Background Treatment with elexacaftor/tezacaftor/ivacaftor (ETI) has been shown to improve clinical outcomes in people with cystic fibrosis (pwCF). Here, we investigated whether these benefits are associated with the modulation of oxidative stress. Methods Levels of oxidative stress markers including 8-isoprostane (8-IP), 8-hydroxy-2’deoxyguanosine (8-OHdG) and protein carbonyls and activities of antioxidant enzymes such as superoxide dismutase (SOD) and catalase (CAT) were measured in systemic and airway samples from clinically stable pwCF (n=26) at baseline and 2 or 3 and 6 months after initiation of ETI therapy. For comparison, measurements were also performed in healthy control subjects. Results Baseline levels of oxidative stress markers and antioxidant activities were higher in pwCF than in healthy controls (p<0.05). ETI treatment resulted in improvements in a wide range of clinical parameters in pwCF. In addition, one in two patients had ceased producing sputum while receiving ETI treatment. A reduction in the levels of sputum oxidative stress markers was observed 2 or 3 months (for 8-OHdG and protein carbonyls) and 6 months (for 8-IP) after ETI initiation (p<0.05). Sputum SOD activity showed a similar reduction (p<0.05) upon treatment. In contrast, modulator treatment had no effect on the levels of oxidative stress markers and antioxidant activities in plasma. Extrapulmonary manifestations of CF were not improved by ETI therapy either. Conclusions Our data suggest that the beneficial clinical effect of ETI therapy is accompanied by a decrease in airway but not systemic oxidative stress in pwCF.

Major mutations of SERPINA1, the gene encoding alpha1-antitrypsin (A1AT), are known to cause severe emphysema. Our study aimed to investigate the role of major mutations modulating A1AT levels in several lung pathologies and control groups. Blood samples were collected from healthy non-smokers (N0 = 85), healthy smokers (N0 = 291), healthy ex-smokers (N0 = 127), smokers with chronic obstructive lung disease (COPD, N0 = 187), ex-smokers with COPD (N0 = 64), and patients with asthma (N0 = 194), interstitial lung disease (ILD) (N0 = 93), sarcoidosis (N0 = 30) and cystic fibrosis (N0 = 26). Clinical and respiratory parameters, A1AT levels, the extent of emphysema and comorbidities on low-dose CT scans were evaluated, and patients answered a smoking history and comorbidity questionnaire. A1AT single-nucleotide polymorphisms were determined for the S, Z, M2/M4, 0 and eQTL locations by SNP probes using real-time PCR. A1AT levels showed significant differences between cigarette smoke-induced and other lung diseases. Compared to controls, A1AT levels were found to be lower in sarcoidosis and increasingly higher in smokers and patients with COPD, ILD and CF, respectively. The presence and pattern of emphysema were found to influence A1AT levels: lower values were observed in COPD patients without emphysema, while higher values were observed in patients with central and panlobular emphysema. Antitrypsin levels increased with COPD GOLD stages and asthma GINA stages. Variable A1AT levels were also found in ILD subgroups. The distribution of variants at the S, Z, M2/M4 and 0 polymorphic sites and the eQTL location showed no significant differences between patient groups with impaired lung function, except for Z heterozygotes, which were prevalent in patients with severe asthma. The eQTL TT genotypes had higher A1AT levels and the occurrence of emphysema and/or bronchitis was increased. A1AT levels correlated with several clinical and respiratory parameters in pulmonary patients, while FEV1/FVC inversely correlated with levels of A1AT. Molar antielastase activity was increased in smokers and patients with lung diseases; however, in COPD, antielastase activity decreased. The most reduced antielastase activity could be found in CF. Certain genotypes were characterized by increased cardiovascular comorbidity scores and antitrypsin levels. Our data suggest that in addition to emphysema, A1AT may play an important role in the development of a wide variety of lung diseases and cardiovascular comorbidities. Further research is needed to clarify the role of A1AT and its regulation in lung pathologies.

