biofilm                                                           41 (12.4)                     32 (11.2)                 9 (20.0)               0.10**
 Bacteria (from 0 = absent to 4 = numerous)                      0.0 (0.0-1.0)                 0.0 (0.0-1.0)            0.0 (0.0-2.0)             0.06**
 Spores (from 0 = absent to 4 = numerous)                        0.0 (0.0-0.0)                 0.0 (0.0-0.0)            0.0 (0.0-0.0)            < 0.001*
 Need to blow the nose                                           3.0 (2.0-4.0)                 3.0 (2.0-4.0)            4.0 (4.0-5.0)            < 0.001*
 Sneezing                                                        3.0 (2.0-4.0)                 3.0 (2.0-3.0)            4.0 (3.0-4.0)            < 0.001*
 Rhinorrhoea                                                     3.0 (2.0-4.0)                 3.0 (1.0-4.0)            4.0 (3.0-5.0)            < 0.001*
 Nasal obstruction                                               4.0 (3.0-5.0)                 4.0 (3.0-4.0)            5.0 (5.0-5.0)            < 0.001*
 Smell and taste dysfunction                                     3.0 (2.0-4.0)                 3.0 (2.0-4.0)            5.0 (4.0-5.0)            < 0.001*
 Postnasal drip                                                  2.0 (1.0-3.0                  2.0 (1.0-3.0)            3.0 (3.0-4.0)            < 0.001*
 Thick nasal discharge                                           2.0 (1.0-3.0)                 2.0 (0.0-3.0)            3.0 (3.0-4.0)            < 0.001*
 Cough                                                           1.0 (0.0-2.0)                 1.0 (0.0-2.0)            3.0 (2.0-3.0)            < 0.001*
 Ear fulness                                                     0.0 (0.0-2.0)                 0.0 (0.0-2.0)            2.0 (1.0-3.0)            < 0.001*
 Dizziness                                                       0.0 (0.0-0.0)                 0.0 (0.0-0.0)             0.0 (0.01.0)            < 0.001*
 Ear pain                                                        0.0 (0.0-1.0)                 0.0 (0.0-0.0)            1.0 (0.0-2.0)            < 0.001*
 Facial pain                                                     1.0 (0.0-2.0)                 0.0 (0.0-2.0)            2.0 (1.0-3.0)            < 0.001*
 Difficulty falling asleep                                       2.0 (0.0-3.0)                 1.0 (0.0-2.0)            3.0 (3.0-4.0)            < 0.001*
 Walking up at night                                             0.0 (0.0-2.0)                 0.0 (0.0-1.0)            2.0 (1.0-3.0)            < 0.001*
 Lack of a good night’s sleep                                    2.0 (0.0-3.0)                 2.0 (0.0-3.0)            4.0 (3.0-4.0)            < 0.001*
 Waking up tired                                                 2.0 (0.0-3.0)                 2.0 (0.0-3.0)            4.0 (2.0-4.0)            < 0.001*
 Fatigue                                                         2.0 (0.0-3.0)                 1.0 (0.0-3.0)            3.0 (3.0-4.0)            < 0.001*
 Reduced productivity                                            1.0 (0.0-3.0)                 1.0 (0.0-2.0)            3.0 (2.0-4.0)            < 0.001*
 Reduced concentration                                           1.0 (0.0-3.0)                 1.0 (0.0-2.0)            3.0 (2.0-4.0)            < 0.001*
 Frustration irritability                                        2.0 (0.0-3.0)                 1.0 (0.0-3.0)            3.0 (3.0-4.0)            < 0.001*
 Sadness                                                         0.0 (0.0-2.0)                 0.0 (0.0-2.0)            3.0 (2.0-4.0)            < 0.001*
 Embarrassment                                                   0.0 (0.0-3.0)                 0.0 (0.0-2.0)         3.0 (2.0     - 4.0)         < 0.001*
Data are reported as count with percentage; mean with standard deviation; and median with interquartile range. ^ p value is referred to univariate comparisons between groups. *: p
< 0.05; **: p < 0.20 (not significant, but included in the multivariate analysis).




                                                                                                                                                                               79
M. Gelardi et al.




Table IV. Significant factors predicting severe score.
                                                                       Univariate                       Multivariate
                                                                        p value                     OR (95% IC); p value
 Allergy                                                               < 0.001*                146.72 (13.67-1574.46); < 0.001
 Cytotype                                      Eosinophils          Overall: < 0.001*                         Ref.
                                         Eosinophils + mast cells                                  4.07 (1.03-16.17); 0.046
                                               Mast cells                                                    0.29
                                               Neutrophils                                                   0.99
 Nasal obstruction                                                      < 0.001*                 10.06 (3.83-26.41); < 0.001
 Postnasal drip                                                         < 0.001*                    1.98 (1.14-3.45); 0.015
 Difficulty falling asleep                                              < 0.001*                    1.92 (1.20-3.07); 0.006
 Embarrassment                                                          < 0.001*                  2.53 (1.59-4.04); < 0.001



