10.14639/0392-100X-N0716
Objective. The introduction of monoclonal antibody (mAb) therapies represents a promising treatment for refractory chronic rhinosinusitis (CRS). We assessed the effects of selected mAbs (omalizumab, mepolizumab, benralizumab) on CRS in severe asthmatic patients in a real-life setting. Methods. A prospective observational study on severe asthmatic patients, treated with 3 different mAb (omalizumab, mepolizumab, benralizumab), and comorbid CRS was conducted. All patients were followed for 52 weeks. The degree of nasal control, SinoNasal Outcome Test (SNOT) 22, Nasal Polyp Score (NPS), Lund Kennedy Score (LKS) were collected at baseline and at 52-week. Results. 40 patients (33 with nasal polyps) were studied. 33 patients (82.5%) had uncontrolled nasal disease at baseline, and 15 (37.5%) were uncontrolled after 52 weeks. Significant improvement was observed for SNOT 22 (P &lt; 0.001), SNOT 1-12 (P &lt; 0.001) and degree of nasal control (P &lt; 0.001). Differences in NPS (P = 0.130) and LKS (P = 0.124) were not significant. Net change in the above-mentioned parameters among the three treatment groups was not significantly different. Conclusions. The study shows an improvement of nasal symptoms after 52 weeks of mAb treatment, which was not associated with significant improvement of endoscopic findings. Larger studies are needed to assess the real-life efficacy of mAbs in CRS.
application/xml
1827-675X
716
6
en
Paolo Castelnuovo
https://creativecommons.org/licenses/by-nc-nd/4.0
ACTA Otorhinolaryngologica Italica
biological therapies
Effects of biological therapies on chronic rhinosinusitis in severe asthmatic patients
Text.Serial.Journal
https://www.actaitalica.it/
40
Rhinology
2021-01-21
2020-02-26
2021-01-21
2021-01-21
1
Paolo Castelnuovo
2020
10.14639/0392-100X-N0716
Department of Otorhinolaryngology, University of Insubria and ASST Sette Laghi, Varese, Italy; Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy
1827-675X
6
biological therapies
Effects of biological therapies on chronic rhinosinusitis in severe asthmatic patients
https://www.actaitalica.it/article/download/716/496
40
ACTA OTORHINOLARYNGOLOGICA ITALICA 2020;40:435-443; doi: 10.14639/0392-100X-N0716




Rhinology


Effects of biological therapies on chronic
rhinosinusitis in severe asthmatic patients
L’efficacia delle terapie biologiche sulla rinosinusite cronica nel paziente asmatico severo
Francesco Bandi1,2*, Stefania Gallo2*, Andrea Preti4,5, Francesco Mozzanica4,6, Dina Visca7,8, Margherita Marelli9,
Enrico Maddalone2, Cinzia Gambarini9, Adriano Vaghi10, Antonio Spanevello7,8, Paolo Castelnuovo2,3
1
  Department of Otolaryngology-Head and Neck Surgery, European Institute of Oncology, Milan, Italy; 2 Department of
Otorhinolaryngology, University of Insubria and ASST Sette Laghi, Varese, Italy; 3 Department of Biotechnology and Life Sciences,
University of Insubria, Varese, Italy; 4 Department of Otorhinolaryngology, IRCCS Multimedica, Milano, Italy; 5 Department of
Medicine and Surgery, University of Insubria, Varese, Italy; 6 Department of Biomedical and Clinical Sciences, University of Milan,
Italy; 7 Istituti Clinici Scientifici Maugeri IRCCS, Respiratory Rehabilitation of the Institute of Tradate, Italy; 8 Department of Medicine
and Surgery, Respiratory Diseases, University of Insubria, Varese-Como, Italy; 9 Department of Pulmonology, ASST Sette Laghi,
Varese, Italy; 10 ASST-Rhodense, UOC Pneumologia, Garbagnate Milanese, Milan, Italy
*
  F. Bandi and S. Gallo contributed equally to the work.


SUMMARY
Objective. The introduction of monoclonal antibody (mAb) therapies represents a promising treat-
ment for refractory chronic rhinosinusitis (CRS). We assessed the effects of selected mAbs (omali-
zumab, mepolizumab, benralizumab) on CRS in severe asthmatic patients in a real-life setting.
Methods. A prospective observational study on severe asthmatic patients, treated with 3
different mAb (omalizumab, mepolizumab, benralizumab), and comorbid CRS was con-
ducted. All patients were followed for 52 weeks. The degree of nasal control, SinoNasal              Received: February 26, 2020
Outcome Test (SNOT) 22, Nasal Polyp Score (NPS), Lund Kennedy Score (LKS) were                       Accepted: September 6, 2020
collected at baseline and at 52-week.
Results. 40 patients (33 with nasal polyps) were studied. 33 patients (82.5%) had uncon-             Correspondence
trolled nasal disease at baseline, and 15 (37.5%) were uncontrolled after 52 weeks. Sig-             Bandi Francesco
nificant improvement was observed for SNOT 22 (P < 0.001), SNOT 1-12 (P < 0.001) and                 Department of Otolaryngology-Head and Neck
degree of nasal control (P < 0.001). Differences in NPS (P = 0.130) and LKS (P = 0.124)              Surgery, European Institute of Oncology (IEO)
were not significant. Net change in the above-mentioned parameters among the three treat-            via Ripamonti 435, 20141 Milano
                                                                                                     Tel. +39 02 57489490. Fax +39 02 94379216
ment groups was not significantly different.
                                                                                                     E-mail: bandi.francesco@gmail.com
Conclusions. The study shows an improvement of nasal symptoms after 52 weeks of mAb
treatment, which was not associated with significant improvement of endoscopic findings.
                                                                                                     Funding
Larger studies are needed to assess the real-life efficacy of mAbs in CRS.                           None.
KEY WORDS: chronic rhinosinusitis, nasal polyps, asthma, monoclonal antibody,
biological therapies                                                                                 Conflict of interest
                                                                                                     The Authors declare no conflict of interest.

