Inflammatory endotypes of CRSwNP and responses to COVID-19.

PURPOSE OF REVIEW: Coronavirus disease 2019 (COVID-19), a disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has quickly become a great public health hazard globally. Nasal epithelial cells are an important site for SARS-CoV-2 infection and replication. The purpose of this review is to summarize recent findings on the endotypes of chronic rhinosinusitis with nasal polyps (CRSwNP) and the potential impact of SARS-CoV-2 infection. RECENT FINDINGS: Endotypes of CRSwNP are characterized by type 1, type 2 and type 3 inflammation according to patterns of inflammatory cells and the cytokines expressed in nasal tissue. Nasal epithelial cells show the highest expression of angiotensin-converting enzyme 2 (ACE2), the receptor for attachment and entry of SARS-CoV-2 into host cells, among all investigated cells in the respiratory tree. SARS-CoV-2 infection likely leads to increased activation of T-helper-1 (Th1) cell responses. Recent studies further suggest that ACE2 may be upregulated by type 1 and downregulated by type 2 inflammatory cytokines in nasal epithelial cells. SUMMARY: Expression of ACE2 in nasal epithelial cells is influenced by inflammatory endotypes of CRSwNP. Type 1 inflammation in nasal tissue may increase the risk of SARS-CoV-2 infection by upregulating ACE2 expression. However, clinical association between CRSwNP and COVID-19 is still unclear.

A Decade of Clinical Advances in Chronic Rhinosinusitis: 2012-2022.

The field of chronic rhinosinusitis (CRS) is constantly evolving. In the past 10 years, key advancements in basic and translational research as well as clinical studies have improved our understanding and management of CRS. Notably, treatment options have expanded to include novel therapeutic drugs, devices, and surgical techniques. Assessments of patient symptoms and their impact on quality of life have become more standardized. Progress has also been made in both determining the true prevalence of CRS and recognizing comorbidities that can impact CRS severity. Practice guidelines have also shifted from expert opinion to more data-driven analyses. This review highlights major clinical advancements made in the field of CRS over the past 10 years as well as identifies current gaps in knowledge that can form the basis for new areas of study over the next decade.

Transcriptomics unravels molecular changes associated with cilia and COVID-19 in chronic rhinosinusitis with nasal polyps.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a common upper respiratory tract complication where the pathogenesis is largely unknown. Herein, we investigated the transcriptome profile in nasal mucosa biopsies of CRSwNP patients and healthy individuals. We further integrated the transcriptomics data with genes located in chromosomal regions containing genome-wide significant gene variants for COVID-19. Among the most significantly upregulated genes in polyp mucosa were CCL18, CLEC4G, CCL13 and SLC9A3. Pathways involving "Ciliated epithelial cells" were the most differentially expressed molecular pathways when polyp mucosa and non-polyp mucosa from the same patient was compared. Natural killer T-cell (NKT) and viral pathways were the most statistically significant pathways in the mucosa of CRSwNP patients compared with those of healthy control individuals. Upregulated genes in polyp mucosa, located within the genome-wide associated regions of COVID-19, included LZTFL1, CCR9, SLC6A20, IFNAR1, IFNAR2 and IL10RB. Interestingly, the second most over-expressed gene in our study, CLEC4G, has been shown to bind directly to SARS-CoV-2 spike's N-terminal domain and mediate its entry and infection. Our results on altered expression of genes related to cilia and viruses point to the de-regulation of viral defenses in CRSwNP patients, and may give clues to future intervention strategies.

SWOT Analysis of Chronic Rhinosinusitis Care Anno 2022.

Chronic rhinosinusitis (CRS) is a prevalent chronic condition with dynamic developments in diagnostic and therapeutic approaches given the recent updated guidelines and novel therapeutic approaches. A critical reflection on clinical practice of CRS care in 2022 is needed, hence providing hints for better care. This review provides an overall evaluation of the current approach of CRS care, including strengths, weaknesses, opportunities, and threat related to the current care pathways in most regions worldwide. Strengths of current CRS care are mainly related to effective treatment options allowing personalized care, with preventive and curative goals included in the current guidelines. However, a large portion of patients with CRS remain uncontrolled given the multiple weaknesses in CRS care, related to several factors such as underdiagnosis, undertreatment, and suboptimal coordination of care among health care providers. The opportunities for better care are ample given the possibility of implementing optimal care following guidelines, including preventive interdisciplinary strategies and patient-oriented treatment plans. In 2022, CRS represents a chronic condition that is subject to a (r)evolution of care with good opportunities for better outcomes and health economic savings.

