10.14639/0392-100X-suppl.1-43-2023-01
Objective. This narrative review analyses factors affecting recurrence of Chronic rhinosinusitis with nasal polyps (CRSwNP) after surgery, such as type, extension and completeness of endoscopic sinus surgery (ESS). We also described new implications in the management of recurrences after the advent of biologics. Methods. We identified four topics: definition of disease state; factors linked to recurrence of polyps; evaluation and management of recurrence in clinical practice. Results. We analysed the differences between exacerbation and recurrence, as well as the concept of “controlled disease”. We focused on potential predictors of recurrence after ESS, such as type 2 inflammation, asthma, aspirin-exacerbated respiratory disease, incomplete initial surgery and lack of adherence to long-term post-operative local corticosteroids. We discussed the new aspects of diagnosis and treatment of recurrences after surgery, summarising our suggestions in a detailed algorithm for practical management of patients with recurrent disease. Conclusions. The results emphasised the importance of accurate evaluation of patients with CRSwNP recurrence, focusing on the reasons of failure and risk of disease progression, in order to guide personalised interventions. It is crucial to define the concept of appropriate surgery, which affects the choice between starting a biologic or repeating surgery.
text/xml
1827-675X
2602
en
Jacopo Galli
http://creativecommons.org/licenses/by-nc-nd/4.0
ACTA Otorhinolaryngologica Italica
biologics
How to manage recurrences after surgery in CRSwNP patients in the biologic era: a narrative review
Text.Serial.Journal
https://www.actaitalica.it/
43
Annual congress report
2023-04-21
2023-04-19
2023-04-28
2023-04-28
S3-S13
1
Jacopo Galli
2023/04/21
10.14639/0392-100X-suppl.1-43-2023-01
S3
Unit of Otorhinolaryngology, “A. Gemelli” University Hospital Foundation IRCCS, Rome, Italy; Department of Head, Neck and Sensory Organs, Catholic University of Sacred Heart, Rome, Italy
1827-675X
biologics
S13
How to manage recurrences after surgery in CRSwNP patients in the biologic era: a narrative review
https://www.actaitalica.it/article/download/2602/938
43
ACTA OTORHINOLARYNGOLOGICA ITALICA 2023;43(SUPPL.1):S3-S13; doi: 10.14639/0392-100X-suppl.1-43-2023-01




Rhinology section


How to manage recurrences after surgery in CRSwNP
patients in the biologic era: a narrative review
Gestione delle recidive di poliposi nasale dopo chirurgia nell’era dei biologici:
review narrativa
Eugenio De Corso1, Stefano Settimi1,2, Claudio Montuori2, Alessandro Cantiani2, Marco Corbò2,
Giuseppe Alberto Di Bella2, Fabio Sovardi3, Fabio Pagella3, Mario Rigante1, Giulio Cesare Passali1,2,
Gaetano Paludetti1, Jacopo Galli1,2
1
  Unit of Otorhinolaryngology, “A. Gemelli” University Hospital Foundation IRCCS, Rome, Italy; 2 Department of Head, Neck and
Sensory Organs, Catholic University of Sacred Heart, Rome, Italy; 3 Department of Clinical, Surgical, Diagnostic and Pediatric
Sciences, University of Pavia, Pavia, Italy


SUMMARY
Objective. This narrative review analyses factors affecting recurrence of Chronic rhinosi-
nusitis with nasal polyps (CRSwNP) after surgery, such as type, extension and complete-
ness of endoscopic sinus surgery (ESS). We also described new implications in the manage-
ment of recurrences after the advent of biologics.
Methods. We identified four topics: definition of disease state; factors linked to recurrence
of polyps; evaluation and management of recurrence in clinical practice.
Results. We analysed the differences between exacerbation and recurrence, as well as the
concept of “controlled disease”. We focused on potential predictors of recurrence after ESS,
such as type 2 inflammation, asthma, aspirin-exacerbated respiratory disease, incomplete
initial surgery and lack of adherence to long-term post-operative local corticosteroids. We
discussed the new aspects of diagnosis and treatment of recurrences after surgery, sum-
marising our suggestions in a detailed algorithm for practical management of patients with
recurrent disease.                                                                                Received: January 23, 2023
Conclusions. The results emphasised the importance of accurate evaluation of patients with        Accepted: January 30, 2023
CRSwNP recurrence, focusing on the reasons of failure and risk of disease progression, in
order to guide personalised interventions. It is crucial to define the concept of appropriate     Correspondence
surgery, which affects the choice between starting a biologic or repeating surgery.               Stefano Settimi
                                                                                                  Department of Head-Neck and Sensory Organs,
KEY WORDS: chronic rhinosinusitis, nasal polyps, recurrent disease, control of disease,           Catholic University of Sacred Heart, largo F. Vito 1,
biologics                                                                                         00168, Rome, Italy
                                                                                                  Tel. +39 06 30154439
                                                                                                  E-mail: settimi.stefano90@gmail.com
RIASSUNTO
Obiettivo. Abbiamo valutato i fattori che influenzano il rischio di recidiva dopo chirurgia:
tipo, estensione e completezza della ESS. Abbiamo poi descritto le nuove implicazioni nella         How to cite this article: De Corso E, Settimi S,
gestione delle recidive con l’avvento dei biologici.                                                Montuori C, et al. How to manage recurrences
Metodi. Abbiamo analizzato: definizione di stato di malattia; fattori legati alla recidiva          after surgery in CRSwNP patients in the biologic
                                                                                                    era: a narrative review. Acta Otorhinolaryngol
di poliposi dopo chirurgia; iter diagnostico e gestione pratica della recidiva di malattia.
                                                                                                    Ital 2023;43(SUPPL.1):S3-S13. https://doi.
Risultati. È stata analizzata la differenza tra esacerbazione e recidiva, insieme al concetto       org/10.14639/0392-100X-suppl.1-43-2023-01
di “controllo di malattia”. Sono stati valutati i fattori predittivi di recidiva: infiammazione
di tipo 2, asma, malattia respiratoria esacerbata dall’aspirina, incompletezza dell’intervento
iniziale e non aderenza ai corticosteroidi locali a lungo termine dopo chirurgia. Abbiamo poi     © Società Italiana di Otorinolaringoiatria
                                                                                                  e Chirurgia Cervico-Facciale
descritto gli aspetti di diagnosi e trattamento delle recidive dopo chirurgia riassumendoli in
un algoritmo dettagliato per la gestione pratica dei pazienti con recidiva di malattia.
                                                                                                                 OPEN ACCESS
Conclusioni. I dati hanno dimostrato l’importanza di un’accurata valutazione, incentra-
ta sul rischio di fallimento chirurgico, per guidare le decisioni nel pianificare successivi      This is an open access article distributed in accordance with
                                                                                                  the CC-BY-NC-ND (Creative Commons Attribution-Non-
trattamenti. Cruciale è definire il concetto di chirurgia appropriata, che può influenzare la     Commercial-NoDerivatives 4.0 International) license. The
scelta tra inizio del biologico o nuova chirurgia.                                                article can be used by giving appropriate credit and mentio-
                                                                                                  ning the license, but only for non-commercial purposes and
PAROLE CHIAVE: rinosinusite cronica, poliposi nasale, malattia ricorrente, controllo di           only in the original version. For further information: https://
malattia, biologici                                                                               creativecommons.org/licenses/by-nc-nd/4.0/deed.en




                                                                                                                                                            S3
E. De Corso et al.