Background:Due to its increasing prevalence and suboptimal treatment, non-tuberculous mycobacterial (NTM) infection is an emerging problem in patients with cystic fibrosis (CF). Detailed description of regional NTM prevalence and distribution, and identification of predictors of NTM acquisition in CF are essential to optimise treatment and surveillance guidelines. Methods:A retrospective, multi-center analysis was conducted between the years 2020 and 2022 on data from 232 adult patients registered in the Hungarian CF Registry in 2022. In a case-control analysis of NTM-positive (n = 39) and NTM-negative (n = 73) CF patients, demographic, clinical, and microbiological data were analysed to identify potential predictors for NTM acquisition. The distribution of NTM species, their antibiotic susceptibility patterns were also evaluated. Results:The prevalence of NTM-positive sputum increased from 4.7 % to 12.9 % over study period. The most prevalent NTMs were M. avium complex (41.0 %), M. abscessus complex (MABSC) (38.5 %) and M. xenopi (15.4 %). MABSC strains were highly resistant to doxycycline, fluoroquinolones, and sulfonamides, while amikacin, macrolides, tigecycline and linezolid were often effective. Forced expiratory volume in 1 s (FEV1) was lower in the NTM-positive group at the index date and 1 and 2 years before NTM detection (p < 0.01), predicting NTM infection. Previous NTM-positive sputum culture enhanced the risk of NTM reacquisition in the airway (odds ratio: 7). Conclusion:The results demonstrate a high prevalence of NTM in the Hungarian adult CF population and a high rate of multidrug-resistant MABSC isolates in their sputum. The risk of acquiring airway NTM is higher in CF patients with significantly impaired lung function and previous respiratory mycobacteriosis.

Underserved and hard-to-reach population groups are under-represented in vaccine trials. Thus, we aimed to identify the challenges of vaccine trial participation of these groups in member countries of the VACCELERATE network. Seventeen National Coordinators (NC), each representing their respective country (15 European countries, Israel, and Turkey), completed an online survey. From 15 eligible groups, those that were more frequently declared underserved/hard-to-reach in vaccine research were ethnic minorities (76.5%), persons experiencing homelessness (70.6%), illegal workers and refugees (64.7%, each). When prioritization for education on vaccine trials was considered, ethnic groups, migrants, and immigrants (5/17, 29.4%) were the groups most frequently identified by the NC as top targets. The most prominent barriers in vaccine trial participation affecting all groups were low levels of health literacy, reluctance to participate in trials due to engagement level, and low levels of trust in vaccines/vaccinations. This study highlighted population groups considered underserved/hard-to-reach in countries contained within the European region, and the respective barriers these groups face when participating in clinical studies. Our findings aid with the design of tailored interventions (within—and across—countries of the European region) and with the development of strategies to overcome major barriers in phase 2 and phase 3 vaccine trial participation.

Introduction: The COVID-19 pandemic has posed serious challenges for healthcare. Immunization against SARS-CoV-2 was initially effective, but the immune response gradually waned as time passed. As protection declined and new virus variants emerged, the incidence of virus infection increased even among those who had been vaccinated three times. In this study, we compared the immune response to booster vaccination and subsequent SARS-CoV-2 infection in previously uninfected individuals. Methods: Humoral immune responses were monitored by an IgG serological assay detecting neutralizing antibodies. Cellular immune responses were monitored by a SARS-CoV-2 specific interferon-gamma release assay. Results: A significant proportion of the participants in our previous booster vaccination study were subsequently infected with SARS-CoV-2. The immune response of 16 of these volunteers was followed up over several months. IgG levels peaked after approximately 1 month in both conditions, but at significantly higher levels upon viral infection than following vaccination (26.1 and 15.0 S/CO, respectively). Circulating IgG levels 4 months after booster vaccination were only 39% of the 1-month maximum. After viral infection, the corresponding value was 78%. Similar differences were observed at the cellular level, but there was no correlation between humoral and cellular immune responses. Conclusion: Compared to the effects of vaccination, SARS-CoV-2 infection elicits a more pronounced immune response, both cellular and humoral, which declines significantly more slowly with time.

