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Background/Objectives: Bronchial wash for microbiological cultivation and/or multiplex polymerase chain reaction (PCR) is often routinely performed during bronchoscopy independent of the indication for bronchoscopy. This study aimed to determine and compare the pathogen spectrum evaluated by culture and PCR in bronchial secretion samples with regard to the underlying lung pathology. Methods: In this retrospective analysis, microbiological results from bronchial washes performed from February 2022 to September 2022 were collected in 245 patients (48.2% male, mean age 63.0 ± 13.9 years). Samples were assessed for bacteria/fungi culture and reported depending on the underlying pathology. Additional PCR was performed in 216 patients and compared to the results of the culture. Results: Cultivation and PCR revealed positive results in 20% and 24.5% of the cases, respectively. Microbiological culture most likely revealed a positive result in patients with hemoptysis (44.4%) and pulmonary infections (29.6%) among various indications for bronchoscopy, and PCR most likely identified a pathogen in patients with hemoptysis (66.7%) and COPD (36.4%). Active smoking and an increased CRP were revealed as significant predictors for a positive culture ( p < 0.0001 and p = 0.021). The concordance rate between culture and PCR for identifying pathogenic microorganisms was 84.3%, resulting in a moderate agreement (kappa coefficient 0.54 [95% CI: 0.34-0.68]). Conclusion: PCR and culture moderately agreed, showing additional PCR testing only to be beneficial if restricted to proper indications, providing rapid diagnosis and therefore leading to immediate therapeutic decisions., Competing Interests: The authors declare no conflicts of interest related to this manuscript.

Background: Patients with asthma with >10 pack-years are frequently excluded from asthma trials. Little is known about how smoking affects their characteristics and therefore may impact treatment choices., Objective: To evaluate the impact of cumulative smoking history on the characteristics of patients with severe asthma., Methods: We analyzed pulmonary function tests, asthma control, exacerbation rate, and biomarkers. We compared active and ex-smokers (=ever-smokers) versus never-smokers and performed linear models for 3 groups stratified by smoking history (<10 pack-years [py], 10-20 py, and >20 py). Data were obtained from the severe asthma registry German Asthma Net., Results: We included 2478 patients: 65 (2.6%) active smokers, 1005 (40.6%) ex-smokers, and 1408 (56.8%) never-smokers. Of the 1070 ever-smokers, 529 patients (21.3%) had <10 py, 304 (12.3%) 10-20 py, and 237 (9.6%) >20 py. Cumulative smoking history was associated with worse asthma control (>20 py: Asthma Control Test -1.76 [-2.76; -0.77] points [P < .001]; mini-Asthma Quality of Life Questionnaire -0.31 [-0.53; -0.10] points [P = .004]), whereas exacerbation rate and maintenance oral corticosteroid (OCS) doses were similar (P = .13 and P = 1.0). Cumulative smoking history was associated with smoking-related lung injury, for example, diffusing capacity for carbon monoxide (-0.37 mmol/min/kPa for 10-20 py [P = .014], respectively, -0.92 for >20 py [P < .001]), but forced expiratory volume in 1 second (FEV1) and FEV1 reversibility were similar. Cumulative smoking history was furthermore associated with 0.84 [0.73; 0.97]-fold lower fractional exhaled nitric oxide (FeNO) concentrations (P = .007), whereas blood eosinophil count and IgE levels were comparable (BEC: P = 1.0 and IgE: P = .49)., Conclusions: Cumulative smoking history in patients with asthma is associated with worse disease control, lower FeNO levels, and smoking-related lung injuries. Despite these differences, key asthma characteristics such as BEC, IgE, OCS dose, and exacerbation rates remain similar. If thoroughly examined and selected, patients with >10 py may also qualify for targeted treatments., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Sex-based differences in histological subtypes, in frequencies of mutations, and differences in response to the various therapeutic approaches in lung cancer are well studied. In general, the literature is controversial, and the large majority of the investigations may not provide evidence from the last decade., Objective: The objective of the current study was to reveal timely sex-based differences in patients with lung cancer in the era of immunotherapy and molecularly targeted agents., Methods: We retrospectively analyzed a consecutive cohort of 286 patients (female:male ratio 134:152/47 %:53 %) who were diagnosed with lung cancer between 2020 and 2022 in the pulmonology department of the Medical University of Vienna, Austria. Demographic characteristics, histological subtypes, the PD-L1 expression on tumor cells, presence of mutations, treatment, and survival of male and female patients were compared., Results: The smoking rate in women with lung cancer was significantly lower than in men (p = 0.005). The rate of targetable mutations was significantly higher in female patients (52 % vs. 30 %, p = 0.011). There were no significant differences in age at diagnosis, body mass index, lung function parameters, histological subtypes, PD-L1 protein expression, disease stage, and survival between men and women (all p > 0.05)., Conclusion: Female Caucasian patients seem to have a higher susceptibility to lung cancer. Although the rate of genetic alterations is similar in both sexes, actionable driver mutations are significantly more common in women., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2025 The Authors.)

Background: Clinical studies of biologics in severe asthma exclude smokers or ex-smokers (ExS) with over 10 pack-years (py). Thus, the effectiveness of this therapy in ExS with severe asthma is not well understood., Objectives: To assess the impact of smoking on clinical efficiency of biologics in patients with severe asthma from the German Asthma Net, a comprehensive international registry., Methods: This analysis included 1129 patients (55.8% female, mean age: 53.82 ± 14.67 years), of whom 56% were never-smokers (NS), whereas 44% were ExS (<10 py: 22.9%, 10-20 py: 10.3%, and >20 py: 10.6%). They received benralizumab (38.3%), dupilumab (28.9%), mepolizumab (18.3%), omalizumab (14%), or reslizumab (0.5%)., Results: Biologic therapy significantly improved asthma control, measured by change in Asthma Control Test, Asthma Control Questionnaire-5, and Mini-Asthma Quality of Life Questionnaire, lung function, reduced exacerbations, and daily oral prednisolone dose in all patients at week 52. Of note, no significant differences in asthma control between NS and ExS at week 52 (P = .48, .09, and .15, respectively) were observed. Also, lung function improvement (forced expiratory volume in 1 second, forced vital capacity, total lung capacity, peak expiratory flow, mean expiratory flow at 50%, P > .05), and reduction in acute exacerbation (P = .8) and oral corticosteroid doses (P = .15) were comparable in NS and ExS. Markers of type 2 inflammation, such as fraction of exhaled nitric oxide and blood eosinophils, decreased in ExS similar to NS (P = .29 and P = .48, respectively)., Conclusion: ExS with severe asthma experienced similar improvements in asthma control, exacerbations, lung function, and biomarkers as NS after 1 year of biologics, suggesting that severe asthmatics even with a substantial smoking history can benefit from biologic therapy., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Many patients with severe coronavirus disease 2019 pneumonia exhibit signs of microthrombosis. Previous studies discussed intravenous fibrinolytic agents as potential add-on therapy in these patients. Therefore, we propose the inhalative administration of fibrinolytics as a possible safer alternative., Case Presentation: This case series describes five white male patients, aged 51-78 years, treated with off-label inhalation of alteplase between November and December 2020. All patients suffered from severe severe acute respiratory syndrome coronavirus 2 infection with respiratory failure. Pulmonary embolism was ruled out by pulmonary angiogram in computed tomography scans, and all patients showed signs of coronavirus disease 2019 pneumonia. Four patients improved clinically, while one patient with advanced chronic diseases died due to multiple organ failure. No directly associated adverse effects were observed following inhalation of alteplase., Conclusion: This case series warrants further attention to investigate inhalative alteplase as an additional treatment in patients with severe coronavirus disease 2019 infection., Competing Interests: Declarations. Ethics approval and consent to participate: Five patients underwent “off-label” treatment with nebulized alteplase at the department of pulmonology of the university/tertiary hospital of Vienna between 2 November and 15 December 2020. Data were collected in January 2021. This retrospective case series report was approved by our institutional ethics committee (2362/2020). Consent for publication: Written informed consent was obtained from three patients or the next of kin for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal. In two cases, no contact could be established with the patient or next of kin. Competing interests: The authors declare that they have no competing interests., (© 2024. The Author(s).)

In many cases sarcoidosis is a multisystemic disease that requires interdisciplinary medical cooperation in the diagnostics, treatment and medical care during follow-up. Due to the often chronic course, it is of utmost importance to include patients with their priorities and wishes at an early stage and extensively in disease management and to establish a shared decision making whenever possible. In the process of writing this joint position paper, the expert group on interstitial and orphan lung diseases of the Austrian Society for Pulmonology and the working group on rheumatological lung disorders of the Austrian Society for Rheumatology and Rehabilitation sought to include patient advocacy groups as well as experts for rare organ manifestations of sarcoidosis. This position paper is not only meant to reflect current scientific and clinical standards but should also focus the national expertise and by networking and exchange to be a first step to strengthen cooperation between stakeholders to ultimately improve care for patients with sarcoidosis., (© 2024. The Author(s).)

PD-1 (programmed cell death protein-1)/PD-L1 (programmed cell death ligand 1) as well as IL-10 (interleukin-10)/IL-10R (interleukin-10 receptor) interactions play a major role in tumor immune evasion in various malignancies. Several studies investigated the expression of PD-1 on T lymphocytes in pleural effusions (PE) in patients with malignant diseases. However, results in malignant pleural effusions (MPE) compared to benign PE (BPE) are underreported. In this prospective study, 51 patients (median age 66 years, IQR 54-78, 47% male) with PE of malignant or benign origin at the Medical University of Vienna between March 2021 and November 2022 were enrolled and divided into three groups according to the cytological results (group 1: MPE [n = 24, 47%]; group 2: BPE in malignant disease [n = 22, 43%]; group 3: BPE in benign disease [n = 5, 10%]). In the cytological samples, T cells were analyzed for the expression of PD-1 and IL-10R via flow cytometry. In MPE, the proportion of PD-1+ T lymphocytes on CD4+ cells was significantly lower than in BPE (40.1 vs. 56.3 in group 1 vs. 3, p = 0.019). Moreover, a significantly lower expression of PD-1+ IL-10R+ CD8+ (9.6 vs. 35.2 in group 1 vs. 2, p = 0.016; 9.6 vs. 25.0 in group 1 vs. 3, p = 0.032) and a significantly higher expression of PD-1-IL-10R-CD8+ T lymphocytes (43.7 vs. 14.0 in group1 vs. 2, p = 0.045; 43.7 vs. 23.3 in group 1 vs. 3, p = 0.032) were observed in MPE when compared to BPE. The frequency of T cells expressing PD-1 and IL-10R on CD8+ T cells is significantly lower in MPE compared to BPE regardless of the underlying disease indicating a different microenvironment in PE driven by the presence of tumor cells. Our observation spotlights the possible involvement of PD-1 and IL-10R in MPE., (© 2024. The Author(s).)

