Algorithm for the Management of Primary Diffuse Chronic Rhinosinusitis

Chronic rhinosinusitis (CRS) is a debilitating disease with a significant impact on the quality of life (QoL). Its management has changed significantly in the last decade. The most recent EPOS document proposed a new classification of CRS (CRS) [1] based on three aspects: is it primary or secondary to another disease, is the disease localized or diffuse and what is the presumed dominant endotype. This new classification significantly impacts CRS management. Localised disease is usually managed through surgery. Diffuse disease, indicating generalized inflammation, needs anti-inflammatory treatment. Here, surgery may have an adjunctive role. The possibilities of endotyping the disease have led to further differentiation of treatment options. In this algorithm, we focus on primary diffuse CRS. Most CRS patients respond favourably to appropriate medical treatment such as nasal corticosteroids and saline nasal irrigation. If not, further treatment usually involves functional endoscopic sinus surgery (FESS). A majority of the patients responds favourably to FESS, only 19% (95% confidence interval, 14%–24%) needs revision surgery [2]. Until recently, patients with a type2-dominant endotype were frequently treated with courses of oral corticosteroids (OCS) in conjunction with nasal corticosteroids. OCS have a rapid and significant, but short-lived effect on the symptoms of type2 CRS, especially also on olfaction, a symptom that is difficult to treat otherwise. For that reason, in former times, patients with severe uncontrolled disease were often treated with repetitive, or even with continuous low dose OCS, like in severe asthma. However, recent studies have further emphasised the detrimental (long-term) effects of even limited amounts of OCS, like osteoporosis and diabetes mellitus [3]. Therefore, we feel it is no longer warranted to treat with long-term OCS in the light of new treatment options. A breakthrough in the treatment of primary diffuse CRS has been the development of biologics for CRS with nasal polyps (in Western societies usually type2 CRS) [4]. Over the recent years, EPOS/EUFOREA have proposed a set of indication and evaluation criteria that lead to good results in real-world studies [5-7]. To further pursue our ambitions of care to reach remission or even cure, a number of questions need an answer [6]. We do not have sufficient data to guide us in choosing the best biologics for a particular patient. Here, we lack easily available and reliable biomarkers. We do know that the previous reaction to OCS is a good predictor for the response to type2-targeted biologics, especially concerning olfaction [8]. Biologics are potentially disease-modifying drugs, but we still do not know how long a patient needs to be treated to change the natural history of the disease and achieve cure [6]. The possibilities of tapering biologics has just been started to be evaluated but seems very promising [4]. Data for the management of non-type2 are less convincing, with good evidence for saline rinsing, preferably with addition of xylitol, and very limited evidence for the use of long- term antibiotics with notable side effects [1]. In this EPOS2020-based algorithm (Figure 1), the position of biologics is influenced by the present price setting. It is ethically difficult to use a very expensive treatment, when cheaper options suffice to achieve disease control in the majority of patients. However, we are not able to predict which patients will eventually remain uncontrolled and thus could be potential candidates for earlier intervention with biologics and whether this would increase the chance of remission and/or cure [9]. One hopes that in the near future, biologicals indicated in this algorithm become as widely available as possible worldwide. Moreover, we expect more biologics, with a broader potential, to become available. Also, we expect that new indications for treatment options for CRS will follow our endotype-based classification instead of using unreliable phenotyping as has been done in the past. Most patients with primary diffuse CRS respond favourably to appropriate medical treatment such as nasal corticosteroids and/in saline rinsing. The concept of ‘treatable traits’ further helps to guide us towards our goal of precision medicine. When patients remain uncontrolled, it is important to endotype the patient, before deciding on next steps. For patients with type2-dominant disease, a short course of systemic corticosteroids on top on the nasal corticosteroids can be an option. In young atopic patients with asthma and a sensitisation to fungi, allergic fungal rhinosinusitis should be considered, especially in areas with warm and humid climate. In these patients, further (radiological) evaluation and functional endoscopic sinus surgery (FESS) is advised. For non-type2 disease, a treatment of several weeks to months with an antibiotics, preferably a macrolide, can be considered, although the evidence is very limited. For patients with all endotypes, that need further treatment, FESS is advised. A majority of the patients responds favourably to FESS. Many surgeons, however, believe the results in type2-dominant disease to be less favourable than in non-type2 disease although evidence is limited because most studies are done before endotyping was performed. The option of biologics has significantly improved the level of control, even leading to remission, in severely diseased patients with a type2 disease profile. Especially the impact of biologics on olfaction is noteworthy. If biologics are available, we feel it is no longer warranted, to treat patients with type2 disease with long-term systemic corticosteroids or repetitive surgeries. Data for the management of non-type 2 is less convincing, with good evidence for saline rinsing, preferably with addition of xylitol, and very limited evidence for the use of long-term antibiotics. In patients with uncontrolled non-type2 disease always consider that the CRS could be secondary to a systemic disease like vasculitis or immunodeficiency. W.J.F., E.C., P.W.H., R.J.H., C.H. and S.R. were involved in the development of the algorithm. W.J.F. drafted the first version of the manuscript that was adjusted and corrected by E.C., P.W.H., R.J.H., C.H. and S.R. W.J.F., E.C., P.W.H., R.J.H., C.H. and S.R. were involved in critical revision of the manuscript and approved the final version. The Department of Otorhinolaryngology of the Amsterdam University Medical centre, received grants for research in Rhinology from: Novartis, EU, GSK and Sanofi-Aventis. Wytske Fokkens received consultation and/or speaker fees from Dianosic, GSK, Novartis, Sanofi-Aventis/Regeneron and AstraZeneca. Eugenio de Corso received lecture fees and participations on expert board meeting of GSK, Novartis, Sanofi, Firma and AstraZeneca. Richard J Harvey is consultant/advisory board with Medtronic, Novartis, Glaxo-Smith-Kline and Neil Med Pharmaceuticals. He has been on the speakers' bureau for Sanofi, Viatris, Proctor and Gamble, Glaxo-Smith-Kline, Astra-Zeneca, Meda Pharmaceuticals and Seqirus. He is research grant recipient Glaxo-Smith-Kline, Sanofi and Stallergenes. Peter Hellings has received honoraria and/or research grants from Sanofi/Regeneron, GSK, Vialtris and ALK. Claire Hopkins is an advisory board member of AstraZeneca, BioInspire Technologies, Dianosic, GlaxoSmithKline and Sanofi. Sietze Reitsma reports grants, consulting fees and honoraria from Sanofi and Novartis and GSK. The authors have nothing to report.