IntroductionTobacco smoking generates airway inflammation in chronic obstructive pulmonary disease (COPD), and its involvement in the development of lung cancer is still among the leading causes of early death. Therefore, we aimed to have a better understanding of the disbalance in immunoregulation in chronic inflammatory conditions in smoker subjects with stable COPD (stCOPD), exacerbating COPD (exCOPD), or non-small cell lung cancer (NSCLC).MethodsSmoker controls without chronic illness were recruited as controls. Through extensive mapping of single cells, surface receptor quantification was achieved by single-cell mass cytometry (CyTOF) with 29 antibodies. The CyTOF characterized 14 main immune subsets such as CD4+, CD8+, CD4+/CD8+, CD4−/CD8−, and γ/δ T cells and other subsets such as CD4+ or CD8+ NKT cells, NK cells, B cells, plasmablasts, monocytes, CD11cdim, mDCs, and pDCs. The CD4+ central memory (CM) T cells (CD4+/CD45RA−/CD45RO+/CD197+) and CD4+ effector memory (EM) T cells (CD4+/CD45RA−/CD45RO+/CD197−) were FACS-sorted for RNA-Seq analysis. Plasma samples were assayed by Luminex MAGPIX® for the quantitative measurement of 17 soluble immuno-oncology mediators (BTLA, CD28, CD80, CD27, CD40, CD86, CTLA-4, GITR, GITRL, HVEM, ICOS, LAG-3, PD-1, PD-L1, PD-L2, TIM-3, TLR-2) in the four studied groups.ResultsOur focus was on T-cell-dependent differences in COPD and NSCLC, where peripheral CD4+ central memory and CD4+ effector memory cells showed a significant reduction in exCOPD and CD4+ CM showed elevation in NSCLC. The transcriptome analysis delineated a perfect correlation of differentially expressed genes between exacerbating COPD and NSCLC-derived peripheral CD4+ CM or CD4+ EM cells. The measurement of 17 immuno-oncology soluble mediators revealed a disease-associated phenotype in the peripheral blood of stCOPD, exCOPD, and NSCLC patients.DiscussionThe applied single-cell mass cytometry, the whole transcriptome profiling of peripheral CD4+ memory cells, and the quantification of 17 plasma mediators provided complex data that may contribute to the understanding of the disbalance in immune homeostasis generated or sustained by tobacco smoking in COPD and NSCLC.

BACKGROUND:The inconsistent European vaccine trial landscape rendered the continent of limited interest for vaccine developers. The VACCELERATE consortium created a network of capable clinical trial sites throughout Europe. VACCELERATE identifies and provides access to state-of-the-art vaccine trial sites to accelerate clinical development of vaccines. METHODS:Login details for the VACCELERATE Site Network (vaccelerate.eu/site-network/) questionnaire can be obtained after sending an email to. Interested sites provide basic information, such as contact details, affiliation with infectious disease networks, main area of expertise, previous vaccine trial experience, site infrastructure and preferred vaccine trial settings. In addition, sites can recommend other clinical researchers for registration in the network. If directly requested by a sponsor or sponsor representative, the VACCELERATE Site Network pre-selects vaccine trial sites and shares basic study characteristics provided by the sponsor. Interested sites provide feedback with short surveys and feasibility questionnaires developed by VACCELERATE and are connected with the sponsor to initiate the site selection process. RESULTS:As of April 2023, 481 sites from 39 European countries have registered in the VACCELERATE Site Network. Of these, 137 (28.5 %) sites have previous experience conducting phase I trials, 259 (53.8 %) with phase II, 340 (70.7 %) with phase III, and 205 (42.6 %) with phase IV trials, respectively. Infectious diseases were reported as main area of expertise by 274 sites (57.0 %), followed by any kind of immunosuppression by 141 (29.3 %) sites. Numbers are super additive as sites may report clinical trial experience in several indications. Two hundred and thirty-one (47.0 %) sites have the expertise and capacity to enrol paediatric populations and 391 (79.6 %) adult populations. Since its launch in October 2020, the VACCELERATE Site Network has been used 21 times for academic and industry trials, mostly interventional studies, focusing on different pathogens such as fungi, monkeypox virus, Orthomyxoviridae/influenza viruses, SARS-CoV-2, or Streptococcus pneumoniae/pneumococcus. CONCLUSIONS:The VACCELERATE Site Network enables a constantly updated Europe-wide mapping of experienced clinical sites interested in executing vaccine trials. The network is already in use as a rapid-turnaround single contact point for the identification of vaccine trials sites in Europe.