Background: Invasive aspergillosis is a severe fungal infection that affects multiple organ systems including the CNS and the lungs. Isavuconazole, a novel triazole antifungal agent, has demonstrated promising activity against Aspergillus spp. However, data on the penetration of isavuconazole into the CNS and ELF and intracellular accumulation remain limited., Materials and Methods: We conducted a prospective single-centre pharmacokinetic (PK) study in 12 healthy volunteers. Subjects received seven doses of 200 mg isavuconazole to achieve an assumed steady-state. After the first and final infusion, plasma sampling was conducted over 8 and 12 h, respectively. All subjects underwent one lumbar puncture and bronchoalveolar lavage, at either 2, 6 or 12 h post-infusion of the final dose. PBMCs were collected in six subjects from blood to determine intracellular isavuconazole concentrations at 6, 8 or 12 h. The AUC/MIC was calculated for an MIC value of 1 mg/L, which marks the EUCAST susceptibility breakpoint for Aspergillus fumigatus and Aspergillus flavus., Results: C max and AUC0-24h of isavuconazole in plasma under assumed steady-state conditions were 6.57 ± 1.68 mg/L (mean ± SD) and 106 ± 32.1 h·mg/L, respectively. The average concentrations measured in CSF, ELF and in PBMCs were 0.07 ± 0.03, 0.94 ± 0.46 and 27.1 ± 17.8 mg/L, respectively. The AUC/MIC in plasma, CSF, ELF and in PBMCs under steady-state conditions were 106 ± 32.1, 1.68 ± 0.72, 22.6 ± 11.0 and 650 ± 426 mg·h/L, respectively., Conclusion: Isavuconazole demonstrated moderate penetration into ELF, low penetrability into CSF and high accumulation in PBMCs. Current dosing regimens resulted in sufficient plasma exposure in all subjects to treat isolates with MICs ≤ 1 mg/L., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Chronic rhinosinusitis (CRS) is a persistent nasal and paranasal sinus mucosa inflammation comprising two phenotypes, namely CRS with nasal polyps (CRSwNP) and without (CRSsNP). CRSwNP can be associated with asthma and hypersensitivity to non-steroidal anti-inflammatory drug (NSAID) in a syndrome known as NSAID-exacerbated respiratory disease (N-ERD). Furthermore, CRS frequently intertwines with respiratory allergies. This study investigated levels of 33 different nasal and serum cytokines and phenotypic characteristics of peripheral blood mononuclear cells (PBMCs) within cohorts of CRS patients (n = 24), additionally examining the influence of comorbid respiratory allergies by mass cytometry. N-ERD patients showed heightened type 2 nasal cytokine levels. Mass cytometry revealed increased activated naive B cell levels in CRSwNP and N-ERD, while resting naive B cells were higher in CRSsNP. Th2a cell levels were significantly elevated in allergic subjects, but not in CRS groups. In conclusion, there are distinct immunological features in PBMCs of CRS phenotypes and allergy., Competing Interests: Declaration of competing interest SS served as a speaker and/or consultant and/or advisory board member for Sanofi, GSK, and Novartis. SS is an investigator for Novartis and AstraZeneca (grants paid to his institution). JED served as a speaker and/or consultant and/or advisory board member for Sanofi, Allergopharma, AstraZeneca, GSK, and Novartis. JED is an investigator for Novartis and AstraZeneca (grants paid to her institution)., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

After the GINA update in 2019, the proportion of SMART therapy increased with evidence for better disease control in SMART patients compared to SABA alone https://bit.ly/3SSPX1C., Competing Interests: Conflict of interest: C.A. Hinze has nothing to disclose. Conflict of interest: R. Ehmann has nothing to disclose. Conflict of interest: M. Jandl has nothing to disclose. Conflict of interest: K. Milger reports fees for lectures or consultation from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Novartis and Sanofi, all outside the submitted work. Conflict of interest: O. Schmidt reports fees for lectures or consultations from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Novartis and Sanofi, all outside the submitted work. Conflict of interest: C. Schulz reports fees for lectures or consultations from AstraZeneca, Novartis and Sanofi, all outside the submitted work. Conflict of interest: D. Skowasch reports fees for lectures or consultation from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Janssen, MSD and Sanofi, all outside the submitted work. Conflict of interest: T. Welte and/or his institution received grants advisory/lecture/clinical trial fees and non-financial support from BMBF (German Ministry of Research and Education), AstraZeneca, GSK, Sanofi Aventis and Biotest, outside the submitted work. Conflict of interest: R. Buhl reports grants to Mainz University from Boehringer Ingelheim, GSK, Novartis, and Roche, as well as personal fees from AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Chiesi, Cipla, GSK, Novartis, Roche, Sanofi and Teva, all outside the submitted work. Conflict of interest: E. Hamelmann is funded by the BMBF (CHAMP, project number 01GL1742D) for characterisation of children and adolescents with severe asthma; he reports personal fees from ALK, Boehringer Ingelheim, GSK, Leti Pharma, Novartis, Nutricia, Sanofi and Stallergenes, all outside the submitted work. Conflict of interest: M. Idzko has received fees for lectures and/or advisory board meetings from Alk Pharma, AstraZeneca, Berlin-Chemie, Chiesi, CSL-Behring, Jansen & Jansen, Menarini, Novartis, Roche, Sanofi Aventis and Teva, all outside the submitted work. Conflict of interest: C. Taube has nothing to disclose. Conflict of interest: S. Korn has received fees for lectures and/or advisory board meetings from AstraZeneca, Chiesi, GSK, Novartis, Roche, Sanofi Aventis and Teva, all outside the submitted work. Conflict of interest: H. Suhling reports fees for lectures or consultation from AstraZeneca, GSK, Novartis and Sanofi, all outside the submitted work., (Copyright ©The authors 2024.)

The programmed cell death-ligand 1 (PD-L1) protein expression on tumor cells predicts the efficacy of immunotherapy in patients with non-small cell lung cancer. However, the assessment of PD-L1 expression on tumor cells has limited power for selecting patients for immunotherapy due to intra-tumoral heterogeneity and inter-tumoral heterogeneity of PD-L1 expression, the inter-observer variability in scoring PD-L1 staining, and reproducibility. These difficulties and pitfalls in interpreting the PD-L1 assessment are discussed in detail in this review., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: APN01 is a soluble recombinant human angiotensin-converting enzyme 2 (rhACE2), a key player in the renin-aldosterone-angiotensin system (RAAS). In clinical studies, APN01 was administered intravenously only, so far. The aim of this study (ClinicalTrials.gov: NCT05065645) was to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of inhaled APN01., Methods: This was a phase I, double-blind, placebo-controlled, dose-escalation study. Inhalation was conducted via a nebuliser over 15 min in three single ascending dose (SAD) cohorts (n=24) and two multiple ascending dose (MAD) cohorts (n=16: every 12 h for 7 days). Doses in the SAD cohort were 1.25, 2.5 and 5 mg·mL -1 ; doses in the MAD cohort were 2.5 and 5 mg·mL -1 . Safety (including adverse events (AEs), laboratory findings and lung function results), PK and PD data were assessed., Results: In the SAD and MAD cohorts, treatment-related AEs were slightly more frequent in the active treatment group than in the placebo group. AEs were mild to moderate, with no dose-limiting toxicities. No clinically relevant changes in lung function and laboratory results were observed. The mean maximum observed plasma concentration ( C max ) values after single and multiple doses of 5 mg·mL -1 APN01 were 1.88 and 6.61 ng·mL -1 , respectively. Among the PD variables, significance was found for ACE2 and angiotensin 1-5., Conclusions: The application of aerosolised APN01 is safe and well tolerated after single and multiple doses. By achieving a high local concentration in the lungs and low systemic bioavailability, inhaled rhACE2 may present a therapeutic option in ACE2-related diseases., Competing Interests: Conflict of interest: This work was supported by Apeiron Biologics and conducted as contract research at the Medical University of Vienna, Department of Pulmology and Department of Clinical Pharmacology. The funder did not have any role in the execution of the study or interpretation of data. The academic authors declare no conflict of interest., (Copyright ©The authors 2024.)