Chronic Rhinosinusitis and COVID-19.

The COVID-19 pandemic has raised awareness about olfactory dysfunction, although a loss of smell was present in the general population before COVID-19. Chronic rhinosinusitis (CRS) is a common upper airway chronic inflammatory disease that is also one of the most common causes of olfactory dysfunction. It can be classified into different phenotypes (ie, with and without nasal polyps) and endotypes (ie, type 2 and non-type 2 inflammation). However, scientific information regarding CRS within the context of COVID-19 is still scarce. This review focuses on (1) the potential effects of severe acute respiratory syndrome coronavirus 2 infection on CRS symptoms, including a loss of smell, and comorbidities; (2) the pathophysiologic mechanisms involved in the olfactory dysfunction; (3) CRS diagnosis in the context of COVID-19, including telemedicine; (4) the protective hypothesis of CRS in COVID-19; and (5) the efficacy and safety of therapeutic options for CRS within the context of COVID-19.

Rhinology in review: from COVID-19 to biologicals.

We look back at the end of what soon will be seen as an historic year, from COVID-19 to real-world introduction of biologicals influencing the life of our patients. This review describes the important findings in Rhinology over the past year. A large body of evidence now demonstrates loss of sense of smell to be one of the most common symptoms of COVID-19 infection; a meta-analysis of 3563 patients found the mean prevalence of self-reported loss to be 47%. A number of studies have now shown long-term reduced loss of smell and parosmia. Given the high numbers of people affected by COVID-19, even with the best reported recovery rates, a significant number worldwide will be left with severe olfactory dysfunction. The most prevalent causes for olfactory dysfunction, besides COVID-19 and upper respiratory tract infections in general, are trauma and CRSwNP. For these CRSwNP patients a bright future seems to be starting with the development of treatment with biologics. This year the Nobel prize in Medicine 2021 was awarded jointly to David Julius and Ardem Patapoutian for their discoveries of receptors for temperature and touch which has greatly enhanced our understanding of nasal hyperreactivity and understanding of intranasal trigeminal function. Finally, a new definition of chronic rhinitis has been proposed in the last year and we have seen many papers emphasizing the importance of endotyping patients in chronic rhinitis and rhinosinusitis in order to optimise treatment effect.

Identification of Broad Anti-Coronavirus Chemical Agents for Repurposing Against SARS-CoV-2 and Variants of Concern (preprint)

