Endotype of Chronic Rhinosinusitis with Nasal Polyps in Morocco

Abstract

Background

With the advent of biotherapies, endotyping of chronic rhinosinusitis with nasal polyps (CRSwNP) is becoming more and more important to optimize therapeutic management. While the majority of CRSwNPs in the United States, Europe, and Japan exhibit type 2 eosinophil-dominant inflammation response, other parts of Asia display mixed patterns including neutrophil-dominant inflammation. Until now, no study has focused on the proportion of inflammation patterns in Morocco or anywhere on the African continent. We aim to fill this gap by studying tissue inflammatory response in our operated patients.

Material and methods

After searching the database of the pathology department, we retrieved from the archives the stained pathology slides of all our patients who underwent surgery for CRSwNP over 5 years from 2017 to 2021. We counted then the number of eosinophils in the lamina propria at high-power magnification to determine the predominant inflammatory pattern.

Results

A total of 35 reports were collected. We found that eosinophilic inflammation was predominant, accounting for 97% of the cases.

Conclusions

The CRSwNP endotype in our region would mainly be type 2. However, our results must be confirmed by multicenter studies involving a large number of patients.

Introduction

Chronic rhinosinusitis (CRS) is a common disorder with various clinical presentations. Diagnostic criteria include at least two nasosinusal symptoms, an abnormal CT scan, and a course of more than 12 weeks [1]. The traditional classification of CRS phenotypes is "with" and "sine" (without) nasal polyps (CRSwNP and CRSsNP). This simple classification is easily recognized by clinicians [1, 2]. Traditionally, CRSwNPs and CRSsNPs were also differentiated at the cellular level, with CRSwNPs exhibiting a predominantly T-helper (Th) 2 inflammatory pattern; in contrast to CRSsNPs, which are characterized primarily by a Th1/Th17 inflammatory pattern (Table 1) [3].

Table 1.

Classic characterization of CRSsNP and CRSwNP [3]

Phenotype	CRSsNP	CRSwNP
Endotype	Non-type 2 (TH1 or TH17)	Type 2 (TH2)
Predominant inflammatory cells	Neutrophils	Eosinophils
Cytokines	IL-6, IL-8, or IL-17, Transforming Growth Factor β, Type I interferons	IL-4, IL-5, IL-13, IL-25, and/or IL-33

CRSwNP is frequently associated with more severe symptoms[3]. It affects 1–4% of the population and accounts for 25–40% of CRS[1]. Patients frequently have an atopic background and present with associated asthma in 26–48% of cases and Samter's triad in 10% of cases [association with asthma and aspirin-exacerbated respiratory disease (AERD)] [1]. In Morocco, 46.6–55.8% of operated patients have asthma and 5.2–19.2% have AERD [4–6]. CRSwNP has a significant impact on patients' quality of life [7].

It is important to differentiate between "clinical" phenotypes and "pathophysiological" endotypes. For example, the CRS "phenotype" can be caused by many pathophysiological mechanisms, involving type 1, 2, or 3 immune responses, and thus should be classified into different endotypes. Similarly, several phenotypes such as CRSwNP with late-onset asthma, AERD, and allergic fungal rhinosinusitis have the same endotype, in this case, type 2 immune response [8]. Bachert and Zhang proposed the first analysis of CRS endotypes based on Th1 and Th2 profiles in 2012 [9]. Then Tomassen et al. [10] proposed in 2016 a 10-category classification based on Interleukin (IL)-5, eosinophil, and IgE levels. The European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS) 2020 experts panel proposed a new classification of CRS by separating primary and secondary forms, then according to mucosal involvement (focal or unilateral, diffuse or bilateral), and then according to endotype: Type 2 (with Interleukin IL-4, IL-5 and IL-13, eosinophils and IgE) and non-type 2 (with IL-17 and neutrophils) [11]. All events of type 2 inflammatory response can potentially serve as biomarkers (such as type 2 cytokines for example). Blood and tissue eosinophils and total IgE blood levels are the most useful in practice [8]. According to EPOS 2020, type 2 disease is characterized by tissue eosinophils ≥ 10/HPF (High powered field) OR blood eosinophils ≥ 250 U/l OR blood IgE ≥ 100 IU/ml [11]. With the advent of biomarkers, an optimal approach would be to identify the endotype at the first visit. Indeed, the type 2 immune response is associated with more severe disease, more asthmatic comorbidity, and more recurrence after surgery, but it is also associated with better corticosensitivity [1, 8]. However, there can be discordances; in a study of 535 Chinese patients, increased blood eosinophilia was found to be associated with surgical failure, even in a group of twenty patients with normal tissue eosinophilia [12].

A better understanding of the pathophysiological mechanisms of CRSwNP has led to the development of innovative therapies with promising results: monoclonal antibody-based biotherapies specifically targeting the type 2 immune response [7]. This is likely to be a major turning point in the management of CRSwNP. Also, an antibody targeting the pathophysiological role of neutrophils has been tested in primates [13, 14]. As a result, endotyping has become increasingly important in predicting the need for, but also the response to, biotherapies [8].

