When approaching a possible diagnosis of CRS the definition of rhinosinusitis provided by the EPOS 2020 guidelines must be rigorously applied. The guidelines define as CRS symptoms allowing to formulate a diagnosis the following: “presence of a nasal sinus inflammation characterized by the presence of two or more symptoms at least one of which must be nasal blockage / obstruction / congestion or rhinorrhea associated more or less with pressure or facial pain and more or less with reduction or loss of smell”. [epos2020] Other associated symptoms can be sore throat, cough, dysphonia, general malaise, or fever. Moreover, in order to define rhinosinusitis as chronic, symptoms must have been lasting for at least 12 weeks. [epos2020] The presence of atypical and/or localized symptoms should prompt the clinician towards other secondary forms (odontogenic sinusitis, sinonasal tumors, vasculitis etc.) (15, 16).

In order to better characterize the clinical phenotype and to identify possible factors affecting CRS control, it is essential to collect information on the presence of any comorbidities such as atopic dermatitis, asthma, urticaria, diabetes mellitus, and gastroesophageal reflux. The presence of one or more of these conditions can guide the diagnostic process (pinpointing towards type 2 inflammation) and must be considered when choosing the treatment strategy (e.g., long-term use of systemic steroids).

Information must also be collected on the patient’s general health conditions, paying particular attention to conditions that can lead to a diagnosis of secondary CRS as well as to comorbidities that can affect and/or limit the possible therapeutic options (e.g., uncontrolled diabetes mellitus, glaucoma, hypertension etc.).

The general drug history provides us with further information on the patient’s general state of health. The collection of anamnestic data on previous pharmacological treatments of rhinosinusitis must be conducted by differentiating between transnasal therapies (both in terms of duration and adherence to therapy) and systemic steroid therapies, by calculating the number of cycles per year and the dose taken/year. This last information is of fundamental importance as it allows to determine the effectiveness of the therapy as well as the excessive use of systemic steroids (17). Finally, data on previous surgical interventions must be careful collected by calculating the number, the type, the extent, as well as the time elapsed since the last surgical procedure performed (18).

Patients’ quality of life (QoL) should be the primary goal of every treatment; therefore, its quantification represents an essential step to manage correctly diseases such as CRS.

Numerous scales have been proposed for the quantification of symptoms, but no instrument or patient reported outcome measure (PROM) is completely satisfactory (19). The most used are the generic visual analog scale (VAS), the symptom-specific VAS and the Sino-Nasal Outcome Test-22 (SNOT-22). -

Generic VAS: on a scale from 0 to 10, where 0 corresponds to no impact, the patient is asked how much the symptoms of rhinosinusitis impact on their own quality of life.

Nasal endoscopy is a fundamental diagnostic step to accurately evaluate the nasal cavities and to define in detail the presence and type of any alteration (22). Additionally, the use of image enhancing filters such as Narrow Band Imaging (NBI) (Olympus Medical System Corporation, Tokyo, Japan) and Storz Professional Image Enhancement System (SPIES—Karl Storz, Tuttlingen, Germany), that emphasize the mucosal vascularization, can provide useful information for the differential diagnosis between inflammatory and neoplastic forms (23). Nasal endoscopy must be considered as a first level examination.

Endoscopic evaluation can be performed using rigid or flexible optics. When possible, rigid optical fibers are preferably used as they provide better image quality, allow for more precise examination of nasal cavities and meatuses and allow the use of the second hand for intranasal maneuvers such as aspiration of secretions and the collection of samplings for microbiological and / or histological examinations. The authors suggest a preparation of the nasal cavity with a mixture of decongestant and anesthetic in case of an examination with rigid optics, while the anesthetic can be avoided if using flexible scopes only: however, the evidence behind this practice is low at present (24).

The endoscopic evaluation is standardized in the so-called “three-pass technique”, which should be employed during all assessments. [epos2020] First, we must examine the respiratory district by evaluating the nasal floor, the inferior meatus, the inferior turbinate, the inferior portion of the nasal septum and the choana, starting from the nasal valve to the nasopharynx. The second pastime evaluates the medial compartment by visualizing the middle and upper portion of the nasal septum, the head of the middle turbinate, the olfactory cleft and the explorable portion of the ethmoid- sphenoid recess. The third step examines the lateral wall of the nose by evaluating the uncinate process, the explorable portion of the ostiomeatal complex, the lower portion of the middle turbinate, paying attention to its tail and the area of the fontanelles.

In case of CRS, the severity of the inflammatory process is examined with semi-quantitative staging systems.

