Visualizing in deceased COVID-19 patients how SARS-CoV-2 attacks the respiratory and olfactory mucosae but spares the olfactory bulb.

Anosmia, the loss of smell, is a common and often the sole symptom of COVID-19. The onset of the sequence of pathobiological events leading to olfactory dysfunction remains obscure. Here, we have developed a postmortem bedside surgical procedure to harvest endoscopically samples of respiratory and olfactory mucosae and whole olfactory bulbs. Our cohort of 85 cases included COVID-19 patients who died a few days after infection with SARS-CoV-2, enabling us to catch the virus while it was still replicating. We found that sustentacular cells are the major target cell type in the olfactory mucosa. We failed to find evidence for infection of olfactory sensory neurons, and the parenchyma of the olfactory bulb is spared as well. Thus, SARS-CoV-2 does not appear to be a neurotropic virus. We postulate that transient insufficient support from sustentacular cells triggers transient olfactory dysfunction in COVID-19. Olfactory sensory neurons would become affected without getting infected.

Genetic Spectrum and Clinical Characteristics of Patients with Primary Ciliary Dyskinesia: a Belgian Single Center Study.

PURPOSE: We aimed to examine the correlation between clinical characteristics and the pathogenic gene variants in patients with Primary Ciliary Dyskinesia (PCD). METHODS: We conducted a retrospective single-center study in patients with PCD followed at the University Hospitals Leuven. We included patients with genetically confirmed PCD and described their genotype, data from ultrastructural ciliary evaluation and clinical characteristics. Genotype/phenotype correlations were studied in patients with the most frequently involved genes. RESULTS: We enrolled 74 patients with a median age of 25.58 years. The most frequently involved genes were DNAH11 (n = 23) and DNAH5 (n = 19). The most frequent types of pathogenic variants were missense (n = 42) and frameshift variants (n = 36) and most patients had compound heterozygous variants (n = 44). Ciliary ultrastructure (p < 0.001), situs (p = 0.015) and age at diagnosis (median 9.50 vs 4.71 years, p = 0.037) differed between DNAH11 and DNAH5. When correcting for situs this difference in age at diagnosis was no longer significant (p = 0.973). Patients with situs inversus were diagnosed earlier (p = 0.031). Respiratory tract microbiology (p = 0.161), lung function (cross-sectional, p = 0.829 and longitudinal, p = 0.329) and chest CT abnormalities (p = 0.202) were not significantly different between DNAH11 and DNAH5 variants. CONCLUSION: This study suggests a genotype-phenotype correlation for some of the evaluated clinical characteristics of the two most frequently involved genes in this study, namely DNAH11 and DNAH5.

Expert curation of the human and mouse olfactory receptor gene repertoires identifies conserved coding regions split across two exons.

BACKGROUND: Olfactory receptor (OR) genes are the largest multi-gene family in the mammalian genome, with 874 in human and 1483 loci in mouse (including pseudogenes). The expansion of the OR gene repertoire has occurred through numerous duplication events followed by diversification, resulting in a large number of highly similar paralogous genes. These characteristics have made the annotation of the complete OR gene repertoire a complex task. Most OR genes have been predicted in silico and are typically annotated as intronless coding sequences. RESULTS: Here we have developed an expert curation pipeline to analyse and annotate every OR gene in the human and mouse reference genomes. By combining evidence from structural features, evolutionary conservation and experimental data, we have unified the annotation of these gene families, and have systematically determined the protein-coding potential of each locus. We have defined the non-coding regions of many OR genes, enabling us to generate full-length transcript models. We found that 13 human and 41 mouse OR loci have coding sequences that are split across two exons. These split OR genes are conserved across mammals, and are expressed at the same level as protein-coding OR genes with an intronless coding region. Our findings challenge the long-standing and widespread notion that the coding region of a vertebrate OR gene is contained within a single exon. CONCLUSIONS: This work provides the most comprehensive curation effort of the human and mouse OR gene repertoires to date. The complete annotation has been integrated into the GENCODE reference gene set, for immediate availability to the research community.

Real-life assessment of chronic rhinosinusitis patients using mobile technology: The mySinusitisCoach project by EUFOREA.