Endemic human coronaviruses (hCoVs) 229E and OC43 cause respiratory disease with recurrent infections, while severe acute respiratory syndrome (SARS)-CoV-2 spreads across the world with impact on health and societies. Here, we report an image-based multicycle infection procedure with α-coronavirus hCoV 229E-eGFP in an arrayed chemical library screen of 5440 clinical and preclinical compounds. Toxicity counterselection and challenge with the β-coronaviruses OC43 and SARS-CoV-2 in tissue culture and human airway epithelial explant cultures (HAEEC) identified four FDA-approved compounds with oral availability. Methylene blue (MB, used for the treatment of methemoglobinemia), Mycophenolic acid (MPA, used in organ transplantion) and the anti-fungal agent Posaconazole (POS) had the broadest anti-CoV spectrum. They inhibited the shedding of SARS CoV 2 and variants-of-concern (alpha, beta, gamma) from HAEEC in either pre- or post exposure regimens at clinically relevant dosage. Co-treatment of cultured cells with MB and the FDA-approved SARS-CoV-2 RNA-polymerase inhibitor Remdesivir reduced the effective anti-viral dosage of MB by 2-fold, and Remdesivir by 4 to 10-fold, indicated by BLISS independence syner-gy modelling. Neither MB, MPA or POS affected the cell delivery of SARS-CoV-2 or OC43 (+)sense RNA, but blocked subsequent viral RNA accumulation in cells. Unlike Remdesivir, MB, MPA or POS did not reduce the release of viral RNA in post exposure regimen, thus indicating infection inhibition at a post-replicating step as well. In summary, the data emphasize the power of unbiased, full cycle compound screens to identify and repurpose broadly acting drugs against coronaviruses.Funding Information: We acknowledge financial support from the Swiss National Science foundation (SNSF) to UFG and GT (31CA30_196177 / 1), the NCCR Chemical Biology supported by the SNSF for purchasing the BSF-EPFL repurposing collection, and a special Coronavirus Research grant from the University of Zurich to UFG. Declaration of Interests: UFG has been a consultant and stock owner in 3V-Biosciences (now Sagimet Biosciences), and a consultant to F. Hoffmann-La Roche Ltd. The authors filed a patent application on the use of MPA for the treatment of COVID-19 (EP20213904, European Patent Office, University of Zurich).Ethical Approval: Nasal polyp epithelial cells and bronchial epithelial cells were purchased from Epithelix SARL (Geneva, Switzerland). Mucilair™ cells were reconstituted from patients undergoing surgical nasal polypectomy or bronchial biopsies, respectively. All samples from Epithelix SARL were obtained with informed consent, according to the declaration of Helsinki on biomedical research (Hong Kong amendment, 1989), and received approval from local ethics committee (commission cantonale d’éthique de la recherche CCER de Genève).Coronavirus storage and procedures have been registered and validated by the Swiss Federal Office for the Environment (Bundesamt für Umwelt, BAFU) and the Swiss Federal Office of Public Health (Bundesamt für Gesundheit, BAG); Ecogen A203032-00, registered the 01-Sep-2020 for a duration of 5-years for the University of Zurich (Department of Molecular Life Sciences).

Pediatric Allergic Fungal Sinusitis: A Clinical Review.

Allergic fungal sinusitis (AFS) is the most common type of fungal sinus infection. AFS is a robust allergic reaction to inhaled soil fungi that causes sinus inflammation, and the fungal debris then accumulates in the sinus cavities. This accumulation can cause nasal polyps, facial pain and pressure, bone remodeling of the face, and even bone erosion, which can cause damage to the eyes and brain. AFS can also cause thick, sticky nasal mucus and postnasal drip, and it can affect the sense of smell. Most patients with AFS are adolescents who also have chronic symptoms of allergic rhinitis and asthma. Endoscopic sinus surgery to remove the disease and open the sinus cavities is the main treatment approach. Adjuvant immunotherapy is helpful in reducing the inflammatory response and preventing future recurrence of this allergy-mediated condition. [Pediatr Ann. 2021;50(7):e297-e303.].

Novel therapeutic approaches targeting endotypes of severe airway disease.

Introduction: Severe asthma and chronic rhinosinusitis (CRS), with nasal polyps (CRSwNP) and without nasal polyps (CRSsNP), are heterogeneous diseases characterized by different mechanistic pathways (endotypes) and variable clinical presentations (phenotypes).Areas covered: This review provides the clinician with an overview of the prevalence and clinical impact of severe chronic upper and lower airways disease and suggests a novel therapeutic approach with biological agents with possible biomarkers. To select relevant literature for inclusion in this review, we conducted a literature search using the PubMed database, using terms 'severe airways disease' AND 'endotype' AND 'treatment.' The literature review was performed for publication years 2010-2020, restricting the articles to humans and English language publications.Expert opinion: The coronavirus disease (COVID-19) pandemic has brought forth many challenges for patients with severe airway disease and healthcare practitioners involved in care. These patients could have an increased risk of developing severe SARS-CoV-2 disease, although treatment with biologics is not associated with a worse prognosis. Eosinopenia on hospital admission plays a key role as a diagnostic and prognostic biomarker.

Sinonasal polyposis complicated with extradural abscess and lateral rectus palsy.