The most used are: •

Nasal Polyp Score (NPS): it evaluates the extension of polypoid growths within the nasal cavities (25) (Figure 1). This system provides a grading from 0 to 4 for each nasal cavity, as follows: ◦

0, polyp not visible;

Nasal cytology allows the clinicians to understand the cellular composition of the nasal epithelium. Through this assessment, several conditions can be identified, such as: non-allergic rhinitis with eosinophils (NARES), non-allergic rhinitis with mast cells (NARMA), non-allergic rhinitis with neutrophils (NARNE) and eosinophil-mastcells non-allergic rhinitis—(NARESMA). Citology assessment is convenient, affordable, and provides several information that can help in the diagnosis and treatment of severe form of CRS. Precisely, the microscopical finding of eosinophils, mast cells, bacteria, spores and mycotic hyphae, is considered a sign of nasal pathology (27).

An accurate diagnosis of IgE-mediated sensitization to allergens is essential to quantify the prognosis and to guide the therapeutic choices in patients with CRS (28).

The main diagnostic method is represented by skin prick tests (SPT) and measurement of serum total and allergen-specific IgE. Basophil degranulation test (BAT) and nasal provocation tests remain third-level allergology investigations (29). As a working definition, the EPOS 2020 has proposed an IgE level of >100 UI as a possible marker for type 2 endotype. [epos2020].

SPT represents a cheap, easy to perform and to read, safe and quick evaluation. The allergen extracts used during the test must be relevant to the geographical area, thus the local pollen calendar should be consulted to set up a proper panel of allergens to test. The test is operator-dependent; thus, it must be performed by trained personnel. It is mandatory that a positive (histamine 0.1%) and a negative control are applied to rule out false positive and negative results (these latter may occur when the patient assumes antihistamines). It must be remembered that SPT use whole extracts, therefore they reveal the presence of IgE against all the components of the allergenic source, including cross-reactive proteins (30).

Finally, in vitro allergy diagnostics is indicated in cases of discrepancy between clinical history and SPT results, or when SPT cannot be performed (31).

Patients with CRS and allergies often live with debilitating olfactory disfunctions, indeed the prevalence of smell disorders is 60%–80% in these patients. Smell disorders can be divided into quantitative and qualitative disorders. Quantitative dysfunction includes: anosmia (complete loss of smell) and hyposmia (partial loss of smell). These can derive from various causes, the most common being viral infections, nasal sinus pathologies, hormonal disorders and head injuries, but they can also be a wake-up call for cognitive disorders such as Parkinson disease, Alzheimer disease or Multiple Sclerosis.

CRS-associated smell disorder has four peculiar clinical features: it is fluctuating, heavily steroid- dependent, it shows a pattern of low threshold and preserved identification scores, as well as it shows a preserved retro nasal olfactory function.

Clinical evaluation:

Several methods have been used to evaluate olfactory function or dysfunction: 1.

Subjective evaluation: can be made by using proper questionnaires. Among these, the SNOT-22 is one of the most commonly used. It measures the loss of smell or taste (using a 5-point Likert scale) and the consequences of chronic rhinosinusitis such as reduced productivity, concentration and frustration.

Radiological examinations are necessary to investigate the paranasal bony walls, and to get information that cannot be obtained with nasal endoscopy (such as the interface of polyps/neoformations with deep structures). Nose and paranasal sinuses CT scan is the gold standard of radiological examinations for nasal sinus pathologies. The methodology is now standardized as it involves image acquisition in the axial, coronal and sagittal projections with a slice thickness of <3 mm. Moreover, the bone and soft tissue window acquisitions are now commonly employed in every exam. This radiological assessment provides anatomical details that are fundamental for planning a surgical intervention. Maxillo-facial CT scan is also a useful tool for staging disease severity. Among the various radiological staging systems, the most used both in clinical trials and in daily clinical practice is the Lund Mackay score. •

Lund Mackay score: it is based on the evaluation of the opacification of the paranasal sinuses by assigning a score for each affected sinus ranging from: 0 no opacification, 1 partial opacification, 2 total opacification; with the exception of the ostiomeatal complex where 0 and 2 refers to clear and obstructed, respectively. The sum of the individual scores of both nasal cavities provides a value that is indicative of the severity of the disease. Chronic rhinosinusitis can be considered severe with a score > 12.

The serum dosage of some parameters is of fundamental importance both in the diagnosis and endotyping of CRS and in the differential diagnosis of CRS with the vasculitic forms. However, the results of blood tests do not have an absolute value but must be correlated with the patient’s clinical history.

In primary CRS, total number of eosinophils >250 and total IgE >100 are considered pathological or suspected for a type 2 form. For lower values, however, a type 2 inflammation cannot be excluded as those could be related to a non-florid phase of the inflammation or could be caused by a recent systemic steroid therapy.

