Publications by authors named "Tobias Welte"

543 Publications

Preventing cardiovascular events after pneumonia with aspirin: one step forward, but still many to go.

Eur Respir J 2021 Feb 11;57(2). Epub 2021 Feb 11.

Dept of Respiratory Medicine, Hannover Medical School, Member of the German Center of Lung Research, Hannover, Germany.

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http://dx.doi.org/10.1183/13993003.03778-2020DOI Listing
February 2021

COVID-19 immune signatures reveal stable antiviral T cell function despite declining humoral responses.

Immunity 2021 02;54(2):340-354.e6

Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Hannover, Germany. Electronic address:

Cellular and humoral immunity to SARS-CoV-2 is critical to control primary infection and correlates with severity of disease. The role of SARS-CoV-2-specific T cell immunity, its relationship to antibodies, and pre-existing immunity against endemic coronaviruses (huCoV), which has been hypothesized to be protective, were investigated in 82 healthy donors (HDs), 204 recovered (RCs), and 92 active COVID-19 patients (ACs). ACs had high amounts of anti-SARS-CoV-2 nucleocapsid and spike IgG but lymphopenia and overall reduced antiviral T cell responses due to the inflammatory milieu, expression of inhibitory molecules (PD-1, Tim-3) as well as effector caspase-3, -7, and -8 activity in T cells. SARS-CoV-2-specific T cell immunity conferred by polyfunctional, mainly interferon-γ-secreting CD4 T cells remained stable throughout convalescence, whereas humoral responses declined. Immune responses toward huCoV in RCs with mild disease and strong cellular SARS-CoV-2 T cell reactivity imply a protective role of pre-existing immunity against huCoV.
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http://dx.doi.org/10.1016/j.immuni.2021.01.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871825PMC
February 2021

Alpha-1 antitrypsin deficiency impairs lung antibacterial immunity in mice.

JCI Insight 2021 Feb 8;6(3). Epub 2021 Feb 8.

Division of Experimental Pneumology.

Alpha-1 antitrypsin (AAT) is a major inhibitor of serine proteases in mammals. Therefore, its deficiency leads to protease-antiprotease imbalance and a risk for developing lung emphysema. Although therapy with human plasma-purified AAT attenuates AAT deficiency-related emphysema, its impact on lung antibacterial immunity is poorly defined. Here, we examined the effect of AAT therapy on lung protective immunity in AAT-deficient (KO) mice challenged with Streptococcus pneumoniae. AAT-KO mice were highly susceptible to S. pneumoniae, as determined by severe lobar pneumonia and early mortality. Mechanistically, we found that neutrophil-derived elastase (NE) degraded the opsonophagocytically important collectins, surfactant protein A (SP-A) and D (SP-D), which was accompanied by significantly impaired lung bacterial clearance in S. pneumoniae-infected AAT-KO mice. Treatment of S. pneumoniae-infected AAT-KO mice with human AAT protected SP-A and SP-D from NE-mediated degradation and corrected the pulmonary pathology observed in these mice. Likewise, treatment with Sivelestat, a specific inhibitor of NE, also protected collectins from degradation and significantly decreased bacterial loads in S. pneumoniae-infected AAT-KO mice. Our findings show that NE is responsible for the degradation of lung SP-A and SP-D in AAT-KO mice affecting lung protective immunity in AAT deficiency.
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http://dx.doi.org/10.1172/jci.insight.140816DOI Listing
February 2021

Deterioration and Mortality Risk of COPD Patients Not Fitting into Standard GOLD Categories: Results of the COSYCONET Cohort.

Respiration 2021 Jan 22:1-10. Epub 2021 Jan 22.

Department of Internal Medicine V, Comprehensive Pneumology Center (CPC), Member of the German Center for Lung Research (DZL), University of Munich (LMU), Munich, Germany,

Background: Patients with COPD-specific symptoms and history but FEV1/FVC ratio ≥0.7 are a heterogeneous group (former GOLD grade 0) with uncertainties regarding natural history.

Objective: We investigated which lung function measures and cutoff values are predictive for deterioration according to GOLD grades and all-cause mortality.