Background The pan-European VACCELERATE network aims to implement the first transnational harmonized and sustainable vaccine trial Volunteer Registry, being a single entry point for potential volunteers of large-scale vaccine trials across Europe. This work exhibits a set of harmonized vaccine trial–related educational and promotional tools for the general public, designed and disseminated by the pan-European VACCELERATE network. Objective This study primarily aimed to design and develop a standard toolkit to increase positive attitudes and access to trustworthy information for better access and increased recruitment to vaccine trials for the public. More specifically, the produced tools are focused on inclusiveness and equity, and are targeting different population groups, including underserved ones, as potential volunteers for the VACCELERATE Volunteer Registry (older individuals, migrants, children, and adolescents). The promotional and educational material is aligned with the main objectives of the Volunteer Registry to increase public literacy and awareness regarding vaccine-related clinical research or trials and trial participation, including informed consent and legal issues, side effects, and frequently asked questions regarding vaccine trial design. Methods Tools were developed per the aims and principles of the VACCELERATE project, focusing on trial inclusiveness and equity, and are adjusted to local country-wise requirements to improve public health communication. The produced tools are selected based on the cognitive theory, inclusiveness, and equity of differently aged and underrepresented groups, and standardized material from several official trustworthy sources (eg, COVID-19 Vaccines Global Access; the European Centre for Disease Prevention and Control; the European Patients’ Academy on Therapeutic Innovation; Gavi, the Vaccine Alliance; and the World Health Organization). A team of multidisciplinary specialists (infectious diseases, vaccine research, medicine, and education) edited and reviewed the subtitles and scripts of the educational videos, extended brochures, interactive cards, and puzzles. Graphic designers selected the color palette, audio settings, and dubbing for the video story-tales and implemented QR codes. Results This study presents the first set of harmonized promotional and educational materials and tools (ie, educational cards, educational and promotional videos, extended brochures, flyers, posters, and puzzles) for vaccine clinical research (eg, COVID-19 vaccines). These tools inform the public about possible benefits and disadvantages of trial participation and build confidence among participants about the safety and efficacy of COVID-19 vaccines and the health care system. This material has been translated into several languages and is intended to be freely and easily accessible to facilitate dissemination among VACCELERATE network participant countries and the European and global scientific, industrial, and public community. Conclusions The produced material could help fill knowledge gaps of health care personnel, providing the appropriate future patient education for vaccine trials, and tackling vaccine hesitancy and parents’ concerns for potential participation of children in vaccine trials.

Background: Eosinophilic chronic obstructive pulmonary disease (COPD) may represent a distinct disease phenotype. The aim of this study was to investigate the occurrence of eosinophilia in the next exacerbation of patients experiencing a severe acute exacerbation of COPD (AECOPD). Methods: Clinical parameters were measured in AECOPD patients (n=179), first at the time of hospital admission, and again at discharge following treatment. Patients were divided into eosinophilic (n=39) and noneosinophilic (n=140) groups based on blood eosinophil count results on admission. Patients were followed for 3 years to phenotype the next relapses. Data are presented as mean with SEM or median with IQR. Results: Eosinophilic AECOPD patients (≥2% and/or ≥200 cells/µL) had lower C-reactive protein levels and more pronounced improvement in FEV1 after treatment compared to noneosinophilic subjects (p<0.05 for each). The proportion of patients having no or at least one relapse during follow-up did not differ between eosinophilic (46.2 vs. 53.8%) and noneosinophilic (39.3 vs. 60.7%) groups (p=NS). However, while only 47.6% of patients with eosinophilic exacerbation had an eosinophilic relapse, the majority of noneosinophilic patients (81.2%) suffered from a similar type of exacerbation as the next episode (p<0.05). Rate of exacerbations was comparable in the eosinophilic and noneosinophilic groups (0.762±0.108 vs. 0.898±0.076, p>0.05). The median time to first eosinophilic and noneosinophilic relapses was also similar (174 [52-277] vs. 186 [70-436] days, p>0.05). Conclusions: The noneosinophilic phenotype may be more stable than the eosinophilic ones in patients experiencing severe relapses of AECOPD.

