How to manage recurrences after surgery in CRSwNP patients in the biologic era: a narrative review| ACTA Otorhinolaryngologica Italica

Abstract

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.

Introduction

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a heterogeneous disease with a large spectrum of severity related to the underlying inflammatory mechanisms, which may lead to the persistence or recurrence of nasal polyps ¹. In fact, the predominant inflammatory pathway may affect the clinical manifestations of the disease and response to medical and surgical interventions ^2,3.

For this reason, treatment was developed as a comprehensive approach, including long-term management with intranasal corticosteroids (INCS), brief cycles of antibiotics and systemic steroids to manage exacerbation of symptoms, and functional endoscopic sinus surgery (FESS) in case of failure after an adequate medical treatment ². Nevertheless, polyp recurrence with inadequate control of symptoms is a common condition even after FESS, and can be observed in a large proportion of patients up to 18-24 months ³; for these reasons, CRSwNP remains a challenging clinical entity to treat due to its propensity for recurrence.

FESS has been considered the standard of care over the years, although patients with diffuse polyposis and frequent recurrences represent an important subgroup of patients in whom refractory disease may limit the long-term benefit obtained from a standard surgical approach ³. Different interventions have been used, ranging from minimally invasive surgery to nasalisation and reboot surgery, in an attempt to improve treatment outcomes ¹. Several authors considered the method of surgery an important factor to prevent recurrence, and many reports demonstrated that the incomplete opening of all sinus cells plays a key role in the failure of primary surgery. Furthermore, several factors have been taken into consideration as potentially influencing the rate of recurrence, namely asthma, Widal disease, occupational dust exposure, allergy, extension of the disease at the time of surgery, type and extension of surgery including frontal sinusotomy, and history of previous multiple surgeries ³.

The aim of this narrative review is to describe factors that may affect recurrence after surgery, including technical aspects such as type, extension and completeness of surgery. We furthermore described how the management of recurrence has radically changed in clinical practice with the advent of biologics, which leads to the possibility to achieve disease control even in difficult-to-treat patients.

How to define disease state in chronic rhinosinusitis with nasal polyps

Over the years, an intriguing issue has been measuring and defining the disease state in CRSwNP patients. In this context, researchers have focused for years on the concept of recurrence, particularly in the sense of failure after surgery, but a widely accepted definition has never been reached. All this becomes even more complicated considering the different aspects of the concept of recurrence, including symptoms, quality of life, endoscopic appearance and inflammatory process. Roughly speaking, for a recurrence of polyposis it is not enough to consider the macroscopic reappearance of polyps and disregard the persistence of symptoms and the residual inflammatory process that may progressively increase the need for medical treatments, and especially steroids, to control symptoms ⁵.

Given these premises, the next step is to clarify the difference between exacerbation of symptom’s and recurrence of disease in CRSwNP patients. Acute exacerbation is defined as a temporary worsening of symptom intensity with return to baseline, usually after an intervention with systemic corticosteroids and/or antibiotics. A bacterial infection is often considered the triggering factor, but in reality it can be due to several underlying factors playing within a complex background: worsening of allergic rhinitis, acute viral respiratory infection, exacerbation of asthma, or other stress factors ⁴. Acute exacerbation in CRSwNP has a significant influence on the patients’ quality of life as well as on healthcare costs. Though its definition has always been descriptive, Wu et al. ⁵ suggested that it is associated with an average 7.83 point decline in SNOT-22 and that patients with comorbidities (hay fever, asthma, sinus surgery history, high body mass index) are at greatest risk of acute exacerbations in CRSwNP, especially during the winter season. In addition, acute exacerbation in CRSwNP appears to be associated with significant increases in serum levels of biomarkers (cystatin and periostin) and cytokines (IL-5, IL-6, MPO, etc.) ⁵.

If we literally analyse the terminology, an exacerbation is defined as an aggravation and implies an increase of a problem against background of disease ⁶, such as in an acute exacerbation of chronic rhinosinusitis (AECRS) ⁴; on the other hand, recurrence is defined as a comeback (return, repeat, occurring again) and implies a disease episode after a period without the problem. For this reason, the term recurrence is often used after a type of surgery that usually led to a resolution of the symptoms for a variable period of time⁵. In fact, many clinical factors (i.e. allergy, stage of nasal polyposis at the time of surgery) and type of treatments (surgical technique, adherence to post-operative topical steroids) may impact the timing of post-operative recurrence. Non steroidal anti-inflammatory drug-exacerbated respiratory disease (NSAID-ERD), asthma and especially non-adherence to intranasal steroid therapy are the most common factors significantly associated with early post-operative recurrence ⁷. Indeed, literature data strongly supports the statement that post-operative topical steroids prescribed routinely in practice can effectively prevent recurrence after endonasal surgery.

