High burden of clonal mast cell disorders and hereditary α-tryptasemia in patients who need Hymenoptera venom immunotherapy.

BACKGROUND: In patients who require venom immunotherapy (VIT), there is a need to identify underlying mast cell (MC) disorders since these may affect the risk and severity of future sting reactions and the long-term effectiveness of VIT. METHODS: 1319 individuals with Hymenoptera venom allergy (HVA) who needed VIT from referral centers in Slovenia, Austria, Croatia, and Poland underwent examination for KIT p.D816V in peripheral blood leukocytes (PBL) using a highly sensitive PCR test and tryptase genotyping by digital droplet PCR. We also included 183 control individuals with large local reactions (LLRs) to Hymenoptera stings and with asymptomatic sensitization to Hymenoptera venoms. RESULTS: 285 of 1319 individuals recommended for VIT (21.6%) were positive for KIT p.D816V in PBL, preferably those who present with severe reaction (33.9% [n = 207 of 610] with Ring-Messmer grade 3-4 vs. 11% [n = 78 of 709] with Grade 1-2; p < .0001), whereas only 1.3% (n = 2 of 152) of controls with LLR and none with asymptomatic sensitization (n = 31) had KIT p.D816V. KIT p.D816V allelic burden was higher in those with severe reaction (median 0.018% [n = 207] in Grade 3-4 vs. 0.001% [n = 78] in Grade 1-2; p < .0001), and the majority had normal baseline serum tryptase levels (69% [n = 196 of 285]). All KIT p.D816V-positive individuals (n = 41) who underwent bone marrow (BM) biopsy were found to have underlying clonal diseases, principally BM mastocytosis. HαT was also associated with severe HVA and symptoms (p < .01), and remarkably, 31.0% (n = 31 of 100) were found to have concomitant KIT p.D816V. Concomitant HαT and KIT p.D816V showed an additive effect, and having both was associated with the highest risk for severe HVA, even higher than having either HαT or KIT p.D816V alone (OR = 3.8; p < .01). CONCLUSIONS: By employing prospective universal tryptase genotyping and examination for KIT p.D816V in PBL in large HVA populations, we have demonstrated a high burden of clonal MC disorders and HαT in patients who require VIT.

Genomic Landscape of Susceptibility to Severe COVID-19 in the Slovenian Population.

Determining the genetic contribution of susceptibility to severe SARS-CoV-2 infection outcomes is important for public health measures and individualized treatment. Through intense research on this topic, several hundred genes have been implicated as possibly contributing to the severe infection phenotype(s); however, the findings are complex and appear to be population-dependent. We aimed to determine the contribution of human rare genetic variants associated with a severe outcome of SARS-CoV-2 infections and their burden in the Slovenian population. A panel of 517 genes associated with severe SARS-CoV-2 infection were obtained by combining an extensive review of the literature, target genes identified by the COVID-19 Host Genetic Initiative, and the curated Research COVID-19 associated genes from PanelApp, England Genomics. Whole genome sequencing was performed using PCR-free WGS on DNA from 60 patients hospitalized due to severe COVID-19 disease, and the identified rare genomic variants were analyzed and classified according to the ACMG criteria. Background prevalence in the general Slovenian population was determined by comparison with sequencing data from 8025 individuals included in the Slovenian genomic database (SGDB). Results show that several rare pathogenic/likely pathogenic genomic variants in genes CFTR, MASP2, MEFV, TNFRSF13B, and RNASEL likely contribute to the severe infection outcomes in our patient cohort. These results represent an insight into the Slovenian genomic diversity associated with a severe COVID-19 outcome.

Clonal mast cell disorders and hereditary α-tryptasemia as risk factors for anaphylaxis.