Introduction                                                    recurrence, particularly in the sense of failure after surgery,
                                                                but a widely accepted definition has never been reached.
Chronic rhinosinusitis with nasal polyps (CRSwNP) is a          All this becomes even more complicated considering the
heterogeneous disease with a large spectrum of severity re-     different aspects of the concept of recurrence, including
lated to the underlying inflammatory mechanisms, which          symptoms, quality of life, endoscopic appearance and in-
may lead to the persistence or recurrence of nasal polyps 1.    flammatory process. Roughly speaking, for a recurrence
In fact, the predominant inflammatory pathway may affect        of polyposis it is not enough to consider the macroscopic
the clinical manifestations of the disease and response to      reappearance of polyps and disregard the persistence of
medical and surgical interventions 2,3.                         symptoms and the residual inflammatory process that may
For this reason, treatment was developed as a comprehen-        progressively increase the need for medical treatments, and
sive approach, including long-term management with intra-       especially steroids, to control symptoms 5.
nasal corticosteroids (INCS), brief cycles of antibiotics and   Given these premises, the next step is to clarify the differ-
systemic steroids to manage exacerbation of symptoms,           ence between exacerbation of symptom’s and recurrence
and functional endoscopic sinus surgery (FESS) in case of       of disease in CRSwNP patients. Acute exacerbation is de-
failure after an adequate medical treatment 2. Nevertheless,    fined as a temporary worsening of symptom intensity with
polyp recurrence with inadequate control of symptoms is a       return to baseline, usually after an intervention with sys-
common condition even after FESS, and can be observed           temic corticosteroids and/or antibiotics. A bacterial infec-
in a large proportion of patients up to 18-24 months 3; for     tion is often considered the triggering factor, but in reality
these reasons, CRSwNP remains a challenging clinical en-        it can be due to several underlying factors playing within a
tity to treat due to its propensity for recurrence.             complex background: worsening of allergic rhinitis, acute
FESS has been considered the standard of care over the          viral respiratory infection, exacerbation of asthma, or other
years, although patients with diffuse polyposis and fre-        stress factors 4. Acute exacerbation in CRSwNP has a sig-
quent recurrences represent an important subgroup of pa-        nificant influence on the patients’ quality of life as well as
tients in whom refractory disease may limit the long-term       on healthcare costs. Though its definition has always been
benefit obtained from a standard surgical approach 3. Dif-      descriptive, Wu et al. 5 suggested that it is associated with
ferent interventions have been used, ranging from minimal-      an average 7.83 point decline in SNOT-22 and that patients
ly invasive surgery to nasalisation and reboot surgery, in an   with comorbidities (hay fever, asthma, sinus surgery his-
attempt to improve treatment outcomes 1. Several authors        tory, high body mass index) are at greatest risk of acute ex-
considered the method of surgery an important factor to         acerbations in CRSwNP, especially during the winter sea-
prevent recurrence, and many reports demonstrated that the      son. In addition, acute exacerbation in CRSwNP appears
incomplete opening of all sinus cells plays a key role in       to be associated with significant increases in serum levels
the failure of primary surgery. Furthermore, several factors    of biomarkers (cystatin and periostin) and cytokines (IL-5,
have been taken into consideration as potentially influenc-     IL-6, MPO, etc.) 5.
ing the rate of recurrence, namely asthma, Widal disease,       If we literally analyse the terminology, an exacerbation
occupational dust exposure, allergy, extension of the dis-      is defined as an aggravation and implies an increase of
ease at the time of surgery, type and extension of surgery      a problem against background of disease 6, such as in an
including frontal sinusotomy, and history of previous mul-      acute exacerbation of chronic rhinosinusitis (AECRS) 4;
tiple surgeries 3.                                              on the other hand, recurrence is defined as a comeback
The aim of this narrative review is to describe factors that    (return, repeat, occurring again) and implies a disease epi-
may affect recurrence after surgery, including technical as-    sode after a period without the problem. For this reason,
pects such as type, extension and completeness of surgery.      the term recurrence is often used after a type of surgery
We furthermore described how the management of recur-           that usually led to a resolution of the symptoms for a vari-
rence has radically changed in clinical practice with the ad-   able period of time5. In fact, many clinical factors (i.e.
vent of biologics, which leads to the possibility to achieve    allergy, stage of nasal polyposis at the time of surgery)
disease control even in difficult-to-treat patients.            and type of treatments (surgical technique, adherence to
                                                                post-operative topical steroids) may impact the timing of
How to define disease state in chronic rhinosinusitis           post-operative recurrence. Non steroidal anti-inflammato-
with nasal polyps                                               ry drug-exacerbated respiratory disease (NSAID-ERD),
Over the years, an intriguing issue has been measuring and      asthma and especially non-adherence to intranasal steroid
defining the disease state in CRSwNP patients. In this con-     therapy are the most common factors significantly associ-
text, researchers have focused for years on the concept of      ated with early post-operative recurrence 7. Indeed, litera-



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                                                                      Management of CRSwNP recurrence after surgery in the era of biologics




ture data strongly supports the statement that post-opera-         and in EUFOREA 2019 the concept of disease severity was
tive topical steroids prescribed routinely in practice can         mainly based on the impact of disease on the quality of
effectively prevent recurrence after endonasal surgery.            life and its local extension, using clinical indicators such as
Over the years, ENT specialists have been aware that the           VAS, SNOT-22 and NPS 9. The EPOS2020 Steering Com-
goal of the treatment of a complex chronic disease such            mittee4 identified as cut-offs for severe CRSwNP a VAS
as CRSwNP was not to cure, but to control, distressing             > 7, SNOT-22 > 40, NPS > 5 and smell scores indicative
symptoms, to improve the quality of life by enhancing              of anosmia to specific tests. The EUFOREA expert panel
physical, cognitive, and social functionality, to prevent          lowered this parameter as follows: SNOT-22 > 35, loss of
secondary conditions and minimise the risk of recurrence           smell score (0-3) > 2 points or VAS ≥ 5 and NPS ≥ 4 9.
after surgery 4. For this reason, in the past years priority has   These outcomes were taken into account because they were
been given to achieving and maintaining clinical control in        those adopted in clinical trials; however, prescriptive rules
CRSwNP, having the same concept of “disease control” as a          may change from country to country. In Italy, regulatory
reference point 8. Therefore, in EPOS2012 this concept was         authorities placed greater importance on the failure of pre-
introduced for the first time and defined as “a disease state      vious surgery or on the occurrence of complications during
in which the patient does not have symptoms, or the symp-          surgery and failure after at least 2 short courses of systemic
toms are not bothersome, possibly combined with a healthy          corticosteroids in the previous year. Regarding severity,
or almost healthy mucosa and the need for local medication         SNOT 22 > 40 and NPS > 5 were taken as a reference.
only” 9. Accordingly, the following parameters were com-           In conclusion, it is clear from literature data that the defini-
bined: control of the four major sinonasal symptoms (nasal         tion of disease state is a crucial element in the management
blockage, rhinorrhoea/postnasal drip, facial pain/pressure,        of CRSwNP. If an acute exacerbation is considered a tem-
smell), sleep disturbance and/or fatigue, endoscopic aspect        porary worsening of symptom intensity, the term “recur-
of nasal mucosa and medical intake. Based on the pres-             rence” usually refers to the reappearance of symptoms after
ence of none, one or more items of this list, patients were        a long period of very well controlled disease as may happen
divided into those with well controlled, partly controlled,        after surgery. In the era of new biologics in order to identify
and uncontrolled rhinosinusitis 10. Lately, the EPOS2020           the candidates for treatment, the definitions of “disease se-
Steering Committee specified that the 4 major symptoms             verity ” and “non-control” have become crucial.
should be specifically related to CRSwNP and not to other
factors. The most striking example was craniofacial pain,          Factors linked to the recurrence of polyps after endoscopic
which could be related to other non-sinus causes.                  sinus surgery, including extension of surgery
It is clear from what has been described so far that CRSwNP        Functional endoscopic sinus surgery (FESS) has been con-
patient may still have persistent symptoms, despite any            sidered, over the years, as the standard surgical procedure
recommended medical treatment and the best surgical ap-            for CRSwNP which cannot be controlled with the recom-
proach. These patients were first defined in EPOS2012 as to        mended medical therapy. Nonetheless, even if surgery has
be affected by “difficult-to-treat” CRSwNP 8. This concept         been shown to increase the quality of life in the short term
was further reinforced in EPOS2020 4, where the authors in         with the rapid resolution, especially of obstructive symp-
fact emphasised that patients who do not reach an accept-          toms, recurrence of symptoms can often occur. Long-term
able level of control despite adequate surgery, intranasal         follow-up after FESS has documented revision surgery
corticosteroid treatment and up to two short courses of an-        rates ranging between 15% and 50% across single and mul-
tibiotics or systemic corticosteroids in the last year should      ti-institutions 5-11. Therefore, in the attempt to achieve an
be considered to have difficult-to-treat rhinosinusitis 4-10.      adequate disease control, many patients repeated treatment
The importance of what has been said so far is even greater        with systemic steroids and/or subsequent multiple revision
when we consider the advent of new treatment alternatives.         surgeries in the past. Over the last years, medical therapies
With the advent of biologics, in fact, we have the opportu-        have also become more effective, and the long-term post-
nity to significantly improve the disease state of these pa-       surgical application of topical steroid spray or rinses has
tients to such an extent that they can be brought back to a        been demonstrated to prolong good disease control after
state of normality for a long period of time. However, it is       surgery 12; for this reason, intranasal corticosteroids are
first necessary to identify candidates for biological treat-       likely to remain the mainstay strategy for these patients.
ment, and for this reason the concept of non-control be-           Recurrence of nasal polyps after sinus surgery may occur
came crucial.                                                      for several reasons. These could include underlying mecha-
Experts in the fields have tried to define disease severity        nisms of inflammatory disease, such as type 2 inflamma-
and non-control as rigorously and precisely as possible,           tion, aspirin-exacerbated respiratory disease (AERD),