BACKGROUND: Chronic rhinosinusitis (CRS) is a chronic inflammatory disease associated with a substantial personal and socioeconomic burden. Monitoring of patient-reported outcomes by mobile technology offers the possibility to better understand real-life burden of CRS. METHODS: This study reports on the cross-sectional evaluation of data of 626 users of mySinusitisCoach (mSC), a mobile application for CRS patients. Patient characteristics of mSC users were analysed as well as the level of disease control based on VAS global rhinosinusitis symptom score and adapted EPOS criteria. RESULTS: The mSC cohort represents a heterogeneous group of CRS patients with a diverse pattern of major symptoms. Approximately half of patients reported nasal polyps. 47.3% of all CRS patients were uncontrolled based on evaluation of VAS global rhinosinusitis symptom score compared to 40.9% based on adapted EPOS criteria. The impact of CRS on sleep quality and daily life activities was significantly higher in uncontrolled versus well-controlled patients. Half of patients had a history of FESS (functional endoscopic sinus surgery) and reported lower symptom severity compared to patients without a history of FESS, except for patients with a history of more than 3 procedures. Patients with a history of FESS reported higher VAS levels for impaired smell. CONCLUSION: Real-life data confirm the high disease burden in uncontrolled CRS patients, clearly impacting quality of life. Sinus surgery improves patient-reported outcomes, but not in patients with a history of more than 3 procedures. Mobile technology opens a new era of real-life monitoring, supporting the evolution of care towards precision medicine.

Differential antiviral activities of respiratory syncytial virus (RSV) inhibitors in human airway epithelium.

Objectives: We report the use of reconstituted 3D human airway epithelium cells (HuAECs) of bronchial origin in an air-liquid interface to study respiratory syncytial virus (RSV) infection and to assess the efficacy of RSV inhibitors in (pre-)clinical development. Methods: HuAECs were infected with RSV-A Long strain (0.01 CCID50/cell, where CCID50 represents 50% cell culture infectious dose in HEp2 cells) on the apical compartment of the culture. At the time of infection or at 1 or 3 days post-infection, selected inhibitors were added and refreshed daily on the basal compartment of the culture. Viral shedding was followed up by apical washes collected daily and quantifying viral RNA by RT-qPCR. Results: RSV-A replicates efficiently in HuAECs and viral RNA is shed for weeks after infection. RSV infection reduces the ciliary beat frequency of the ciliated cells as of 4 days post-infection, with complete ciliary dyskinesia observed by day 10. Treatment with RSV fusion inhibitors resulted in an antiviral effect only when added at the time of infection. In contrast, the use of replication inhibitors (both nucleoside and non-nucleoside) elicited a marked antiviral effect even when the start of treatment was delayed until 1 day or even 3 days after infection. Levels of the inflammation marker RANTES (mRNA) increased ∼200-fold in infected, untreated cultures (at 3 weeks post-infection), but levels were comparable to those of uninfected cultures in the presence of PC786, an RSV replication inhibitor, suggesting that an efficient antiviral treatment might inhibit virus-induced inflammation in this model. Conclusions: Overall, HuAECs offer a robust and physiologically relevant model to study RSV replication and to assess the efficacy of antiviral compounds.

Olfactory function in patients with nonsyndromic orofacial clefts and their unaffected relatives.

Nonsyndromic orofacial clefting is one of the most frequently occurring congenital conditions. The aim of the study was to investigate the prevalence and nature of reduced olfactory function in patients with nonsyndromic cleft lip and/or cleft palate (NSCL/P) and their unaffected first-degree relatives. Olfactory function was tested using the Sniffin' Sticks identification test in patients with NSCL/P, in their unaffected relatives, and in control subjects. MR imaging was performed to measure olfactory bulb (OB) volumes and olfactory sulcus (OS) depths. A reduced olfactory function was seen in significantly more patients with NSCL/P (p = .002) than in control subjects, regardless of the cleft type. Strikingly, unaffected relatives of patients with NSCL/P also had a higher rate of hyposmia (p = .001). In hyposmic patients, the OB volumes (left: p = .01 and right: p = .003) and the depth of the left OS (p = .02) were significantly smaller than in controls. In hyposmic relatives, both OS depths (left: p = .02 and right: p = .03) were significantly smaller. Patients with NSCL/P and their unaffected relatives have an increased prevalence of reduced olfactory function, associated with changes in the central olfactory structures.

European Respiratory Society guidelines for the diagnosis of primary ciliary dyskinesia.