RIASSUNTO
Obiettivi. L’introduzione degli anticorpi monoclonali (mAb) rappresenta una promettente                How to cite this article: Bandi F, Gallo S, Preti
                                                                                                       A, et al. Effects of biological therapies on chron-
risorsa per il trattamento delle rinosinusiti croniche (RSC) refrattarie. Obiettivo dello stu-
                                                                                                       ic rhinosinusitis in severe asthmatic patients. Ac-
dio è valutare l’efficacia del trattamento biologico sulla RSC nel paziente asmatico severo            ta Otorhinolaryngol Ital 2020;40:435-443. https://
in un contesto real-life.                                                                              doi.org/10.14639/0392-100X-N0716
Metodi. È stato condotto uno studio osservazionale di 52 settimane su pazienti asmatici
severi, trattati con 3 diversi mAb (omalizumab, mepolizumab, benralizumab), e con RSC                © Società Italiana di Otorinolaringoiatria
come comorbidità. Sono stati raccolti raccolti dati riguardanti il grado di controllo nasale,        e Chirurgia Cervico-Facciale
il SinoNasal Outcome Test (SNOT) 22, il Nasal Polyp Score (NPS), il Lund Kennedy Score
(LKS) al baseline e a 52 settimane.                                                                                 OPEN ACCESS
Risultati. Sono stati analizzati 40 pazienti (33 con polipi nasali). 33 pazienti (82.5%) pre-        This is an open access article distributed in accordance with
sentavano una RSC non controllata al baseline, 15 (37.5%) soffrivano ancora di RSC non               the CC-BY-NC-ND (Creative Commons Attribution-Non-
controllata dopo 52 settimane. Un miglioramento significativo è descritto per lo SNOT 22             Commercial-NoDerivatives 4.0 International) license. The
                                                                                                     article can be used by giving appropriate credit and mentio-
(P < 0.001), lo SNOT 1-12 (P < 0.001) e il grado di controllo nasale (P < 0.001); differenze
                                                                                                     ning the license, but only for non-commercial purposes and
nel NPS (P = 0.130) e LKS (P = 0.124) sono risultate non significative. Il cambiamento netto         only in the original version. For further information: https://
dei sopracitati parametri tra i tre gruppi di trattamento non era significativamente differente.     creativecommons.org/licenses/by-nc-nd/4.0/deed.en




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F. Bandi et al.




Conclusioni. Lo studio evidenzia a 52 settimane di trattamento con mAb un miglioramento dei sintomi, non associato a cambiamenti signifi-
cativi dei riscontri endoscopici. Sono necessari studi più ampi per determinare l’efficacia nella real-life dei mAb nella RSC.
PAROLE CHIAVE: rinosinusite cronica, polipi nasali, asma, anticorpi monoclonali, terapie biologiche



Introduction                                                          of patients with severe asthma treated with biologicals and
                                                                      with CRS as a comorbidity. Secondary endpoints included
Chronic rhinosinusitis (CRS) is a heterogeneous inflamma-
                                                                      evaluation of endoscopic sinonasal changes, variations in
tory disease with an as-yet-undefined aetiology. A complex
                                                                      patient-reported outcomes and in the degree of nasal dis-
combination of altered immunity, genetics and environmen-             ease control over 52 weeks of treatment.
tal factors (microbiome, allergy, etc.) seems to play a coop-
erative role in disease initiation and progression 1. Going
beyond its rooted phenotypes (with nasal polyps, CRSwNP;              Materials and methods
without nasal polyps, CRSsNP), CRS is nowadays consid-                Study population
ered an umbrella term for different clinical entities mirror-         An observational study was conducted at the ENT Depart-
ing diverse biomolecular inflammatory processes, the endo-            ment of a single tertiary care centre enrolling subjects af-
types 2. Extensive knowledge on CRS pathophysiological                fected by severe uncontrolled asthma, eligible for mAb
mechanisms would be entirely speculative, except endotypes            therapy, and with CRS as a comorbidity between July 2017
become a potential therapeutic target.                                and May 2019. The study was concluded in June 2020.
Since CRS is closely connected to asthma by the “unified              Included patients were over 18 years old, with a negative
airways” theory 3, it is no surprise that not only pathogen-          clinical history for genetic syndromes, congenital or ac-
esis, but also therapeutic principles may be similar in both          quired immunodeficiency, autoimmune disorders, malig-
sections of the airways. Thus, biological therapies current-          nancy or history of head and neck cancer, and drug abuse.
ly approved for severe asthma may represent a treatment               Patients were addressed by pulmonologists to specific bio-
option for refractory CRS cases, who can count only on                logical agents (anti-IgE, omalizumab; anti-IL5, mepoli-
courses of oral corticosteroids (OCS), antibiotics or repeat-         zumab; anti-IL5R, benralizumab) to treat severe asthma
ed sinus surgeries, with failures ranging from 20 to 40%              according to GINA guidelines 13-16 within 1 month from our
according to different series 4,5.                                    baseline evaluation and were monitored with regular clini-
The efficacy of biological agents in the treatment of asthma          cal and endoscopic assessments every 3 months. For ana-
is widely reported and documented in literature 6; mean-              lytical reasons and in order to align data, the 52-week visit
while several research studies are documenting encour-                after first mAb dosing was set as a follow-up cut-point.
aging results for CRS, as well 7,8. In Italy, 3 monoclonal            Rhinologists involved in the study did not intervene in
antibodies (mAb) are approved for the treatment of severe             treatment selection which depended exclusively on features
asthma in clinical practice: omalizumab (anti-IgE), me-               of asthma. We point out that all patients presented a type 2
polizumab (anti-IL5) and benralizumab (anti-IL5R). Phase              inflammation profile of the airways, defined by blood eo-
III trials are currently evaluating the efficacy of the same          sinophil count ≥ 250 cells/mm3 and/or peripheral total IgE
mAbs in patients affected by CRSwNP. Therefore, to date,              ≥ 100 kU/L at the time of enrollment 17.
in Italy, the indication to start a biological therapy falls in       The study was conducted in compliance with the Helsinki
the purview of pneumological practice and dependent on                Declaration and with policies approved by the Insubria
the coexistence of severe asthma.                                     Board of Ethics. Informed consent was obtained from all
While several randomised clinical trials (RCT) have high-             participants included in the study.
lighted the efficacy of mAbs in CRSwNP 9-12, the current
literature still lacks observational studies evaluating the re-       Study methods
sponse to biological treatments in real-life.                         CRS was confirmed and classified as controlled, partly con-
Therefore, while waiting to actively take part, as rhinolo-           trolled or uncontrolled according to EPOS guidelines 17,18.
gists, in treatment indications and selection of biological           Data concerning demographic features, CRS and asthma
therapies, we report our preliminary real-life data regarding         onset, smoking habits, non-steroidal anti-inflammatory
the clinical effects of selected mAbs (omalizumab, mepoli-            drug (NSAID) intolerance, blood eosinophil count, periph-
zumab and benralizumab) on CRS in adult patients treated              eral IgE count, nasal therapies, need for OCS for airways
for severe asthma. The primary endpoint was to portray                exacerbations, previous nasal surgeries, adverse events
the main clinical CRS-related characteristics of a cohort             (AEs) were collected in an electronic database 19.