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E. De Corso et al.




allergic fungal rhinosinusitis (AFRS), or cystic fibrosis. In-    specificity (area under the curve = 0.969; p < 0.001). A tis-
complete initial surgery or lack of adherence to a long-term      sue eosinophil proportion of > 27% of total cells or a tis-
post-operative medical therapy may be other factors predis-       sue eosinophil absolute count of > 55 eosinophils per high
posing to the recurrence of polyps 2,13. A meta-analysis 14       power field may act as a reliable prognostic indicator for
including 45 studies with 34,220 subjects concluded that          nasal polyp recurrence within 2 years after surgery 17. Like-
the factors associated with increased recurrence rates in-        wise, the presence of mucosal eosinophilia was the most
cluded allergic fungal rhinosinusitis (28.7%), aspirin-exac-      important risk factor for recurrence in CRSwNP, according
erbated respiratory disease (27.2%), asthma (22.6%), prior        to other authors18. Finally, De Corso et al. 17 found that the
polypectomy (26.0%), and surgery prior to 2008 (22.7%).           pre-operative inflammatory pattern may differently be as-
The latter refers to a historical period when steroid rinses as   sociated with poor disease control; in particular: persistent
medical adjunctive treatment were not used in routine clini-      neutrophilia presented a relative risk (RR) of poor control
cal practice. Furthermore, the authors considered revision        of 3.10 (CI: 1.24-7.71), persistent eosinophilia showed a
rates for the first surgery compared to subsequent surgeries      RR of 8.42 (CI: 2.72-15.12) and mixed eosinophilic and
and found a significant difference (14.3% vs 26.4%, respec-       neutrophilic CRSwNP a RR of 25.11 (CI: 19.41-30.01).
tively). These findings suggest that revision surgery itself is   They also confirmed that asthma, allergy, blood eosinophil-
a risk factor for subsequent surgery; such an “aggressive”        ia, and ASA triad were strong predictors of poor control 19.
phenotype, in fact, can be the reflection of a more severe        Moreover, when analysing the distribution of CRSwNP re-
underlying endotype of disease or, possibly, patients who         currence rates among countries, heterogeneous rates of re-
do not adhere to medical therapy or comply with follow-up         currence and revision surgery have been found 14,20, which
visits.                                                           can be related to different underlying inflammatory pat-
Tsuzuki et al. 15 recently conducted a study to identify pos-     terns. Eosinophilic disease is known to be more aggressive
sible predictors of CRSwNP progression after FESS. It is          than the neutrophilic counterpart, and regions with higher
worth noting that in their research patients were stratified      rates of eosinophilic disease will likely also have higher
according to eosinophilic (n = 205) and non-eosinophilic          rates of revision surgery. In Asian countries, CRSwNP
chronic rhinosinusitis (n = 76). In the eosinophilic group,       tends to be non-eosinophil-dominant, with higher rates of
multivariate analyses showed that young adulthood – to-           neutrophilic CRSwNP and type 1 inflammatory profiles. In
gether with bronchial asthma, high CT score in the pre-           contrast, CRSwNP tissues from Western countries showed
operative stage and the presence of polyps in the frontal         higher rates of type 2-mediated cytokine expression and a
sinus during FESS – were predictors of disease progres-           higher proportion of eosinophilic-predominant disease 20.
sion after surgery. In the non-eosinophilic chronic rhinosi-      With regards to the extent of surgery, polypectomy – as a
nusitis group, pre-operative CT score and intra-operative         less aggressive and substantially inadequate surgical ap-
sphenoid sinus polyps were identified as significant factors      proach – is more likely to result in the return of the disease
in the univariate analyses, although none were identified         after surgery. This is the consequence of an incomplete
as an independent factor in multivariate analysis. Finally,       opening of the paranasal sinuses, which results in a par-
the authors confirmed that in non-eosinophilic CRSwNP             tial removal of diseased tissue and limited access provided
the post-operative course is more favourable compared to          for on-going topical medications. Since the introduction
eosinophilic CRSwNP.                                              of the concept of “functional endoscopic sinus surgery
These data seem to confirm that tissue eosinophilia is            (FESS)” 21, surgical treatments have evolved, and authors
a hallmark of severity in CRSwNP, and its role in polyp           have suggested that patients who undergo more extensive
recurrence is a subject of much investigation. This data is       surgery have a higher chance of achieving adequate long-
consistent with that reported by Lou et al. 16, which in a        term disease control 22. This theory assumed that radical
retrospective analysis enrolled 387 patients with CRSwNP          surgery could reduce the inflammatory load in the parana-
who were followed over a > 24-month period. In total,             sal sinuses and provide wide and patent sinus ostia, thereby
55.3% of patients (214/387) experienced recurrence. Tis-          enhancing symptomatic relief and facilitating better topical
sue eosinophilia markedly outweighed other parameters             management. Of note, Wu et al. 5 demonstrated that the op-
and correlated with polyp recurrence. Statistical analyses        erative technique on the part of the surgeon may reduce the
indicated that a cut-off value of 27% tissue eosinophils          time interval between sinus surgeries in patients with re-
predicted recurrence, with 96.7% sensitivity and 92.5%            currence of nasal polyps; in particular, they focused on the
specificity (area under the curve = 0.969; p < 0.001); and        performance of middle turbinate resection during sinus sur-
an absolute count of 55 eosinophils per high power field          gery, which appears to extend the time interval until a new
predicted recurrence with 87.4% sensitivity and 97.1%             revision procedure is required. This can be explained by