The diagnosis of primary ciliary dyskinesia is often confirmed with standard, albeit complex and expensive, tests. In many cases, however, the diagnosis remains difficult despite the array of sophisticated diagnostic tests. There is no "gold standard" reference test. Hence, a Task Force supported by the European Respiratory Society has developed this guideline to provide evidence-based recommendations on diagnostic testing, especially in light of new developments in such tests, and the need for robust diagnoses of patients who might enter randomised controlled trials of treatments. The guideline is based on pre-defined questions relevant for clinical care, a systematic review of the literature, and assessment of the evidence using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach. It focuses on clinical presentation, nasal nitric oxide, analysis of ciliary beat frequency and pattern by high-speed video-microscopy analysis, transmission electron microscopy, genotyping and immunofluorescence. It then used a modified Delphi survey to develop an algorithm for the use of diagnostic tests to definitively confirm and exclude the diagnosis of primary ciliary dyskinesia; and to provide advice when the diagnosis was not conclusive. Finally, this guideline proposes a set of quality criteria for future research on the validity of diagnostic methods for primary ciliary dyskinesia.

Lung structure-function correlation in patients with primary ciliary dyskinesia.

BACKGROUND: Primary ciliary dyskinesia (PCD) is a rare disease, characterised by chronic airway infection. In cystic fibrosis, FEV1 is insensitive to detect patients with structural damage, and Lung Clearance Index (LCI) was proposed as a better marker of early lung damage. In PCD, the relationship between functional and structural abnormalities has been less studied. We aimed to re-examine this in a cohort of children and adults with mild to moderate PCD. METHODS: Thirty-eight patients with PCD (5.2-25.0 years) and 70 healthy controls (4.4-25.8 years) were recruited to compare LCI, measured by N2 multiple breath washout and FEV1 in a prospective observational trial. In a subset of 30 patients who underwent chest imaging, structural abnormalities were evaluated with cystic fibrosis computed tomography (CFCT) scores. RESULTS: LCI was abnormal in 28 of 38 patients and a moderate correlation was observed between LCI and FEV1 (r=-0.519, p=0.001). Moreover, LCI correlated well with CFCT total score (r=0.800, p<0.001) and also with subscores for airway wall thickening (r=0.809, p<0.001), mucus plugging (r=0.720, p<0.001) and bronchiectasis (r=0.494, p<0.001). Concordance was seen between LCI and CFCT in 25 of 30 (83%) patients, but between FEV1 and CFCT in only 16 of 30 (53%) patients. LCI was more sensitive (90.9%, 95% CI 70.8 to 98.6) to detect patients with structural abnormalities than FEV1 (36.4%, 95% CI 17.2 to 59.3). CONCLUSIONS: We demonstrated that measuring LCI in patients with PCD is of clinical relevance; it was more frequently abnormal than FEV1, correlated well with CFCT and was more sensitive than FEV1 to detect patients with structural abnormalities.

Capsaicin treatment reduces nasal hyperreactivity and transient receptor potential cation channel subfamily V, receptor 1 (TRPV1) overexpression in patients with idiopathic rhinitis.

BACKGROUND: Idiopathic rhinitis (IR) is a prevalent condition for which capsaicin nasal spray is the most effective treatment. However, the mechanisms underlying IR and the therapeutic action of capsaicin remain unknown. OBJECTIVE: We sought to investigate the molecular and cellular bases of IR and the therapeutic action of capsaicin. METHODS: Fourteen patients with IR and 12 healthy control subjects (HCs) were treated with intranasal capsaicin. The therapeutic effect was assessed in patients with IR by using visual analog scale and therapeutic response evaluation scores, and nasal hyperreactivity was evaluated by means of cold dry air provocation. Nasal samples served to measure the levels of neuromediators and expression of chemosensory cation channels, protein gene product 9.5 (PGP 9.5), and the mast cell marker c-kit. The effects of capsaicin were also tested in vitro on human nasal epithelial cells and mast cells. RESULTS: Patients with IR had higher baseline transient receptor potential cation channel subfamily V, receptor 1 (TRPV1) expression in the nasal mucosa and higher concentrations of substance P (SP) in nasal secretions than HCs. Symptomatic relief was observed in 11 of 14 patients with IR after capsaicin treatment. Expression of TRPV1; transient receptor potential cation channel subfamily M, receptor 8 (TRPM8); and PGP 9.5 was only reduced in patients with IR after capsaicin treatment. Capsaicin did not alter c-KIT expression or nasal epithelial morphology in patients with IR and HCs nor did it induce apoptosis or necrosis in cultured human nasal epithelial cells and mast cells. CONCLUSION: IR features an overexpression of TRPV1 in the nasal mucosa and increased SP levels in nasal secretions. Capsaicin exerts its therapeutic action by ablating the TRPV1-SP nociceptive signaling pathway in the nasal mucosa.