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Sensitization for common inhalants was evaluated on the          Table I. Demographic data of the cohort (n = 40).
basis of recent pre-existing skin or blood tests as defined by    Variable                                         Value
the Global Atlas Test Panel for Europe 20.                        Age (years)                                       54.4 (range 31-73)
Symptoms were collected through the Italian version of the        Sex, M:F                                          12 (30%):28 (70%)
SinoNasal Outcome Test 22 (SNOT 22) questionnaire 21              Smoke
and analysed both as total (SNOT 22) and partial (SNOT            Active                                                 2/40 (5%)
1-12) scores, and as individual symptoms 22,23.                   Ex-smoker                                             12/40 (30%)
                                                                  Non smoker                                            26/40 (65%)
Endoscopic findings of the entire cohort were scaled ac-
                                                                  Inhalant sensitisation                               29/40 (72.5%)
cording to the Lund-Kennedy Score (LKS) 24 and the size           Seasonal                                              3/29 (10.3%)
of nasal polyps in the CRSwNP subgroup was calculated             Perennial                                             8/29 (27.6%)
through the Nasal Polyp Score (NPS) 25.                           Both                                                 18/29 (62.1%)
Patients were further sorted into three different subgroups       NSAID intolerance                                    11/40 (27.5%)
depending on the type of mAb therapy (anti-IgE, anti-IL5          CRSwNP                                               33/40 (82.5%)
and anti-IL5R groups) and reassessed by means of the              CRSsNP                                                7/40 (17.5%)
above-mentioned outcome measures.                                 CRS onset
                                                                  Early (< 40 y)                                        20/40 (50%)
Statistical analysis                                              Late (≥ 40 y)                                         20/40 (50%)
The Kolmogorov-Smirnov test was used to check the nor-            Asthma onset
                                                                  Early (< 40 y)                                       17/40 (42.5%)
mality of the distribution. Since this test demonstrated that     Late (≥ 40 y)                                        23/40 (57.5%)
the distribution was not normal, non-parametric tests were        CRS vs asthma onset
used. In particular, the median and interquartile ranges          Concordant                                           21/40 (52.5%)
were calculated for all variables. The Mann-Whitney test          CRS followed by asthma                                4/40 (10%)
and Fisher test were used to compare the distribution of          Asthma followed by CRS                               15/40 (37.5%)
                                                                 M: male; F: female; NSAID: non-steroidal anti-inflammatory drugs; CRSwNP: chronic
continuous and non-continuous variables between the pre          rhinosinusitis with nasal polyps; CRSsNP: chronic rhinosinusitis without nasal polyps; y:
and post-treatment periods and between the three treatment       years old; CRS: chronic rhinosinusitis
groups. For all statistical comparisons an α = 0.05 was
used.
                                                                 Table II. Surgical history of the cohort.
Results                                                           Number of operated patients                                       30/40 (75%)