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                                                                   Management of CRSwNP recurrence after surgery in the era of biologics




the fact that the removal of the middle turbinate enhances      to undergo FESS, radical endoscopic sinus surgery (RESS),
space for ventilation and sinuses drainage and improves the     or RESS+Draf 3 surgery. RESS and RESS+Draf 3 strategies
penetration of local corticosteroids. Middle turbinectomy       achieved better short-term (1 year) outcomes than FESS, al-
may also increase airflow to the olfactory clefts and allow     though post-operative recurrence rates were similarly high
faster recover of smell impairment.                             (95.6%-96.1%) in all groups at 5 years. Nevertheless, RESS
Over the years, authors advocating for more extensive sur-      and RESS+Draf 3 provided a lower long-term revision sur-
gery supported the hypothesis that a classical FESS ap-         gery rate and a longer interval to recurrence post-surgery
proach might be inadequate for all cases, and especially        than FESS, which was negatively correlated with tissue and
those with refractory nasal polyps. For this reason, Bachert    peripheral blood eosinophil percentage. The authors con-
et al. 23 proposed to differentiate surgical approaches on      cluded that CRSwNP with asthma is a systemic disease that
the basis of the inflammatory endotype. Nevertheless, the       frequently recurs and, while radical surgery (RESS) pro-
type of surgery that should be used for distinct endotypes      longs recurrence time and improves olfaction, rhinorrhoea,
of CRSwNP is controversial. Authors have demonstrated           and quality of life in the short-term, compared to standard
that an extended surgical approach may lead to better re-       FESS, the combination of Draf 3 with RESS does not pro-
sults than traditional FESS 24,25. Friedman and colleagues 26   vide better clinical outcomes than RESS alone.
reported that an extended revision decreased post-operative     In conclusion, literature data confirms that type 2 inflam-
recurrence from 19.2% to < 5% at 18-48 months. Likewise,        mation, asthma, aspirin-exacerbated respiratory disease, in-
Jankowski et al. 24 in a retrospective study demonstrated       complete initial surgery and lack of adherence to long-term
that the radical (RESS: full ESS including Draf IIA fron-       post-operative local corticosteroids are the most important
tal sinusotomy, and resection of the inferior two-third of      predictors of disease recurrence after surgery. Furthermore,
middle turbinate) procedure decreased the recurrence rates      some authors demonstrated that an extended surgical ap-
from 58.3% to 22.7% compared to functional ethmoidec-           proach may lead to better results than traditional FESS;
tomy 26. Another study reported that the radical approach       however, these results need to be confirmed with dedicated
significantly decreased the need for revision surgery from      clinical trials, thus reducing the bias derived from incor-
12.3% to 4.0% at 36 months compared to FESS 27.                 rect clinical stratification or inadequate endotyping of the
Patients who had undergone previous surgery 3 years or          disease.
less before the index procedure had the highest rates of fur-
ther surgical treatment. In a multiple regression, the time     How to evaluate patients with recurrence after surgery
interval between previous operations was a better predic-       in clinical practice
tor of subsequent revision surgery than asthma. In addition,    Based on the above, it is clear that it is necessary to strictly
NSAID-ERD comorbidity was the strongest predictor of            follow-up the patient in order to constantly evaluate not on-
the need for further surgery, while more extensive surgery      ly the early, but also the medium- and long-term results af-
was associated with lower revision rates 28.                    ter surgery. The evaluation of patients with recurrence after
Chen et al. 25 also revealed that extensive endoscopic si-      surgery is even more crucial. In practice, it is important to
nus surgery (EESS: polypectomy, resection of inferior           predict the risk of disease progression and of a possible sur-
two-thirds of both middle turbinate and superior turbinate,     gical failure in order to guide the decisions about person-
total ethmoidectomy, antrostomies of maxillary, fron-           alised interventions, bearing in mind that new non-surgical
tal, and sphenoid sinuses) for patients with concomitant        therapies, including biologics, have recently changed the
CRSwNP and asthma may improve subjective olfaction              management of this disease.
and endoscopic appearance. Additionally, an extensive           The first aspect to consider, especially if it has not yet been
study reported that complete sphenoethmoidectomy, max-          done before, is to try to pheno-endotype the patient, even
illary antrostomy, and the endoscopic modified Lothrop          if a universally adopted diagnostic protocol for stratifica-
procedure (EMLP-Draf 3) are successful in most patients         tion is not currently available. Guidelines recently 4 sug-
with aspirin-exacerbated respiratory disease (AERD) and         gested to refer patients to an additional work-up in order to
CRSwNP. This surgical approach facilitates the on-going         define the comorbidities and risk factors that may predict
topical medical therapy in patients with AERD 29.               disease progression. This is why it is important to gather
Finally, Zhang and collaborators1 recently studied the long-    as much information as possible about the inflammatory
term clinical outcomes of all the above-mentioned surgical      mechanisms associated with polyposis, including the level
strategies for patients with recurrent CRSwNP and asthma.       of serum biomarkers (blood eosinophilia, serum IgE) as
In fact, they enrolled 81 patients with CRSwNP and asthma       well as local ones (local eosinophilia), in addition to clini-
in a 5-year prospective study, who were randomly assigned       cal factors such as asthma, NASAID-ERD, autoimmune



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E. De Corso et al.