The association between Hymenoptera venom-triggered anaphylaxis (HVA) and clonal mast cell-related disorders (cMCD) has been known for decades. However, recent breakthroughs in peripheral blood screening for KIT p.D816V missense variant have revealed the true extent of this clinical association whilst adding to our understanding of the underlying aetiology. Thus, recent large studies highlighted the presence of KIT p.D816V among 18.2% and 23% of patients with severe Hymenoptera venom-triggered anaphylaxis. A significant proportion of those patients have normal serum basal tryptase (BST) levels, with no cutaneous findings such as urticaria pigmentosa or other systemic findings such as organomegaly that would have suggested the presence of cMCD. These findings of an increased prevalence suggest that the impact of cMCD on anaphylaxis could be clinically underestimated and that the leading question for clinicians could be changed from 'how many patients with cMCD have anaphylaxis?' to 'how many patients with anaphylaxis have cMCD?'. The discovery of hereditary α-tryptasemia (HαT)-a genetic trait caused by an increased copy number of the Tryptase Alpha/Beta 1 (TPSAB1) gene-, first described in 2016, is now known to underlie the majority of cases of elevated BST outside of cMCD and chronic kidney disease. HαT is the first common heritable genetic modifier of anaphylaxis described, and it is associated with increased risk for severe HVA (relative risk = 2.0), idiopathic anaphylaxis, and an increased prevalence of anaphylaxis in patients with cMCD, possibly due to the unique activity profile of α/ß -tryptase heterotetramers that may potentiate immediate hypersensitivity reaction severity. Our narrative review aims to highlight recent research to have increased our understanding of cMCD and HαT, through recent lessons learned from studying their association with HVA. Additionally, we examined the studies of mast cell-related disorders in food and drug allergy in an effort to determine whether one should also consider cMCD and/or HαT in cases of severe anaphylaxis triggered by food or drugs.

Increased Focus on Internal Body Sensations Is Associated with Higher Patient-Perceived Severity of Allergic Rhinitis.

BACKGROUND: Monitoring allergic rhinitis (AR) severity with objective biomarkers is important for the clinical management of patients as well as for research purposes. The most commonly used tool for the assessment of AR severity is the Total Nasal Symptom Score (TNSS). Objective biomarkers like skin prick test size or specific IgE levels do not correlate with TNSS. OBJECTIVE: We hypothesize that the psychological factors are the missing link between patient-perceived severity of AR and objective biomarkers. METHOD: Thirty-nine patients (median age: 34 years; 21 [54%] female) with grass pollen-related AR were enrolled in our study. Patients allergic for perennial allergens and allergens with potentially overlapping seasons including cypress, ash/olive, plane, and nettle families were excluded. Patient-reported outcomes included symptom score, medication scores, combined score, and Juniper Mini Rhinitis Quality of Life Questionnaire (minRQLQ). Psychometric evaluation was performed using 5 different psychological questionnaires that measure 13 different psychological factors. RESULTS: There was a significant correlation between the symptom score and private body consciousness (r = 0.50, p = 0.001) and neuroticism (R = 0.41 and p = 0.01). There was also a statistically significant correlation between the combined score and private body consciousness (r = 0.49 and p = 0.001) and with perceiving and understanding emotions (r = 0.34 and p = 0.04). The miniRQLQ score had a positive correlation with private body consciousness (r = 0.55 and p = 0.002) and observing (r = 0.42 and p = 0.02). CONCLUSIONS: Our data suggest that patients who are more aware of internal stimuli, as well as those who are highly self-conscious and somatically concerned tend to experience more severe AR symptoms.

Routine KIT p.D816V screening identifies clonal mast cell disease in patients with Hymenoptera allergy regularly missed using baseline tryptase levels alone.

BACKGROUND: Clonal mast cell disorders and elevated basal serum tryptase (BST) levels with unknown cause(s) are associated with severe Hymenoptera venom-triggered anaphylaxis (HVA). However, some individuals with clonal disease have a normal BST level (<11.4 ng/mL). OBJECTIVE: Our aim was to evaluate whether screening for KIT p.D816V in the blood is a useful clinical tool to risk-stratify patients with venom allergy. METHODS: We prospectively recruited 374 patients with Hymenoptera allergy and no overt signs of mastocytosis who were referred to our center during the years 2018 and 2019. KIT p.D816V was determined in their peripheral blood by quantitative PCR, and tryptase genotyping was performed by droplet digital PCR. RESULTS: In all, 351 patients (93.9%) had normal levels of BST, and KIT p.D816V was detected in 8% of patients (28 of 351), predominantly in patients with the most severe Mueller grade IV anaphylaxis (18.2% [24 of 132] vs 1.8% in patients with lower grades [4 of 88 with grade III and 0 of 131 with other grades]; P < .001). In grade IV patients with a normal BST level, KIT p.D816V was associated with more severe symptoms, including a significantly higher frequency of loss of consciousness (58.3% [14 of 24] vs 34.3% [37 of 108]; P = .03) and absence of skin symptoms (41.7% [10 of 24] vs 15.7% [17 of 108]; P = .004). Among patients with a normal BST level, KIT p.D816V (OR = 10.25 [95% CI = 3.75-36.14]; P < .0001) was the major risk factor associated with severe HVA. Hereditary α-tryptasemia (HαT) due to increased germline copies of TPSAB1 encoding α-tryptase was the most common cause (65.2% [15 of 23]) of elevated BST level in patients with HVA, and together with KIT p.D816V, it accounted for 90% of BST level elevations (20 of 23) in patients with HVA. CONCLUSION: These results indicate that routine KIT p.D816V screening identifies clonal disease in high-risk patients with HVA who are regularly missed when BST level is used alone.