Methods: We used visit 1-4 data of the COSYCONET cohort. Logistic and Cox regression analyses were used to identify relevant parameters. GOLD 0 patients were categorized according to whether they maintained grade 0 over the following 2 visits or deteriorated persistently into grades 1 or 2. Their clinical characteristics were compared with those of GOLD 1 and 2 patients.

Results: Among 2,741 patients, 374 GOLD 0, 206 grade 1, and 962 grade 2 patients were identified. GOLD 0 patients were characterized by high symptom burden, comparable to grade 2, and a restrictive lung function pattern; those with FEV1/FVC above 0.75 were unlikely to deteriorate over time into grades 1 and 2, in contrast to those with values between 0.70 and 0.75. Regarding mortality risk in GOLD 0, FEV1%predicted and age were the relevant determinants, whereby a cutoff value of 65% was superior to that of 80% as proposed previously.

Conclusions: Regarding patients of the former GOLD grade 0, we identified simple criteria for FEV1/FVC and FEV1% predicted that were relevant for the outcome in terms of deterioration over time and mortality. These criteria might help to identify patients with the typical risk profile of COPD among those not fulfilling spirometric COPD criteria.
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http://dx.doi.org/10.1159/000513010DOI Listing
January 2021

Adjuvant therapeutic plasma exchange in septic shock.

Intensive Care Med 2021 Jan 20. Epub 2021 Jan 20.

Department of Gastroenterology, Hepatology and Endocrinology, Medical School Hannover, Carl-Neuberg-Street 1, 30625, Hannover, Germany.

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http://dx.doi.org/10.1007/s00134-020-06339-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7816555PMC
January 2021

Circulating cardiovascular microRNAs in critically ill COVID-19 patients Short title: microRNA signatures in COVID-19.

Eur J Heart Fail 2021 Jan 9. Epub 2021 Jan 9.

Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany.

Aims: Corona virus disease 2019 (COVID-19) is a still growing pandemic, causing many deaths and socio-economic damage. Elevated expression of the SARS-CoV-2 entry receptor ACE2 on cardiac cells of patients with heart diseases may be related to cardiovascular burden. We have thus analysed cardiovascular and inflammatory microRNAs (miRs), sensitive markers of cardiovascular damage, in critically ill, ventilated patients with COVID-19 or Influenza associated acute respiratory distress syndrome (Influenza-ARDS) admitted to intensive care unit (ICU) and healthy controls.

Methods And Results: Circulating miRs (miR-21, miR-126, miR-155, miR-208a and miR-499) were analyzed in a discovery cohort consisting of patients with mechanically-ventilated COVID-19 (n = 18) and healthy controls (n = 15). A validation study was performed in an independent cohort of mechanically-ventilated COVID-19 patients (n = 20), Influenza-ARDS patients (n = 13) and healthy controls (n = 32). In both cohorts RNA was isolated from serum and cardiovascular disease/inflammatory-relevant miR concentrations were measured by miR-specific TaqMan PCR analyses. In both the discovery and the validation cohort, serum concentration of miR-21, miR-155, miR-208a and miR-499 were significantly increased in COVID-19 patients compared to healthy controls. Calculating the area under the curve (AUC) using ROC-analysis miR-155, miR-208a and miR-499 showed a clear distinction between COVID-19 and Influenza-ARDS patients.

Conclusion: In this exploratory study, inflammation and cardiac myocyte-specific miRs were upregulated in critically ill COVID-19 patients. Importantly, miR profiles were able to differentiate between severely ill, mechanically-ventilated Influenza-ARDS and COVID-19 patients, indicating a rather specific response and cardiac involvement of COVID-19.
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http://dx.doi.org/10.1002/ejhf.2096DOI Listing
January 2021

Comparison of anticoagulation strategies for veno-venous ECMO support in acute respiratory failure.

Crit Care 2021 01 4;24(1):701. Epub 2021 Jan 4.

Department of Anaesthesiology and Critical Care Medicine, University Hospital Bonn, Bonn, Germany.