disease, allergy, etc. All this information is useful because    symptoms seems to increase the probability of obtaining a
the identification of different pheno-endotypes is relevant      significant improvement of symptoms after surgery 32,33 and
in clinical practice and far-reaching in making decisions        the need for revision surgery in the future 34. Nevertheless,
about the management of CRSwNP, especially if the pa-            there is broad consensus that these aspects should be as-
tient is candidate for targeted and personalised therapeutic     sessed by validated questionnaires that measure the percep-
protocols 20.                                                    tion of disease severity in terms of its impact on the quality
Establishing the response to previous treatments is a rel-       of life (PROMs). Many validated patient-reported outcome
evant aspect in patients with recurrence. For this reason, it    measures (PROMs) are used to evaluate CRSwNP, but on-
is important to evaluate the need for systemic steroids in       ly a few are directly focused on disease control. Among
the last years, the adherence to local corticosteroids, and      these, the highest quality validated PROMs for adults with
the disease control after these treatments. It is important      CRSwNP are the Sino Nasal Outcome Test-22 (SNOT-22),
to verify that the previously administered therapy was ap-       the Questionnaire of Olfactory Disorders (QOD), the Si-
propriate and proportionated, although over the years the        nus Control Test (SCT), and the EuroQol five-dimensional
“adequacy” of a medical therapy has never been well de-          questionnaire (EQ-5D). Another validated test is the vis-
fined in terms of drugs used, mode of administration and         ual analogue scale (VAS) related to sinonasal symptoms
duration of treatment. However, it is mandatory to verify        and the Total Nasal Symptom Score (TNSS). In addition,
if patients have been prescribed a therapy with daily local      each of these questionnaires provides insight on different
corticosteroid and if they have been adherent to it. Like-       aspects of CRSwNP. More specifically, the SNOT-22 ex-
wise, it is important to define the number and type of pre-      amines the quality of life (QoL) related to sinonasal symp-
vious surgeries, the technique adopted by the surgeon, the       toms, the QOD examines the olfactory-specific QoL, the
time interval between surgeries, the time from the last sur-     SCT measures disease control and, finally, the EQ-5D as-
gery, and whether the previous surgery was adequate. It is       sesses the general QoL. SNOT-22 proved to be one of the
difficult to define precisely when surgical treatment can be     most reliable tools to measure the quality of life – as well
considered appropriate, especially if we consider that, in       as the most important predictor of surgical referral – and
practice, the extent of the surgical procedure is left to the    strongly affects the patients’ choice. In recent years, the
surgeon’s criteria, which makes it particularly complex to       concept of MCID (minimal clinically important differ-
draw conclusions about its effect on disease control.            ence) has been introduced, which consists in the minimum
Recently Reitsma et al. proposed a new score based on            change of measure for a given outcome that the patient may
post-operative CT examination to define the extent of sur-       be able to perceive. If we consider the SNOT-22, the MCID
gery 30. This score, called ACCESS (Amsterdam Classifi-          corresponds to a change of 8.9 points, or 12 points for pa-
cation on Completeness of Endoscopic Sinus Surgery), is          tients undergoing medical treatment. Thus, adequate surgi-
similar to the Lund-Mackay score (LM) but is based on            cal treatment should ensure an improvement in SNOT-22
bony boundaries rather than sinus opacification. Sites of        corresponding to a change equal to or greater than the
interest are the same of the LM score: ostiomeatal com-          MCID. However, a recent study on 2,263 patients showed
plex, maxillary sinus, anterior ethmoid, posterior ethmoid,      that the achievement of the MCID is strongly influenced
sphenoid sinus, and frontal sinus 31. A score from 0 to 2 is     by the pre-operative SNOT-22, and that patients with a low
assigned to each site: 0 indicates that the site is “function-   preoperative SNOT-22 often do not achieve the MCID, but
ally open” and does not require further surgery; 1 indicates     are nevertheless satisfied in terms of improved quality of
that previous surgery involved the site, but it was insuffi-     life 33-35.
cient to ensure an adequate opening; 2 is assigned if the        Another important aspect to consider when assessing the
site was not involved. The ostiomeatal complex can only be       severity of the disease is its extension, which can be as-
evaluated with a score of 0 or 2, like the LM score. Overall,    sessed through either radiological or endoscopic scores.
6 sites per side are evaluated and, adding up all the scores     Endoscopic systems are very useful, because they are eas-
obtained, we get the total score, which can range from 0         ily repeatable during follow-up, without major risks for pa-
to a maximum of 24. Lower total scores indicate that an          tients. Various nasal polyp (NP) scoring systems have been
adequate surgery was performed for most sinuses, while           proposed and used in the literature, including the Lund-
higher scores indicate a reduced extent of previous surgery.     Kennedy endoscopic scoring system, the peri-operative si-
Of particular importance is also the evaluation of disease       nus endoscopic scoring system (POSE) 36, DIP endoscopic
severity. In this context, not only is it crucial to measure     scoring system and modified Lund-Kennedy (MLK) en-
specific symptom severity, but also to assign a score to its     doscopic scoring system. However, no single system has
burden on the quality of life. The severity of pre-operative     been identified as superior. It was recently demonstrated



S8
                                                                       Management of CRSwNP recurrence after surgery in the era of biologics




in a meta-analysis 37 that current NP endoscopic scoring            How to manage recurrence in practice
systems are not associated with PROMs such as SNOT-22,              For years the medical approach to CRSwNP has been
nasal congestion scores, and TNSS or with objective meas-           based on the use of intranasal corticosteroids (INCS), sa-
ures of olfaction, and for this reason NP grading systems           line nasal rinses, short courses of oral corticosteroids with
with improved clinical utility are needed.                          or without antibiotics (for acute exacerbations) and anti-
With regards to radiologic scoring, CT scans are mostly             leukotrienes/antihistamines, added as optional treatment.
used to evaluate the extent of the pathology and the need           FESS, instead 44, has been considered when maximal medi-
for surgery in CRS 38. The Lund-Mackay (LM) staging                 cal therapy was inadequate to achieve complete control of
is actually the most widely used CT-staging system. Lit-            symptoms, also enabling to better deliver future topical
erature data 39,40 seems to confirm that it poorly correlates       medical therapies 45,46. Nevertheless, these options may be
with the severity of symptoms and PROMs, but that it does           associated with recurrences, and patients may require re-
correlate well with other markers of disease severity, and          vision surgery, especially in difficult-to-treat patients who
specifically the need of surgery and its outcome. Some au-          may require high levels of systemic corticosteroids and/or
thors 38 demonstrated an association between the change in          multiple sinonasal surgeries, with an increasingly high risk
SNOT-22 scores and the preoperative Lund-Mackay, sug-               of peri-operative complications and a progressively shorter
gesting that the subjects with higher Lund-Mackay scores            time of symptom control between surgeries 45,46. Over the
have the most to gain from surgery; in addition, they ob-           last two years, the use of biologic drugs targeting specific
served a small correlation between the Lund-Mackay score            immunologic mediators of type 2 inflammation underlying
and revision surgery rates at 36 months. Likewise, it was 41        the CRSwNP pathophysiology has radically changed the
suggested that another radiologic score at baseline, before         approach to the management of severe cases; for this rea-
ESS, may be able to predict the need for revision surgery,          son, it has become widely common in our country, and its
and for that reason it may be useful in predicting CRS out-         effectiveness in real-life has been demonstrated 47,48 with
comes.                                                              encouraging outcomes, which are even better than clinical
Increasingly important in CRSwNP patients is the assess-            trial results 49.
ment of the olfactory function 42. Impairment of the sense          According to the position paper of the Italian Committee on
of smell is one of the symptoms that has the greatest impact        the use of biologics 50, the role of surgery should be recon-
on the patients’ quality of life, and its severe impairment         sidered in light of these new therapeutic opportunities. The
is one of the established EPOS criteria for starting biolog-        first distinction to be made is between first-time surgery
ics 4. For this reason, the need to routinely measure olfacto-      and revision surgery. After the arrival of biologics on the
ry sensitivity in clinical practice using specific instruments      market, guidelines 5,9,50 suggested that if a patient has never
has increased. The assessment of olfaction has always been          undergone surgery, FESS should be taken into considera-
a challenge for otolaryngologists, but in recent years semi-        tion since it improves control of the disease by improving
objective tests such as UPSIT and Sniffin’s Sticks have be-         INCS penetration in the sino-nasal district 51. Nevertheless,
come widespread, allowing precise severity scores and cut-          it cannot be ruled out that this trend may change in the fu-
offs 43. Of note, it was 42 recently suggested that olfaction       ture, especially in light of preliminary evidence showing
correlates with the degree of inflammation and that – clini-        that, for some biologics, the results appear to be independ-
cally – it should be considered as an indicator of CRSwNP           ent from previous surgery 52. However, this topic is beyond
severity. For this reason, they suggested that quantitative         the scope of this article, and the authors are keen to em-
assessment of smell function, with well-established and             phasise that, when comparing surgery and biologics, it is
reliable tools, should be routinely performed because it ap-        not merely a question of comparing treatment outcomes,
pears to be useful to objectively assess the effectiveness of       but other aspects should be considered, including safety,
CRSwNP treatment over time.                                         contraindications to surgery, comorbidities, patients’ per-
In conclusion, the evaluation in clinical practice of patients      spectives, sustainability of the healthcare systems, etc. 50-53.
with recurrence after surgery requires additional diagnostic        Specific real-world analyses in these directions will allow
workup in order to define the disease state and to identify         further considerations to be made. Another relevant topic
difficult-to-treat patients. In particular, the correct identifi-   is the prediction of surgical failure. It has been 18,54 demon-
cation of different pheno-endotype of the disease, especial-        strated that disease control with FESS plus long-term local
ly if the patient is a candidate for targeted and personalised      corticosteroids is very difficult to achieve in the presence of
therapeutic protocols; evaluation of the disease control af-        negative predictors of surgical outcomes (asthma, allergy,
ter previous treatments; evaluation of disease severity, in-        blood eosinophilia, NSAID-ERD, high load local inflam-
cluding the extension of the disease and smell impairment.          mation, specific preoperative inflammatory patterns), and