Acute respiratory distress syndrome (ARDS) is associated with high morbidity and mortality resulting from a direct or indirect injury of the lung. It is characterized by a rapid alveolar injury, lung inflammation with neutrophil accumulation, elevated permeability of the microvascular-barrier leading to an aggregation of protein-rich fluid in the lungs, followed by impaired oxygenation in the arteries and eventual respiratory failure. Very recently, we have shown an involvement of the Gq-coupled P2Y2 purinergic receptor (P2RY2) in allergic airway inflammation (AAI). In the current study, we aimed to elucidate the contribution of the P2RY2 in lipopolysaccharide (LPS)-induced ARDS mouse model. We found that the expression of P2ry2 in neutrophils, macrophages and lung tissue from animals with LPS-induced ARDS was strongly upregulated at mRNA level. In addition, ATP-neutralization by apyrase in vivo markedly attenuated inflammation and blocking of P2RY2 by non-selective antagonist suramin partially decreased inflammation. This was indicated by a reduction in the number of neutrophils, concentration of proinflammatory cytokines in the BALF, microvascular plasma leakage and reduced features of inflammation in histological analysis of the lung. P2RY2 blocking has also attenuated polymorphonuclear neutrophil (PMN) migration into the interstitium of the lungs in ARDS mouse model. Consistently, treatment of P2ry2 deficient mice with LPS lead to an amelioration of the inflammatory response showed by reduced number of neutrophils and concentrations of proinflammatory cytokines. In attempts to identify the cell type specific role of P2RY2, a series of experiments with conditional P2ry2 knockout animals were performed. We observed that P2ry2 expression in neutrophils, but not in the airway epithelial cells or CD4 + cells, was associated with the inflammatory features caused by ARDS. Altogether, our findings imply for the first time that increased endogenous ATP concentration via activation of P2RY2 is related to the pathogenesis of LPS-induced lung inflammation and may represent a potential therapeutic target for the treatment of ARDS and predictably assess new treatments in ARDS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Kargarpour, Cicko, Köhler, Zech, Stoshikj, Bal, Renner, Idzko and El-Gazzar.)

Background: Current guidelines on the management of chronic cough do not provide recommendations for the operation of specialist cough clinics. The objective of the present study was to develop expert consensus on goals and standard procedures for specialist cough clinics., Methods: We undertook a modified Delphi process, whereby initial statements proposed by experts were categorised and presented back to panellists over two ranking rounds using an 11-point Likert scale to identify consensus., Results: An international panel of 57 experts from 19 countries participated, with consensus reached on 15 out of 16 statements, covering the aims, roles and standard procedures of specialist cough clinics. Panellists agreed that specialist cough clinics offer optimal care for patients with chronic cough. They also agreed that history taking should enquire as to cough triggers, cough severity rating scales should be routinely used, and a minimum of chest radiography, spirometry and measurements of type 2 inflammatory markers should be undertaken in newly referred patients. The importance of specialist cough clinics in promoting clinical research and cough specialty training was acknowledged. Variability in healthcare resources and clinical needs between geographical regions was noted., Conclusions: The Delphi exercise provides a platform and guidance for both established cough clinics and those in planning stages., Competing Interests: Conflict of interest: W-J. Song declares grants from Merck Sharp & Dohme Corp. and AstraZeneca, consulting fees from Merck, Bellus, AstraZeneca, Shionogi and GSK, and lecture fees from Merck, AstraZeneca, GSK, Sanofi and Novartis, outside the submitted work; and is Deputy Chief Editor of this journal. K.F. Chung has received honoraria for participating on advisory board meetings of GSK, AstraZeneca, Novartis, Merck, Nocion, Shionogi and Reckitt Benckiser, and on the scientific advisory board of the Clean Breathing Institute supported by GSK Health Care Consumer Products; he has also been remunerated for speaking engagements by AstraZeneca, Novartis and Merck. M. Dąbrowska reports fees from MSD for consultations on chronic cough and fees from Chiesi Poland for lectures on chronic cough. P. Dicpinigaitis reports consultant fees from Algernon, Boehringer Ingelheim, Bellus, Chiesi, Merck and Trevi, outside the submitted work. P.G. Gibson reports grant funding to his institution from GSK, MRFF and NHMRC; and funding to present educational lectures from AstraZeneca, GSK and Novartis, outside the submitted work. C.D. Ribas has acted as consultant for GSK, AstraZeneca and Sanofi; and has received funding for travel or speaker fees from ALK, Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Menarini, Novartis, Stallergenes and Pfizer. J.H. Hull has received advisory fees from MSD Pharmaceuticals and is a medical advisor to Bellus Health; he is an Associate Editor of this journal. P. Kardos received personal consultation fees from Bayer, Klosterfrau, Merck Sharp & Dohme and Shionogi; honoraria for presentations from Bionorica, Engelhard, Klosterfrau, Merck Sharp & Dohme and Schwabe; and clinical trial participation fees from Bellus and Merck Sharp & Dohme. F. Lavorini received grants for research from Chiesi Farmaceutici, GSK and MSD Italy; and honoraria for talks or participation in advisory boards from AstraZeneca, Chiesi Farmaceutici, GSK, Menarini International, MSD Italy, HIKMA, Cipla and Trudell International. A.H. Morice has received consulting fees from Bayer, Bellus, Merck, NeRRi and Shionogi; lecture fees from Boehringer Ingelheim, Merck and Chiesi; and grant support from Bayer, Bellus, Merck, Nocion, Philips, NeRRi and Shionogi, outside the submitted work; and is an Associate Editor of this journal. A. Niimi reports grants from KYORIN Pharmaceutical Co., Ltd; payment or honoraria for speaker's fees from AstraZeneca K.K., KYORIN Pharmaceutical Co. Ltd, GSK K.K., Sanofi K.K. and Novartis Pharma K.K.; and participation on a data safety monitoring or advisory board of KYORIN Pharmaceutical Co., Ltd and MSD K.K. S.M. Parker reports advisory fees from Merck and Trevi. I. Satia reports grants and personal fees from Merck Canada, Bellus Health and GSK; clinical trial participation from Bayer; and personal fees from Respiplus, Genentech and AstraZeneca, outside the submitted work; and is an Associate Editor of this journal. The other authors declare that they have no competing interests., (Copyright ©The authors 2023.)

Background: For therapy of severe asthma 5 monoclonal antibodies have been available in Germany up to November 2022, but no clear rules exist on choice of initial therapy, assessment of response, and switch., Objective: To assess current practice on all aspects of biologic therapy by specialists in Germany., Methods: A questionnaire was created by specialists for severe asthma, which was tested and modified by further experts. We invited 119 pulmonologists of the German Asthma Net (GAN) to complete the survey and used SoSci Survey and SPSS for data collection and analysis., Results: Forty-seven pulmonologists took part in the survey with a median annual number of patients treated with biologics of 35, 55% worked in an outpatient practice, and 40% in a hospital. Exacerbations and oral steroid use were the most important factors for the decision to start a biologic therapy. Accordingly, these parameters were also the most relevant for assessment of response. Most participants considered type-2 inflammation biomarkers and comorbidities (foremost CRSwNP and AD) for choosing initial biologic. Asthma Control Test (ACT) was the most common instrument for assessing status of disease control. There was no consensus on thresholds for response of pulmonary function tests including FEV1, FVC, and RV. Eighty-five percent of participants distinguished between "responders", "partial responders" and "non-responders". Comorbidities played an important role for the decision to switch to another biologic, eg, when initial therapy had insufficient effectiveness on CRSwNP., Conclusion: This study provides a detailed insight into current opinions and practice of biologic use in severe asthma in Germany., Competing Interests: HS reports fees for lectures or consultations from Astrazeneca, GSK, Novartis, Sanofi all outside the submitted work. DS reports fees for lectures or consultations from AstraZeneca, Bayer, Boehringer Ingelheim, Chiesi, GSK, Janssen, MSD, Sanofi, all outside the submitted work. KCB reports speaker fees from AstraZeneca, GSK, Novartis, Sanofi all outside the submitted work. CM no conflicts of interest. RB reports consulting fees or honoraria for lectures from ALK, AstraZeneca, Berlin-Chemie, Boehringer-Ingelheim, Chiesi, Cipla, GSK, Novartis, Roche, Sanofi, and TEVA, and grants to Mainz University Hospital for research or clinical trials, or both from Boehringer Ingelheim, GSK, Novartis, and Roche. RE no conflicts of interest. EH is funded by the German Ministry of Education and Research (BMBF) (CHAMP, Project Number: 01GL1742D) for characterisation of children and adolescents with severe asthma. He reports personal fees from ALK, Boehringer Ingelheim, GSK, Leti Pharma, Novartis, Nutricia, Sanofi, and Stallergenes all outside the submitted work. MI reports personal fees from AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Chiesi, CSL-Behring, Menarini, MSD, Novartis, Roche, Sanofi, all outside the submitted work. MJ no conflicts of interest. CS received personal fees from AstraZeneca, Boehringer Ingelheim, Novartis, and Sanofi, all outside the submitted work. OS reports speaker fees from AstraZeneca, Novartis, Sanofi and Boehringer Ingelheim, all outside the submitted work. CT no conflicts of interest. KM reports speaker fees from AstraZeneca, GSK, Novartis, Sanofi, all outside the submitted work. SK reports speaker fees from AstraZeneca, GSK, Novartis, Sanofi, all outside the submitted work., (© 2023 The Authors.)