Over the years, ENT specialists have been aware that the goal of the treatment of a complex chronic disease such as CRSwNP was not to cure, but to control, distressing symptoms, to improve the quality of life by enhancing physical, cognitive, and social functionality, to prevent secondary conditions and minimise the risk of recurrence after surgery ⁴. For this reason, in the past years priority has been given to achieving and maintaining clinical control in CRSwNP, having the same concept of “disease control” as a reference point ⁸. Therefore, in EPOS2012 this concept was introduced for the first time and defined as “a disease state in which the patient does not have symptoms, or the symptoms are not bothersome, possibly combined with a healthy or almost healthy mucosa and the need for local medication only” ⁹. Accordingly, the following parameters were combined: control of the four major sinonasal symptoms (nasal blockage, rhinorrhoea/postnasal drip, facial pain/pressure, smell), sleep disturbance and/or fatigue, endoscopic aspect of nasal mucosa and medical intake. Based on the presence of none, one or more items of this list, patients were divided into those with well controlled, partly controlled, and uncontrolled rhinosinusitis ¹⁰. Lately, the EPOS2020 Steering Committee specified that the 4 major symptoms should be specifically related to CRSwNP and not to other factors. The most striking example was craniofacial pain, which could be related to other non-sinus causes.

It is clear from what has been described so far that CRSwNP patient may still have persistent symptoms, despite any recommended medical treatment and the best surgical approach. These patients were first defined in EPOS2012 as to be affected by “difficult-to-treat” CRSwNP ⁸. This concept was further reinforced in EPOS2020 ⁴, where the authors in fact emphasised that patients who do not reach an acceptable level of control despite adequate surgery, intranasal corticosteroid treatment and up to two short courses of antibiotics or systemic corticosteroids in the last year should be considered to have difficult-to-treat rhinosinusitis ^4-10.

The importance of what has been said so far is even greater when we consider the advent of new treatment alternatives. With the advent of biologics, in fact, we have the opportunity to significantly improve the disease state of these patients to such an extent that they can be brought back to a state of normality for a long period of time. However, it is first necessary to identify candidates for biological treatment, and for this reason the concept of non-control became crucial.

Experts in the fields have tried to define disease severity and non-control as rigorously and precisely as possible, and in EUFOREA 2019 the concept of disease severity was mainly based on the impact of disease on the quality of life and its local extension, using clinical indicators such as VAS, SNOT-22 and NPS ⁹. The EPOS2020 Steering Committee⁴ identified as cut-offs for severe CRSwNP a VAS > 7, SNOT-22 > 40, NPS > 5 and smell scores indicative of anosmia to specific tests. The EUFOREA expert panel lowered this parameter as follows: SNOT-22 > 35, loss of smell score (0-3) > 2 points or VAS ≥ 5 and NPS ≥ 4 ⁹. These outcomes were taken into account because they were those adopted in clinical trials; however, prescriptive rules may change from country to country. In Italy, regulatory authorities placed greater importance on the failure of previous surgery or on the occurrence of complications during surgery and failure after at least 2 short courses of systemic corticosteroids in the previous year. Regarding severity, SNOT 22 > 40 and NPS > 5 were taken as a reference.

In conclusion, it is clear from literature data that the definition of disease state is a crucial element in the management of CRSwNP. If an acute exacerbation is considered a temporary worsening of symptom intensity, the term “recurrence” usually refers to the reappearance of symptoms after a long period of very well controlled disease as may happen after surgery. In the era of new biologics in order to identify the candidates for treatment, the definitions of “disease severity ” and “non-control” have become crucial.