Sinogenic intracranial and orbital complications are infrequent complications of chronic rhinosinusitis with nasal polyposis (CRSwNP), leading to potentially fatal intracranial and orbital sequelae. The mortality and morbidity associated with these complications remain high despite the widespread use of antibiotics. We report a patient with CRSwNP presenting with acute onset extradural empyema and sixth nerve palsy in whom the diagnosis was delayed, necessitating early surgical intervention. Our case shows that delay in management and underdiagnosis of sinusitis with nasal polyposis can lead to devastating complications. A high index of suspicion, early recognition of the clinical findings and radiological evaluation with contrast-enhanced CT of paranasal sinuses, orbit and brain are essential to rule out fatal complications associated with CRSwNP. Timely endoscopic intervention and the use of antibiotics can lead to good outcomes, even in complicated cases.

Highlights in the advances of chronic rhinosinusitis.

Chronic rhinosinusitis (CRS) is a complex upper airway inflammatory disease with a broad spectrum of clinical variants. As our understanding of the disease pathophysiology evolves, so too does our philosophy towards the approach and management of CRS. Endotyping is gaining favour over phenotype-based classifications, owing to its potential in prognosticating disease severity and delivering precision treatment. Endotyping is especially useful in challenging CRS with nasal polyposis cases, for whom novel treatment options such as biologicals are now available. The latest European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS2020) reflects these changes with updated rhinosinusitis classifications and new integrated care pathways. With the coronavirus disease 2019 (COVID-19) pandemic, physicians and rhinologists have to balance the responsibility of managing their patients' upper airway while adequately protecting themselves from droplet and aerosol transmission. This review summarises the key updates from EPOS2020, endotype-based classification and biomarkers. The role of biologicals in CRS and the lessons we can draw from their use in severe asthma will be examined. Finally, the principles of CRS management during COVID-19 will also be discussed.

Rhinology on the move despite Covid-19!

The October 2020 issue of Rhinology is a very interesting edition as it illustrates how world-wide colleagues pave the way for a better future of patients affected by nose and sinus diseases. After the successful launch of EPOS2020 in Spring 2020, the editorial team of Rhinology is proud to present to you the latest and most exciting data in Rhinology research. Getting insight into the complexity and relevance of proteomics in CRS, epithelial-mesenchymal contribution to CRS, zinc levels in nasal and systemic compartment of CRS, nasal biomarkers of CRSwNP that predict recurrence of disease after sinus surgery, and the odor identification test for children, called "U-Sniff", and FID scores (Frequency, Intensity and Duration) scores for epistaxis are all in the 2020 October issue and highly relevant for Rhinology practice. These studies build further on the solid grounds of previous Rhinology research meeting the unmets needs in the field.

Differential expression of Angiotensin-Converting Enzyme 2 in Nasal Tissue of Patients with Chronic Rhinosinusitis with Nasal Polyps (preprint)

The coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) became a pandemic and a global health emergency. The SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2) is highly expressed in nasal epithelial cells and plays a major role in cellular entry leading to infection. High expression of ACE2 has been suggested to be a potential risk factor for virus infection and disease severity. However the profile of ACE2 gene expression in diseases of the upper airways remains poorly understood. We herein investigated ACE2 gene expression in the nasal tissues of a cohort of Swedish patients with chronic rhinosinusitis with nasal polyps (CRSwNPs) using RT-qPCR. ACE2 mRNA expression was significantly reduced in the nasal mucosa of CRSwNP patients compared to that of controls. Moreover, we observed a sex-dependant difference in nasal ACE2 expression, where significantly lower levels of the ACE2 transcript were detected in the nasal mucosa of only female CRSwNP patients. These findings indicate that CRSwNP patients with a decrease in ACE2 gene expression may thereby be less prone to be infected by SARS-CoV-2. These results enhance our understanding on the profile of ACE2 expression in the nasal mucosa of patients with upper airway diseases, and their susceptibility to infection with SARS-CoV-2.

EUFOREA expert board meeting on uncontrolled severe chronic rhinosinusitis with nasal polyps (CRSwNP) and biologics: Definitions and management.