A cohort of 40 severe asthmatic patients was examined. 33         Type of surgery
                                                                  Polypectomy                                                      5/30 (16.7%)
patients (82.5%) were affected by CRSwNP, and 7 patients          Anterior FESS                                                    2/30 (6.7%)
(17.5%) were affected by CRSsNP. Demographic data are             FESS                                                              6/30 (20%)
reported in Table I.                                              ESS                                                             13/30 (43.3%)
                                                                  ESS + Draf III frontal sinusotomy                                4/30 (13.3%)
Eighteen patients (45%) were in continuative or intermit-
tent OCS treatment for control of airway exacerbations; 30        Mean number of surgeries for each patient                      2.9 (range 1-13)
patients (75%) had a history of endoscopic sinus surgery          Mean age at first surgery                                     42.1 (range 18-59)
and the most frequent procedure was full-house endoscopic         Last surgery performed before mAb                                24/30 (80%)
sinus surgery with removal of middle turbinate (ESS) (13          Last surgery performed during mAb                                 6/30 (20%)
patients, 43.3%). 20 subjects (66.7%) underwent more than        FESS: functional endoscopic sinus surgery; ESS: endoscopic sinus surgery; mAb:
                                                                 monoclonal antibody
1 endoscopic procedure, with a mean of 2.9 surgeries per
patient. All operated patients performed a sinus CT scan
before the last surgery and the mean Lund-Mackay score
was 16.5 ± 4.0 (range 6-22). The majority of operated pa-        2.6 ± 1.9 (median 2, IQR 1.2-4) and mean 52-week NPS
tients (24 patients, 80%) underwent the last surgery before      was 2.0 ± 2.1 (median 2, IQR 0-2.7). Differences between
the introduction of the mAb; in 6 subjects (20%) surgery         scores at baseline and at 52-week were not significant at
was performed during mAb treatment. Further details on           Mann-Whitney test with P = 0.124 for LKS and P = 0.130
surgical treatments are specified in Table II.                   for NPS.
Mean baseline LKS was 5.4 ± 2.7 (median 5, IQR 4-7)              The mean baseline SNOT 22 score was 56.4 ± 27.3 (range
and mean 52-week LKS was 4.8 ± 3.1 (median 4, IQR                8-104; median 57,5, IQR 35.7-80) and SNOT 1-12 was
3-6.2). In the CRSwNP subgroup, mean baseline NPS was            33.1 ± 14.5 (range 4-59; median 35, IQR 24-45.2). The



                                                                                                                                                    437
F. Bandi et al.




mean 52-week SNOT 22 score was 30.5 ± 21.2 (range                                             poor response on the lower airways; for the same reason,
1-83; median 26.5, IQR 14-47) and SNOT 1-12 was                                               2 patients suspended mepolizumab after 5.0 ± 1.4 months
17.5 ± 11.7 (range 0-46; median 17.5, IQR 6.7-26). Dif-                                       and started benralizumab for unsuccessful control of asth-
ferences between scores at baseline and at 52-week were                                       ma symptoms.
found significant at Mann-Whitney test with P < 0.001 for                                     Demographics of treatment groups are shown in Table III.
SNOT 22 score and P < 0.001 for SNOT 1-12 score. Statis-                                      Differences concerning inhalants sensitisation (P = 0.196),
tically significant differences were also found for individu-                                 NSAID intolerance (P = 0.411), prevalence of nasal pol-
al sinonasal symptoms such as nasal blockage (P < 0.001),                                     yps (P = 0.892), CRS onset (P = 0.818), asthma onset
rhinorrhoea (P < 0.001), hyposmia (P = 0.023), facial pain                                    (P = 0.625), endoscopic sinus surgeries (P = 0.431), chron-
(P = 0.027) and ear fullness (P = 0.006).                                                     ic OCS treatment (P = 0.638) and nasal steroid treatment
Nasal disease at baseline was partly controlled in 7 patients                                 (P = 0.258) were not significantly different.
(17.5%) and uncontrolled in 33 patients (82.5%). No pa-                                       Differences concerning parameters as SNOT scores and in-
tient was controlled at baseline. At 52-weeks, nasal disease                                  dividual symptoms, LKS, NPS and blood eosinophil count
was controlled in 6 patients (15%), partly controlled in 19                                   between baseline and at 52-week in each treatment group
(47.5%) and uncontrolled in 15 (37.5%). In detail, the nasal                                  are shown in Table IV.
disease score remained unchanged in 20 patients (50%),                                        Briefly, improvements in SNOT 22 and SNOT 1-12 scores
irrespective of baseline status (15 uncontrolled, 5 partly                                    were evident in all three groups, with anti-IgE and anti-
controlled), whereas 20 patients (50%) clinically improved                                    IL5 groups reaching a significant difference between base-
with 16 patients climbing one rank of the nasal disease                                       line and 52 weeks for both parameters. Moreover, anti-IL5
scale and 4 patients climbing two ranks. Overall, a positive                                  significantly reduced nasal blockage (P = 0.001) and ear
behavioural trend is evident (P < 0.001).                                                     fullness (P = 0.026) scores, whereas anti-IL5R significantly
No serious AEs were reported in our cohort. However, 25                                       reduced the rhinorrhoea score (P = 0.040).
patients (62.5%) reported minor AEs. Complaints included                                      A significant change was observed in nasal disease control
nasopharyngitis (17/40, 42.5%), oropharyngeal pain (15/40,                                    at 52 weeks in all three treatment groups (Fig. 1).
37.5%), back pain (11/40, 27.5%), arthralgia (10/40, 25%),                                    Concerning endoscopic parameters, no significant varia-
influenza (8/40, 20%) and pyrexia (2/40, 5%).                                                 tions were evident for LKS between baseline and 52 weeks
                                                                                              in any treatment group. Only anti-IL5 significantly re-
Subgroup analysis: anti-IgE, anti-IL5 and anti-IL5R groups                                    duced NPS in the subgroup of patients with nasal polyps
Eleven patients (27.5%) were addressed to omalizumab                                          (P = 0.029). However, once the 3 patients on treatment with
therapy, 20 (50%) to mepolizumab and the remaining 9                                          mepolizumab and operated on during the 52-week observa-
(22.5%) to benralizumab. Seven patients (17.5%) had a                                         tion period were excluded from the analysis, this signifi-
history of a previous mAb treatment. In particular, 5 pa-                                     cance was lost (P = 0.096).
tients, first selected for omalizumab after an average of                                     Blood eosinophil count was available at baseline for 37
26.4 ± 15.6 months were switched to mepolizumab due to                                        patients and at 52 weeks for only 29 patients. No differ-