Background: Blood eosinophil count is a marker of steroid responsiveness in stable chronic obstructive pulmonary disease (COPD). The aim of this study was to assess the relationship between blood eosinophils and clinical outcomes in patients experiencing a severe acute exacerbation of COPD (AECOPD). Methods: Clinical parameters were measured in AECOPD patients (n=183), first at the time of hospital admission, and again at discharge following treatment. Patients were divided into eosinophilic (n=38) and noneosinophilic (n=145) groups based on blood eosinophil count results on admission. In a subset of patients (n=84) eosinophils in the sputum were also determined. Data are presented as mean±SEM or median with IQR. Results: Eosinophilic AECOPD patients (≥2% and/or ≥200 cells/µL) had higher fractional exhaled nitric oxide (FENO) (15.7 [5.4-27.8] vs. 7.6 [5.0-17.1] ppb, p<0.05), but lower C-reactive protein (22.4±6.1 vs. 54.6±7.7 mg/L, p<0.05) levels compared to noneosinophilic subjects. Moreover, the magnitude of the increase in forced expiratory volume in one second (ΔFEV1) after treatment was greater in this group (11.0 [5.0-15.1] vs. 7.2 [2.0-13.5] %, p<0.05). Although blood eosinophils were related with sputum eosinophils (r=0.36, p<0.005), the predictive accuracy of blood eosinophil count for sputum eosinophilia (≥2%) was only modest (ROC AUC: 0.70, p<0.05). FENO was a better predictor of airway eosinophilia (ROC AUC: 0.80, p<0.005). Conclusions: Eosinophilic AECOPD patients have lower systemic inflammatory marker levels and more improvements in airflow limitation posttreatment. The surrogate markers to detect airway eosinophilia are not of equal value.

Aims: Major mutations of SERPINA1, the gene encoding α1-antitrypsin (A1AT) are known to cause severe emphysema. Our study aimed to investigate the role of various heterozygotic mutations in modulating A1AT levels in COPD and control groups. Patients and methods: Blood samples (n=715) were collected from healthy non-smokers, healthy smokers, healthy ex-smokers, smokers with COPD, and ex-smokers with COPD. Clinical and respiratory parameters, A1AT levels, and low dose CT scans were evaluated. DNA was extracted, A1AT single nucleotide polymorphisms were determined for S, Z, M, 0 locations by SNP probes (Life Technologies) using Real-time PCR. Statistical analysis was performed by ANOVA tests and Spearman rank correlation. Results: A1AT levels were significantly higher in the COPD groups (1.47±0.24 g/L) compared to healthy smokers (1.37±0.2) or non-smokers (1.34±0.26)(p<0.001). There were no differences in the distribution of S, Z, M, 0 SNPs between groups. A1AT levels were inversely correlated to FEV1 in healthy smokers, ex-smokers with COPD. A1AT level in MZ and MS heterozygotes was significantly lower (0.87±0.1, 1.23±0.14, p<0,01) than MM groups (1.39±0.22), but FEV1/FVC was higher (75.6%±2.8) in MS group. A1AT levels in patients with emphysema seemed higher than those with no emphysema however only patients with mixed emphysema and bronchitis phenotype showed significant difference compared to patients with neither (1.6±0.28 vs1.43±0.22, p<0.05). Conclusions: Major A1AT mutations in heterozygotic form do not distinguish between patients with or without COPD. A1AT levels differ between clinically relevant COPD phenotypes. Further research is needed to clarify the role of A1AT in smoke-related pathologies.

Background: SARS-CoV-2 vaccines are expected to induce both cellular and humoral immune responses, however, the dynamics and correlation between the two types of immunity are not precisely understood. Aims: Assessing IgG levels and T-cell response induced by SARS-CoV-2 vaccines and investigating the correlation between cellular and humoral immune responses. Methods: Blood samples were taken from 166 respiratory healthcare professionals at four time-points: first before administering the booster vaccine, then on day 28, 56 and 120 post-vaccination. For the assessment of humoral immune response anti-Spike protein IgG ELISA was used, while T-cell response was tested by interferon-gamma-release-assay. Results: Out of 166 patients, 120 individuals presented positive result for interferon-gamma, while 100 had positive results for IgG. The positivity rate of cellular immune response was found to be significantly higher than humoral between the second and third doses of anti-COVID vaccines (P<0,05). Participants, who have had SARS-CoV-2 infection before the first two shots, the immune response was detectable at a statistically higher rates than in the COVID naϊve group. The third dose triggered different dynamics regarding the IgG titers and T-cell response. Four months after the administration of the booster shot both humoral and cellular immune response were detectable simultaneously. Conclusions: After the first two doses, the cellular immune response was found to last longer than humoral, especially in previously infected individuals. Measuring the T-cell responses to SARS-CoV-2 vaccines may complement the antibody tests currently used in clinical practice.