Factors linked to the recurrence of polyps after endoscopic sinus surgery, including extension of surgery

Functional endoscopic sinus surgery (FESS) has been considered, over the years, as the standard surgical procedure for CRSwNP which cannot be controlled with the recommended medical therapy. Nonetheless, even if surgery has been shown to increase the quality of life in the short term with the rapid resolution, especially of obstructive symptoms, recurrence of symptoms can often occur. Long-term follow-up after FESS has documented revision surgery rates ranging between 15% and 50% across single and multi-institutions ^5-11. Therefore, in the attempt to achieve an adequate disease control, many patients repeated treatment with systemic steroids and/or subsequent multiple revision surgeries in the past. Over the last years, medical therapies have also become more effective, and the long-term post-surgical application of topical steroid spray or rinses has been demonstrated to prolong good disease control after surgery ¹²; for this reason, intranasal corticosteroids are likely to remain the mainstay strategy for these patients.

Recurrence of nasal polyps after sinus surgery may occur for several reasons. These could include underlying mechanisms of inflammatory disease, such as type 2 inflammation, aspirin-exacerbated respiratory disease (AERD), allergic fungal rhinosinusitis (AFRS), or cystic fibrosis. Incomplete initial surgery or lack of adherence to a long-term post-operative medical therapy may be other factors predisposing to the recurrence of polyps ^2,13. A meta-analysis ¹⁴ including 45 studies with 34,220 subjects concluded that the factors associated with increased recurrence rates included allergic fungal rhinosinusitis (28.7%), aspirin-exacerbated respiratory disease (27.2%), asthma (22.6%), prior polypectomy (26.0%), and surgery prior to 2008 (22.7%). The latter refers to a historical period when steroid rinses as medical adjunctive treatment were not used in routine clinical practice. Furthermore, the authors considered revision rates for the first surgery compared to subsequent surgeries and found a significant difference (14.3% vs 26.4%, respectively). These findings suggest that revision surgery itself is a risk factor for subsequent surgery; such an “aggressive” phenotype, in fact, can be the reflection of a more severe underlying endotype of disease or, possibly, patients who do not adhere to medical therapy or comply with follow-up visits.

Tsuzuki et al. ¹⁵ recently conducted a study to identify possible predictors of CRSwNP progression after FESS. It is worth noting that in their research patients were stratified according to eosinophilic (n = 205) and non-eosinophilic chronic rhinosinusitis (n = 76). In the eosinophilic group, multivariate analyses showed that young adulthood – together with bronchial asthma, high CT score in the pre-operative stage and the presence of polyps in the frontal sinus during FESS – were predictors of disease progression after surgery. In the non-eosinophilic chronic rhinosinusitis group, pre-operative CT score and intra-operative sphenoid sinus polyps were identified as significant factors in the univariate analyses, although none were identified as an independent factor in multivariate analysis. Finally, the authors confirmed that in non-eosinophilic CRSwNP the post-operative course is more favourable compared to eosinophilic CRSwNP.

These data seem to confirm that tissue eosinophilia is a hallmark of severity in CRSwNP, and its role in polyp recurrence is a subject of much investigation. This data is consistent with that reported by Lou et al. ¹⁶, which in a retrospective analysis enrolled 387 patients with CRSwNP who were followed over a > 24-month period. In total, 55.3% of patients (214/387) experienced recurrence. Tissue eosinophilia markedly outweighed other parameters and correlated with polyp recurrence. Statistical analyses indicated that a cut-off value of 27% tissue eosinophils predicted recurrence, with 96.7% sensitivity and 92.5% specificity (area under the curve = 0.969; p < 0.001); and an absolute count of 55 eosinophils per high power field predicted recurrence with 87.4% sensitivity and 97.1% specificity (area under the curve = 0.969; p < 0.001). A tissue eosinophil proportion of > 27% of total cells or a tissue eosinophil absolute count of > 55 eosinophils per high power field may act as a reliable prognostic indicator for nasal polyp recurrence within 2 years after surgery ¹⁷. Likewise, the presence of mucosal eosinophilia was the most important risk factor for recurrence in CRSwNP, according to other authors¹⁸. Finally, De Corso et al. ¹⁷ found that the pre-operative inflammatory pattern may differently be associated with poor disease control; in particular: persistent neutrophilia presented a relative risk (RR) of poor control of 3.10 (CI: 1.24-7.71), persistent eosinophilia showed a RR of 8.42 (CI: 2.72-15.12) and mixed eosinophilic and neutrophilic CRSwNP a RR of 25.11 (CI: 19.41-30.01). They also confirmed that asthma, allergy, blood eosinophilia, and ASA triad were strong predictors of poor control ¹⁹. Moreover, when analysing the distribution of CRSwNP recurrence rates among countries, heterogeneous rates of recurrence and revision surgery have been found ^14,20, which can be related to different underlying inflammatory patterns. Eosinophilic disease is known to be more aggressive than the neutrophilic counterpart, and regions with higher rates of eosinophilic disease will likely also have higher rates of revision surgery. In Asian countries, CRSwNP tends to be non-eosinophil-dominant, with higher rates of neutrophilic CRSwNP and type 1 inflammatory profiles. In contrast, CRSwNP tissues from Western countries showed higher rates of type 2-mediated cytokine expression and a higher proportion of eosinophilic-predominant disease ²⁰.