Table III. Characteristics and differences between treatment groups. P is calculated with a non-parametric Mann-Whitney test.
                                               Anti-IgE group                 Anti-IL5 group               Anti-IL5R group                                             P
                                                   n = 11                         n = 20                         n=9
 Inhalant sensitisation                                11/11 (100%)                        12/20 (60%)                         8/9 (88.9%)                         0.196
 NSAID intolerance                                     3/11 (27.2%)                        7/20 (35%)                          1/9 (11.1%)                         0.411
 CRSwNP                                                9/11 (81.8%)                        17/20 (85%)                         7/9 (77.8%)                         0.892
 CRS onset                                                                                                                                                         0.818
 Early (< 40 y)                                        5/11 (45.4%)                        11/20 (55%)                         4/9 (44.4%)
 Late (≥ 40 y)                                         6/11 (54.5%)                        9/20 (45%)                          5/9 (55.6%)
 Asthma onset                                                                                                                                                      0.625
 Early (< 40 y)                                        4/11 (36.4%)                        10/20 (50%)                         3/9 (33.3%)
 Late (≥ 40 y)                                         7/11 (63.6%)                        10/20 (50%)                         6/9 (66.7%)
 Endoscopic sinus surgery                              7/11 (63.6%)                        15/20 (65%)                         8/9 (88.9%)                         0.431
 Chronic OCS therapy                                   6/11 (54.5%)                        9/20 (45%)                          3/9 (33.3%)                         0.638
 Nasal steroid therapy                                 5/11 (45.4%)                        14/20 (70%)                         7/9 (77.8%)                         0.258
NSAID: non-steroidal anti-inflammatory drugs; CRSwNP: chronic rhinosinusitis with nasal polyps; CRS: chronic rhinosinusitis; y: years old; OCS: oral corticosteroids




438
                                                                                                                                                         A real-life study




Table IV. Differences between baseline and 52-week measurements of se-
lected variables in each treatment group. P is calculated with a non-parametric
Mann-Whitney test.
                                          Anti-IgE group
                                               n = 11
                                Baseline                    52-week                  P
                                      median (IQR 25th 75th)
 SNOT 22               48 (33-78.5)                    22.5 (12-33.5)             0.047
 SNOT 1-12#            27 (19.5-44)                    13.5 (5.2-24.5)            0.047
 Nasal blockage°          4 (3-4)                        2.5 (0.25-3)             0.116
 Rhinorrhea°             2.5 (2-4)                      1.25 (0.6-1.9)            0.400
 Facial pain°             2 (0-4)                           0 (0-2)               0.133
 Ear fullness°           3 (0.5-4)                        2 (0-2.75)              0.519
 Hyposmia°                4 (2-5)                           1 (0-4)               0.365
 LKS                     6 (4.5-8)                         4 (3.5-8)              0.401
 NPS*                     3 (2-5)                           3 (2-5)               0.989
 Blood eosinophils§ 660 (457.5-1162.5)                490 (122.5-532.5)           0.083
                                                 Anti-IL5 group
                                                     n = 20
                                Baseline                    52-week                  P
                                      median (IQR 25th 75th)
 SNOT 22                    64.5 (42.7-80.5)           37.5 (10.5-55.5)           0.002
                                                                                              Figure 1. Graphic representation of the degree of nasal control in the three
 SNOT 1-12#                  36 (25.5-47.2)              19 (6.7-28)              0.001       treatment groups and variations between baseline and week 52.
 Nasal blockage°                 4 (3-5)                  2 (0.75-3)              0.001
 Rhinorrhea°                   4.5 (2.5-5)                2.25 (1-3)              0.076
 Facial pain°                    1 (0-5)                    0 (0-3)               0.127
 Ear fullness°                 3 (1.75-5)                  0.5 (0-3)              0.026
 Hyposmia°                     5 (0.75-5)                  1 (0-3.5)              0.068       ence in baseline blood eosinophil count was evident among
 LKS                            4.5 (4-6)                 4 (2.75-6)              0.253       the three treatment groups (P = 0.129). Differences at
 NPS*                            2 (2-3)                    0 (0-2)               0.029
                                                                                              Mann-Whitney test between baseline eosinophil count and
                                                                                              52 weeks were significant in the anti-IL5 and anti-IL5R
 Blood eosinophils§         700 (375-1005)               80 (45-100)              0.001
                                                                                              groups (P = 0.001 and P = 0.026, respectively).
                                                Anti-IL5R group
                                                      n=9                                     Mean net changes of scores between the three treatment
                                Baseline                    52-week                  P
                                                                                              groups along the 52-week observation period are shown
                                                                                              in Table V. No significant difference was evident in any of
                                      median (IQR 25th 75th)
                                                                                              the parameters analysed among the three groups by Mann-
 SNOT 22                       56 (33-70)                  24 (16-27)             0.063
                                                                                              Whitney test (net change SNOT 22 P = 0.951; net change
 SNOT 1-12#                    35 (26-39)                   13 (9-25)             0.024       SNOT 1-12 P = 0.815; net change LKS P = 0.565; net
 Nasal blockage°                 3 (3-4)                     1 (0-3)              0.222       change NPS P = 0.061).
 Rhinorrhea°                   2.5 (2.2-3)                   1 (1-2)              0.040
 Facial pain°                    0 (0-4)                     0 (0-1)              0.666
                                                                                              Discussion
 Ear fullness°                   3 (0-3)                     0 (0-2)              0.136
 Hyposmia°                       5 (3-5)                     4 (0-5)              0.546       The treatment of refractory CRS is intensively debated
 LKS                             6 (3-6)                     4 (3-7)              0-796       in the literature, especially since biological drugs have
 NPS*                           2 (0.5-2)                    2 (1-3)              0.710       shown excellent results in the treatment of asthma. While
 Blood eosinophils§          400 (350-560)                80 (0-287.5)            0.026       several RCTs have highlighted the efficacy of mAbs in
SNOT: SinoNasal Outcome Test; LKS: Lund-Kennedy Score; NPS: Nasal Polyp Score                 CRSwNP 9-12, observational studies evaluating the response
#
  SNOT 1-12 represents a SNOT 22 sub-category which assesses rhinologic, ear and              to biological treatments in real-life are limited 26-30.
facial symptoms. SNOT 1-12 value is therefore the sum of the values of the 12 items
that composes this subcategory (maximum value 60)                                             Although an observational study may have several limita-
°
  Listed symptoms are individual items of the SNOT 22, each one assessed by a 5-point scale   tions, the application of clinical trial results to clinical prac-
*
  NPS was calculated only in the CRSwNP subgroup in each treatment arm
§
  Blood eosinophils are expressed as number of cells per mm3                                  tice is not often straightforward. Issues, such as restrictive