Diagnostic accuracy of nitric oxide measurements to detect primary ciliary dyskinesia.

BACKGROUND: Primary Ciliary Dyskinesia (PCD) is an orphan disease characterized by recurrent respiratory infections and an increased prevalence of situs inversus and male infertility. Low nasal Nitric Oxide (nNO) is used as a new test to diagnose PCD. The test sensitivity is good, but specificity has not been studied widely. Therefore, we evaluated the diagnostic accuracy of low nNO to diagnose PCD in a large cohort, including healthy patients and different disease controls. MATERIALS AND METHODS: Nasal nitric oxide was measured during plateau exhalation against resistance (nNOplat) and during tidal breathing (nNOtid). Moreover, we measured fractional exhaled NO (FENO). We included 226 patients: 38 with PCD, 49 healthy controls, and 139 disease controls (cystic fibrosis, humoral immunodeficiency, and asthma). RESULTS: The nNOplat cut-off value of 300 ppb provided the best sensitivity (89·5%) and specificity (87·3%) to detect PCD. There was overlap between PCD and disease controls: 16·5% of disease controls had a false-positive result. nNOtid correlated with nNOplat (r=0·912), but values differed (P=0·0001). The nNOtid cut-off of 200 ppb had a sensitivity of 89·5% and a specificity of 80·6% to detect PCD. The FENO cut-off of 10 ppb had an acceptable sensitivity (89·5%), but a low specificity (58·3%). Positive and negative likelihood ratios were suboptimal for all tests. CONCLUSIONS: nNOplat, nNOtid and FENO measurements overlap between PCD and disease controls. Sensitivity is comparable for the three tests. Applying composite scores slightly improves diagnostic accuracy. Given the less than 90% test sensitivity, PCD should be considered in patients with intermediate results.

Series of extranodal natural killer/T-cell lymphoma, nasal type, with periorbital involvement.

PURPOSE: To describe the clinical presentation, diagnosis and treatment of periorbital extranodal natural killer/T-cell lymphoma, nasal type. METHODS: Case series of three patients with periorbital involvement of extranodal natural killer/T-cell lymphoma, nasal type, of whom clinical data, orbital imaging and immunohistochemical analysis were collected. For the purpose of this study, all histopathological and immunohistochemical slides were re-examined. RESULTS: All patients presented with painless eyelid swelling and a history of sinonasal disease, of whom one with bilateral panuveitis, not responding to systemic antibiotics. Extraocular muscle involvement was present in 2 cases upon presentation and in 1 case later on. Initial paranasal and orbital biopsies were negative in 2 patients, with only the second orbital biopsy leading to the diagnosis. Natural killer/T-cell and cytotoxic markers were present in all cases, as well as Epstein-Barr virus encoded RNA in situ hybridization. The patients died respectively 5, 9 and 35 months from diagnosis despite treatment with chemotherapy and radiotherapy. CONCLUSION: Extranodal natural killer/T-cell lymphoma, nasal type, should be suspected in a painless periorbital cellulitis with chronic sinusitis, not responding to conventional therapy. A high index of suspicion is necessary in biopsies showing angiodestruction and necrosis. Epstein-Barr virus encoded RNA in situ hybridization and expert hematopathologist consultation is necessary to decrease the delay in diagnosis.

Protocol for postmortem bedside endoscopic procedure to sample human respiratory and olfactory cleft mucosa, olfactory bulbs, and frontal lobe.

We present a protocol for the rapid postmortem bedside procurement of selected tissue samples using an endoscopic endonasal surgical technique that we adapted from skull base surgery. We describe steps for the postmortem collection of blood, cerebrospinal fluid, a nasopharyngeal swab, and tissue samples; the clean-up procedure; and the initial processing and storage of the samples. This protocol was validated with tissue samples procured postmortem from COVID-19 patients and can be applied in another emerging infectious disease. For complete details on the use and execution of this protocol, please refer to Khan et al. (2021)1 and Khan et al. (2022).2.

Mutations in CCDC39 and CCDC40 are the major cause of primary ciliary dyskinesia with axonemal disorganization and absent inner dynein arms.