Uncontrolled severe chronic rhinosinusitis with nasal polyps (CRSwNP) is the most bothersome phenotype of chronic rhinosinusitis; it is typically characterized by a type 2 inflammatory reaction and by comorbidities, including asthma, nonsteroidal anti-inflammatory drug-exacerbated respiratory disease, and allergies. Here, the European Forum for Research and Education in Allergy and Airway Diseases proposes structured definitions to enable communication between clinicians and provides a practical algorithm to define type 2 inflammation in CRSwNP in daily clinical practice. A rational approach for the treatment of uncontrolled severe CRSwNP is discussed; it consists of evaluating the perspective and risks of surgery and efficacy and adverse events of biologics on the basis of currently available data. Further, possible combinations of surgery and biologics are discussed, and a rationale is provided. Here, it is of importance to adequately counsel the patient about both approaches to enable a decision-making process with an informed patient. Criteria for the selection of a biologic drug are provided, as several biologics for uncontrolled severe CRSwNP will be available in many countries within a short time. Further, suggestions for monitoring of the drug effects that support recognition of responders to the therapy and, subsequently, the decision regarding continuation or discontinuation of the biologic are proposed.

Distinct expression of SARS-CoV-2 receptor ACE2 correlates with endotypes of chronic rhinosinusitis with nasal polyps.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry factors, ACE2 and TMPRSS2, are highly expressed in nasal epithelial cells. However, the association between SARS-CoV-2 and nasal inflammation in chronic rhinosinusitis with nasal polyps (CRSwNP) has not been investigated. We thus investigated the expression of SARS-CoV-2 entry factors in nasal tissues of CRSwNP patients, and their associations with inflammatory endotypes of CRSwNP. METHODS: The expression of ACE2 and TMPRSS2 was assessed in nasal tissues of control subjects and eosinophilic CRSwNP (ECRSwNP) and nonECRSwNP patients. The correlations between ACE2/TMPRSS2 expression and inflammatory indices of CRSwNP endotypes were evaluated. Regulation of ACE2/TMPRSS2 expression by inflammatory cytokines and glucocorticoids was investigated. RESULTS: ACE2 expression was significantly increased in nasal tissues of nonECRSwNP patients compared to ECRSwNP patients and control subjects, and positively correlated with the expression of IFN-γ, but negatively correlated with tissue infiltrated eosinophils, and expression of IL5 and IL13. IFN-γ up-regulated ACE2 expression while glucocorticoid attenuated this increase in cultured nasal epithelial cells. Genes co-expressed with ACE2 were enriched in pathways relating to defence response to virus in nasal tissue. TMPRSS2 expression was decreased in nasal tissues of CRSwNP patients compared to control subjects and not correlated with the inflammatory endotypes of CRSwNP. Glucocorticoid treatment decreased ACE2 expression in nasal tissues of nonECRSwNP patients, but not in ECRSwNP patients, whereas TMPRSS2 expression was not affected. CONCLUSION: These findings indicate that ACE2 expression, regulated by IFN-γ, is increased in nasal tissues of nonECRSwNP patients and positively correlates with type 1 inflammation.

Management of patients with chronic rhinosinusitis during the COVID-19 pandemic-An EAACI position paper.

BACKGROUND: Chronic rhinosinusitis is regarded as a chronic airway disease. According to WHO recommendations, it may be a risk factor for COVID-19 patients. In most CRSwNP cases, the inflammatory changes affecting the nasal and paranasal mucous membranes are type-2 (T2) inflammation endotypes. METHODS: The current knowledge on COVID-19 and on treatment options for CRS was analyzed by a literature search in Medline, Pubmed, international guidelines, the Cochrane Library and the Internet. RESULTS: Based on international literature, on current recommendations by WHO and other international organizations as well as on previous experience, a panel of experts from EAACI and ARIA provided recommendations for the treatment of CRS during the COVID-19 pandemic. CONCLUSION: Intranasal corticosteroids remain the standard treatment for CRS in patients with SARS-CoV-2 infection. Surgical treatments should be reduced to a minimum and surgery preserved for patients with local complications and for those with no other treatment options. Systemic corticosteroids should be avoided. Treatment with biologics can be continued with careful monitoring in noninfected patients and should be temporarily interrupted during the course of the COVID-19 infection.