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Table V. Differences in net change of selected scores between treatment              scopic changes of nasal polyps as the primary outcome of
groups.                                                                              treatment.
                            Anti-IgE        Anti-IL5       Anti-IL5R                 Gevaert et al. 11 reported a significant reduction in pol-
                             group           group          group
                             n = 11          n = 20         n=9
                                                                                     yp size compared to baseline in the omalizumab group
                                                                                     (P = 0.001), which also presented a significantly lower NPS
                              mean ± SD         mean ± SD         mean ± SD
                                                                                     than the placebo arm throughout the entire treatment pe-
 Net change SNOT 22           24.6 ± 27.1       26.9 ± 20.6       25.3 ± 26.9
                                                                                     riod (P = 0.02). Another study by Gevaert et al. 10 reported
 Net change SNOT 1-12          14 ± 14.3        16.9 ± 10.6       14.7 ± 16.3        a significant reduction of NPS in the mepolizumab group
 Net change LKS                1.0 ± 1.5         0.2 ± 2.8          0.4 ± 2.5        compared to placebo (P = 0.028). Bachert et al. 12 showed a
 Net change NPS*               0.1 ± 0.8         0.8 ± 1.4         -0.3 ± 1.2        significant higher probability of having a reduction of NPS
SNOT: SinoNasal Outcome Test; LKS: Lund-Kennedy Score; NPS: Nasal Polyp Score        in the mepolizumab group vs. placebo (P = 0.031). Differ-
*
  Net change NPS was calculated only in the CRSwNP subgroup in each treatment arm.
                                                                                     ently, Pinto et al. 9 opted for changes in sinus opacification
                                                                                     determined by CT scan as the primary outcome, reporting
enrollment criteria, experimental design limitations, con-                           a significant reduction in inflammation for the omalizumab
flicts of interest (both financial and non-financial), publica-                      group from baseline (P = 0.043), without significant differ-
tion bias and biological variability, can all underlie the dis-                      ences on net change across treatment groups (P = 0.391).
parity between the outcomes achieved from clinical trials                            NPS from baseline and net change across treatments did
compared to those observed in real-life 31.                                          not show significant variations (P = 0.58).
For instance, exclusion criteria from clinical trials encom-                         Our evaluation of endoscopic parameters showed no signif-
pass the absence of nasal polyps or NPS lower than 5 12,                             icant differences in LKS (P = 0.124) and NPS (P = 0.130)
continuative use of high-dose OCS, treatment with another                            between baseline and 52 weeks in the entire cohort; moreo-
biologic in the previous 12 months, asthma exacerbations                             ver, even the net change appeared quite small. Although,
requiring hospitalisation within the period of screening 12,                         at a first glance, only anti-IL5 therapy was able to reduce
OCS and surgical intervention from 1 month before treat-                             NPS, this result should be considered with caution as it
ment until the end of the study, and use of nasal steroid                            was strongly influenced by combination with surgical ap-
therapies for two months after first dose 10.                                        proaches.
Contrarily, the presented study group included both patients                         It is proper to underline that mean baseline NPS in our co-
with CRSwNP (82.5%) and CRSsNP (17.5%); patients                                     hort was clearly lower than in the aforementioned RCTs.
with nasal polyps had a baseline mean NPS of 2.6 ± 1.9;                              This leads to the consideration that mAbs might be effec-
6 patients (15%) underwent a sinonasal surgical procedure                            tive in polyp volume reduction, but not in their full reab-
during mAb therapy, 18 patients (45%) were in chronic                                sorption, so that beyond a certain shrinking threshold there
OCS treatment for control of airway exacerbations and 26                             is no further clinical improvement. Moreover, nasal polyp
patients (65%) were in chronic nasal steroid therapy. In ad-                         formation is known to depend on the complex interplay
dition, a change in mAb therapy was observed in 7 patients                           among different mechanisms orchestrated by a much wider
in order to achieve better control of the lower airways: 5 pa-                       panel of molecules than IgE or IL5. Likewise, the fact that
tients (12.5%) switched from omalizumab to mepolizumab                               LKS did not improve might imply that the impact of these
and 2 patients (5%) from mepolizumab to benralizumab at                              specific drugs on nasal tissue remodeling in a broader sense
the time of enrollment in our study.                                                 (related to mucin production, extracellular matrix modifi-
It follows that, considering the aforementioned exclusion                            cations, epithelial barrier functions) is somewhat limited 32.
criteria, most of our patients would not have been suitable                          Secondary endpoints included, among others, nasal symp-
for a RCT. All of the above, together with the associated                            toms. Pinto et al. 9 reported significant improvement in
non-respiratory comorbidities, explains the extreme vari-                            SNOT 20 with omalizumab (P < 0.05) from baseline, but
ability of patients encountered in the daily practice.                               there was no difference in the net change between omali-
Another element that further enriches our knowledge on                               zumab and placebo (P < 0.78); Gevaert et al. 11 reported
the effectiveness of mAbs is the long-term follow-up. Our                            a significant decrease in symptom scores for nasal con-
52-week observation goes beyond previous literature expe-                            gestion (P = 0.002), anterior rhinorrhoea (P = 0.003),
riences which evaluated patients at shorter times (16 weeks                          hyposmia (P = 0.004), wheeze (P = 0.02) and dyspnoea
for omalizumab 11 and 25 weeks for mepolizumab 12), pro-                             (P = 0.02) and a significant improvement of Short-Form
viding a longer perspective on the effects of biological                             Health Questionnaire 36 (SF-36) in the omalizumab group
therapies in CRS.                                                                    (P = 0.02); Gevaert et al. 10 reported a non-statistically sig-
Most of the RCTs published in the literature select endo-                            nificant improvement of smell, postnasal drip and conges-