                                                                                                                                        S9
E. De Corso et al.




it can be argued that in this subgroup of patients biologics       another biologic should be considered after 4-6 months of
should be taken into consideration even as first-line treat-       treatment with biologics.
ment. Future data will allow to make further considerations        Finally, the question whether to start a biologic in the im-
on this aspect as well.                                            mediate post-operative setting remains challenging, with
The setting is different in CRSwNP patients who already            limited evidence to support this strategy; furthermore, we
underwent at least one previous surgery: in this scenario,         should always consider that the fixed combination of sur-
it is crucial to understand what surgical technique has been       gery and biologic treatment starting in parallel or within a
used and whether the surgery was appropriate or not. This is       short time of one another is not advised, since the response
a hotly debated topic, mainly because a universal definition       of the individual patient to surgery or the biologics would
of “appropriate surgery” is still lacking. In addition, data       be impossible to evaluate.
on the percentage of cases in which surgery can be judged          In conclusion, literature data confirms that the role of sur-
insufficient in CRSwNP patients is specifically missing in         gery should be reconsidered in the era of biologics. On one
the current literature. This is why we believe it is of particu-   hand, FESS should always be taken into consideration in
lar importance to start adopting score systems in practice         case of a treatment-naïve patient; on the other, the setting
that assess the completeness of FESS. At this purpose, the         is different when the patient already underwent at least one
ACCESS score has proven to be a simple and reliable tool           previous surgery; in this case, it is crucial to understand
for measuring the completeness of previous ESS; and pre-           what surgical technique has been used and whether that
cisely for this reason, it may in the future be the one which      surgery was appropriate, and the ACCESS score has proven
is universally adopted in clinical practice 30. Evaluating if      to be a simple and reliable tool for measuring the complete-
a surgery was appropriate is particularly important because        ness of the previous ESS.
in cases where surgery was quite limited, the possibility of
revision surgery could be discussed with the patient. On
                                                                   Conclusions
the other hand, in case of uncontrolled disease after previ-
ous appropriate surgery and good adherence to INCS, it is          Based on EPOS criteria to evaluate disease control, some
appropriate to shift to a biologic 50. In this context, an ade-    authors 10 demonstrated that before the arrival of biolog-
quate counselling is crucial, and it is always recommended         ics at least 40% of CRS patients were uncontrolled at 3-5
in order to discuss all the alternative treatments and pos-        years after FESS. With the advent of biologic agents, it
sibilities with the patient, based on disease control and se-      is very likely that the outcomes will massively improve
verity 54. In consideration of the new personalised medicine       in the near future, increasing the proportion of well con-
requirements, patients should participate in the decision to       trolled patients with optimal surgical and medical therapy.
start with a specific treatment, and for this reason a revision    In this perspective, the choice and timing of different in-
of the clinical factors or the patient’s arguments should be       terventions becomes crucial, especially in recurrent pa-
undertaken to move in one direction or in the other. We re-        tients. Pre-operative counselling thus becomes increas-
ported the recommended steps in evaluating patients with           ingly more important in order to establish the relationship
recurrence in Figure 1, summarising the factors that may           between success and the patient’s goals, focusing on the
influence the decision in favour of revision surgery (long         more bothersome symptoms and the best solution to adopt
term control of symptoms after previous surgery, incom-            for a long-term resolution.
plete surgery, etc.) or of biologics (asthma, NSAID-ERD,           The results of this narrative review highlight the impor-
recurrence within 3 years of surgery, etc.). In patients who       tance of accurate clinical evaluation, focusing on the rea-
underwent multiple surgeries without reaching adequate             sons for failure and the risk of disease progression, in order
control or reported major complications after ESS, or in           to guide further personalised interventions. A crucial point
case of coexisting disabling type 2 disease such as asthma,        is the need to define the concept of appropriate surgery that
contraindication to surgery, high need of systemic corticos-       may affect the choice between starting biologics or repeat-
teroids, the shift to biologics is strongly recommended 55.        ing surgery. At present, the value of the appropriateness of
In this context, collaboration with asthma specialists (pul-       surgery within the diagnostic and therapeutic process has
monologist/allergologist) appears to be crucial, not only at       not yet been well defined, especially in light of the first
baseline but also during treatment; especially if the patient      results obtained in the literature, showing that the effec-
has severe asthma, regular follow-ups are required, bearing        tiveness of certain biologics is independent of the type and
in mind that in case of uncontrolled asthma a shift to a bio-      number of surgeries performed. Further studies should be
logic may be required 56. On the other hand, in case of poor       performed to establish the relative weight to be assigned to
control of sinonasal symptoms, salvage surgery or a shift to       the appropriateness of surgery.



S10
                                                                                    Management of CRSwNP recurrence after surgery in the era of biologics




Figure 1. Flow-chart of recommended steps in evaluating patients with recurrence and factors that may influence the treatment decision.


Conflict of interest statement                                                  Funding
EDC: participations in experts board meeting of GSK,                            This research received no specific grant from any funding
Novartis, Sanofi, Astrazeneca. SS: participations in experts                    agency in the public, commercial, or not-for-profit sec-
board meeting of GSK. CM, AC, MC, GADB, FS, FP, MR,                             tors.
GCP, JG: none.




                                                                                                                                                   S11
E. De Corso et al.