However, there are geographic disparities. In contrast to the predominantly Th2 inflammatory pattern of CRSwNPs seen in the United States, Europe, and Japan, CRSwNPs in other parts of Asia tend to have mixed patterns, including neutrophil-dominant polyps (50% of East Asian patients) [1, 7]. It is important for any specialist involved to be aware of these differences to optimize diagnosis and treatment [8]. In the era of biotherapies, no study has so far sought to confirm precisely the dominant inflammatory profile of CRSwNP in Morocco (but also on the whole African continent). We aim to fill this gap by studying the inflammatory response histologically in our surgical patients.

Material and Methods

We present a retrospective study over 5 years from 2017 to 2021. We performed a search with the keyword "nasal polyps" in the pathology department database to identify all patients who underwent surgery for CRSwNP in our ENT department. The corresponding deidentified hematoxylin and eosin-stained slides were retrieved from the archives. They were then all analyzed by the same observer independently of any personal, clinical, biological, or radiological data. The number of eosinophils in the lamina propria was counted at high-power magnification (×400). By the EPOS 2020 criteria, tissue eosinophilic inflammation is defined by a number of tissue eosinophils exceeding 10/HPF.

Results

A total of 35 pathology reports from CRSwNP patients were collected. The respiratory epithelium showed polyploid architecture with sporadic squamous metaplasia, whereas the underlying stroma was edematous, fibrous, or slightly myxoid. The inflammatory infiltrate was predominantly mononuclear (lymphoplasmacytic). Eosinophilic inflammation was observed in 34 cases (97%) (Fig. 1). An inflammatory infiltrate with neutrophils and rare eosinophils was observed in only one case (3%) (Fig. 2).

Fig. 1.

Inflammatory cells of a sinonasal polyp composed of a mixture of lymphocytes, plasma cells, neutrophils (black arrows), and predominant eosinophils > 10/HPF (red arrows). (H&E × 400)

Fig. 2.

Inflammatory cells of a sinonasal polyp composed of a mixture of lymphocytes, plasma cells, neutrophil clusters (black circle), and rare eosinophils < 10 /HPF (red arrow). (H&E × 400)

Discussion

CRSwNP has complex pathophysiology with local, systemic, microbial, environmental, genetic, and iatrogenic factors [1, 7]. The initial epithelial aggression by environmental factors (bacteria, viruses, fungi, allergens, etc.) would lead to a chronic inflammatory response and then the generation and perpetuation of polyps [1]. The pathophysiology of CRSwNP has many similarities with that of asthma [1].

Endotyping CRSwNP has many benefits: (1) improving diagnostic criteria; (2) better understanding the clinical manifestation of the disease and its association with asthma; (3) predicting disease severity and progression; (4) predicting response to treatment, especially immunotherapy; (5) selecting surgical strategy and correlating with recurrence after surgery; (6) optimizing care by providing personalized therapies, and (7) reducing the financial burden to society [1, 3, 7, 8, 10]. Future clinical success will depend on the availability of endotyping [7].

Currently, the treatment of CRSwNP is based on continuous local corticosteroid therapy. Short courses of systemic corticosteroids are indicated for severe CRSwNP, not to exceed two courses per year. Desensitization may be attempted in case of AERD. Functional endoscopic endonasal surgery is indicated when medical treatment is insufficient.

In CRSwNP refractory to those treatments, several monoclonal antibodies targeting type 2 immune response have demonstrated efficacy: Omalizumab (anti-IgE), Mepolizumab (anti-IL-5), Benralizumab (anti-IL-5R), and Dupilumab, an anti-IL-4 receptor that inhibits IL-4 and IL-13 signaling, which was the first immunotherapy approved for patients with CRSwNP by the FDA and EU in 2019 [15–19]. However, these biotherapies are expensive and require endotyping for the proper selection of responder patients [2, 3, 10].

There is extreme diversity in terms of endotypes of CRS in Europe, China, Japan, and Australia [20]. In contrast to the type 2 dominant CRSwNPs found in the United States, Europe, and Japan, mixed inflammatory patterns are found in Asia, including neutrophil-dominant polyps [7]. The percentage of type 2 immune responses ranges from 15% in some areas of China to 95% in moderate to severe cases in Europe [8, 21]. Genetic, geographic, and climatic factors may influence the inflammatory profile; indeed, second-generation Asian patients living in the United States have maintained their non-type 2 status, whereas the proportion of type 2 inflammation is increasing significantly in Thailand [20].

To our knowledge, the proportions of inflammatory patterns of CRSwNPs have not been considered in Africa before. In our study, tissue eosinophilic inflammation was predominant in 97% of cases. Therefore, the predominant inflammatory pattern in our region would be similar to that observed in the United States, Europe, and Japan; with all that this implies in terms of prognosis and treatment. Indeed, biotherapies targeting the type 2 immune response could be effective and have their place in the therapeutic arsenal. Now all of our patients have at least one eosinophils blood count, with a tissue eosinophils count in case of surgery. However, our single-center retrospective study has some limitations due to the recruitment of surgical patients with a priori severe disease. Our results should be confirmed by multicenter studies involving a larger number of patients.

Author Contributions

All authors contributed, read, and approved the final manuscript.

Funding

No funding for this study.

Data Availability

Not applicable.

Code Availability

Not applicable.

Declarations

Competing interests

The authors declare that they have no competing interests.

Ethics Approval

Not Applicable (this study does not include any interaction with human subjects or access to identifiable private information).