With regards to the extent of surgery, polypectomy – as a less aggressive and substantially inadequate surgical approach – is more likely to result in the return of the disease after surgery. This is the consequence of an incomplete opening of the paranasal sinuses, which results in a partial removal of diseased tissue and limited access provided for on-going topical medications. Since the introduction of the concept of “functional endoscopic sinus surgery (FESS)” ²¹, surgical treatments have evolved, and authors have suggested that patients who undergo more extensive surgery have a higher chance of achieving adequate long-term disease control ²². This theory assumed that radical surgery could reduce the inflammatory load in the paranasal sinuses and provide wide and patent sinus ostia, thereby enhancing symptomatic relief and facilitating better topical management. Of note, Wu et al. ⁵ demonstrated that the operative technique on the part of the surgeon may reduce the time interval between sinus surgeries in patients with recurrence of nasal polyps; in particular, they focused on the performance of middle turbinate resection during sinus surgery, which appears to extend the time interval until a new revision procedure is required. This can be explained by the fact that the removal of the middle turbinate enhances space for ventilation and sinuses drainage and improves the penetration of local corticosteroids. Middle turbinectomy may also increase airflow to the olfactory clefts and allow faster recover of smell impairment.

Over the years, authors advocating for more extensive surgery supported the hypothesis that a classical FESS approach might be inadequate for all cases, and especially those with refractory nasal polyps. For this reason, Bachert et al. ²³ proposed to differentiate surgical approaches on the basis of the inflammatory endotype. Nevertheless, the type of surgery that should be used for distinct endotypes of CRSwNP is controversial. Authors have demonstrated that an extended surgical approach may lead to better results than traditional FESS ^24,25. Friedman and colleagues ²⁶ reported that an extended revision decreased post-operative recurrence from 19.2% to < 5% at 18-48 months. Likewise, Jankowski et al. ²⁴ in a retrospective study demonstrated that the radical (RESS: full ESS including Draf IIA frontal sinusotomy, and resection of the inferior two-third of middle turbinate) procedure decreased the recurrence rates from 58.3% to 22.7% compared to functional ethmoidectomy ²⁶. Another study reported that the radical approach significantly decreased the need for revision surgery from 12.3% to 4.0% at 36 months compared to FESS ²⁷.

Patients who had undergone previous surgery 3 years or less before the index procedure had the highest rates of further surgical treatment. In a multiple regression, the time interval between previous operations was a better predictor of subsequent revision surgery than asthma. In addition, NSAID-ERD comorbidity was the strongest predictor of the need for further surgery, while more extensive surgery was associated with lower revision rates ²⁸.

Chen et al. ²⁵ also revealed that extensive endoscopic sinus surgery (EESS: polypectomy, resection of inferior two-thirds of both middle turbinate and superior turbinate, total ethmoidectomy, antrostomies of maxillary, frontal, and sphenoid sinuses) for patients with concomitant CRSwNP and asthma may improve subjective olfaction and endoscopic appearance. Additionally, an extensive study reported that complete sphenoethmoidectomy, maxillary antrostomy, and the endoscopic modified Lothrop procedure (EMLP-Draf 3) are successful in most patients with aspirin-exacerbated respiratory disease (AERD) and CRSwNP. This surgical approach facilitates the on-going topical medical therapy in patients with AERD ²⁹.