Heritable risk for severe anaphylaxis associated with increased α-tryptase-encoding germline copy number at TPSAB1.

BACKGROUND: An elevated basal serum tryptase level is associated with severe systemic anaphylaxis, most notably caused by Hymenoptera envenomation. Although clonal mast cell disease is the culprit in some individuals, it does not fully explain this clinical association. OBJECTIVE: Our aim was to determine the prevalence and associated impact of tryptase genotypes on anaphylaxis in humans. METHODS: Cohorts with systemic mastocytosis (SM) and venom as well as idiopathic anaphylaxis from referral centers in Italy, Slovenia, and the United States, underwent tryptase genotyping by droplet digital PCR. Associated anaphylaxis severity (Mueller scale) was subsequently examined. Healthy volunteers and controls with nonatopic disease were recruited and tryptase was genotyped by droplet digital PCR and in silico analysis of genome sequence, respectively. The effects of pooled and recombinant human tryptases, protease activated receptor 2 agonist and antagonist peptides, and a tryptase-neutralizing mAb on human umbilical vein endothelial cell permeability were assayed using a Transwell system. RESULTS: Hereditary α-tryptasemia (HαT)-a genetic trait caused by increased α-tryptase-encoding Tryptase-α/ß1 (TPSAB1) copy number resulting in elevated BST level-was common in healthy individuals (5.6% [n = 7 of 125]) and controls with nonatopic disease (5.3% [n = 21 of 398]). HαT was associated with grade IV venom anaphylaxis (relative risk = 2.0; P < .05) and more prevalent in both idiopathic anaphylaxis (n = 8 of 47; [17%; P = .006]) and SM (n = 10 of 82 [12.2%; P = .03]) relative to the controls. Among patients with SM, concomitant HαT was associated with increased risk for systemic anaphylaxis (relative risk = 9.5; P = .007). In vitro, protease-activated receptor-2-dependent vascular permeability was induced by pooled mature tryptases but not α- or ß-tryptase homotetramers. CONCLUSIONS: Risk for severe anaphylaxis in humans is associated with inherited differences in α-tryptase-encoding copies at TPSAB1.

A Novel Mutation in the FOXC2 Gene: A Heterozygous Insertion of Adenosine (c.867insA) in a Family with Lymphoedema of Lower Limbs without Distichiasis.

BACKGROUND: Primary lymphoedema is a rare genetic disorder characterized by swelling of different parts of the body and highly heterogenic clinical presentation. Mutations in several causative genes characterize specific forms of the disease. FOXC2 mutations are associated with lymphoedema of lower extremities, usually distichiasis and late onset. PATIENTS AND METHODS: Subjects from three generations of a family with lymphoedema of lower limbs without distichiasis were searched for mutations in the FOXC2 gene. RESULTS: All affected family members with lymphoedema of lower limbs without distichiasis, and still asymptomatic six years old girl from the same family, carried the same previously unreported insertion of adenosine (c.867insA) in FOXC2. CONCLUSIONS: Identification of a novel mutation in the FOXC2 gene in affected family members of three generations with lymphoedema of lower limbs without distichiasis, highlights the high phenotypic variability caused by FOXC2 mutations.

Remission of chronic urticaria in patients treated with omalizumab.

