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I need help reviewing a scientific paper entitled “Chronic rhinosinusitis with polyps and comorbid asthma: results of reslizumab treatment“

Transition from standardization to personalized treatment have led to the separation of such heterogeneous diseases as asthma and chronic rhinosinusitis (CRS) into clinically similar groups called phenotypes. From the clinical viewpoint CRS is commonly divided into two phenotype-based groups on the presence (CRSwNP) or absence of nasal polyps (CRSsNP). The first phenotype is associated with eosinophilic or Th2-polarized inflammation while the second – with neutrophilic or non-Th2-polarized one [1]. In 80-90% of patients suffering from CRS with polyps, a significant systemic and local eosinophilia is identified, along with an increase in the local level of Th2-dependent cytokines, such as interleukin 4, 5, 9, 13, 25, 33 (IL-4, IL-5, IL-9, IL-13, IL-25, IL-33), increased expression of the receptors to IL-5 and local production of immunoglobulin E (IgE), while the key mediator of eosinophilic inflammation is IL-5, which provides activation, chemotaxis and survival of eosinophils [2]. In the international consensus document EPOS 2020 [3], a new classification was proposed, according to which chronic rhinosinusitis is divided into primary and secondary, and each of these groups is divided, depending on the prevalence of the process, into localized and diffuse forms of CRS. Diffuse primary chronic rhinosinusitis is divided by the nature of the dominant inflammatory endotype into 2 groups: type 2 (Th2 type) and non-type 2 (non-Th2 type). The Th2 type group includes chronic rhinosinusitis with nasal polyps/eosinophilic rhinosinusitis, allergic fungal rhinosinusitis and central compartment allergic disease; the non-Th2 type group includes non-eosinophilic rhinosinusitis. CRS with polyps is often combined with asthma. In patients with asthma, CRSwNP is detected in 7-16% of cases and more than 80% have X-ray signs of inflammatory diseases of the paranasal sinuses [4, 5], while in 26-48% of patients with CRSwNP the concomitant disease is asthma [6, 7]. These comorbid diseases mutually burden each other: on the one hand, asthma in patients with CRSwNP is much more severe [8, 9], on the other hand, this group of patients is characterized by more frequent reсurrence of polyps after surgical treatment [10]. Asthma is also a group of clinical variants that differ in pathophysiological parameters, the type and severity of inflammation, the response to corticosteroid therapy, and many other factors. Currently there are several phenotypes of asthma: allergic, non-allergic (eosinophilic), asthma with permanent obstruction, infection-dependent, asthma with late onset, asthma associated with obesity [11, 12]. Inflammation in eosinophilic asthma has similar features to that in patients having CRSwNP: an increased content of eosinophils in the mucosa, in sputum and in blood, Th2-type of inflammatory reaction with hyperproduction of IL-5 and eosinophil cationic protein (ECP) [13]. In the last decade, a new promising direction has appeared in the treatment of asthma – targeted therapy with humanized monoclonal antibodies (biologics) [14, 15]. The correlation between the severity of CRSwNP and eosinophilic asthma, the proximity of the endotypes of these diseases [16] along with the successful use of biologics for the treatment of severe asthma [14] explain the interest in the research of the possibility of using this group of drugs in patients with CRSwNP [17, 18, 19, 20]. Objective. The aim of the research was to study the dynamics of nasal symptoms in patients with CRSwNP combined with asthma during reslizumab treatment. Reslizumab is a humanized monoclonal antibody with a high affinity for IL-5. Reslizumab specifically binds to IL-5, causing a restriction of differentiation, chemotaxis, activation and survival of eosinophils [21, 13], thereby reducing the level of eosinophilic inflammation and remodeling of the respiratory tract. Discussion. In our research we have evaluated the dynamics of nasal symptoms when using reslizumab in patients with severe eosinophilic asthma. The presence of CRSwNP was detected in 15 of the 18 studied patients, 3 patients had symptoms of chronic rhinitis as a manifestation of NARES. Changes in the CT were present in 100% of cases. Along with a noticeable improvement in asthma control, which was confirmed by studies of lung function, patients showed clinical, endoscopic, radiological signs of a decrease in the severity of nasal symptoms. The improvement in the quality of life was confirmed by the results of SNOT-22, which revealed a decrease in symptoms such as rhinorrhea, nasal obstruction, hyposmia and sleep disorders. The data of endoscopic examination revealed a reduction of polyps in 1 out of 15 patients, which indicates the possibility of reverse development of remodeling of the nasal mucosa during targeted therapy. No positive dynamics of nasal symptoms and the course of asthma was noticed in one patient with AERD. In the case of another patient control over asthma symptoms was achieved (an increase in AST from 8 to 22 and FEV1 from 86% to 106%), however the growth of polyps continued (TPS increased from 2 to 5). The improvements observed in patients with CRSwNP and comorbid asthma testify that reslizumab affects eosinophilic inflammation of both the lower and upper respiratory tracts. The results of our clinical study coincide with the conclusions of earlier observations [18, 23]. In the literature there is certain evidence that the presence of polyps in patients with eosinophilic asthma allows predicting a positive result in the treatment with reslizumab. Thus, S. F. Weinstein et al. [5] performed a retrospective analysis of the patient-reported medical histories of 953 patients with inadequately controlled asthma treated with reslizumab for 52 weeks. 150 patients (16%) had self-reported CRSwNP, endoscopic examination of the nasal cavity and CT of the paranasal sinuses were not conducted. Despite these serious limitations, the authors proved that patients with CRSwNP were highly responsive to treatment with reslizumab. We also noted more significant positive changes in AST and spirometry indicators in patients having CRS with nasal polyps. Patients without nasal polyps with recurrent symptoms of rhinitis (rhinorrhea, sneezing, nasal congestion) are of particular interest. These patients were observed for a long time with a diagnosis of allergic rhinitis. However, the detected eosinophilia of the rhinocytogram (up to 75%), an increase in the ECP content in the blood and at least twice the negative results of the allergic tests allowed us to diagnose these patients with NARES. In the group of patients with CRS with nasal polyps, it was possible to detect the anamnestic presence of similar symptoms at the beginning of the disease. These results confirm the previously suggested assumption that NARES may be a predictor of the development of AERD, non-IgE-related asthma and nasal polyps [24]. The study of the cytokine profile of inflammation clarifies the pathogenetic features of various phenotypes of the disease, which determines the direction of targeted therapy [25, 6, 26]. However, the studies of the content of cytokines in the tissues of polyps and the nasal mucosa [6] are currently beyond the scope of practical health care. Today the prediction criterion for the effectiveness of reslizumab is an increase in the number of eosinophils in the blood of more than 400 cells/ml. Further studies of the use of monoclonal antibodies should reveal additional clinical criteria for the selection of patients with CRS with polyps for the use of this group of drugs. Conclusions. Reslizumab treatment of patients with eosinophilic asthma and concomitant chronic rhinosinusitis with nasal polyps and chronic non-allergic rhinitis (NARES) leads not only to improved control of asthma symptoms, but also to a significant regression of nasal symptoms. Clinical significance. Currently, the indications for the treatment of chronic rhinosinusitis with polyps have been registered in dupilumab alone. Studies of the effects of other biologics can not only expand the their indications, but also identify possible advantages in the selection of drugs for the treatment of different types of CRS.