Background: Extracorporeal membrane oxygenation (ECMO) support in acute respiratory failure may be lifesaving, but bleeding and thromboembolic complications are common. The optimal anticoagulation strategy balancing these factors remains to be determined. This retrospective study compared two institutional anticoagulation management strategies focussing on oxygenator changes and both bleeding and thromboembolic events.

Methods: We conducted a retrospective observational cohort study between 04/2015 and 02/2020 in two ECMO referral centres in Germany in patients receiving veno-venous (VV)-ECMO support for acute respiratory failure for > 24 h. One centre routinely applied low-dose heparinization aiming for a partial thromboplastin time (PTT) of 35-40 s and the other routinely used a high-dose therapeutic heparinization strategy aiming for an activated clotting time (ACT) of 140-180 s. We assessed number of and time to ECMO oxygenator changes, 15-day freedom from oxygenator change, major bleeding events, thromboembolic events, 30-day ICU mortality, activated clotting time and partial thromboplastin time and administration of blood products. Primary outcome was the occurrence of oxygenator changes depending on heparinization strategy; main secondary outcomes were the occurrence of severe bleeding events and occurrence of thromboembolic events. The transfusion strategy was more liberal in the low-dose centre.

Results: Of 375 screened patients receiving VV-ECMO support, 218 were included in the analysis (117 high-dose group; 101 low-dose group). Disease severity measured by SAPS II score was 46 (IQR 36-57) versus 47 (IQR 37-55) and ECMO runtime was 8 (IQR 5-12) versus 11 (IQR 7-17) days (P = 0.003). There were 14 oxygenator changes in the high-dose group versus 48 in the low-dose group. Freedom from oxygenator change at 15 days was 73% versus 55% (adjusted HR 3.34 [95% confidence interval 1.2-9.4]; P = 0.023). Severe bleeding events occurred in 23 (19.7%) versus 14 (13.9%) patients (P = 0.256) and thromboembolic events occurred in 8 (6.8%) versus 19 (19%) patients (P = 0.007). Mortality at 30 days was 33.3% versus 30.7% (P = 0.11).

Conclusions: In this retrospective study, ECMO management with high-dose heparinization was associated with lower rates of oxygenator changes and thromboembolic events when compared to a low-dose heparinization strategy. Prospective, randomized trials are needed to determine the optimal anticoagulation strategy in patients receiving ECMO support.
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http://dx.doi.org/10.1186/s13054-020-03348-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780376PMC
January 2021

Impact of unilateral diaphragm elevation on postoperative outcomes in bilateral lung transplantation - a retrospective single-center study.

Transpl Int 2021 Jan 4. Epub 2021 Jan 4.

Department of Cardiothoracic, Transplant and Vascular Surgery, Hannover Medical School, Hannover, Germany.

This study evaluated the impact of unilateral diaphragm elevation following bilateral lung transplantation on postoperative course. Patient data for all lung transplantations performed at our institution between 01/2010 and 12/2019 were reviewed. Presence of right or left diaphragm elevation was retrospectively evaluated using serial chest X-rays performed while patients were standing and breathing spontaneously. Right elevation was defined by a > 40 mm difference between right and left diaphragmatic height. Left elevation was present if the left diaphragm was at the same height or higher than the right diaphragm. In total, 1093/1213 (90%) lung transplant recipients were included. Of these, 255 (23%) patients exhibited radiologic evidence of diaphragm elevation (right, 55%; left 45%; permanent, 62%). Postoperative course did not differ between groups. Forced expiratory volume in 1 second, forced vital capacity and total lung capacity were lower at 1-year follow-up in patients with permanent than in patients with transient or absent diaphragmatic elevation (P = 0.038, P < 0.001, P = 0.002, respectively). Graft survival did not differ between these groups (P = 0.597). Radiologic evidence of diaphragm elevation was found in 23% of our lung transplant recipients. While lung function tests were worse in patients with permanent elevation, diaphragm elevation did not have any relevant impact on outcomes.
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http://dx.doi.org/10.1111/tri.13812DOI Listing
January 2021

Plasma Acute Phase Proteins as Predictors of Chronic Lung Allograft Dysfunction in Lung Transplant Recipients.