In recent years, tremendous efforts have been devoted to characterizing the inflammatory processes in chronic obstructive pulmonary disease (COPD) in order to provide more personalized treatment for COPD patients. While it has proved difficult to identify COPD-specific inflammatory pathways, the distinction between eosinophilic and non-eosinophilic airway inflammation has gained clinical relevance. Evidence has shown that sputum eosinophil counts are increased in a subset of COPD patients and that these patients are more responsive to oral or inhaled corticosteroid therapy. Due to feasibility issues associated with sputum cell profiling in daily clinical practice, peripheral blood eosinophil counts and fractional exhaled nitric oxide levels have been evaluated as surrogate biomarkers for assessing the extent of airway eosinophilia in COPD patients, both in stable disease and acute exacerbations. The diagnostic value of these markers is not equivalent and depends heavily on the patient’s condition at the time of sample collection. Additionally, the sensitivity and specificity of these tests may be influenced by the patient’s maintenance treatment. Overall, eosinophilic COPD may represent a distinct disease phenotype that needs to be further investigated in terms of prognosis and treatment outcomes.

Purpose:Cytokines are extracellular signaling proteins that have been widely implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). Here, we investigated cytokine expression both at the mRNA and protein level in the sputum of healthy individuals, stable COPD patients, and those experiencing a severe acute exacerbation (AECOPD) requiring hospitalization.Patients and Methods:Sputum was collected in 19 healthy controls, 25 clinically stable COPD patients, and 31 patients with AECOPD. In AECOPD patients sample collection was performed both at the time of hospital admission and at discharge following treatment. Sputum supernatant was analyzed by an antibody microarray detecting 120 cytokines simultaneously, while the mRNA expression of 14 selected cytokines in sputum cells was investigated by real-time PCR (qPCR).Results:Proteomic analysis identified interleukin (IL)-6 and growth-regulated oncogene (GRO)α as the only sputum cytokines that were differentially expressed between stable COPD patients and healthy controls. At the onset of AECOPD, several cytokines exhibited altered sputum expression compared to stable COPD. Recovery from AECOPD induced significant changes in the sputum cytokine protein profile; however, the length of hospitalization was insufficient for most cytokines to return to stable levels. With regard to gene expression analysis by qPCR, we found that bone morphogenetic protein (BMP)-4 was up-regulated, while IL-1α, monokine-induced by interferon-γ (MIG), and BMP-6 were down-regulated at the mRNA level in patients with AECOPD compared to stable disease.Conclusion:The sputum cytokine signature of AECOPD differs from that of stable COPD. Protein level changes are asynchronous with changes in gene expression at the mRNA level in AECOPD. The observation that the levels of most cytokines do not stabilize with acute treatment of AECOPD suggests a prolonged effect of exacerbation on the status of COPD patients.

Aims: Healthcare workers are at increased risk of SARS-CoV-2 infection and were among the first to be vaccinated against the virus. We aimed to estimate the level and duration of protection the vaccines provide against infection by monitoring the humoral immune response mounted after each vaccination. Methods: 177 and 102 respiratory health professionals were recruited before receiving initial Pfizer-Biontech and booster vaccines, respectively. Serum levels of RBD-specific IgG antibodies were measured at various time points; the unit of measurement was signal/cut-off (S/CO). Results: In previously uninfected participants, IgG production was slow to start in response to the first vaccination and only reached the positive range shortly before the second vaccination on day 21. Following the first vaccination, IgG production peaked on day 28, whereas following the booster vaccination IgG levels peaked more rapidly but at a significantly lower level (43.7 vs. 22.0 S/CO, p<0.0001). Stratification by sex and mean age showed no difference in maximum IgG levels. In most participants, IgG levels declined rapidly after both the initial and booster vaccination, but 4 months after vaccination, the booster vaccine provided a significantly higher proportion of circulating IgG compared to the maximum level (30.6% vs. 21.9%). The number of COVID-positive cases 4 months after vaccination was higher for the booster vaccine. Conclusions: Based on IgG titers, the Pfizer-Biontech booster vaccine appears to provide a longer-lasting humoral immune response compared to the first vaccination, but this may still confer less protection against new virus variants.