Purpose: Several studies have shown that SARS-CoV-2 can induce a massive release of cytokines which contributes to disease severity and mortality. Therefore, cytokine levels in the serum may help to predict disease severity and survival in COVID-19 patients., Methods: In this prospective trial, 88 patients who were hospitalised for COVID-19 were enrolled. Blood samples for serum peptide measurements were taken at the time closest to hospitalisation, at day 5, 9 and 13 (±1). The concentrations of cytokines (IL-1α, IL-1β, IL-1RA, IL-6, L-7, L-10, IFN-γ and TNF-α), chemokines (CCL-3, CCL-4 and CCL-7) and growth factors (G-CSF, GM-CSF and VEGF) were assessed and correlated with the type of ventilation, occurrence of consolidations on imaging and the level of care., Results: COVID-19 patients (median age 68 years, IQR 55-77) stayed in hospital between 5-171 days. Compared to patients in the general care unit, patients in the intermediate care unit (IMCU) and intensive care unit (ICU) presented significantly elevated serum IL-6 (p = 0.004) and lower IFN-γ levels (p = 0.005), respectively. The peak inspiratory pressure in ventilated patients correlated positively with IL-1RA, G-CSF and inversely with IFN-γ serum levels (all p<0.05). VEGF serum levels inversely correlated with the fraction of inspired oxygen in patients receiving high-flow nasal canula oxygen therapy (p = 0.047). No significant correlation between serum concentrations of the measured peptides and the type of ventilation, occurrence of radiological consolidations or in-hospital mortality has been observed., Conclusion: IL1-RA, IL-6, IFN-γ, G-CSF, CCL-7 and VEGF serum levels could prove helpful as biomarkers to assess disease severity and the need for intensive care in COVID-19 patients., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Gysan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: The Severe Asthma Registry, founded by German Asthma Net (GAN) in 2011, is a prospective registry recording clinical parameters from participating centers in Germany, Austria and Switzerland. This article presents the baseline characteristics of severe asthma patients from Austrian centers., Methods: We analyzed the baseline visit data of all patients recruited to the GAN Severe Asthma Registry from participating Austrian centers., Results: Baseline visit data were available for 214 Austrian severe asthma patients from 6 Austrian centers from 2013 to 2022. Mean age was 53.7 years. Mean BMI was 26.4 kg/m2. More than a third (37.4%) of all patients had daily daytime asthma symptoms at baseline and had to use their reliever medication at least once per day. Forty-one percent of patients were classified as uncontrolled according to GINA and 24.8% as partially controlled at baseline visit. The median annual exacerbation frequency was 3 in the previous 12 months. At the time of baseline visit, 23.4% of all patients had regular treatment with oral corticosteroids. Furthermore, 23.9% had received any severe asthma monoclonal antibody prior to the baseline visit. There were no notable differences in baseline characteristics between patients categorized by smoking history or measurable type 2 inflammation., Conclusions: This study provides the first multi-center characterization of Austrian severe asthma patients. Patients in this cohort had better asthma control and less frequent exacerbations compared to most international registries., Competing Interests: Declaration of competing interest Andreas Renner: None. Slagjana Stoshikj: Speaker fees from AstraZeneca, all outside the submitted work. Wolfgang Pohl: Speaker fees from AstraZeneca, Chiesi, GSK, Novartis, and Sanofi, all outside the submitted work. Christina Bal: speaker fees from AstraZeneca and IVEPA, all outside the submitted work. Matthias Reisinger: None. Judith Löffler-Ragg: None. Angela Zacharasiewicz: None. Roland Buhl: Grants to Mainz University and personal fees from Boehringer Ingelheim, GSK, Novartis, and Roche, as well as personal fees from AstraZeneca, Chiesi, Cipla, Sanofi, and Teva, all outside the submitted work. Eckard Hamelmann: funded by the German Ministry of Education and Reserch (BMBF) as consortional partner in CHAMP (01GL1742D) for research in severe asthma in children. Christian Taube: None. Stephanie Korn: speaker fees from AstraZenca, GSK, Novartis, and Sanofi, all outside the submitted work. Marco Idzko: lecture fees from AstraZeneca, Bayer, Berlin-Chemie, Boehringer Ingelheim, Chiesi, CSL-Behring, GSK, Menarini, MSD, Novartis, Roche, Sanofi, and Thermofischer; and advisory board fees from Alk-Pharma, AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Chiesi, CSL-Behring, GSK, Novartis, and Sanofi, all outside the submitted work., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Asthma is increasingly recognized as heterogeneous, characterized by different endotypes, with obesity not only a distinct phenotype but a risk factor for severe asthma., Objective: We sought to understand the associations of obesity with relevant parameters of severe asthma, including asthma control, disease burden, and lung function., Methods: The German Asthma Net registry is a multicenter international real-life registry capturing long-term follow-up data. This analysis included 2213 patients (52 ± 16 years, 58% female, 29% with obesity [body mass index ≥30 kg/m 2 ], 4.2 ± 4.3 exacerbations/year). The primary analysis assessed relationships between BMI and variables through univariate tests, followed by a multiple regression model. Secondary outcomes regarded clinically relevant variables in relation to weight groups., Results: Patients with obesity were more frequently female, more likely to have depression and gastroesophageal reflux, and suffered from worse asthma control, lower quality of life, reduced static lung volumes, more pronounced hypoxemia, and higher blood neutrophil counts, all statistically significant. Blood eosinophils, exhaled nitric oxide, and total IgE were independent of obesity. In the multiple regression analysis, obesity was significantly associated with more frequent reflux and depression, reduced static lung function values, older age, poor asthma control, and long-acting muscarinic antagonist therapy, and inversely associated with bronchiectasis and nonsmoking status., Conclusion: In this large, well-characterized cohort, we identified the association of obesity with a significantly higher disease burden and a similar portfolio of inflammation type 2 markers in patients with and without obesity; therefore, patients with obesity seem similarly eligible for the treatment with biologics targeting these disease endotypes., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Allergic airway inflammation (AAI) is a chronic respiratory disease that is considered a severe restriction in daily life and is accompanied by a constant risk of acute aggravation. It is characterized by IgE-dependent activation of mast cells, infiltration of eosinophils, and activated T-helper cell type 2 (Th2) lymphocytes into airway mucosa. Purinergic receptor signaling is known to play a crucial role in inducing and maintaining allergic airway inflammation. Previous studies in an ovalbumin (OVA)-alum mouse model demonstrated a contribution of the P2Y2 purinergic receptor subtype (P2RY2) in allergic airway inflammation. However, conflicting data concerning the mechanism by which P2RY2 triggers AAI has been reported. Thus, we aimed at elucidating the cell-type-specific role of P2RY2 signaling in house dust mite (HDM)-driven model of allergic airway inflammation. Thereupon, HDM-driven AAI was induced in conditional knockout mice, deficient or intact for P2ry2 in either alveolar epithelial cells, hematopoietic cells, myeloid cells, helper T cells, or dendritic cells. To analyze the functional role of P2RY2 in these mice models, flow cytometry of bronchoalveolar lavage fluid (BALF), cytokine measurement of BALF, invasive lung function measurement, HDM re-stimulation of mediastinal lymph node (MLN) cells, and lung histology were performed. Mice that were subjected to an HDM-based model of allergic airway inflammation resulted in reduced signs of acute airway inflammation including eosinophilia in BALF, peribronchial inflammation, Th2 cytokine production, and bronchial hyperresponsiveness in mice deficient for P2ry2 in alveolar epithelial cells, hematopoietic cells, myeloid cells, or dendritic cells. Furthermore, the migration of bone-marrow-derived dendritic cells and bone-marrow-derived monocytes, both deficient in P2ry2 , towards ATP was impaired. Additionally, we found reduced levels of MCP-1/CCL2 and IL-8 homologues in the BALF of mice deficient in P2ry2 in myeloid cells and lower concentrations of IL-33 in the lung tissue of mice deficient in P2ry2 in alveolar epithelial cells. In summary, our results show that P2RY2 contributes to HDM-induced airway inflammation by mediating proinflammatory cytokine production in airway epithelial cells, monocytes, and dendritic cells and drives the recruitment of lung dendritic cells and monocytes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Schneble, El-Gazzar, Kargarpour, Kramer, Metekol, Stoshikj and Idzko.)

Background: Recently, criteria for evaluation of response to biologics have been proposed and the concept of clinical remission has gained attention as a possible goal even in severe asthma., Objective: To analyze the response and remission in the German Asthma Net severe asthma registry cohort., Methods: We included adults not using a biologic at baseline (V0) and compared patients treated between V0 and 1-year visit (V1) without using a biologic (group A) to patients starting with a biologic after V0 and continuing it up to V1 (group B). We applied the Biologics Asthma Response Score to quantify composite response in good, intermediate, or insufficient. We defined clinical remission (R) as absence of significant symptoms (Asthma Control Test score ≥ 20 at V1) in the absence of exacerbations and oral corticosteroid therapy., Results: Group A included 233 and group B 210 patients, the latter receiving omalizumab (n = 33), mepolizumab (n = 40), benralizumab (n = 81), reslizumab (n = 1), or dupilumab (n = 56). At baseline, group B had less often an allergic phenotype (35.2% vs 41.6%), lower Asthma Control Test score (median, 12 vs 14), more exacerbations in the past year (median, 3 vs 2), and more often high-dose inhaled corticosteroid treatment (71.4% vs 51.5%) than group A. After 1 year of treatment, rates of response (good: 61.4% vs 34.8%; intermediate: 26.7% vs 42.9%; insufficient: 11.9% vs. 22.3%) and/or clinical remission (37.6% vs 17.2%) were higher in group B than in group A., Conclusions: Despite more severe asthma at baseline, patients treated with biologics had a markedly higher probability of achieving good clinical response and/or remission than patients treated without biologics., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Treatment of acute respiratory distress syndrome (ARDS) represents a severe complication of coronavirus disease 2019 (COVID-19) infection and is often challenging in intensive care treatment. Potential positive effects of intravenous cyclophosphamide have been reported in interstitial lung diseases (ILDs). However, there are no data on the use of high-dose cyclophosphamide in therapy-resistant COVID-19 ARDS. We report the case of a 32-year-old male patient admitted to the intensive care unit (ICU) of the Medical University of Vienna due to severe COVID-19 ARDS who required venovenous extracorporeal membrane oxygenation (ECMO) with a total runtime of 85 days. Despite all these therapeutic efforts, he remained in a condition of therapy-resistant ARDS. Unfortunately, the patient was denied for lung transplantation. However, a significant improvement in his respiratory condition was achieved after the administration of an intravenous regimen of cyclophosphamide and prednisolone. After a period of consecutive stabilization, the patient was transferred to the normal ward after 125 days of intensive care treatment. There is a substantial lack of therapeutic options in therapy-resistant ARDS. Our case report suggests that cyclophosphamide may represent a new treatment strategy in therapy-resistant ARDS. Due to its severe adverse effect profile, cyclophosphamide should be used after careful evaluation of a patient's general condition.