440
                                                                                                                  A real-life study




tion in patients treated with mepolizumab, while Bachert        with mild or moderate asthma (unpublished data). Moreo-
et al. 12 reported greater improvement with mepolizumab         ver, patients presenting with this latter combination are pe-
compared to placebo for SNOT 22 (P = 0.005) and indi-           nalised because they are currently beyond the prescriptive
vidual symptoms such as rhinorrhoea (P < 0.001), mucus          limits of mAbs therapy in Italy.
in throat (P < 0.001), nasal blockage (P = 0.002) and loss      Some reflections arise about the degree of nasal disease
of smell (P < 0.001).                                           control as proposed by EPOS: the presence of particular
In our study, an improvement of symptoms was evident            symptoms, such as refractory smell loss and rhinorrhoea, is
with a significant reduction of SNOT 22 (P < 0.001), SNOT       very common in all CRS stages, despite good overall con-
1-12 (P < 0.001) and individual symptoms such as nasal          trol of disease; sleep disturbance or fatigue may be related
blockage (P < 0.001), rhinorrhoea (P < 0.021), hypos-           to other general conditions that are not strictly connected
mia (P = 0.023), facial pain (P = 0.027) and ear fullness       to CRS; endoscopic findings of healthy or almost healthy
(P = 0.006). However, subgroup analysis showed similar          mucosa is limited in clinical practice to very mild forms of
improvements only for some of these symptoms and not            CRS. This would mean that a revised and more accurate
shared by all treatment arms. It is reasonable to think that    definition of disease control might down-stage patients de-
this discrepancy is mainly due to the limited number of in-     fined as uncontrolled and not responsive to treatments.
dividuals in each subgroup.                                     No serious AEs were reported in the entire cohort, but mi-
It clearly emerges from these comparisons that, in real-life,   nor AEs occurred in 25 patients (62.5%). The most com-
the classic primary endpoint of RCTs was not achieved,          mon were nasopharyngitis (42.5%), oropharyngeal pain
even though overall symptom improvement was statisti-           (37.5%) and back pain (27.5%). These findings appear
cally significant. One possible explanation is that patients    concordant with previous reports 10.
treated with mAbs for asthma, in which a significant re-        The limits of our study first encompass the small sample
duction in pulmonary exacerbations and an overall im-           size and its diversity in terms of patient characteristics and
provement of lower airways obstruction occurs, may also         treatments. Larger and more uniform series are needed to
perceive an improvement in nasal symptoms that is not           verify these preliminary results.
necessarily related to objective nasal findings 33,34.          Second, all patients were on mAb treatment and therefore
A further consideration is unavoidable. It is reasonable        we lack a control group.
to ask whether the only improvement in patient-reported         Subgroup analysis between CRSwNP and CRSsNP, al-
symptoms is sufficient to define a good outcome or whether      though conceptually consistent with the indications for the
the lack of a significant improvement in endoscopic find-       use of biological drugs in CRS, was not conducted because
ings may be related to a faulty choice of mAb. In other         the size of the CRSsNP sample was too small for signifi-
words, are we satisfied only with improvement in symp-          cant statistical considerations. In the literature, this dichot-
toms or should we consider changing therapy when no en-         omous classification is increasingly cornered in favour of
doscopic improvement is observed? According to current          an endotype-based definition from which it emerges that
guidelines, a “moderate response” to a biological treatment     these two phenotypes may share the same inflammatory
(fulfillment of 3-4 criteria) would theoretically be achieved   mechanisms 35 and, thus, be potentially manageable in a
regardless of variations in nasal polyp size and only an “ex-   similar manner.
cellent response” would be defined on the fulfillment of all    We have shortcomings regarding biological parameters:
5 evaluation criteria 17.                                       peripheral eosinophil count was missing for some patients,
Coupling the objective and subjective aspects of the dis-       peripheral IgE were dosed only once before starting treat-
ease, together with other items as proposed by the EPOS         ment in the anti-IgE group, other biomarkers of type 2 in-
multimodal scale for CRS control (i.e. sleep disturbance        flammation (i.e. tissue eosinophil count, serum periostin,
or fatigue, systemic medications needed to control dis-         exhaled and nasal nitric oxide) were unavailable.
ease) 17,18, we were able to show a significant difference on   Moreover, we were not able to assess radiologic changes
control of nasal disease between baseline and 52 weeks in       after treatment. Indeed, CT scan are repeated in daily prac-
all treatment groups. Interestingly, although all patients in   tice only in refractory cases in expectation of a surgical
the cohort were (for obvious reasons) affected by severe        procedure or a clinical need.
asthma, we found that 17.5% of patients presented with a        Although all patients self-reported an overall improvement
partly controlled CRS at baseline. This suggests the pos-       of asthma-related quality of life, this feedback was not veri-
sible coexistence of mild or moderate nasal disease in pa-      fied through validated questionnaires.
tients with severe lower airways comorbidity and, at the        Lastly, we did not extensively evaluate the impact of sur-
same time, the potential association of severe forms of CRS     gery on outcomes; although mAb treatment groups did not