INTRODUCTION: This study examined the remission probability and duration in chronic spontaneous urticaria (CSU) patients resistant to second-generation H1-antihistamines (sgAHs) undergoing omalizumab treatment. METHODS: This is a retrospective observational study of 176 adult CSU patients exhibiting a significant pruritus component (≥ 8) of the weekly urticaria activity score (UAS7) despite four daily sgAH tablets and starting omalizumab treatment with 300 mg every 4 weeks. After excluding 13 nonresponders, we analyzed 163 omalizumab responders (mean age 51.8 years, 74.4% female). The intervals between applications were increased. Discontinuation was considered for patients that remained asymptomatic on a gradually reduced dosage (to 150 mg every 12 weeks) without sgAHs. RESULTS: Omalizumab discontinuation was possible in 25.8% (42/163). The duration of omalizumab treatment before remission ranged from 7 to 63 months. Twenty-one patients (50.0%) maintained complete remission until the end of the observation period (September 2021) for 8 to 68 months. Of the relapsed patients, 71.4% (15/21) effectively controlled CSU with sgAHs. Six patients (28.6%; 6/21) required omalizumab reintroduction after 6 to 40 months of remission, responding favorably. CONCLUSIONS: The study shows that a quarter of severe CSU patients achieve long-term remission. In addition, sgAHs effectively manage symptoms in a majority of relapsed cases, and those requiring omalizumab reintroduction respond favorably.

Clinically accessible amplitude-based multiplex ddPCR assay for tryptase genotyping.

Hereditary α tryptasemia (HαT) is an autosomal dominant trait characterized by increased TPSAB1 copy number (CN) encoding α-tryptase. The determination of HαT is being discussed as an important biomarker to be included in risk assessment models and future diagnostic algorithms for patients with mastocytosis and anaphylaxis. Due to the complex genetic structure at the human tryptase locus, genetic testing for tryptase gene composition is presently notably limited and infrequently pursued. This study aimed to develop, optimise and validate a multiplex droplet digital PCR (ddPCR) assay that can reliably quantify α- and ß-tryptase encoding sequences in a single reaction. To optimise the ddPCR conditions and establish an amplitude-based multiplex ddPCR assay, additional primers and probes, a thermal gradient with varying annealing temperatures, different primers/probe concentrations, and various initial DNA quantities were tested. Results obtained from all 114 samples analysed using multiplex ddPCR were identical to those obtained through the use of original duplex assays. Utilizing this multiplex ddPCR assay, in contrast to conducting distinct duplex ddPCRs, presents noteworthy benefits for tryptase genotyping. These advantages encompass a substantial threefold decrease in material costs and considerable time savings. Consequently, this approach exhibits high suitability and particularly captures interest for routine clinical implementation.

Personalization matters: the effect of sex in multivitamin-multimineral-based cancer prevention.

The prevention of non-communicable diseases like cancer contributes to healthy aging. Dietary supplements might support such prevention; their effect likely depends on the personal characteristics of the individuals receiving them. To evaluate the influence of sex on reducing cancer incidence with multivitamin-multimineral (MVM) supplementation, sex-specific results of the efficacy of MVM supplementation for cancer prevention were collected and meta-analyzed (using fixed effect (FE) and random effect (RE) models). Three trials included in the "US Preventive Services Task Force Recommendation Statement Report regarding Vitamin, Mineral, and Multivitamin Supplementation to Prevent Cardiovascular Disease and Cancer" were used, namely, COSMOS, SU.VI.MAX, and PHS2. A total of 28,558 men and 20,542 women were included. Multivitamin-multimineral supplementation significantly reduced cancer incidence in the entire population (HR 0.93 [95% CI, 0.88-0.99], FE and RE); sex-specific meta-analysis showed beneficial effects of supplementation in men (HR 0.91 [95% CI, 0.85-0.97] (FE)/0.88 [95% CI, 0.77-1.01] (RE)); however, there was no effect in women (HR 1.00 [95% CI, 0.88-1.14], FR and RE); (Pdifference = 0.17). Sex could influence the effect of MVM supplementation in reducing cancer incidence, with supplementation being effective only in male individuals. These results might be informative for future research and public health policy makers.

The CC2D2B is a novel genetic modifier of the clinical phenotype in patients with hereditary angioedema due to C1 inhibitor deficiency.