The management of asthma has fundamentally changed during the past decades. The present guideline for the diagnosis and treatment of asthma was developed for respiratory specialists who need detailed and evidence-based information on the new diagnostic and therapeutic options in asthma. The guideline shows the new role of biomarkers, especially blood eosinophils and fractional exhaled NO (FeNO), in diagnostic algorithms of asthma. Of note, this guideline is the first worldwide to announce symptom prevention and asthma remission as the ultimate goals of asthma treatment, which can be achieved by using individually tailored, disease-modifying anti-asthmatic drugs such as inhaled steroids, allergen immunotherapy or biologics. In addition, the central role of the treatment of comorbidities is emphasized. Finally, the document addresses several challenges in asthma management, including asthma treatment during pregnancy, treatment of severe asthma or the diagnosis and treatment of work-related asthma., Competing Interests: Eine Übersicht der Interessenkonflikte findet sich im Internet unter http://awmf.org; AWMF-Registriernummer 020-009., (Thieme. All rights reserved.)

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Background: Elevated levels of extracellular adenosine triphosphate (ATP) modulate immunologic pathways and are considered to be a danger signal in inflammation, lung fibrosis and cancer. Macrophages can be classified into two main types: M1 macrophages are classically activated, pro-inflammatory macrophages, whereas M2 macrophages are alternatively activated, pro-fibrotic macrophages. In this study, we examined the effect of ATP on differentiation of native human monocytes into these macrophage subtypes. We characterized M1 and M2 like macrophages by their release of Interleukin-1beta (IL-1β) and Chemokine (C-C motif) ligand 18 (CCL18), respectively., Results: Monocytes were stimulated with ATP or the P2X7 receptor agonist Benzoylbenzoyl-ATP (Bz-ATP), and the production of various cytokines was analyzed, with a particular focus on CCL18 and IL-1β, along with the expression of different purinergic receptors. Over a 72 h period of cell culture, monocytes spontaneously differentiated to M2 like macrophages, as indicated by an increased release of CCL18. Immediate stimulation of monocytes with ATP resulted in a dose-dependent reduction in CCL18 release, but had no effect on the concentration of IL-1β. In contrast, delayed stimulation with ATP had no effect on either CCL18 or IL-1β release. Similar results were observed in a model of inflammation using lipopolysaccharide-stimulated human monocytes. Stimulation with the P2X7 receptor agonist Bz-ATP mimicked the effect of ATP on M2-macrophage differentiation, indicating that P2X7 is involved in ATP-induced inhibition of CCL18 release. Indeed, P2X7 was downregulated during spontaneous M2 differentiation, which may partially explain the ineffectiveness of late ATP stimulation of monocytes. However, pre-incubation of monocytes with PPADS, Suramin (unselective P2X- and P2Y-receptor blockers) and KN62 (P2X7-antagonist) failed to reverse the reduction of CCL18 by ATP., Conclusions: ATP prevents spontaneous differentiation of monocytes into M2-like macrophages in a dose- and time-dependent manner. These effects were not mediated by P2X and P2Y receptors., (© 2023. The Author(s).)

Chronic obstructive pulmonary disease (COPD) is considered one of the leading causes of mortality. Cardiovascular comorbidities are diagnosed often in COPD patients, not only because of the common risk factors these two diseases share, but also because of the systemic inflammation which characterizes COPD and has deleterious effects in the cardiovascular system. The comorbid cardiovascular diseases in COPD result in several difficulties in the holistic treatment of these patients and affect outcomes such as morbidity and mortality. Several studies have reported that mortality from cardiovascular causes is common among COPD patients, while the risk for acute cardiovascular events increases during COPD exacerbations and remains high for a long time even after recovery. In this review, we focus on the prevalence of cardiovascular comorbidities in COPD patients, presenting the evidence regarding the interaction of the pathophysiological pathways which characterize each disease. Furthermore, we summarize information regarding the effects of cardiovascular treatment on COPD outcomes and vice versa. Finally, we present the current evidence regarding the impact of cardiovascular comorbidities on exacerbations, quality of life and survival of COPD patients.

Background: Symptoms of mental stress are a hallmark of the COVID-19 pandemic. We hypothesized that just testing for COVID-19 could act as an effective stressor for persisting symptoms of mental distress including posttraumatic stress disorder. Our study aimed to determine whether personal beliefs on individual control and competence (locus of control, LoC) correlate with symptoms of mental distress and positive screening for post-traumatic stress disorder during a 9-month observational period., Methods: Between March and December 2021, we applied online versions of the Questionnaire on Competence and Control Expectations (FKK), the Depression, Anxiety, and Stress Score (DASS), the Short Screening Scale for DSM-IV Posttraumatic Stress Disorder (PTSD), and a medical history questionnaire for COVID-19 symptoms (visit 1). 48 hours after negative COVID-19 testing, DASS was repeated to address relief effects on mental distress (visit 2). Following 90 days (visit 3), development of mental distress was addressed by a combination of DASS and PTSD, while the possible long-term manifestation of PTSD was evaluated 9 months later (visit 4)., Results: At visit 1, 7.4 percent of the total sample ( n = 867) demonstrated a positive screening for PTSD, while after nine months (at visit 4), 8.9 percent of the remaining sample ( n = 204) had positive screening results. The mean age was 36.2 years; 60.8% were women, 39.2% men. In contrast to individuals with negative PTSD screening, these participants demonstrated a significantly different LoC personality profile. This was confirmed by the results of both DASS and the COVID-19 medical history questionnaire., Conclusion: Following testing for COVID-19, individuals with positive long-term PTSD screening present with significantly different personality traits than those w/o suggesting that self-confidence and effective control over one's own actions serve as a protective function against mental distress., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Guttmann-Ducke, Klinger, Ziesche, Otzelberger, Idzko, Ponocny, Prantl and Ponocny-Seliger.)

Interstitial lung disease comprises numerous clinical entities posing significant challenges towards a prompt and accurate diagnosis. Amongst the contributing factors are intricate pathophysiological mechanisms, an overlap between conditions, and interobserver disagreement. We developed a model for patient clustering offering an additional approach to such complex clinical cases. The model is based on surface phenotyping of over 40 markers on immune cells isolated from bronchoalveolar lavage in combination with clinical data. Based on the marker expression pattern we constructed an individual immune cell profile, then merged these to create a global profile encompassing various pathologies. The contribution of each participant to the global profile was assessed through dimensionality reduction tools and the ensuing similarity between samples was calculated. Our model enables two approaches. First, assessing the immune cell population landscape similarity between patients within a diagnostic group allows rapid identification of divergent profiles, which is particularly helpful for cases with uncertain diagnoses. Second, sample clustering is based exclusively on the calculated similarity of the immune cell profiles, thereby removing physician bias and relying on cellular nearest neighbors., Competing Interests: Declarations of Competing Interest None, (Copyright © 2023. Published by Elsevier B.V.)

Mass cytometry (MC) is a powerful method for mapping complex cellular systems at single-cell levels, based on the detection of cellular proteins. Numerous studies have been performed using human blood, but there is a lack of protocols describing the processing and labeling of bronchoalveolar lavage fluid (BALF) and nasal polyps (NP) for acquisition by MC. These specimens are essential in the investigation of immune cell characteristics in airway diseases such as asthma and chronic rhinosinusitis with NP (CRSwNP). Here we optimized a workflow for processing, labeling, and acquisition of BALF and NP cells by MC. Among three methods tested for NP digestion, combined enzymatic/mechanical processing yielded maximum cell recovery, viability and labeling patterns compared to the other methods. Treatment with DNAse improved sample acquisition by MC. In a final step, we performed a comparison of blood, BALF and NP cell composition using a 31-marker MC antibody panel, revealing expected differences between the different tissue but also heterogeneity among the BALF and NP samples. We here introduce an optimized workflow for the MC analysis of human NP and BALF, which enables comparative analysis of different samples in larger cohorts. A deeper understanding of immune cell characteristics in these samples may guide future researchers and clinicians to a better disease management., Competing Interests: SVS served as a speaker and/or consultant and/or advisory board member for Sanofi, GSK, and Novartis. SVS is an investigator for Novartis and AstraZeneca grants paid to his institution. JE-D served as a speaker and/or consultant and/or advisory board member for Sanofi, Allergopharma, AstraZeneca, GSK, and Novartis. JE-D is an investigator for Novartis and AstraZeneca grants paid to her institution. MR-H was supported by a grant of AstraZeneca, MZ by a grant of the lower country of Austria. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Rocha-Hasler, Müller, Wagner, Tu, Stanek, Campion, Bartosik, Zghaebi, Stoshikj, Gompelmann, Zech, Mei, Kratochwill, Spittler, Idzko, Schneider and Eckl-Dorna.)