J Inflamm Res 2020 30;13:1021-1028. Epub 2020 Nov 30.

CHU de Nantes, Centre National De Référence Mucoviscidose Nantes-Roscoff, Nantes, France.

Cumulating reports suggest that acute phase proteins (APPs) have diagnostic and prognostic value in different clinical conditions. Among others, APPs are proposed to serve as markers that help to control the outcome of transplant recipients. Here, we questioned whether plasma concentrations of APPs mirror the development of chronic lung allograft dysfunction (CLAD). We performed blinded analysis of serial plasma samples retrospectively collected from 35 lung transplanted patients, of whom 25 developed CLAD and 10 remained stable during the follow-up period of 3 to 4.5 years. Albumin (ALB), alpha1-antitrypsin (AAT), high sensitivity C-reactive protein (CRPH), antithrombin-3 (AT3), ceruloplasmin (CER), and alpha2-macroglobulin (A2MG) were measured by the nephelometric method. We found that within the first six months post-transplantation, levels of A2MG, CER and AAT were higher in stable patients relative to those who later developed CLAD. Moreover, in stable patient's plasma CRPH levels decreased during the follow-up period whereas opposite, in those developing CLAD, the CRPH gradually increased. The ALB levels became significantly lower at the end of the follow-up period in CLAD relative to a stable group. A logistic regression model based on A2MG, CER and AT3 at cut-offs levels of ≥175.5 mg/dL, ≥37.8 mg/dL and ≥27.35 mg/dL enabled to discriminate between stable and CLAD patients with a sensitivity of 87.5%, 100% and 62.5%, and specificity of 65.9%, 72.7% and 79.5%, respectively. We identified A2MG (below 175.5 mg/dL) as an independent predictor of CLAD (hazard ratio 11.5, 95% CI (1.5-91.3), p<0.021). Our findings suggest that profiles of certain APPs may help to predict the development of lung dysfunction at the very early stages after transplantation.
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http://dx.doi.org/10.2147/JIR.S272662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721309PMC
November 2020

Role of the COX2-PGE axis in -induced exacerbation of experimental fibrosis.

Am J Physiol Lung Cell Mol Physiol 2021 Mar 9;320(3):L377-L392. Epub 2020 Dec 9.

Division of Experimental Pneumology, Hannover Medical School, Hannover, Germany.

Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease (ILD) associated with high morbidity and mortality. Patients with ILD frequently develop an acute exacerbation of their disease, which may be triggered by viral and/or bacterial infections. Prostaglandin E (PGE) is an eicosanoid released in a cyclooxygenase-2 (COX2)-dependent manner and is considered to contribute to regulation of lung fibrosis. However, its role in infection-induced exacerbation of lung fibrosis is poorly defined. We found significantly increased levels of PGE in lung tissue of patients with ILD. Increased levels of PGE were also found in lung tissue of mice with AdTGF-β1-induced lung fibrosis and even more so in exacerbated lung fibrosis. Type II alveolar epithelial cells (AT II cells) and alveolar macrophages (AM) contributed to PGE release during exacerbating fibrosis. Application of parecoxib to inhibit PGE synthesis ameliorated lung fibrosis, whereas intratracheal application of PGE worsened lung fibrosis in mice. Both interventions had no effect on -exacerbated lung fibrosis. Together, we found that the COX2-PGE axis has dual roles in fibrosis that may offset each other: PGE helps resolve infection/attenuate inflammation in fibrosis exacerbation but accentuates TGF-β/AT II cell-mediated fibrosis. These data support the efficacy of COX/PGE interventions in the setting of non-exacerbating lung fibrosis.
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http://dx.doi.org/10.1152/ajplung.00024.2020DOI Listing
March 2021

SARS-CoV-2-triggered Immune Reaction: For COVID-19, Nothing Is as Old as Yesterday's Knowledge.

Authors:
Tobias Welte

Am J Respir Crit Care Med 2021 01;203(2):156

Department of Respiratory Medicine Medizinische Hochschule Hannover, Germany.

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http://dx.doi.org/10.1164/rccm.202011-4194EDDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874429PMC
January 2021

Immunoglobulin Deficiency as an Indicator of Disease Severity in Patients with COVID-19.