Finally, Zhang and collaborators¹ recently studied the long-term clinical outcomes of all the above-mentioned surgical strategies for patients with recurrent CRSwNP and asthma. In fact, they enrolled 81 patients with CRSwNP and asthma in a 5-year prospective study, who were randomly assigned to undergo FESS, radical endoscopic sinus surgery (RESS), or RESS+Draf 3 surgery. RESS and RESS+Draf 3 strategies achieved better short-term (1 year) outcomes than FESS, although post-operative recurrence rates were similarly high (95.6%-96.1%) in all groups at 5 years. Nevertheless, RESS and RESS+Draf 3 provided a lower long-term revision surgery rate and a longer interval to recurrence post-surgery than FESS, which was negatively correlated with tissue and peripheral blood eosinophil percentage. The authors concluded that CRSwNP with asthma is a systemic disease that frequently recurs and, while radical surgery (RESS) prolongs recurrence time and improves olfaction, rhinorrhoea, and quality of life in the short-term, compared to standard FESS, the combination of Draf 3 with RESS does not provide better clinical outcomes than RESS alone.

In conclusion, literature data confirms that type 2 inflammation, asthma, aspirin-exacerbated respiratory disease, incomplete initial surgery and lack of adherence to long-term post-operative local corticosteroids are the most important predictors of disease recurrence after surgery. Furthermore, some authors demonstrated that an extended surgical approach may lead to better results than traditional FESS; however, these results need to be confirmed with dedicated clinical trials, thus reducing the bias derived from incorrect clinical stratification or inadequate endotyping of the disease.

How to evaluate patients with recurrence after surgery in clinical practice

Based on the above, it is clear that it is necessary to strictly follow-up the patient in order to constantly evaluate not only the early, but also the medium- and long-term results after surgery. The evaluation of patients with recurrence after surgery is even more crucial. In practice, it is important to predict the risk of disease progression and of a possible surgical failure in order to guide the decisions about personalised interventions, bearing in mind that new non-surgical therapies, including biologics, have recently changed the management of this disease.

The first aspect to consider, especially if it has not yet been done before, is to try to pheno-endotype the patient, even if a universally adopted diagnostic protocol for stratification is not currently available. Guidelines recently ⁴ suggested to refer patients to an additional work-up in order to define the comorbidities and risk factors that may predict disease progression. This is why it is important to gather as much information as possible about the inflammatory mechanisms associated with polyposis, including the level of serum biomarkers (blood eosinophilia, serum IgE) as well as local ones (local eosinophilia), in addition to clinical factors such as asthma, NASAID-ERD, autoimmune disease, allergy, etc. All this information is useful because the identification of different pheno-endotypes is relevant in clinical practice and far-reaching in making decisions about the management of CRSwNP, especially if the patient is candidate for targeted and personalised therapeutic protocols ²⁰.

Establishing the response to previous treatments is a relevant aspect in patients with recurrence. For this reason, it is important to evaluate the need for systemic steroids in the last years, the adherence to local corticosteroids, and the disease control after these treatments. It is important to verify that the previously administered therapy was appropriate and proportionated, although over the years the “adequacy” of a medical therapy has never been well defined in terms of drugs used, mode of administration and duration of treatment. However, it is mandatory to verify if patients have been prescribed a therapy with daily local corticosteroid and if they have been adherent to it. Likewise, it is important to define the number and type of previous surgeries, the technique adopted by the surgeon, the time interval between surgeries, the time from the last surgery, and whether the previous surgery was adequate. It is difficult to define precisely when surgical treatment can be considered appropriate, especially if we consider that, in practice, the extent of the surgical procedure is left to the surgeon’s criteria, which makes it particularly complex to draw conclusions about its effect on disease control.

Recently Reitsma et al. proposed a new score based on post-operative CT examination to define the extent of surgery ³⁰. This score, called ACCESS (Amsterdam Classification on Completeness of Endoscopic Sinus Surgery), is similar to the Lund-Mackay score (LM) but is based on bony boundaries rather than sinus opacification. Sites of interest are the same of the LM score: ostiomeatal complex, maxillary sinus, anterior ethmoid, posterior ethmoid, sphenoid sinus, and frontal sinus ³¹. A score from 0 to 2 is assigned to each site: 0 indicates that the site is “functionally open” and does not require further surgery; 1 indicates that previous surgery involved the site, but it was insufficient to ensure an adequate opening; 2 is assigned if the site was not involved. The ostiomeatal complex can only be evaluated with a score of 0 or 2, like the LM score. Overall, 6 sites per side are evaluated and, adding up all the scores obtained, we get the total score, which can range from 0 to a maximum of 24. Lower total scores indicate that an adequate surgery was performed for most sinuses, while higher scores indicate a reduced extent of previous surgery.