Background and Objective: Hyponatremia and the syndrome of inappropriate antidiuretic hormone secretion (SIADH) are associated with and can be caused by tuberculosis (TB) through meningitis by locally invading the hypothalamus, adrenal, or pituitary glands or possibly through ectopic ADH production. This study assessed the association of TB mortality with hyponatremia and SIADH in a large cohort of a university hospital in Austria., Methods: This retrospective study enrolled patients with hyponatremia and patients diagnosed with TB from 01/2001-11/2019 to assess the prevalence of TB in hyponatremia and TB morbidity and mortality in patients with and without hyponatremia. Sex, age, microbiological results, laboratory tests and comorbidities were analysed and used to calculate survival rates., Results: Of 107.532 patients with hyponatremia (0.07%) and 186 patients with TB (43%), 80 patients were diagnosed with both-hyponatremia and TB. Only three TB patients had SIADH, precluding further SIADH analysis. In hyponatremia, young age and high CRP levels showed significant associations with TB diagnosis (p<0.0001). Survival rates of patients diagnosed with TB with moderate to profound hyponatremia were significantly lower than those without hyponatremia (p = 0.002)., Conclusion: In this study of a large cohort from a tertiary care hospital in a non-endemic area of TB, 0.07% of patients presenting with hyponatremia, but especially younger patients and patients with high CRP values, were diagnosed with TB. Crucially, patients with moderate to profound hyponatremia had a significantly higher mortality rate and thus required increased medical care., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Dr. Bal reports personal fees (lecture fee) from: AstraZeneca, IVEPA (Interessensverband Endoskopie Personal Austria) outside the submitted work. Univ. Prof. Dr. Gompelmann reports personal fees (lecture and travel fees) from: Pulmonx, AstraZeneca, BerlinChemie, Novartis, Böhringer Ingelheim, Olympus, Uptake Medical, Grifols, outside the submitted work. Univ. Prof. Dr. Krebs has nothing to disclose. Dr. Antoniewicz, PhD reports personal fees (lecture fee) from: Pfizer, Medizin Medien Austria GmbH, Merck & Co Inc., Janssen-Cilag Pharma GmbH, outside the submitted work. Univ. Prof. Dr. Idzko reports personal fees (lecture fee) from: AstraZeneca, Bayer, Berlin-Chemie, Boehringer Ingelheim, Chiesi, CSL-Behring, GSK, Menarini, MSD, Novartis, Roche, Sanofi, Thermofischer and advisory board fees from Alk-Pharma, AstraZeneca, BerlinChemie, Boehringer Ingelheim, Chiesi, CSL-Behring, GSK, Novartis, Sanofi, outside the submitted work. The other authors have nothing to disclose. For this study, we received no funding from the following commercial sources, which provided lecture fees to some of the authors outside of the submitted work (see above): AstraZeneca, Pulmonx, BerlinChemie, Novartis, Böhringer Ingelheim, Olympus, Uptake Medical, Grifols, Bayer, Roche, Sanofi and Pfizer. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Chronic obstructive pulmonary disease (COPD) is associated with elevated ATP levels in the extracellular space. Once released, ATP serves as danger signal modulating immune responses by activating purinergic receptors. Accordingly, purinergic signalling has been implicated in respiratory inflammation associated with cigarette smoke exposure. However, the role of P2X4-signalling has not been fully elucidated yet., Methods: Here, we analysed the P2X4 mRNA expression in COPD patients as well as cigarette smoke-exposed mice. Furthermore, P2X4-signalling was blocked by either using a specific antagonist or genetic depletion of P2rx4 in mice applied to an acute and prolonged model of cigarette smoke exposure. Finally, we inhibited P2X4-signalling in macrophages derived from THP-1 before stimulation with cigarette smoke extract., Results: COPD patients exhibited an increased P2X4 mRNA expression in cells isolated from the bronchoalveolar lavage fluid and peripheral mononuclear cells. Similarly, P2rx4 expression was elevated in lung tissue of mice exposed to cigarette smoke. Blocking P2X4-signalling in mice alleviated cigarette smoke induced airway inflammation as well as lung parenchyma destruction. Additionally, human macrophages derived from THP-1 cells released reduced concentrations of proinflammatory cytokines in response to cigarette smoke extract stimulation when P2X4 was inhibited., Conclusion: Taken together, we provide evidence that P2X4-signalling promotes innate immunity in the immunopathologic responses induced by cigarette smoke exposure., (© 2022. The Author(s).)

Background: Long-lasting symptoms following SARS-CoV2-infection have been described in several studies. However, there is only limited knowledge about the ongoing pathophysiology and the association with pathological findings in medical examinations., Methods: In this post hoc analysis of a prospective trial, 135 patients following COVID-19 were enrolled and grouped with respect to the presence or absence of respiratory ongoing symptoms following COVID-19. Pulmonary function test (PFT), diffusion capacity measurement (TLCO SB and TLCO/VA), blood gas analysis (BGA), laboratory tests and high-resolution computed tomography (HRCT) of patients with persistent respiratory symptoms were compared to those of asymptomatic patients., Results: In this analysis, 71% (96/135) of all patients (mean age 49 years; range 20-91 years) reported long-lasting symptoms after a median (IQR) of 85 days (60-116) following COVID-19 whereby 57.8% (78/135) complained about persistent pulmonary symptoms. Pathological findings in blood test, PFT, TLCO, BGA and/or HRCT were found in 71.8% and 64.1% of patients with and without long-lasting respiratory symptoms respectively. Patients with persistent respiratory symptoms were significantly younger and presented a significant lower FVC (%), TLC (L), and TLCO SB compared to asymptomatic patients (p < 0.05). The multiple logistic regression results in a significant effect of age (p = 0.004) and TLCO SB (p = 0.042)., Conclusion: Following COVID-19, a large proportion of patients experience ongoing symptoms, whereby the respiratory symptoms are the predominant complaints. Compared to asymptomatic patients, patients with ongoing symptoms were younger and presented a significant lower FVC, TLC and TLCO SB. The multiple logistic regression demonstrated only a significant association between the TLCO SB as the only PFT parameter and the perceived symptoms., (© 2022. The Author(s).)

The Austrian Society of Pneumology (ASP) launched a first statement on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in May 2020, at a time when in Austria 285 people had died from this disease and vaccinations were not available. Lockdown and social distancing were the only available measures to prevent more infections and the breakdown of the health system. Meanwhile, in Austria over 13,000 patients have died in association with a SARS-CoV‑2 infection and coronavirus disease 2019 (COVID-19) was among the most common causes of death; however, SARS-CoV‑2 has been mutating all the time and currently, most patients have been affected by the delta variant where the vaccination is very effective but the omicron variant is rapidly rising and becoming predominant. Particularly in children and young adults, where the vaccination rate is low, the omicron variant is expected to spread very fast. This poses a particular threat to unvaccinated people who are at elevated risk of severe COVID-19 disease but also to people with an active vaccination. There are few publications that comprehensively addressed the special issues with SARS-CoV‑2 infection in patients with chronic lung diseases. These were the reasons for this updated statement. Pulmonologists care for many patients with an elevated risk of death in case of COVID-19 but also for patients that might be at an elevated risk of vaccination reactions or vaccination failure. In addition, lung function tests, bronchoscopy, respiratory physiotherapy and training therapy may put both patients and health professionals at an increased risk of infection. The working circles of the ASP have provided statements concerning these risks and how to avoid risks for the patients., (© 2022. The Author(s).)

A 53-year old female patient with history of hypocomplementaemic urticarial vasculitis syndrome (HUVS) and polyarteritis nodosa presented with progressive dyspnoea on exertion due to emphysema. Lung function revealed a severe obstructive ventilator disorder with a forced expiratory volume in 1 second of 22% of predicted, and a significant hyperinflation with a residual volume of 321% of predicted. Multi-detector computed tomography (MDCT) scan and quantitative CT analysis (StratX software) confirmed a lower lobe predominant emphysema. Considering the young age, the very severely impaired lung function, the relatively low nicotine abuse, the exclusion of alpha-1 antitrypsin deficiency, together with the known diagnosis of HUVS, the emphysema was more likely due to the vasculitis than to a typical chronic obstructive lung disease. MDCT scan showed that particularly the segment 8 of the right lower lobe was severely emphysematous destroyed and hyperinflated. Invasive Chartis® measurement revealed no significant collateral ventilation of the isolated segment 8 of the right lower lobe, so that an endobronchial valve placement was performed. Three months following intervention, the MDCT scan revealed a complete collapse of the segment 8 on the right, which was associated with a significant clinical benefit and a mild reduction of the hyperinflation in the lung function test., (© 2022 The Authors. Published by Elsevier Ltd.)

Heart rate (HR) responses to maximal exercise are commonly used for the prescription of training intensities in pulmonary rehabilitation. Those intensities are usually based on fixed percentages of peak HR (HRpeak), heart rate reserve (HRR), or peak work load (Wpeak), and rarely on HRs at the individual ventilatory thresholds (VT1 and VT2) derived from cardiopulmonary exercise testing (CPET). For patients suffering from interstitial lung disease (ILD), data on cardiorespiratory responses to CPET are scarce. Thus, the aim of this study was to record cardiorespiratory responses to CPET and to compare fixed HR percentages with HRs at VT1 and VT2 in ILD patients. A total of 120 subjects, 80 ILD patients and 40 healthy controls, underwent a symptom-limited CPET. From the ILD patient, 32 suffered from idiopathic pulmonary fibrosis (IPF), 37 from connective tissue disease (CTD), and 11 from sarcoidosis. HRs at fixed percentages, that is, at 70%HRpeak, at 70%Wpeak, and at 60%HRR were significantly lower in the ILD patients compared with the control group (p-values: 0.001, 0.044, and 0.011). Large percentages of HR values at 70%Wpeak and 60%HRR ranged between the HRs at VT1 and VT2 in ILD subgroups and controls as well. HRs at 70%HRpeak were lower than HRs at VT1 in 66% of the IPF patients, 54% of the CTD patients, and 55% of patients with sarcoidosis compared with 18% in the control group. Our findings demonstrate a considerable scattering of fixed HR percentages compared with HRs at the individual VTs derived from CPET in ILD patients. These findings may provide valuable information for the prescription of exercise intensity in pulmonary rehabilitation of ILD patients., (© 2021 The Authors. Scandinavian Journal of Medicine & Science In Sports published by John Wiley & Sons Ltd.)

Emergency hematopoiesis is the driving force of the inflammatory response to myocardial infarction (MI). Increased proliferation of hematopoietic stem and progenitor cells (LSK) after MI enhances cell production in the bone marrow (BM) and replenishes leukocyte supply for local cell recruitment to the infarct. Decoding the regulation of the inflammatory cascade after MI may provide new avenues to improve post-MI remodeling. In this study, we describe the influence of adenosine diphosphate (ADP)-dependent P2Y 12 -mediated signaling on emergency hematopoiesis and cardiac remodeling after MI. Permanent coronary ligation was performed to induce MI in a murine model. BM activation, inflammatory cell composition and cardiac function were assessed using global and platelet-specific gene knockout and pharmacological inhibition models for P2Y 12 . Complementary in vitro studies allowed for investigation of ADP-dependent effects on LSK cells. We found that ADP acts as a danger signal for the hematopoietic BM and fosters emergency hematopoiesis by promoting Akt phosphorylation and cell cycle progression. We were able to detect P2Y 12 in LSK, implicating a direct effect of ADP on LSK via P2Y 12 signaling. P2Y 12 knockout and P2Y 12 inhibitor treatment with prasugrel reduced emergency hematopoiesis and the excessive inflammatory response to MI, translating to lower numbers of downstream progeny and inflammatory cells in the blood and infarct. Ultimately, P2Y 12 inhibition preserved cardiac function and reduced chronic adverse cardiac remodeling after MI. P2Y 12 -dependent signaling is involved in emergency hematopoiesis after MI and fuels post-ischemic inflammation, proposing a novel, non-canonical value for P2Y 12 antagonists beyond inhibition of platelet-mediated atherothrombosis., (© 2022. The Author(s).)