Background: The coronavirus disease 2019 (COVID-19) pandemic has demonstrated the key role that vaccines play against infectious diseases. Although clinical trials were rapidly established during this pandemic, identifying suitable study subjects can be challenging. For this reason, the University Hospital Cologne established a volunteer registry for participation in clinical trials first in Germany, which has now been incorporated into the European VACCELERATE clinical trials network and grew to a European Volunteer Registry. As such, VACCELERATE’s Volunteer Registry aims to become a common entry point for potential volunteers in future clinical trials in Europe. Methods Interested volunteers who would like to register for clinical trials in the VACCELERATE Volunteer Registry can access the registration questionnaire via http://www.vaccelerate.eu/volunteer-registry. Potential volunteers are requested to provide their current country and area of residence, contact information, including first and last name and e-mail address, age, gender, comorbidities, previous SARS-CoV-2 infection and vaccination status, and maximum distance willing to travel to a clinical trial site. The registry is open to both adults and children, complying with national legal consent requirements. Findings: As of January 2022, the questionnaire is available in 9 countries and 11 languages. Up to date, more than 35,000 volunteers have registered, mainly from Germany. Within the first year since its establishment, the VACCELERATE Volunteer Registry has matched 13,719 volunteers to clinical trials. The VACCELERATE Volunteer Registry will be launched in further European countries in the coming months. Interpretation: The VACCELERATE Volunteer Registry is an active single-entry point for European residents interested in COVID-19 clinical trials participation in 9 countries. To date, more than 13,000 registered individuals have been connected to clinical trials in Germany alone. The registry is currently in the implementation phase in 6 additional countries.Funding: The German Volunteer Registry receives funding from the German Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung, BMBF) specifically grant BMBF01KX2040. The VACCELERATE Volunteer Registry, i.e., registries outside Germany, has received funding from the European Union’s Horizon 2020 research and innovation programme (grant agreement No 101037867).Declaration of Interest: None to declare. Ethical Approval: The VACCELERATE Volunteer Registry was approved by the Ethics Committee of the Medical Faculty of the University of Cologne (Cologne, Germany) (Study 20-1536).

Background Chronic obstructive pulmonary disease (COPD) is associated with airway inflammation and bacterial dysbiosis. The relationship between the airway microbiome and bronchial gene expression in COPD is poorly understood. We aimed to identify differences in the airway microbiome from bronchial brushings in patients with COPD and healthy individuals and to investigate whether any distinguishing bacteria are related to bronchial gene expression. Methods For this 16S rRNA gene sequencing and host transcriptomic analysis, individuals aged 45-75 years with mild-to-moderate COPD either receiving or not receiving inhaled corticosteroids and healthy individuals in the same age group were recruited as part of the Emphysema versus Airways Disease (EvA) consortium from nine centres in the UK, Germany, Italy, Poland, and Hungary. Individuals underwent clinical characterisation, spirometry, CT scans, and bronchoscopy. From bronchoscopic bronchial brush samples, we obtained the microbial profiles using 16S rRNA gene sequencing and gene expression using the RNA-Seq technique. We analysed bacterial genera relative abundance and the associations between genus abundance and clinical characteristics or between genus abundance and host lung transcriptional signals in patients with COPD versus healthy individuals, and in patients with COPD with versus without inhaled corticosteroids treatment. Findings Between February, 2009, and March, 2012, we obtained brush samples from 574 individuals. We used 546 of 574 samples for analysis, including 207 from healthy individuals and 339 from patients with COPD (192 with inhaled corticosteroids and 147 without). The bacterial genera that most strongly distinguished patients with COPD from healthy individuals were Prevotella (median relative abundance 33.5%, IQR 14.5-49.4, in patients with COPD vs 47.7%, 31.1-60.7, in healthy individuals; p<0.0001), Streptococcus (8.6%, 3.8-15.8, vs 5.3%, 3.0-10.1; p<0.0001), and Moraxella (0.05%, 0.02-0.14, vs 0.02%, 0-0.07; p<0.0001). Prevotella abundance was inversely related to COPD severity in terms of symptoms and positively related to lung function and exercise capacity. 446 samples had assessable RNA-seq data, 257 from patients with COPD (136 with inhaled corticosteroids and 121 without) and 189 from healthy individuals. No significant associations were observed between lung transcriptional signals from bronchial brushings and abundance of bacterial genera in patients with COPD without inhaled corticosteroids treatment and in healthy individuals. In patients with COPD treated with inhaled corticosteroids, Prevotella abundance was positively associated with expression of epithelial genes involved in tight junction promotion and Moraxella abundance was associated with expression of the IL-17 and TNF inflammatory pathways. Interpretation With increasing severity of COPD, the airway microbiome is associated with decreased abundance of Prevotella and increased abundance of Moraxella in concert with downregulation of genes promoting epithelial defence and upregulation of pro-inflammatory genes associated with inhaled corticosteroids use. Our work provides further insight in understanding the relationship between microbiome alteration and host inflammatory response, which might lead to novel therapeutic strategies for COPD. Copyright (C) 2021 The Author(s). Published by Elsevier Ltd.