Hereditary angioedema due to C1 inhibitor deficiency (HAE-C1-INH) is a rare genetic disorder caused by pathogenic variants in the SERPING1 gene and characterised by swelling and a highly variable clinical phenotype. We aimed to identify novel modifying genetic factors predisposing to the clinical symptoms. We performed whole exome sequencing (WES) and comprehensive bioinformatic analysis in symptomatic and asymptomatic (three duos) family members with HAE-C1-INH. Selected variants identified using WES (present in all asymptomatic and absent in symptomatic patients) were determined using Sanger sequencing. We included 88 clinically well-characterised HAE-C1-INH patients from south-eastern Europe (nine asymptomatic) from 42 unrelated families. We identified 39 variants in 23 genes (ANKRD36C, ARGFX, CC2D2B, IL5RA, IRF2BP2, LGR6, MRPL45, MUC3A, NPIPA1, NRG1, OR5M1, OR5M3, OR5M10, OR8U3, PLCL1, PRSS3, PSKH2, PTPRA, RTP4, SEZ6, SLC25A5, VWA3A, and ZNF790). We selected variants in CC2D2B and PLCL1, which were analysed using Sanger sequencing in the entire group of HAE-C1-INH. We found significant differences in the frequencies of the CC2D2B c.190A>G (rs17383738) variant between symptomatic and asymptomatic patients, where heterozygotes were more common in asymptomatic HAE-C1-INH patients in comparison to symptomatic patients (55 % vs 23%; P = 0.049, OR = 4.24, 95% CI 1.07-14.69). Our study identified novel genetic factors that modify the clinical variability of HAE-C1-INH. We further demonstrated, in a large cohort, the importance of the CC2D2B gene as a disease-modifying factor. Based on linkage disequilibrium analysis, the CCNJ and ZNF518A genes might also be involved in the clinical variability of HAE-C1-INH.

Combination of Experimental and Bioinformatic Approaches for Identification of Immunologically Relevant Protein-Peptide Interactions.

Protein-peptide interactions are an essential player in cellular processes and, thus, of great interest as potential therapeutic agents. However, identifying the protein's interacting surface has been shown to be a challenging task. Here, we present a methodology for protein-peptide interaction identification, implementing phage panning, next-generation sequencing and bioinformatic analysis. One of the uses of this methodology is identification of allergen epitopes, especially suitable for globular inhaled and venom allergens, where their binding capability is determined by the allergen's conformation, meaning their interaction cannot be properly studied when denatured. A Ph.D. commercial system based on the M13 phage vector was used for the panning process. Utilization of various bioinformatic tools, such as PuLSE, SAROTUP, MEME, Hammock and Pepitope, allowed us to evaluate a large amount of obtained data. Using the described methodology, we identified three peptide clusters representing potential epitopes on the major wasp venom allergen Ves v 5.

Predictors of Success of Inpatient Pulmonary Rehabilitation Program in COPD Patients.

Purpose: Pulmonary rehabilitation programs (PR) are an important part of the comprehensive treatment of patients with chronic pulmonary diseases. Patients respond individually to PR. The aim of this study is to identify potential predictors of success of PR to recognise patients who benefit most and to uncover possible reasons for poor response to PR. Patients and Methods: We included 121 patients with chronic obstructive pulmonary disease (COPD) who completed our 4-week inpatient PR without any exacerbations of disease during PR that could potentially affect PR outcomes. Improvement in distance of ≥30 m on the 6-minute walk test (6MWT) after PR was chosen as a primary marker of physical success. Ninety-one patients achieved improvement of ≥30 m on the 6MWT and were thus considered good responders, and 30 patients were poor responders with improvement in the distance of <30 m on the 6MWT. Results: We compared baseline clinical characteristics, medication, lung function, physical capacity, body composition, and laboratory blood tests between groups of good and poor responders. The most prominent differences between groups were associated with differences in baseline body composition and erythrocyte-related parameters. Good responders had significantly lower body water content (p = 0.042) and higher body weight (p = 0.036), body fat content (p = 0.049), dry lean mass (p = 0.021), haemoglobin levels (p = 0.040), erythrocyte count (p = 0.017), haematocrit (p = 0.030) and iron level (p = 0.028). Conclusion: A more muscular body composition and a higher ability to transport oxygen from the blood to the muscles could be beneficial for the outcome of PR.

Genetically defined individual reference ranges for tryptase limit unnecessary procedures and unmask myeloid neoplasms.