Introduction: The German Asthma Net Severe Asthma Registry is collecting long-term data from a large cohort of patients aged ≥6 years with severe asthma. This manuscript presents their baseline characteristics, and identifies relationships with exacerbations and/or poor asthma control., Methods: The registry is collecting routine clinical parameters including: demographics and medical history; disease characteristics (Asthma Control Questionnaire [ACQ]-5, forced expiratory volume in 1 s [FEV 1 ]); exacerbations; and biomarkers (eosinophils, immunoglobulin E [IgE], fractional exhaled nitric oxide [FeNO])., Results: These analyses include data from 2011 patients at 72 sites (91.9% adult). Children (6-17 years) were more likely to be male, whereas more adults were female (males: children/adults 62%/41%). Most were receiving inhaled corticosteroid/long-acting β 2 -agonist combinations (78%/81%); 38.0% of adults were receiving systemic steroids. Asthma control was suboptimal in both groups: 21.5%/13.3% were controlled; 10.4%/49.1% were symptomatic; 33.1%/37.2% received emergency asthma treatment in the previous year. Median blood eosinophil (400/238 cells/μL) and IgE levels (494/186 IU/mL) were higher in children; FeNO was lower (19/35 ppb). Patients with ≥2 exacerbations in the previous year had lower FEV 1 (absolute and % predicted) and IgE, and higher ACQ-5, FeNO and blood eosinophil levels (all p < 0.05). There was a weak, negative correlation between ACQ-5 and FEV 1 % predicted in adults (p < 0.001)., Conclusions: These analyses characterise the typical German patient with severe asthma, and provide information on their overall care. Their planned long-term follow-up will assess whether asthma control can be optimised, how best to do so, and most importantly how such optimisation can benefit patients., (Copyright © 2022. Published by Elsevier Ltd.)

Although asthma is very common affecting 5-10% of the population, the diagnosis of asthma in adults remains a challenge in the real world that results in both over- and under-diagnosis. A task force (TF) was set up by the European Respiratory Society to systematically review the literature on the diagnostic accuracy of tests used to diagnose asthma in adult patients and provide recommendation for clinical practice.The TF defined eight PICO (Population, Index, Comparator, and Outcome) questions that were assessed using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach, The TF utilised the outcomes to develop an evidenced-based diagnostic algorithm, with recommendations for a pragmatic guideline for everyday practice that was directed by real-life patient experiences.The TF support the initial use of spirometry followed, and if airway obstruction is present, by bronchodilator reversibility testing. If initial spirometry fails to show obstruction, further tests should be performed in the following order: FeNO, PEF variability or in secondary care, bronchial challenge. We present the thresholds for each test that are compatible with a diagnosis of asthma in the presence of current symptoms.The TF reinforce the priority to undertake spirometry and recognise the value of measuring blood eosinophils and serum IgE to phenotype the patient. Measuring gas trapping by body plethysmography in patients with preserved FEV 1 /FVC ratio deserves further attention. The TF draw attention on the difficulty of making a correct diagnosis in patients already receiving inhaled corticosteroids, the comorbidities that may obscure the diagnosis, the importance of phenotyping, and the necessity to consider the patient experience in the diagnostic process., Competing Interests: Conflict of interest: Dr. LOUIS reports grants and personal fees from GSK, grants and personal fees from AZ, grants and personal fees from Chiesi, grants and personal fees from Novartis, personal fees from Sanofi, outside the submitted work; . Conflict of interest: Dr. Satia reports grants and personal fees from GSK, personal fees from AstraZeneca, grants and personal fees from Merck, grants from ERS Respire 3 Marie Curie Fellowship, grants from E.J. Moran Campbell Early Career Award, outside the submitted work; . Conflict of interest: Dr. OJANGUREN reports grants and personal fees from ASTRAZENECA, personal fees and non-financial support from BOEHRINGUER-INGELHEIM, personal fees and non-financial support from CHIESI, grants, personal fees and non-financial support from NOVARTIS, personal fees from MSD, personal fees from PURETECH, grants and personal fees from SANOFI, personal fees from BIAL, personal fees from TEVA, grants and personal fees from GSK, outside the submitted work. Conflict of interest: Dr. SCHLEICH reports grants and personal fees from GSK, grants and personal fees from AstraZeneca, personal fees from Chiesi, outside the submitted work. Conflict of interest: Dr. Bonini has nothing to disclose. Conflict of interest: Ms Tonia reports acting as ERS Methodologist . Conflict of interest: Dr. Rigau reports and declares he worked as ERS methodologist until February 2020. Conflict of interest: Dr. ten Brinke reports institutional fees from Research Advisory Boards: GSK, Sanofi, TEVA, AstraZeneca, Boehringer Ingelheim , institutional fees from Lectures AstraZeneca, GSK ,TEVA, SanofiGenzyme, grants from AstraZeneca, GSK ,TEVA, outside the submitted work. Conflict of interest: Dr. Buhl reports personal fees from AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Novartis, Sanofi, Roche and Teva, and grants to Mainz University Hospital from Boehringer Ingelheim, GlaxoSmithKline, Novartis and Roche, all outside the submitted work. Conflict of interest: Dr. Loukides has nothing to disclose. Conflict of interest: Dr. Kocks reports grants, personal fees and non-financial support from AstraZeneca, grants, personal fees and non-financial support from Boehringer Ingelheim, grants and personal fees from Chiesi Pharmaceuticals, grants and personal fees from GSK, grants and personal fees from Novartis, personal fees from MSD, grants and personal fees from TEVA, personal fees from COVIS, outside the submitted work; and Janwillem Kocks holds 72.5% of shares in the General Practitioners Research Institute. Conflict of interest: Dr. Boulet reports grants from Amgen, AstraZeneca, GlaxoSmithKline, Merck, Novartis, Sanofi-Regeneron, grants from AstraZeneca, GlaxoSmithKline. Merck, personal fees from Astra Zeneca, Novartis, GlaxoSmithKline, Merck, Sanofi-Regeneron, personal fees from AstraZeneca, Covis, GlaxoSmithKline, Novartis, Merck, Sanofi, grants and non-financial support from AstraZeneca, Covis, GlaxoSmithKline, Merck, Novartis, non-financial support from Chair of Global Initiative for Asthma (GINA) Board of Directors, President of the Global Asthma Organisation (Interasma) Conflict of interest: Dr. Bourdin reports grants, personal fees, non-financial support and other from GSK, grants, personal fees, non-financial support and other from Astra Zeneca, grants, personal fees, non-financial support and other from Boeringher Ingelheim, personal fees, non-financial support and other from Novartis, personal fees, non-financial support and other from Chiesi Farma, non-financial support and other from Teva, personal fees, non-financial support and other from Sanofi Regeneron, grants, personal fees, non-financial support and other from Actelion / Jansen, other from United Therapeutics, other from Pulsar, personal fees, non-financial support and other from Roche, from null, outside the submitted work. Conflict of interest: Courtney Coleman is an employee of European Lung Foundation. Conflict of interest: Dr. Needham has nothing to disclose. Conflict of interest: Dr. Thomas reports personal fees from GSK, personal fees from Boehringer Ingelheim , personal fees from Chiesi, outside the submitted work; . Conflict of interest: Dr. Idzko has nothing to disclose. Conflict of interest: Dr. Papi reports grants, personal fees, non-financial support and other from GlaxoSmithKline, grants, personal fees and non-financial support from AstraZeneca, grants, personal fees, non-financial support and other from Boehringer Ingelheim, grants, personal fees, non-financial support and other from Chiesi Farmaceutici, grants, personal fees, non-financial support and other from TEVA, personal fees, non-financial support and other from Mundipharma, personal fees, non-financial support and other from Zambon, personal fees, non-financial support and other from Novartis, grants, personal fees and non-financial support from Menarini, personal fees, non-financial support and other from Sanofi/Regeneron, personal fees from Roche, grants from Fondazione Maugeri, grants from Fondazione Chiesi, personal fees from Edmondpharma, outside the submitted work. Conflict of interest: Dr. Porsbjerg reports grants and personal fees from Astra Zeneca, grants and personal fees from GSK, grants and personal fees from Novartis, grants and personal fees from TEVA, grants and personal fees from Sanofi, grants and personal fees from Chiesi, grants from Pharmaxis, outside the submitted work; . Conflict of interest: Dr. Schuermans reports non-financial support from Free University of Brussels, outside the submitted work; . Conflict of interest: Dr. B. Soriano Conflict of interest: Dr. Usmani reports grants and personal fees from astra zeneca, grants and personal fees from boehringer ingelheim, grants and personal fees from chiesi, grants and personal fees from glaxosmithkline, personal fees from napp, personal fees from mundipharma, personal fees from sandoz, personal fees from takeda, grants from edmond pharma, personal fees from cipla, personal fees from covis, personal fees from novartis, personal fees from mereo biopharma, personal fees from orion, personal fees from menarini, personal fees from ucb, personal fees from trudell medical, personal fees from deva, personal fees from kamada, personal fees from covis, outside the submitted work., (Copyright ©The authors 2022. For reproduction rights and permissions contact permissions@ersnet.org.)