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder caused by cilia and sperm dysmotility. About 12% of cases show perturbed 9+2 microtubule cilia structure and inner dynein arm (IDA) loss, historically termed "radial spoke defect." We sequenced CCDC39 and CCDC40 in 54 "radial spoke defect" families, as these are the two genes identified so far to cause this defect. We discovered biallelic mutations in a remarkable 69% (37/54) of families, including identification of 25 (19 novel) mutant alleles (12 in CCDC39 and 13 in CCDC40). All the mutations were nonsense, splice, and frameshift predicting early protein truncation, which suggests this defect is caused by "null" alleles conferring complete protein loss. Most families (73%; 27/37) had homozygous mutations, including families from outbred populations. A major putative hotspot mutation was identified, CCDC40 c.248delC, as well as several other possible hotspot mutations. Together, these findings highlight the key role of CCDC39 and CCDC40 in PCD with axonemal disorganization and IDA loss, and these genes represent major candidates for genetic testing in families affected by this ciliary phenotype. We show that radial spoke structures are largely intact in these patients and propose this ciliary ultrastructural abnormality be referred to as "IDA and microtubular disorganisation defect," rather than "radial spoke defect."

Primary ciliary dyskinesia, an orphan disease.

UNLABELLED: Primary ciliary dyskinesia (PCD) is a rare autosomal recessive disease, caused by specific primary structural and/or functional abnormalities of the motile cilia, in contrast with the transitory abnormalities seen in secondary ciliary dyskinesia. Disease-causing mutations in at least 16 genes have already been identified. The true incidence of PCD may be higher than currently reported, because the diagnosis is challenging and often missed. For the confirmation of PCD, both ciliary motility as well as ciliary ultrastructure must be evaluated. An early and adequate diagnosis and therapy can theoretically prevent bronchiectasis. Measurement of nasal nitric oxide has some value as a screening test but cannot be performed in young children. In the respiratory tract epithelium, impaired mucociliary clearance leads to chronic and/or recurrent upper and lower respiratory tract infections. In up to 75 % of the patients, respiratory manifestations start in the newborn period, although the diagnosis is often missed at that time. During embryogenesis, nodal cilia, which are motile cilia, determine the correct lateralization of the organs. Dysfunction of these cilia leads to random lateralization and thus situs inversus in approximately 50 % of the patients with PCD. The tail of a spermatozoon has a structure similar to that of a motile cilium. Consequently, male infertility due to immotile spermatozoa is often part of the characteristics of PCD. Given the heterogeneity and the rarity of the disorder, therapy is not evidence-based. Many treatment schedules are proposed in analogy with the treatment for cystic fibrosis. CONCLUSION: Respiratory infections, situs inversus and male infertility are typical manifestations of PCD, a rare autosomal recessive disorder.

Upper Airway Disease in Adults with Cystic Fibrosis in the Era of CFTR Modulators.

OBJECTIVES: Chronic rhinosinusitis (CRS) is prevalent in people with cystic fibrosis (PwCF) and is often refractory to treatments. Uncontrolled CRS might negatively impact the lower airways and the quality of life. The aim of this study is to evaluate the burden of cystic fibrosis (CF)-related CRS in the era of CF transmembrane conductance regulator (CFTR) modulators. METHODS: Adult PwCF were asked to fill in a questionnaire on sinonasal complaints, they underwent a nasal endoscopy, bacteriological sampling, and a CT scan. Afterwards, these outcome measures were compared between patients treated with and without modulators. RESULTS: In the 122 included patients, CRS was present in 83%. CFTR modulators were prescribed in 48% of the patients, with a median of 10 months since the start of the treatment. Subjectively, the median SNOT-22 score was 16/110. Objectively, a median Lund-Kennedy score of 6/12 and modified Lund-Mackay score of 10/24 were observed. No correlation could be found between SNOT-22 score and other outcome measures including endoscopy and radiology. Altogether, 21% of the patients had controlled disease. When comparing patients treated with and without modulators, significantly lower CT scores (p = 0.0018) and less bacterial colonization (p = 0.0082) were observed in patients receiving modulators. CONCLUSION: CF-CRS is highly prevalent in our cohort and only the minority of PwCF has a well-controlled disease. A multidisciplinary ENT-pneumology clinic would be beneficial, as there is a high discrepancy between patient-reported symptoms and the extent of the disease. CFTR modulators are promising, as lower CT scores and less bacterial colonization were observed in the modulator group. LEVEL OF EVIDENCE: Level 3 Laryngoscope, 133:2898-2909, 2023.

Leukocyte- and platelet-rich fibrin in endoscopic endonasal skull base reconstruction: study protocol for a multicenter prospective, parallel-group, single-blinded randomized controlled non-inferiority trial.