                                                                                                                             441
F. Bandi et al.




differ in the prevalence of previous endoscopic sinus sur-                            asthma: a systematic review and network meta-analysis. Respir Res
                                                                                      2019;20:179. https://doi.org/10.1186/s12931-019-1138-3
gery (P = 0.431), the variability in the type of surgical pro-
                                                                                 7
                                                                                      Ren L, Zhang N, Zhang L, et al. Biologics for the treatment of chronic
cedure did not allow comparisons between patients. For the                            rhinosinusitis with nasal polyps - state of the art. World Allergy Organ
same reason, thorough endoscopic assessment of outcomes                               J 2019;12:100050. https://doi.org/10.1016/j.waojou.2019.100050
of sinus surgery, which include the evaluation of patency of                     8
                                                                                      Kartush AG, Schumacher JK, Shah R, et al. Biologic agents for the
ostia, presence of scarring, characteristics of nasal secre-                          treatment of chronic rhinosinusitis with nasal polyps. Am J Rhinol
tions (other than LKS items) and microbiological data, was                            Allergy 2019;33:203-11. https://doi.org/10.1177/1945892418814768
not reported.
                                                                                 9
                                                                                      Pinto JM, Mehta N, Di Tineo M, et al. A randomized, double-blind,
                                                                                      placebo-controlled trial of anti-IgE for chronic rhinosinusitis. Rhinol-
                                                                                      ogy 2010;48:318-24. https://doi.org/10.4193/Rhin09.144
Conclusions                                                                      10
                                                                                      Gevaert P, Van Bruaene N, Cattaert T, et al. Mepolizumab, a human-
                                                                                      ized anti-IL-5 mAb, as a treatment option for severe nasal polypo-
The upcoming introduction of biologics in clinical practice                           sis. J Allergy Clin Immunol 2011;128:989-95.e1-8. https://doi.
may represent a promising treatment for refractory CRS.                               org/10.1016/j.jaci.2011.07.056
However, many issues are still open. Among these, RCTs
                                                                                 11
                                                                                      Gevaert P, Calus L, Van Zele T, et al. Omalizumab is effective in al-
                                                                                      lergic and nonallergic patients with nasal polyps and asthma. J Al-
published to date focus only on the CRSwNP phenotype,                                 lergy Clin Immunol 2013;131:110-6.e1. https://doi.org/10.1016/j.
while CRSsNP are also known to present as a consequence                               jaci.2012.07.047
of similar inflammatory pathways.                                                12
                                                                                      Bachert C, Sousa AR, Lund VJ, et al. Reduced need for surgery in
The present observational study showed an improvement                                 severe nasal polyposis with mepolizumab: Randomized trial. J Al-
                                                                                      lergy Clin Immunol 2017;140:1024-31.e14. https://doi.org/10.1016/j.
of nasal symptoms in long-term follow-up that was not as-                             jaci.2017.05.044
sociated with significant variations in endoscopic findings.                     13
                                                                                      Global Initiative for Asthma. Global strategy for asthma management
These preliminary results, of course, need to be verified in                          and prevention. 2017. Available from: www.ginasthma.org
more extensive real-life studies. Moreover, we still lack da-                    14
                                                                                      Global Initiative for Asthma. Global strategy for asthma management
ta about the cost-effectiveness of these therapies, their rela-                       and prevention. 2018. Available from: www.ginasthma.org
tionship with surgery (interdependent or exclusive) and an                       15
                                                                                      Global Initiative for Asthma. Global strategy for asthma management
                                                                                      and prevention. 2019. Available from: www.ginasthma.org
accurate set of selection criteria and predictive biomarkers.                    16
                                                                                      Global Initiative for Asthma. Global strategy for asthma management
Lastly, we do not exclude that in the near future other                               and prevention. 2020. Available from: www.ginasthma.org
treatment options, upstream in the inflammatory cascade,                         17
                                                                                      Fokkens WJ, Lund VJ, Hopkins C, et al. European position paper
will be developed that target the entire spectrum of mech-                            on rhinosinusitis and nasal polyps 2020. Rhinology 2020;58(Suppl
anisms underlying multifactorial diseases, like CRS and                               S29):1-464. https://doi.org/10.4193/Rhin20.600
asthma.                                                                          18
                                                                                      Fokkens WJ, Lund VJ, Mullol J, et al. European position paper on
                                                                                      rhinosinusitis and nasal polyps 2012. Rhinol Suppl 2012;23:1-298.
                                                                                 19
                                                                                      Castelnuovo P, Bandi F, Preti, et al. Implementing strategies for
Acknowledgements                                                                      data collection in chronic rhinosinusitis. Acta Otorhinolaryngol Ital
                                                                                      2018;38:222-4. https://doi.org/10.14639/0392-100X-1993
Andrea Preti is a PhD student of the “Sperimental and                            20
                                                                                      Akdis CA, Hellings, PW, Agache I; European Academy of Allergy
translational medicine” course at University of Insubria.                             and Clinical Immunology, Editors. Global atlas of allergic rhinitis and
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                                                                                      Allergy and Clinical Immunology; 2015.
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