The PNIF is a method that allows the measurement of the quantity of air that can pass through every single nostril. It measures nasal inhalation flow between 30 and 370 L/min. It uses a simple measurement of the speed at which air can move through the nose when inhaling forcefully.

The Asthma control test is a Tools that reflect the multidimensional nature of asthma control and that are easily and quickly administered and interpreted are needed to facilitate the assessment of asthma control in a busy clinical practice. The Asthma Control Test (ACT), a 5-item, patient-administered survey for assessing asthma control was developed to meet this need.

Different devices for the administration of local steroids (sprays, drops, aerosols, irrigations…), different molecules and different dosing schedules have been analyzed.

The results show that there are no significant differences with regard to the different molecules used, nor with regard to the efficacy, let alone the safety of the treatments.

Even the methods of drug delivery are equivalent, even if the nasal spray is certainly easier to administer and improves patient compliance. On the other hand, irrigations using a high-pressure nozzle may be useful in previously operated patients who have large anatomic spaces to reach with therapy.

Nasal corticosteroid administration improves quality of life and overall nasal symptoms when used over the long term and continuously. In patients with CRSwNP, it reduces polyp size and post- surgical recurrence (33).

Nasal washes or irrigations play an important role in the therapy of CRS. They have the role of removing crusts and mucus, improving muco-ciliary clearance, promoting ciliary beat activity, removing biofilm, allergens and inflammatory mediators present on the mucosa and improving hydration.

There are many devices on the market that deliver saline solution at different pressures. High- pressure nasal showers are more effective in the irrigation of maxillary sinuses and frontal recesses, especially in patients undergoing endoscopic surgery.

Hypertonic solution used as a spray has a better effect on nasal congestion and posterior nasal secretions with improvement of the associated cough symptom (34).

The rationale of systemic steroids relies in their high anti-inflammatory and anti-edemigenous activity, reducing the size of polyps and thus improving nasal patency.

No standard molecule is recognized as more effective than others, but prednisone is used in most clinical trials.

Even the dosage is not standardized and will depend on the patient’s comorbidities. On average, the period of administration is 14 days (in the literature it ranges from 7 to 21 days (35) using the highest dose for at least 5–6 days and therefore de-escalating the dosage.

It is important to remember that prolonged treatment with systemic corticosteroids should always be discouraged, as numerous side effects can occur, such as insomnia, mood swings, or elevations in blood pressure, but also more serious ones such as Cushing’s Syndrome, gastrointestinal disorders (even gastric ulceration), decompensated diabetes, favoring cataracts and osteoporosis. Finally, fatal herpes zoster cases have occurred (3). OCS are also recommended preoperatively before FESS because they reduce intraoperative bleeding and they reduce the operative time.

Their use is certainly central in the forms of flare-ups and the effectiveness is especially in cases without polyposis or however most of the work that have given a significance, uses the treatment without a phenotyping of CRS.

The use of biologic drug therapy in CRSwNP from type 2 inflammation must follow international and national guidelines designed to administer the drug exclusively to patients who have a severe disease not responsive to standard drugs and/or who cannot benefit from surgical therapy. This particular attention is important to prevent overtreatment with drugs that, from current knowledge, are proposed as a treatment that is not “disease modifying” and must be taken long-term without the possibility of suspension. In addition, given the significant cost that is not yet comparable to standard therapy, even to a surgical procedure (36), the indication for treatment at the moment must be cautious.

At the moment, the available drug that can be prescribed for severe CRSwNP in Italy is Dupilumab 300 mg (biologic human antibody anti interleukin 4 and interleukin 13) via subcutaneous injection to be administered every 14 days. Other biological drugs, that have already been approved by the European Medicines Agency (EMA) are available, but not yet reimbursed by the Italian national health system, and therefore are not prescribed for the sole purpose of CRSwNP treatment. These are represented by anti-IgE (Omalizumab) and anti-interleukin 5 drugs (Mepolizumab-Benralizumab).

Based on the therapeutic plan established by the Italian Medicines Agency (AIFA), patients with the following characteristics are considered eligible for biologic treatment: age ≥ 18 years; endoscopic diagnosis of severe CRSwNP; NPS > 5 or SNOT-22 > 50; failure of prior medical treatments (at least 2 cycles of systemic corticosteroid in the last year); failure of previous surgical treatment (ascertained by the onset of post-operative complications or by lack of therapeutic response) (Table 1).

The therapy response must be investigated after six months and at one year after starting the biologic treatment. Indeed, the physician should re-evaluate the patient and decide whether the response can be considered sufficient to warrant a long-term prescription.

From “ARIA-ITALIA Multidisciplinary consensus: nasal polyposis and biological drugs” (37).