Author contributions                                                              12
                                                                                       Hopkins C, Slack R, Lund V, et al. Long-term outcomes from the
EDC: conception and design of the study, review of the lit-                            English national comparative audit of surgery for nasal polyposis and
                                                                                       chronic rhinosinusitis. Laryngoscope 2009;119:2459-2465. https://
erature, data analysis and interpretation; drafted the article;                        doi.org/10.1002/lary.20653
SS, AC, MC, GADB: contributed to article draft, review of                         13
                                                                                       Koskinen A, Salo R, Huhtala H, et al. Factors affecting revision rate of
the literature; MR, FP, FS, PGC, JG: revised the article for                           chronic rhinosinusitis. Laryngoscope Invest Otolaryngol 2016;1:96-
important intellectual content and editing. All authors fi-                            105. https://doi.org/10.1002/lio2.27
nally edited the article, gave final approval of the version to                   14
                                                                                       Loftus CA, Soler ZM, Koochakzadeh S, et al. Revision surgery
                                                                                       rates in chronic rhinosinusitis with nasal polyps: meta-analysis of
be submitted, agreed to be accountable for all the aspects of                          risk factors. Int Forum Allergy Rhinol 2020;10:199-207. https://doi.
the work, ensuring that any question related to the accuracy                           org/10.1002/alr.22487
or integrity of any part of the work has been appropriately                       15
                                                                                       Tsuzuki K, Hashimoto K, Okazaki K, et al. Predictors of disease
investigated and resolved.                                                             progression after endoscopic sinus surgery in patients with chron-
                                                                                       ic rhinosinusitis. J Laryngol Otol 2019;133:678-684. https://doi.
                                                                                       org/10.1017/S0022215119001245
Ethical consideration                                                             16
                                                                                       Lou H, Meng Y, Piao Y, et al. Predictive significance of tissue eo-
The research was conducted ethically, with all study pro-                              sinophilia for nasal polyp recurrence in the Chinese population.
cedures being performed in accordance with the require-                                Am J Rhinol Allergy 2015;29:350-356. https://doi.org/10.2500/
ments of the World Medical Association’s Declaration of                                ajra.2015.29.4231
Helsinki. This study did not involve humans and Ethical                           17
                                                                                       De Corso E, Lucidi D, Battista M, et al. Prognostic value of nasal
                                                                                       cytology and clinical factors in nasal polyps development in patients
approval was not applicable.
                                                                                       at risk: can the beginning predict the end? Int Forum Allergy Rhinol
                                                                                       2017;7:861-867. https://doi.org/10.1002/alr.21979
References                                                                        18
                                                                                       Ikeda K, Shiozawa A, Ono N, et al. Subclassification of chronic rhi-
                                                                                       nosinusitis with nasal polyp based on eosinophil and neutrophil. La-
1
     Zhang L, Zhang Y, Gao Y, et al. Long-term outcomes of different                   ryngoscope 2013;123:E1-E9. https://doi.org/10.1002/lary.24154
     endoscopic sinus surgery in recurrent chronic rhinosinusitis with
     nasal polyps and asthma. Rhinology 2020;58:126-135. https://doi.
                                                                                  19
                                                                                       De Corso E, Settimi S, Tricarico L, et al. Predictors of disease con-
     org/10.4193/Rhin19.184                                                            trol after endoscopic sinus surgery plus long-term local corticoster-
                                                                                       oids in CRSwNP. Am J Rhinol Allerg 2021;35:77-85. https://doi.
2
     DeConde AS, Mace JC, Levy JM, et al. Prevalence of polyp re-
                                                                                       org/10.1177/1945892420936196
     currence after endoscopic sinus surgery for chronic rhinosinusitis
     with nasal polyposis. Laryngoscope 2017;127:550-555. https://doi.
                                                                                  20
                                                                                       De Corso E, Baroni S, Settimi S, et al. Sinonasal biomarkers defin-
     org/10.1002/lary.26391                                                            ing type 2-high and type 2-low inflammation in chronic rhinosinusitis
                                                                                       with nasal polyps. J Pers Med 2022;12:1251. https://doi.org/10.3390/
3
     Veloso-Teles R, Cerejeira R. Endoscopic sinus surgery for chronic
     rhinosinusitis with nasal polyps: clinical outcome and predictive fac-            jpm12081251
     tors of recurrence. Am J Rhinol Allergy 2017;31:56-62. https://doi.          21
                                                                                       Stammberger H, Posawetz W. Functional endoscopic sinus surgery.
     org/10.2500/ajra.2017.31.4402                                                     Concept, indications and results of the Messerklinger technique. Eur
4
     Fokkens WJ, Lund VJ, Hopkins C, et al. European Position Paper on                 Arch Otorhinolaryngol 1990;247:63-76. https://doi.org/10.1007/
     Rhinosinusitis and Nasal Polyps 2020. Rhinology 2020;58:1-464.                    BF00183169
     https://doi.org/10.4193/Rhin20.600                                           22
                                                                                       Philpott C, Hopkins C, Erskine S, et al. The burden of revision
5
     Wu AW, Ting JY, Platt MP, et al. Factors affecting time to revision               sinonasal surgery in the UK-data from the chronic rhinosinusitis
     sinus surgery for nasal polyps: a 25-year experience. Laryngoscope                epidemiology study (CRES): a cross-sectional study. BMJ Open
     2014;124:29-33. https://doi.org/10.1002/lary.24213                                2015;5:E006680. https://doi.org/10.1136/bmjopen-2014-006680
6
     Wise SK, Lin SY, Toskala E, et al. International Consensus Statement
                                                                                  23
                                                                                       Bachert C, Akdis CA. Phenotypes and Emerging endotypes of chronic
     on Allergy and Rhinology: allergic rhinitis. Int Forum Allergy Rhinol             rhinosinusitis. J Allergy Clin Immunol Pract 2016;4:621-628. https://
     2018;8:108-352. https://doi.org/10.1002/alr.22073                                 doi.org/10.1016/j.jaip.2016.05.004
7
     Sellami M, Mnejja M, Masmoudi M, et al. Predictive factors for re-           24
                                                                                       Jankowski R, Pigret D, Decroocq F, et al. Comparison of radical
     currence after surgery of nasal polyposis. Rev Laryngol Otol Rhinol               (nasalisation) and functional ethmoidectomy in patients with severe
     (Bord) 2015;136:149-153.                                                          sinonasal polyposis. A retrospective study. Rev Laryngol Otol Rhinol
8
     Fokkens WJ, Lund VJ, Mullol J, et al. EPOS 2012: European position                (Bord) 2006;127:131-140.
     paper on rhinosinusitis and nasal polyps 2012. A summary for otorhi-         25
                                                                                       Chen FH, Deng J, Hong HY, et al. Extensive versus functional en-
     nolaryngologists. Rhinology 2012;50:1-12. https://doi.org/10.4193/                doscopic sinus surgery for chronic rhinosinusitis with nasal polyps
     Rhino12.000                                                                       and asthma: a 1-year study. Am J Rhinol Allergy 2016;30:143-148.
9
     Fokkens WJ, Lund V, Bachert C, et al. EUFOREA consensus on bio-                   https://doi.org/10.2500/ajra.2016.30.4271
     logics for CRSwNP with or without asthma. Allergy 2019;74:2312-              26
                                                                                       Friedman WH, Katsantonis GP. Transantral revision of recurrent
     2319. https://doi.org/10.1111/all.13875                                           maxillary and ethmoidal disease following functional intranasal sur-
10
     van der Veen J, Seys SF, Timmermans M, et al. Real-life study show-               gery. Otolaryngol Head Neck Surg 1992;106:367-371. https://doi.
     ing uncontrolled rhinosinusitis after sinus surgery in a tertiary referral        org/10.1177/019459989210600409
     centre. Allergy 2016;72:282-290. https://doi.org/10.1111/all.12983           27
                                                                                       Masterson L, Tanweer F, Bueser T, et al. Extensive endoscopic sinus
11
     Mendelsohn D, Jeremic G, Wright ED, et al. Revision rates after endo-             surgery: does this reduce the revision rate for nasal polyposis? Eur
     scopic sinus surgery: a recurrence analysis. Ann Otol Rhinol Laryngol             Arch Otorhinolaryngol 2010;267:1557-1561. https://doi.org/10.1007/
     2011;120:162-166. https://doi.org/10.11777/000348941112000304                     s00405-010-1233-z




S12
                                                                                     Management of CRSwNP recurrence after surgery in the era of biologics