Am J Physiol Lung Cell Mol Physiol 2020 Nov 25. Epub 2020 Nov 25.

Nephrologie, Medizinische Hochschule Hannover.

Despite the pandemic status of COVID-19, there is limited information about host risk factors and treatment beyond supportive care. Immunoglobulin G (IgG) could be a potential treatment target. Our aim was to determine the incidence of IgG deficiency and associated risk factors in a cohort of 62 critical ill COVID-19 patients admitted to two German ICUs (72.6% male, median age: 61 years). 13 (21.0%) of the patients displayed IgG deficiency (IgG <7 g/L) at baseline (predominant for the IgG1, IgG2, and IgG4 subclasses). IgG-deficient patients had worse measures of clinical disease severity than those with normal IgG levels (shorter duration from disease onset to ICU admission, lower ratio of PaO to FiO, higher Sequential Organ Failure Assessment score, and higher levels of ferritin, neutrophil-to-lymphocyte ratio and serum creatinine). IgG-deficient patients were also more likely to have sustained lower levels of lymphocyte counts and higher levels of ferritin throughout the hospital stay. Furthermore, IgG-deficient patients compared to those with normal IgG levels displayed higher rates of acute kidney injury (76.9% vs. 26.5%; p=0.005) and death (46.2% vs. 14.3%; p=0.012), longer ICU (28 [6-48] vs. 12 [3-18] days; p=0.012) and hospital length of stay (30 [22-50] vs. 18 [9-24] days; p=0.004). Multivariable logistic regression showed increasing odds of 90-day overall mortality associated with IgG-deficiency (OR 12.8, 95% CI 1.5-108.4; p=0.019). IgG deficiency might be common in critically ill COVID-19 patients, and warrants investigation as both a marker of disease severity as well as a potential therapeutic target.
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http://dx.doi.org/10.1152/ajplung.00359.2020DOI Listing
November 2020

Switch from IL-5 to IL-5-Receptor α Antibody Treatment in Severe Eosinophilic Asthma.

J Asthma Allergy 2020 11;13:605-614. Epub 2020 Nov 11.

Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany.

Background: Anti-IL-5 antibodies represent an established therapy for severe eosinophilic asthma (SEA), but some patients show inadequate response. The objective of this study was to assess the effects of a switch to anti-IL-5Rα therapy in patients with inadequate response to anti-IL-5 therapy.

Methods: In this retrospective multi-centre, real-life study, we analysed all SEA patients switched from anti-IL-5 to anti-IL-5Rα therapy due to inadequate response or intolerability. Pulmonary function tests, blood gas analyses, asthma control tests (ACT) and oral corticosteroid (OCS) usage were analysed and compared at three timepoints: baseline (BL, before anti-IL-5 therapy), timepoint 1 (T1, under anti-IL-5 therapy) and timepoint 2 (T2, under anti-IL-5Rα therapy).

Results: Of 665 patients treated with anti-IL-5 antibodies, 70 were switched to anti-IL-5Rα and 60 were included in the analysis. Median treatment duration was 8 months [IQR 5; 15] for anti-IL-5 and 5 months [IQR 4; 6] for anti-IL-5Rα therapy. FEV was 61% of predicted at BL [IQR 41; 74], 61% [IQR 43; 79] at T1 and 68% [IQR 49; 87] at T2 (p=0.011). ACT score was 10 [IQR 8; 13], 16 [IQR 10; 19] and 19 [IQR 14; 22], respectively (both p<0.001). The number of patients requiring OCS was reduced from 41 (BL) to 32 (T1) and 19 (T2) (both p<0.001). Ten patients discontinued anti-IL-5Rα therapy due to insufficient efficacy (n=7) and adverse events (n=3).

Conclusion: Switching from anti-IL-5 to anti-IL-5Rα therapy in patients with inadequate response was associated with significantly improved FEV, asthma control and OCS reduction.
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http://dx.doi.org/10.2147/JAA.S270298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667509PMC
November 2020

Impact of Education on COPD Severity and All-Cause Mortality in Lifetime Never-Smokers and Longtime Ex-Smokers: Results of the COSYCONET Cohort.