Of particular importance is also the evaluation of disease severity. In this context, not only is it crucial to measure specific symptom severity, but also to assign a score to its burden on the quality of life. The severity of pre-operative symptoms seems to increase the probability of obtaining a significant improvement of symptoms after surgery ^32,33 and the need for revision surgery in the future ³⁴. Nevertheless, there is broad consensus that these aspects should be assessed by validated questionnaires that measure the perception of disease severity in terms of its impact on the quality of life (PROMs). Many validated patient-reported outcome measures (PROMs) are used to evaluate CRSwNP, but only a few are directly focused on disease control. Among these, the highest quality validated PROMs for adults with CRSwNP are the Sino Nasal Outcome Test-22 (SNOT-22), the Questionnaire of Olfactory Disorders (QOD), the Sinus Control Test (SCT), and the EuroQol five-dimensional questionnaire (EQ-5D). Another validated test is the visual analogue scale (VAS) related to sinonasal symptoms and the Total Nasal Symptom Score (TNSS). In addition, each of these questionnaires provides insight on different aspects of CRSwNP. More specifically, the SNOT-22 examines the quality of life (QoL) related to sinonasal symptoms, the QOD examines the olfactory-specific QoL, the SCT measures disease control and, finally, the EQ-5D assesses the general QoL. SNOT-22 proved to be one of the most reliable tools to measure the quality of life – as well as the most important predictor of surgical referral – and strongly affects the patients’ choice. In recent years, the concept of MCID (minimal clinically important difference) has been introduced, which consists in the minimum change of measure for a given outcome that the patient may be able to perceive. If we consider the SNOT-22, the MCID corresponds to a change of 8.9 points, or 12 points for patients undergoing medical treatment. Thus, adequate surgical treatment should ensure an improvement in SNOT-22 corresponding to a change equal to or greater than the MCID. However, a recent study on 2,263 patients showed that the achievement of the MCID is strongly influenced by the pre-operative SNOT-22, and that patients with a low preoperative SNOT-22 often do not achieve the MCID, but are nevertheless satisfied in terms of improved quality of life ^33-35.

Another important aspect to consider when assessing the severity of the disease is its extension, which can be assessed through either radiological or endoscopic scores. Endoscopic systems are very useful, because they are easily repeatable during follow-up, without major risks for patients. Various nasal polyp (NP) scoring systems have been proposed and used in the literature, including the Lund-Kennedy endoscopic scoring system, the peri-operative sinus endoscopic scoring system (POSE) ³⁶, DIP endoscopic scoring system and modified Lund-Kennedy (MLK) endoscopic scoring system. However, no single system has been identified as superior. It was recently demonstrated in a meta-analysis ³⁷ that current NP endoscopic scoring systems are not associated with PROMs such as SNOT-22, nasal congestion scores, and TNSS or with objective measures of olfaction, and for this reason NP grading systems with improved clinical utility are needed.

With regards to radiologic scoring, CT scans are mostly used to evaluate the extent of the pathology and the need for surgery in CRS ³⁸. The Lund-Mackay (LM) staging is actually the most widely used CT-staging system. Literature data ^39,40 seems to confirm that it poorly correlates with the severity of symptoms and PROMs, but that it does correlate well with other markers of disease severity, and specifically the need of surgery and its outcome. Some authors ³⁸ demonstrated an association between the change in SNOT-22 scores and the preoperative Lund-Mackay, suggesting that the subjects with higher Lund-Mackay scores have the most to gain from surgery; in addition, they observed a small correlation between the Lund-Mackay score and revision surgery rates at 36 months. Likewise, it was ⁴¹ suggested that another radiologic score at baseline, before ESS, may be able to predict the need for revision surgery, and for that reason it may be useful in predicting CRS outcomes.