28
     Hopkins C, Lund V. Does time from previous surgery predict subse-          43
                                                                                     Han P, Su T, Qin M, et al. A systematic review of olfactory related
     quent treatment failure in chronic rhinosinusitis with nasal polyps?            questionnaires and scales. Rhinology 2021;59:133-143. https://doi.
     Rhinology 2021;59:277-283. https://doi.org/10.4193/Rhin21.017                   org/10.4193/Rhin20.291
29
     Morrissey DK, Bassiouni A, Psaltis AJ, et al. Outcomes of modified         44
                                                                                     Wynn R, Har-El G. Recurrence rates after endoscopic sinus surgery
     endoscopic Lothrop in aspirin-exacerbated respiratory disease with              for massive sinus polyposis. Laryngoscope 2004;114:811-813. htt-
     nasal polyposis. Int Forum Allergy Rhinol 2016;6:820-825. https://              ps://doi.org/10.1097/00005537-200405000-00004
     doi.org/10.1002/alr.21739                                                  45
                                                                                     De Corso E, Pipolo C, Cantone E, et al. Survey on use of local and
30
     Reitsma S, Adriaensen GFJPM, Cornet ME, et al. The Amsterdam                    systemic corticosteroids in the management of chronic rhinosinusitis
     Classification of Completeness of Endoscopic Sinus Surgery (AC-                 with nasal polyps: identification of unmet clinical needs. J Pers Med
                                                                                     2022;12:897. https://doi.org/10.3390/jpm12060897
     CESS): a new CT-based scoring system grading the extent of surgery.
     Rhinology 2020;58:538-543. https://doi.org/10.4193/Rhin20.165
                                                                                46
                                                                                     Little RE, Schlosser RJ, Smith TL, et al. Disease control after surgery
                                                                                     for chronic rhinosinusitis: prospective, multi-institutional validation
31
     Lund VJ, Mackay IS. Staging in rhinosinusitus. Rhinology                        of the Sinus Control Test. Int Forum Allergy Rhinol 2021;11:106-114.
     1993;31:183-184.                                                                https://doi.org/10.1002/alr.22659
32
     Snidvongs K, Kalish L, Sacks R, et al. Sinus surgery and delivery          47
                                                                                     De Corso E, Settimi S, Montuori C, et al. Effectiveness of dupilumab
     method influence the effectiveness of topical corticosteroids for chron-        in the treatment of patients with severe uncontrolled CRSwNP: a “re-
     ic rhinosinusitis: systematic review and meta-analysis. Am J Rhinol             al-life” observational study in the first year of treatment. J Clin Med
     Allerg 2013;27:221-233. https:doi.org/10.2500/ajra.2013.27.3880                 2022;11:2684. https://doi.org/10.3390/jcm11102684
33
     Rudmik L, Soler ZM, Mace JC, et al. Using preoperative SNOT- 22            48
                                                                                     Cantone E, De Corso E, Ricciardiello F, et al. Olfaction recov-
     score to inform patient decision for Endoscopic sinus surgery. La-              ery following dupilumab is independent of nasal polyp reduction
     ryngoscope 2015;125:1517-1522. https://doi.org/10.1002/lary.25108               in CRSwNP. J Pers Med 2022;12:1215. https://doi.org/10.3390/
34
     Rudmik L, Soler ZM, Hopkins C. Using post-operative SNOT-22                     jpm12081215
     to help predict the probability of revision sinus surgery. Rhinology       49
                                                                                     Bachert C, Han JK, Desrosiers M, et al. Efficacy and safety of
     2016;54:111-116. https://doi.org/10.4193/Rhino15.284                            dupilumab in patients with severe chronic rhinosinusitis with nasal
                                                                                     polyps (LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52):
35
     Hopkins C, Rudmik L, Lund VJ. The predictive value of the pre-
                                                                                     results from two multicentre, randomised, double-blind, placebo-
     operative Sinonasal Outcome Test-22 score in patients undergoing
                                                                                     controlled, parallel-group phase 3 trials. Lancet 2019;394:1638-1650.
     endoscopic sinus surgery for chronic rhinosinusitis. Laryngoscope               https://doi.org/10.1016/S0140-6736(19)31881-1
     2015;125:1779-1784. https://doi.org/10.1002/lary.25318                     50
                                                                                     De Corso E, Bellocchi G, De Benedetto M, et al. Biologics for
36
     Wright ED, Agrawal S. Impact of peri-operative systemic steroids                severe uncontrolled chronic rhinosinusitis with nasal polyps: a
     on surgical outcomes in patients with chronic rhinosinusitis with               change management approach. Consensus of the Joint Commit-
     polyposis: evaluation with the novel Peri-operative Sinus Endoscopy             tee of Italian Society of Otorhinolaryngology on biologics in rhi-
     (POSE) scoring system. Laryngoscope 2007;117:1-28. https://doi.                 nology. Acta Otorhinolaryngol Ital 2022;42:1-16. https://doi.
     org/10.1097/MLG.0b013e31814842f8                                                org/10.14639/0392-100X-N1614
37
     Jeong SS, Chen T, Nguyen SA, et al. Correlation of polyp grading           51
                                                                                     Smith TL, Schlosser RJ, Mace JC, et al. Long-term outcomes of
     scales with patient symptom scores and olfaction in chronic rhinosi-            endoscopic sinus surgery in the management of adult chronic rhi-
     nusitis: a systematic review and meta-analysis. Rhinology 2022 Apr              nosinusitis. Int Forum Allergy Rhinol 2019;9:831-841. https://doi.
     19. https://doi.org/10.4193/Rhin22.011 [Epub Ahead of Print]                    org/10.1002/alr.22369
38
     Hopkins C, Browne JP, Slack R, et al. The Lund-Mackay staging sys-         52
                                                                                     Ottaviano G, Saccardo T, Roccuzzo G, et al. Effectiveness of dupilum-
     tem for chronic rhinosinusitis: how is it used and what does it pre-            ab in the treatment of patients with uncontrolled severe CRSwNP: a
     dict? Otolaryngol Head Neck Surg 2007;137:555-561. https://doi.                 “real-life” observational study in naïve and post-surgical patients. J
     org/10.1016/j.otohns.2007.02.004                                                Pers Med 2022;12:1526. https://doi.org/10.3390/jpm12091526
39
     Wabnitz D, Nair S, Wormald PJ. Correlation between pre-operative
                                                                                53
                                                                                     De Corso E, Furneri G, Salsi D, et al. Cost-utility analysis of dupilum-
     symptom scores, quality-of-life questionnaires and staging with CT              ab for the treatment of chronic rhinosinusitis with nasal polyps
     in patients with chronic rhinosinusitis. Am J Rhinol 2005;19:91-96.             (CRSwNP) in Italy. J Pers Med 2022;12:951. https://doi.org/10.3390/
                                                                                     jpm12060951
40
     Bhattacharyya T, Piccirillo J, Wippold FJ. Relationship between            54
                                                                                     Hellings PW, Fokkens WJ, Orlandi R, et al. The EUFOREA pocket
     patient-based descriptions of sinusitis and paranasal sinus CT. Arch
                                                                                     guide for chronic rhinosinusitis. Rhinology 2023;61:85-89. https://
     Otolaryngol Head Neck Surg 1997;123:1189-1192. https://doi.                     doi.org/10.4193/Rhin22.344
     org/10.1001/archotol.1997.01900110039006                                   55
                                                                                     De Corso E, Bilò MB, Matucci A, et al. Personalized management
41
     Lilja M, Koskinen A, Julkunen-Iivari A, et al. Radiological score               of patients with chronic rhinosinusitis with nasal polyps in clini-
     of computed tomography scans predicts revision surgery of chronic               cal practice: a multidisciplinary consensus statement. J Pers Med
     rhinosinusitis. Acta Otorhinolaryngol Ital 2022;42:63-74. https://doi.          2022;12:846. https://doi.org/10.3390/jpm12050846
     org/10.14639/0392-100X-N1561                                               56
                                                                                     Seccia V, D’Amato M, Scioscia G, et al. Management of patients with
42
     Yan X, Whitcroft KL, Hummel T. Olfaction: sensitive indicator of                severe asthma and chronic rhinosinusitis with nasal polyps: a multi-
     inflammatory burden in chronic rhinosinusitis. Laryngoscope Investig            disciplinary shared approach. J Pers Med 2022;12:1096. https://doi.
     Otolaryngol 2020;5:992-1002. https://doi.org/10.1002/lio2.485                   org/10.3390/jpm12071096




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