Serum tryptase is a biomarker used to aid in the identification of certain myeloid neoplasms, most notably systemic mastocytosis, where basal serum tryptase (BST) levels >20 ng/mL are a minor criterion for diagnosis. Although clonal myeloid neoplasms are rare, the common cause for elevated BST levels is the genetic trait hereditary α-tryptasemia (HαT) caused by increased germline TPSAB1 copy number. To date, the precise structural variation and mechanism(s) underlying elevated BST in HαT and the general clinical utility of tryptase genotyping, remain undefined. Through cloning, long-read sequencing, and assembling of the human tryptase locus from an individual with HαT, and validating our findings in vitro and in silico, we demonstrate that BST elevations arise from overexpression of replicated TPSAB1 loci encoding canonical α-tryptase protein owing to coinheritance of a linked overactive promoter element. Modeling BST levels based on TPSAB1 replication number, we generate new individualized clinical reference values for the upper limit of normal. Using this personalized laboratory medicine approach, we demonstrate the clinical utility of tryptase genotyping, finding that in the absence of HαT, BST levels >11.4 ng/mL frequently identify indolent clonal mast cell disease. Moreover, substantial BST elevations (eg, >100 ng/mL), which would ordinarily prompt bone marrow biopsy, can result from TPSAB1 replications alone and thus be within normal limits for certain individuals with HαT.

Utility of Telomerase Gene Mutation Testing in Patients with Idiopathic Pulmonary Fibrosis in Routine Practice.

Recent studies have suggested that causative variants in telomerase complex genes (TCGs) are present in around 10% of individuals with idiopathic pulmonary fibrosis (IPF) regardless of family history of the disease. However, the studies used a case-control rare variant enrichment study design which is not directly translatable to routine practice. To validate the prevalence results and to establish the individual level, routine clinical practice, and utility of those results we performed next generation sequencing of TCGs on a cohort of well-characterized consecutive individuals with IPF (diagnosis established according to ATS/ERS/JRS/ALAT guidelines). Of 27 IPF patients, three had a family history of idiopathic interstitial pneumonia (familial IPF) and 24 did not (sporadic IPF). Pathogenic/likely-pathogenic variants (according to American College of Medical Genetics criteria) in TCG were found in three individuals (11.1%) of the whole cohort; specifically, they were present in 2 out of 24 (8.3%) of the sporadic and in 1 out of 3 (33.3%) of the patients with familial IPF. Our results, which were established on an individual-patient level study design and in routine clinical practice (as opposed to the case-control study design), are roughly in line with the around 10% prevalence of causative TCG variants in patients with IPF.

Mortality, seasonal variation, and susceptibility to acute exacerbation of COPD in the pandemic year: a nationwide population study.

BACKGROUND: Previous studies have suggested that the coronavirus disease 2019 (COVID-19) pandemic was associated with a decreased rate of acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Data on how the COVID-19 pandemic has influenced mortality, seasonality of, and susceptibility to AECOPD in the chronic obstructive pulmonary disease (COPD) population is scarce. METHODS: We conducted a national population-based retrospective study using data from the Health Insurance Institute of Slovenia from 2015 to February 2021, with 2015-2019 as the reference. We extracted patient and healthcare data for AECOPD, dividing AECOPD into severe, resulting in hospitalisation, and moderate, requiring outpatient care. The national COPD population was generated based on dispensed prescriptions of inhalation therapies, and moderate AECOPD events were analysed based on dispensed AECOPD medications. We extracted data on all-cause and non-COVID mortality. RESULTS: The numbers of severe and moderate AECOPD were reduced by 48% and 34%, respectively, in 2020. In the pandemic year, the seasonality of AECOPD was reversed, with a 1.5-fold higher number of severe AECOPD in summer compared to winter. The proportion of frequent exacerbators (⩾2 AECOPD hospitalisations per year) was reduced by 9% in 2020, with a 30% reduction in repeated severe AECOPD in frequent exacerbators and a 34% reduction in persistent frequent exacerbators (⩾2 AECOPD hospitalisations per year for 2 consecutive years) from 2019. The risk of two or more moderate AECOPD decreased by 43% in 2020. In the multivariate model, pandemic year follow-up was the only independent factor associated with a decreased risk for severe AECOPD (hazard ratio [HR]: 0.71; 95% confidence interval [CI]: 0.61-0.84; p < 0.0001). In 2020, non-COVID mortality decreased (-15%) and no excessive mortality was observed in the COPD population. CONCLUSION: In the pandemic year, we found decreased susceptibility to AECOPD across severity spectrum of COPD, reversed seasonal distribution of severe AECOPD and decreased non-COVID mortality in the COPD population.