Graft-vs. -host disease (GvHD) is a serious and complex immunological complication of haematopoietic stem cell transplantation (HSCT) and is associated with prolonged immunodeficiency and non-relapse mortality. Standard treatment of chronic GvHD comprises steroids in combination with other immunosuppressive agents. Extracorporeal photopheresis (ECP), with its immunomodulatory mechanism, is applied as part of steroid-sparing regimens for chronic GvHD. Immunocompromised, chronically ill patients are at particular risk of severe disease courses of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. T-cell immunity in SARS-CoV-2 infection is well-described but the role of the humoral immune responses is not fully understood. This case report describes a moderate course of SARS-CoV-2 infection in a patient <9 months after HSCT who was suffering from active, severe, chronic GvHD treated with prednisone and ECP. Following HSCT from a matched unrelated donor to cure acute lymphoblastic leukaemia, the 25-year-old male patient experienced multiple infectious complications associated with cytopenia, B-cell dyshomeostasis and autoantibody production followed by development of severe chronic GvHD thereafter at day +212. The steroid-sparing treatment plan consisted of supportive care, topical treatment, prednisone and ECP. He was diagnosed with SARS-CoV-2 infection at day +252, experiencing loss of smell and taste as well as a cough. The patient's oxygen saturation was between 94 and 97% on room air, and computed tomography images showed evolution of typical of SARS-CoV-2 infiltrates. In addition to cytopenia and immune dyshomeostasis, laboratory tests confirmed macrophage activating syndrome, transaminitis and Epstein-Barr virus viraemia. At that time, anti-SARS-CoV-2 monoclonal antibodies were not available in Austria and remdesivir seemed contraindicated. Surprisingly, despite severe lymphopenia the patient developed SARS-CoV-2-specific antibodies within 15 days, which was followed by clearance of SARS-CoV-2 and EBV with resolution of symptoms. Thereafter, parameters of immune dysregulation such as lymphopenia and B-cell dyshomeostasis, the latter characterised by elevated CD21 low B cells and autoantibody expression, normalised. Moreover, we observed complete response of active chronic GvHD to treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zubarovskaya, Hofer-Popow, Idzko, Haas and Lawitschka.)

Objectives: Coronavirus disease 2019 (COVID-19) is a global pandemic affecting individuals to varying degrees. There is emerging evidence that even patients with mild symptoms will suffer from prolonged physical impairment. Methods: In this prospective observational study, lung function, and cardiopulmonary exercise testing have been performed in 100 patients for 3-6 months after COVID-19 diagnosis (post-CoVG). Depending on the severity of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection, patients were divided into asymptomatic, or mild to moderate (mild post-CoVG), and severe post-CoVG [hospitalization with or without intensive care unit/non-invasive ventilation (ICU/NIV)]. Results have been compared with age, sex, and body mass index (BMI) matched control group (CG, N = 50). Results: Both lung function (resting) and exercise capacity (peak workload, Wpeak and peak oxygen uptake, VO 2 peak - % predicted) were considerably affected in patients with severe post-CoV (81.7 ± 27.6 and 86.1 ± 20.6%), compared to the mild post-CoVG (104.8 ± 24.0%, p = 0.001 and 100.4 ± 24.8; p = 0.003). In addition, also the submaximal exercise performance was significantly reduced in the severe post-CoVG (predicted VT1/VO 2 peak; p = 0.013 and VT2/VO 2 peak; p = 0.001). Multiple linear regression analyses revealed that 74 % (adjusted R 2 ) of the variance in relative VO 2 peak of patients who had CoV could be explained by the following variables: lower age, male sex, lower BMI, higher DLCO, higher predicted heart rate (HR) peak, lower breathing reserve (BR), and lower SaO 2 peak, which were related to higher relative VO 2 peak values. Higher NT-proBNP and lower creatinine kinase (CK) values were seen in severe cases compared to patients who experienced mild CoV. Discussion: Maximal and submaximal exercise performance in patients recovering from severe COVID-19 remain negatively affected for 3-6 months after COVID-19 diagnosis. The presented findings reveal that impaired pulmonary, cardiac, and skeletal muscle function contributed to the limitation of VO 2 peak in those patients, which may have important implications on rehabilitation programs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Vonbank, Lehmann, Bernitzky, Gysan, Simon, Schrott, Burtscher, Idzko and Gompelmann.)

Background: Elevated D-dimer is known as predictor for severity of SARS-CoV2-infection. Increased D-dimer is associated with thromboembolic complications, but it is also a direct consequence of the acute lung injury seen in COVID-19 pneumonia., Objectives: To evaluate the rate of persistent elevated D-dimer and its association with thromboembolic complications and persistent ground glass opacities (GGO) after recovery from COVID-19., Methods: In this post hoc analysis of a prospective multicenter trial, patients underwent blood sampling, measurement of diffusion capacity, blood gas analysis, and multidetector computed tomography (MDCT) scan following COVID-19. In case of increased D-dimer (>0,5 μg/ml), an additional contrast medium-enhanced CT was performed in absence of contraindications. Results were compared between patients with persistent D-dimer elevation and patients with normal D-dimer level., Results: 129 patients (median age 48.8 years; range 19-91 years) underwent D-Dimer assessment after a median (IQR) of 94 days (64-130) following COVID-19. D-dimer elevation was found in 15% (19/129) and was significantly more common in patients who had experienced a severe SARS-CoV2 infection that had required hospitalisation compared to patients with mild disease (p = 0.049). Contrast-medium CT (n = 15) revealed an acute pulmonary embolism in one patient and CTEPH in another patient. A significant lower mean pO2 (p = 0.015) and AaDO2 (p = 0.043) were observed in patients with persistent D-Dimer elevation, but the rate of GGO were similar in both patient groups (p = 0.33)., Conclusion: In 15% of the patients recovered from COVID-19, persistent D-dimer elevation was observed after a median of 3 months following COVID-19. These patients had experienced a more severe COVID and still presented more frequently a lower mean pO2 and AaDO2., Competing Interests: NO authors have competing interests.

Dupilumab is a monoclonal antibody against the IL-4 receptor alpha which has shown efficacy in T2 high severe asthmatics in phase 3 randomized controlled trials. The purpose of this real-life study is to demonstrate the real-life effectiveness of dupilumab in Austrian severe asthma patients. We retrospectively analyzed all patients receiving dupilumab at our severe asthma clinic. Thirteen patients have so far received dupilumab at our center. The primary outcome, asthma control questionnaire 6-item scale at 2 weeks, improved by 0.57 points (p = .014), which is statistically and clinically significant. Similarly, the asthma control test at 4 weeks improved by 3.91 points (p = .024), also statistically and clinically significant. Improvements in forced expiratory volume in 1 s at 2 weeks were neither statistically, nor clinically significant. Improvements at 4 weeks (+220 ml, p = .041), and 3 months (+229 ml, p = .006), were statistically significant and clinically borderline significant. No severe adverse events or hypereosinophilia were observed. No adverse events led to treatment discontinuation. Most patients (85%) had previously received monoclonal antibody treatment for severe asthma. Previous monoclonal antibody treatment had been discontinued in these patients due to a lack of clinical response. Dupilumab is effective and safe in Austrian real-life severe asthmatics. It provides a possible treatment strategy for T2 high severe asthmatics who do not qualify for anti-immunoglobulin E or anti-IL5/IL5R monoclonal antibody treatments or do not adequately respond to these., (© 2021 The Authors. Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.)

Purpose: Improved understanding of characteristics that may influence treatment response across phenotypes may help guide treatment decisions., Patients and Methods: This was a post hoc analysis of MENSA, a multicenter, randomized, double-blind, placebo-controlled trial (NCT01691521). Patients aged ≥12 years with severe eosinophilic asthma received mepolizumab (75 mg intravenously or 100 mg subcutaneously) or placebo, plus standard of care, every 4 weeks for 32 weeks. Outcomes assessed were the annualized rate of clinically significant exacerbations and change from baseline in Asthma Control Questionnaire (ACQ)-5 score. Subgroup analyses were performed by baseline blood eosinophil count (<150, ≥150-300, ≥300 cells/μL) within atopic subgroups (non-atopic [specific immunoglobulin E <0.35 kU/L], atopic [≥0.35-17.5 kU/L], strongly atopic [>17.5 kU/L]), and by house dust mite (HDM) sensitivity., Results: Of 576 patients analyzed, 272 were non-atopic, 181 were atopic and 94 were strongly atopic; 29 had missing atopy data. In patients with blood eosinophil counts ≥300 cells/µL, mepolizumab versus placebo reduced clinically significant exacerbations by 74%, 43% and 25% in the non-atopic, atopic and strongly atopic subgroups. Similar reductions were observed in all atopic subgroups in other blood eosinophil count categories where there were sufficient patient numbers for analysis, except for non-atopic patients with baseline blood eosinophil counts of <150 cells/μL. Improvements in ACQ-5 scores of -0.75, -0.73 and -0.78 with mepolizumab versus placebo were observed in non-atopic, atopic and strongly atopic patients with blood eosinophil counts ≥300 cells/µL; consistent improvements in ACQ-5 were not observed in patients with blood eosinophil counts <150 or ≥150-300 cells/μL. Reductions in clinically significant exacerbations with mepolizumab versus placebo were also observed irrespective of sensitivity to HDMs., Conclusion: Mepolizumab was associated with a trend for reductions in clinically significant exacerbations and improved asthma control versus placebo in patients with severe eosinophilic asthma, irrespective of atopic status or HDM sensitivity., Competing Interests: CMP, SM and SWY are all employees and shareholders of GSK. FCA is a former employee of GSK, holds GSK stocks/shares and is currently employed by Avillion US, Inc. MI has received fees from Actelion, AstraZeneca, Bayer, Berlin Chemie, Boehringer Ingelheim, Chiesi, CSL-Behring, Grifols, GSK, MSD, Novartis and Teva. JAD has received personal fees from AstraZeneca, GSK, Novartis and Sanofi-Aventis, has been an investigator for AstraZeneca, GSK, Novartis, Sanofi-Aventis, Grifols, BioCryst, CSL Ltd and Equilium, and holds shares in CSL Ltd. AB has received fees from GSK, Regeneron, Chiesi, AstraZeneca, Teva, Novartis and Boehringer Ingelheim and been an investigator for Novartis and AstraZeneca. The authors report no other conflicts of interest in this work., (© 2021 Prazma et al.)