Int J Chron Obstruct Pulmon Dis 2020 5;15:2787-2798. Epub 2020 Nov 5.

Department of Internal Medicine V, University of Munich (LMU), Comprehensive Pneumology Center, Member of the German Center for Lung Research (DZL), Munich, 80336, Germany.

Background: Beyond smoking, several risk factors for the development of chronic obstructive pulmonary disease (COPD) have been described, among which socioeconomic status including education is of particular interest. We studied the contribution of education to lung function and symptoms relative to smoking in a group of never-smokers with COPD compared to a group of long-time ex-smokers with COPD.

Methods: We used baseline data of the COSYCONET cohort, including patients of GOLD grades 1-4 who were either never-smokers (n=150, age 68.5y, 53.3% female) or ex-smokers (≥10 packyears) for at least 10 years (n=616, 68.3y, 29.9% female). Socioeconomic status was analyzed using education level and mortality was assessed over a follow-up period of 4.5 years. Analyses were performed using ANOVA and regression models.

Results: Spirometric lung function did not differ between groups, whereas CO diffusing capacity and indicators of lung hyperinflation/air-trapping showed better values in the never-smoker group. In both groups, spirometric lung function depended on the education level, with better values for higher education. Quality of life and 6-MWD were significantly different in never-smokers as well as patients with higher education. Asthma, alpha-1-antitrypsin deficiency, and bronchiectasis were more often reported in never-smokers, and asthma was more often reported in patients with higher education. Higher education was also associated with reduced mortality (hazard ratio 0.46; 95% CI 0.22-0.98).

Conclusion: Overall, in the COSYCONET COPD cohort, differences in functional status between never-smokers and long-time ex-smokers were not large. Compared to that, the dependence on education level was more prominent, with higher education associated with better outcomes, including mortality. These data indicate that non-smoking COPD patients' socioeconomic factors are relevant and should be taken into account by clinicians.
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http://dx.doi.org/10.2147/COPD.S273839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7652228PMC
November 2020

Prevalence and Population Attributable Risk for Chronic Airflow Obstruction in a Large Multinational Study.

Am J Respir Crit Care Med 2020 Nov 10. Epub 2020 Nov 10.

Oregon Health Sciences University, Medicine / Pulmonary & Critical Care, Portland, Oregon, United States.

The Global Burden of Disease programme identified smoking, and ambient and household air pollution as the main drivers of death and disability from Chronic Obstructive Pulmonary Disease (COPD). To estimate the attributable risk of chronic airflow obstruction (CAO), a quantifiable characteristic of COPD, due to several risk factors. The Burden of Obstructive Lung Disease study is a cross-sectional study of adults, aged≥40, in a globally distributed sample of 41 urban and rural sites. Based on data from 28,459 participants, we estimated the prevalence of CAO, defined as a post-bronchodilator one-second forced expiratory volume to forced vital capacity ratio < lower limit of normal, and the relative risks associated with different risk factors. Local RR were estimated using a Bayesian hierarchical model borrowing information from across sites. From these RR and the prevalence of risk factors, we estimated local Population Attributable Risks (PAR). Mean prevalence of CAO was 11.2% in men and 8.6% in women. Mean PAR for smoking was 5.1% in men and 2.2% in women. The next most influential risk factors were poor education levels, working in a dusty job for ≥10 years, low body mass index (BMI), and a history of tuberculosis. The risk of CAO attributable to the different risk factors varied across sites. While smoking remains the most important risk factor for CAO, in some areas poor education, low BMI and passive smoking are of greater importance. Dusty occupations and tuberculosis are important risk factors at some sites.
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http://dx.doi.org/10.1164/rccm.202005-1990OCDOI Listing
November 2020

Overexpression of Macrophage-Inducible C-Type Lectin Mincle Aggravates Proinflammatory Responses to with Fatal Outcome in Mice.

J Immunol 2020 Dec 6;205(12):3390-3399. Epub 2020 Nov 6.