Increasingly important in CRSwNP patients is the assessment of the olfactory function ⁴². Impairment of the sense of smell is one of the symptoms that has the greatest impact on the patients’ quality of life, and its severe impairment is one of the established EPOS criteria for starting biologics ⁴. For this reason, the need to routinely measure olfactory sensitivity in clinical practice using specific instruments has increased. The assessment of olfaction has always been a challenge for otolaryngologists, but in recent years semi-objective tests such as UPSIT and Sniffin’s Sticks have become widespread, allowing precise severity scores and cut-offs ⁴³. Of note, it was ⁴² recently suggested that olfaction correlates with the degree of inflammation and that – clinically – it should be considered as an indicator of CRSwNP severity. For this reason, they suggested that quantitative assessment of smell function, with well-established and reliable tools, should be routinely performed because it appears to be useful to objectively assess the effectiveness of CRSwNP treatment over time.

In conclusion, the evaluation in clinical practice of patients with recurrence after surgery requires additional diagnostic workup in order to define the disease state and to identify difficult-to-treat patients. In particular, the correct identification of different pheno-endotype of the disease, especially if the patient is a candidate for targeted and personalised therapeutic protocols; evaluation of the disease control after previous treatments; evaluation of disease severity, including the extension of the disease and smell impairment.

How to manage recurrence in practice

For years the medical approach to CRSwNP has been based on the use of intranasal corticosteroids (INCS), saline nasal rinses, short courses of oral corticosteroids with or without antibiotics (for acute exacerbations) and anti-leukotrienes/antihistamines, added as optional treatment. FESS, instead ⁴⁴, has been considered when maximal medical therapy was inadequate to achieve complete control of symptoms, also enabling to better deliver future topical medical therapies ^45,46. Nevertheless, these options may be associated with recurrences, and patients may require revision surgery, especially in difficult-to-treat patients who may require high levels of systemic corticosteroids and/or multiple sinonasal surgeries, with an increasingly high risk of peri-operative complications and a progressively shorter time of symptom control between surgeries ^45,46. Over the last two years, the use of biologic drugs targeting specific immunologic mediators of type 2 inflammation underlying the CRSwNP pathophysiology has radically changed the approach to the management of severe cases; for this reason, it has become widely common in our country, and its effectiveness in real-life has been demonstrated ^47,48 with encouraging outcomes, which are even better than clinical trial results ⁴⁹.

According to the position paper of the Italian Committee on the use of biologics ⁵⁰, the role of surgery should be reconsidered in light of these new therapeutic opportunities. The first distinction to be made is between first-time surgery and revision surgery. After the arrival of biologics on the market, guidelines ^5,9,50 suggested that if a patient has never undergone surgery, FESS should be taken into consideration since it improves control of the disease by improving INCS penetration in the sino-nasal district ⁵¹. Nevertheless, it cannot be ruled out that this trend may change in the future, especially in light of preliminary evidence showing that, for some biologics, the results appear to be independent from previous surgery ⁵². However, this topic is beyond the scope of this article, and the authors are keen to emphasise that, when comparing surgery and biologics, it is not merely a question of comparing treatment outcomes, but other aspects should be considered, including safety, contraindications to surgery, comorbidities, patients’ perspectives, sustainability of the healthcare systems, etc. ^50-53. Specific real-world analyses in these directions will allow further considerations to be made. Another relevant topic is the prediction of surgical failure. It has been ^18,54 demonstrated that disease control with FESS plus long-term local corticosteroids is very difficult to achieve in the presence of negative predictors of surgical outcomes (asthma, allergy, blood eosinophilia, NSAID-ERD, high load local inflammation, specific preoperative inflammatory patterns), and it can be argued that in this subgroup of patients biologics should be taken into consideration even as first-line treatment. Future data will allow to make further considerations on this aspect as well.