contrary, to consider only one test, SNOT-22 or NPS, does           Therefore, this study underlines the conflicting results
not assure appropriate detection of a potential responder to        among tests concerning the proportion of patients who are
biologic.                                                           eligible for biological therapy. The criteria proposed by the
Consistently, CCG concerns endotype and comorbidity,                regulatory Agency were not selective as about two-thirds
SNOT-22 assesses symptom severity and QoL and NPS                   of patients could be eligible for dupilumab. Differently, the
anatomical aspects. Therefore, the combined use of these            use of the three gradings considerably limited the propor-
tests could be an operative proposal in daily practice.             tion of candidates for biologic therapy.
The strength of this study was the combined use of three
different tests exploring the multifaceted pathogenesis of          Conclusions
CRSwNP, its nationwide enrolment and the real-world set-
                                                                    The present study showed that the combined use of
ting. Thus, the results can mirror routine clinical practice.
                                                                    SNOT-22, NPS, and CCG may be a reasonable option to
Moreover, CCG allows to identify type 2 inflammation by
                                                                    identify patients who are eligible for dupilumab in clinical
quantifying nasal eosinophils and mast cells, thus fulfill-
                                                                    practice. Consistently, symptom severity, quality of life and
ing the requirements of the EPOS document concerning
                                                                    endoscopic findings did not accurately evaluate CRSwNP
the presence of type 2 inflammation for biologic eligibility.
                                                                    severity, and comorbidity and inflammation should also
Consistently, severe CCG definitions includes the presence
                                                                    be measured. Only complete and thorough assessment of
of type 2 biomarkers.
                                                                    CRSwNP patients allows appropriate prescription of bio-
The limitations of this study include the absence of a sam-         logics.
ple size calculation, but the tested hypothesis did not re-
quire a specific number of patients, and also the lack of           Conflict of interest statement
mediators and cytokine assessment, and its cross-sectional          The authors declare no conflict of interest.
design. Moreover, a correct definition of patients suitable
for biologics should include identification of responder            Funding
subjects. However, the identification of responder cannot           This research did not receive any specific grant from fund-
disregard the evaluation of treatment. In this regard, trials       ing agencies in the public, commercial, or not-for-profit
are ongoing to define precise cut-offs of type 2 biomarkers.        sectors.
It also should be noted that the nasal polyp score only de-
scribes the volume of the nasal polyp and omits some en-            Authors’ contributions
doscopic findings such as secretions, mucosal oedema and            MG designed the study and discussed the manuscript, CB,
altered healing, which potentially have a serious impact on         MN, CL, PP, LI, RG, GR, MC collected the data and dis-
the patient’s quality of life. Another limitation of this study     cussed the manuscript. IS and VAQ analysed the data. GC
was the lack of the direct evaluation of sinus and polyp            drafted the manuscript and revised the text.
inflammation. Nasal cytology could not completely reflect
what happens in those tissues. However, the context of the          Ethical consideration
current study was the comparison of three diagnostic tools          This study was approved by the Institutional Ethics of Fog-
in a real-life setting, such as clinical practice.                  gia (approval number/protocol number 28-2020).



80
                                                                                                     Chronic rhinosinusitis with nasal polyps and biologics




The Review Board approved the procedures used in this                         10
                                                                                   Hopkins C, Gillett S, Slack R, et al. Phychometric validity of the
study and patients signed an informed consent.                                     22-item sinonasal outcome test. Clin Otolaryngol 2009;34:447-454.
                                                                                   https://doi.org/10.1111/j.1749-4486.2009.01995.x
The research was conducted ethically, with all study pro-                     11
                                                                                   Gelardi M, Iannuzzi L, De Giosa M, et al. Non-surgical management of
cedures being performed in accordance with the require-                            chronic rhinosinusitis with nasal polyps based on clinical cytological
ments of the World Medical Association’s Declaration of                            grading: a precision medicine-based approach. Acta Otorhinolaryngol
Helsinki.                                                                          Ital 2017;37:38-45. https://doi.org/10.14639/0392-100X-1417
                                                                              12
                                                                                   Gelardi M, Cassano M, Ciprandi G. The clinical relevance of the clin-
                                                                                   ical cytological grading in patients with chronic rhinosinusitis with
Italian Study Group on Nasal Polyps: Luca Amorosa,                                 nasal polyps. J Allergy Clin Immunol 2020;146:462-463. https://doi.
Flavio Arnone, Paolo Luperto, Pasqua Irene Sciancalepore,                          org/10.1016/j.jaci.2020.04.049
Luigi Alonzi, Marilena Tomaiuolo, Alessandro Maselli Del                      13
                                                                                   Gelardi M, Piccininni K, Quaranta N, et al. Olfactory dysfunction in
Giudice, Anna Miglietta, Veronica Seccia, Giovanni Giulio                          patients with chronic rhinosinusitis with nasal polyps is associated
                                                                                   with clinical-cytological grading severity. Acta Otorhinolaryngol Ital
Sulis, Cristiano Caruso, Valentina Rossi, Andrea Ciofalo,                          2019;39:329-335. https://doi.org/10.14639/0392-100X-2426
Consagra Calogera, Antonio Palma, Michela Mancini.                            14
                                                                                   Gelardi M, Iannuzzi L, Quaranta N, et al. Nasal cytology: practical
                                                                                   aspects and clinical relevance. Clin Exp Allergy 2016;46:785-792.
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