BACKGROUND: Recent advances in endoscopic endonasal transsphenoidal approaches (EETA) for skull base lesions have resulted in a significant increase in extent and complexity of skull base defects, demanding more elaborate and novel reconstruction techniques to prevent cerebrospinal fluid (CSF) leakage and to improve healing. Currently, commercially available fibrin sealants are often used to reinforce the skull base reconstruction. However, problems have been reported regarding hypersensitivity reactions, efficacy, and costs. This trial aims to investigate autologous leukocyte- and platelet-rich fibrin (L-PRF) membranes as an alternative for commercially available fibrin glues in EETA-related skull base reconstruction reinforcement. METHODS/DESIGN: This multicenter, prospective randomized controlled trial aims to demonstrate non-inferiority of L-PRF membranes compared to commercially available fibrin sealants in EETA cases (1) without intra-operative CSF-leak as dural or sellar floor closure reinforcement and (2) in EETA cases with intra-operative CSF-leak (or very large defects) in which a classic multilayer reconstruction has been made, as an additional sealing. The trial includes patients undergoing EETA in three different centers in Belgium. Patients are randomized in a 1:1 fashion comparing L-PRF with commercially available fibrin sealants. The primary endpoint is postoperative CSF leakage. Secondary endpoints are identification of risk factors for reconstruction failure, assessment of rhinological symptoms, and interference with postoperative imaging. Additionally, a cost-effectiveness analysis is performed. DISCUSSION: With this trial, we will evaluate the safety and efficacy of L-PRF compared to commercially available fibrin sealants. TRIAL REGISTRATION: ClinicalTrials.gov NCT03910374. Registered on 10 April 2019.

Evaluation of skin prick location on the forearm using a novel skin prick automated test device.

Background: The skin prick test (SPT) is the gold standard for identifying allergic sensitization in individuals suspected of having an inhalant allergy. Recently, it was demonstrated that SPT using a novel skin prick automated test (SPAT) device showed increased reproducibility and tolerability compared to the conventional SPT, among other benefits. Objective: This study aimed to evaluate prick location bias using the novel SPAT device. Methods: A total of 118 volunteers were enrolled in this study and underwent SPATs with histamine (nine pricks) and glycerol control (one prick) solutions on the volar side of their forearms. Imaging of the skin reactions was performed using the SPAT device, and the physician determined the longest wheal diameter by visually inspecting the images using a web interface. Prick location bias was assessed along the medial vs. lateral and proximal vs. distal axes of the forearm. Results: In total, 944 histamine pricks were analyzed. Four medial and four lateral histamine pricks were grouped, and wheal sizes were compared. The longest wheal diameters were not significantly different between the medial and lateral prick locations (p = 0.41). Furthermore, the pricks were grouped by two based on their position on the proximal-distal axis of the forearm. No significant difference was observed among the four groups of analyzed prick locations (p = 0.73). Conclusion: The prick location on the volar side of the forearm did not influence wheal size in SPAT-pricked individuals.

Chronic Rhinosinusitis Outcome Registry (CHRINOSOR): Establishment of an International Outcome Registry Driven by mHealth Technology.

BACKGROUND: Real-world evidence (RWE) is a valuable instrument to better understand the patient journey and effectiveness of therapies. RWE on the prevalence of uncontrolled chronic rhinosinusitis (CRS) and CRS natural course of disease across Europe is scarce. In addition, there is limited RWE that enables comparison of the effectiveness of marketed therapies including topical or systemic corticosteroids, sinus surgery, or biologics. OBJECTIVE: To establish an international CHRonic rhINOSinusitis Outcome Registry (CHRINOSOR) based on real-world data collection enabled by mobile health technology. METHODOLOGY: A digital platform, Galenus Health, supporting patients and physicians in the management of chronic respiratory diseases, is used to collect data on patient profile, disease history, patient outcomes, and a set of relevant clinical outcomes. Adult patients with a diagnosis of CRS are eligible for inclusion. RESULTS: A collaborative scientific network of 17 university ear-nose-throat (ENT) clinics from 10 European countries has been established with the aim to collect real-world data in a longitudinal and standardized manner. The Galenus Health digital platform is currently being implemented in these ENT clinics taking into account legal, privacy, and data security aspects. Up to 300 patients have already been included. CONCLUSIONS: CHRINOSOR is a collaborative effort that aims at improving our understanding of CRS, its comorbidities, and the effectiveness of its treatments. Ultimately, these insights will guide us as scientific community to develop future care pathways informed by RWE.