Chronic obstructive pulmonary disease (COPD) is a destructive inflammatory disease and the genes expressed within the lung are crucial to its pathophysiology. We have determined the RNAseq transcriptome of bronchial brush cells from 312 stringently defined ex-smoker patients. Compared to healthy controls there were for males 40 differentially expressed genes (DEGs) and 73 DEGs for females with only 26 genes shared. The gene ontology (GO) term "response to bacterium" was shared, with several different DEGs contributing in males and females. Strongly upregulated genes TCN1 and CYP1B1 were unique to males and females, respectively. For male emphysema (E)-dominant and airway disease (A)-dominant COPD (defined by computed tomography) the term "response to stress" was found for both sub-phenotypes, but this included distinct up-regulated genes for the E-sub-phenotype (neutrophil-related CSF3R, CXCL1, MNDA) and for the A-sub-phenotype (macrophage-related KLF4, F3, CD36). In E-dominant disease, a cluster of mitochondria-encoded (MT) genes forms a signature, able to identify patients with emphysema features in a confirmation cohort. The MT-CO2 gene is upregulated transcriptionally in bronchial epithelial cells with the copy number essentially unchanged. Both MT-CO2 and the neutrophil chemoattractant CXCL1 are induced by reactive oxygen in bronchial epithelial cells. Of the female DEGs unique for E- and A-dominant COPD, 88% were detected in females only. In E-dominant disease we found a pronounced expression of mast cell-associated DEGs TPSB2, TPSAB1 and CPA3. The differential genes discovered in this study point towards involvement of different types of leukocytes in the E- and A-dominant COPD sub-phenotypes in males and females.

Purpose Fractional exhaled nitric oxide (FENO50) level and peripheral blood eosinophil count may serve as indicators of airway eosinophilia. The aim of this study was to estimate the diagnostic value of these markers for detecting airway eosinophilia in patients with stable chronic obstructive pulmonary disease (COPD) and those experiencing an acute exacerbation (AECOPD). Patients and Methods FENO50 levels, sputum and blood eosinophil counts were assessed in 53 clinically stable ex-smoker COPD patients and 67 ex-smoker COPD patients experiencing a severe exacerbation. In AECOPD, clinical variables were measured at the time of hospital admission and discharge following treatment. Results In stable COPD, blood eosinophil count but not FENO50 level was found to be a good predictor of airway eosinophilia (area under the receiver operating characteristic curve [ROC AUC]: ≥0.82). The sensitivity and the specificity of the test ranged between 75% and 98%, the negative predictive value (NPV) was high (>90%). In AECOPD, FENO50 was predictive for airway eosinophilia (ROC AUC: >0.8) with high NPV (>88%), but with lower sensitivity and specificity (64–70%). In contrast, the predictive accuracy of blood eosinophil count for airway eosinophilia in AECOPD was modest (ROC AUC: 0.54–0.63). The combined use of the two markers provided only limited additional benefit. Correlation analyses supported ROC curve findings. Conclusion In stable COPD the peripheral blood eosinophil count, while in AECOPD the FENO50 level is a good surrogate marker of airway eosinophilia.