The setting is different in CRSwNP patients who already underwent at least one previous surgery: in this scenario, it is crucial to understand what surgical technique has been used and whether the surgery was appropriate or not. This is a hotly debated topic, mainly because a universal definition of “appropriate surgery” is still lacking. In addition, data on the percentage of cases in which surgery can be judged insufficient in CRSwNP patients is specifically missing in the current literature. This is why we believe it is of particular importance to start adopting score systems in practice that assess the completeness of FESS. At this purpose, the ACCESS score has proven to be a simple and reliable tool for measuring the completeness of previous ESS; and precisely for this reason, it may in the future be the one which is universally adopted in clinical practice ³⁰. Evaluating if a surgery was appropriate is particularly important because in cases where surgery was quite limited, the possibility of revision surgery could be discussed with the patient. On the other hand, in case of uncontrolled disease after previous appropriate surgery and good adherence to INCS, it is appropriate to shift to a biologic ⁵⁰. In this context, an adequate counselling is crucial, and it is always recommended in order to discuss all the alternative treatments and possibilities with the patient, based on disease control and severity ⁵⁴. In consideration of the new personalised medicine requirements, patients should participate in the decision to start with a specific treatment, and for this reason a revision of the clinical factors or the patient’s arguments should be undertaken to move in one direction or in the other. We reported the recommended steps in evaluating patients with recurrence in Figure 1, summarising the factors that may influence the decision in favour of revision surgery (long term control of symptoms after previous surgery, incomplete surgery, etc.) or of biologics (asthma, NSAID-ERD, recurrence within 3 years of surgery, etc.). In patients who underwent multiple surgeries without reaching adequate control or reported major complications after ESS, or in case of coexisting disabling type 2 disease such as asthma, contraindication to surgery, high need of systemic corticosteroids, the shift to biologics is strongly recommended ⁵⁵. In this context, collaboration with asthma specialists (pulmonologist/allergologist) appears to be crucial, not only at baseline but also during treatment; especially if the patient has severe asthma, regular follow-ups are required, bearing in mind that in case of uncontrolled asthma a shift to a biologic may be required ⁵⁶. On the other hand, in case of poor control of sinonasal symptoms, salvage surgery or a shift to another biologic should be considered after 4-6 months of treatment with biologics.

Finally, the question whether to start a biologic in the immediate post-operative setting remains challenging, with limited evidence to support this strategy; furthermore, we should always consider that the fixed combination of surgery and biologic treatment starting in parallel or within a short time of one another is not advised, since the response of the individual patient to surgery or the biologics would be impossible to evaluate.

In conclusion, literature data confirms that the role of surgery should be reconsidered in the era of biologics. On one hand, FESS should always be taken into consideration in case of a treatment-naïve patient; on the other, the setting is different when the patient already underwent at least one previous surgery; in this case, it is crucial to understand what surgical technique has been used and whether that surgery was appropriate, and the ACCESS score has proven to be a simple and reliable tool for measuring the completeness of the previous ESS.

Conclusions

Based on EPOS criteria to evaluate disease control, some authors ¹⁰ demonstrated that before the arrival of biologics at least 40% of CRS patients were uncontrolled at 3-5 years after FESS. With the advent of biologic agents, it is very likely that the outcomes will massively improve in the near future, increasing the proportion of well controlled patients with optimal surgical and medical therapy. In this perspective, the choice and timing of different interventions becomes crucial, especially in recurrent patients. Pre-operative counselling thus becomes increasingly more important in order to establish the relationship between success and the patient’s goals, focusing on the more bothersome symptoms and the best solution to adopt for a long-term resolution.

The results of this narrative review highlight the importance of accurate clinical evaluation, focusing on the reasons for failure and the risk of disease progression, in order to guide further personalised interventions. A crucial point is the need to define the concept of appropriate surgery that may affect the choice between starting biologics or repeating surgery. At present, the value of the appropriateness of surgery within the diagnostic and therapeutic process has not yet been well defined, especially in light of the first results obtained in the literature, showing that the effectiveness of certain biologics is independent of the type and number of surgeries performed. Further studies should be performed to establish the relative weight to be assigned to the appropriateness of surgery.

Conflict of interest statement

EDC: participations in experts board meeting of GSK, Novartis, Sanofi, Astrazeneca. SS: participations in experts board meeting of GSK. CM, AC, MC, GADB, FS, FP, MR, GCP, JG: none.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Author contributions

EDC: conception and design of the study, review of the literature, data analysis and interpretation; drafted the article; SS, AC, MC, GADB: contributed to article draft, review of the literature; MR, FP, FS, PGC, JG: revised the article for important intellectual content and editing. All authors finally edited the article, gave final approval of the version to be submitted, agreed to be accountable for all the aspects of the work, ensuring that any question related to the accuracy or integrity of any part of the work has been appropriately investigated and resolved.

Ethical consideration

The research was conducted ethically, with all study procedures being performed in accordance with the requirements of the World Medical Association’s Declaration of Helsinki. This study did not involve humans and Ethical approval was not applicable.

Figures and tables

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

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