Division of Experimental Pneumology, Hannover Medical School, Hannover 30625, Germany;

Macrophage-inducible C-type lectin (Mincle)-dependent sensing of pathogens triggers proinflammatory immune responses in professional phagocytes that contribute to protecting the host against pathogen invasion. In this study, we examined whether overexpression of Mincle that is designed to improve early pathogen sensing by professional phagocytes would improve lung-protective immunity against in mice. Proteomic profiling of alveolar macrophages of Mincle transgenic (tg) mice stimulated with the Mincle-specific pneumococcal ligand glucosyl-diacylglycerol (Glc-DAG) revealed increased Nlrp3 inflammasome activation and downstream IL-1β cytokine release that was not observed in Glc-DAG-stimulated Mincle knockout or Nlrp3 knockout macrophages. Along this line, Mincle tg mice also responded with a stronger Nlrp3 expression and early proinflammatory cytokine release after challenge with , ultimately leading to fatal pneumonia in the Mincle tg mice. Importantly, Nlrp3 inhibitor treatment of Mincle tg mice significantly mitigated the observed hyperinflammatory response to pneumococcal challenge. Together, we show that overexpression of the pattern recognition receptor Mincle triggers increased Glc-DAG-dependent Nlrp3 inflammasome activation in professional phagocytes leading to fatal pneumococcal pneumonia in mice that is amenable to Nlrp3 inhibitor treatment. These data show that ectopic expression of the Mincle receptor confers increased susceptibility rather than resistance to in mice, thus highlighting the importance of an inducible Mincle receptor expression in response to microbial challenge.
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http://dx.doi.org/10.4049/jimmunol.2000509DOI Listing
December 2020

Effect of Therapeutic Plasma Exchange on Immunoglobulin Deficiency in Early and Severe Septic Shock.

J Intensive Care Med 2020 Oct 16:885066620965169. Epub 2020 Oct 16.

Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany.

Background: Deficiency of immunoglobulins of the classes IgG, IgG1, IgA and IgM is associated with severity of disease and mortality in sepsis and septic shock. Therapeutic plasma exchange (TPE) with fresh frozen plasma (FFP) has recently gained attention as an adjunctive therapeutic option in early septic shock. We hypothesized that TPE might modulate immunoglobulin deficiencies besides sole elimination of circulating injurious molecules.

Methods: We conducted a prospective single center study with TPE in 33 patients with early septic shock (onset < 12 h) requiring high doses of norepinephrine (NE > 0.4μg/kg/min). Clinical and biochemical data, including measurement of immunoglobulin subgroups IgG, IgG1, IgM and IgA were obtained before and after TPE. The following immunoglobulin cut-off values were used to analyze subgroups with low immunoglobulin concentrations at baseline (IgG ≤ 6.5, IgG1 ≤ 3, IgM ≤ 1.5 and IgA ≤ 0.35 g/L).

Results: At inclusion, median (IQR) SOFA score was 18 (15-20) and NE dose was 0.8 (0.6-1.2) μg/kg/min. The majority of patients demonstrated profound reductions in immunoglobulins levels of all classes. Globally, immunoglobulin levels were not significantly changed after a single TPE session. However, in patients with low baseline immunoglobulin levels a significant increase in all classes was observed (IgG 1.92 (0.96-3) g/L (+41%), IgG1 2.1 (1.46-2.32) g/L (+96%), IgA 0.44 (0.12-0.62) g/L (59%) and IgM 0.18 (0.14-0.34) g/L (+55%), p < 0.001 for comparison to patients above cut-off).

Conclusions: The majority of early and severe septic shock patients had reduced immunoglobulin levels and a single TPE could attenuate immunoglobulin deficiencies of all classes. The clinical relevance of this observation has to be investigated in a proper designed trial.
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http://dx.doi.org/10.1177/0885066620965169DOI Listing
October 2020

Intestinal current measurement and nasal potential difference to make a diagnosis of cases with inconclusive genetics and sweat test.

BMJ Open Respir Res 2020 10;7(1)

Clinic for Paediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany

Background: Nasal potential difference (NPD) and intestinal current measurements (ICM) are cystic fibrosis transmembrane conductance regulator (CFTR) biomarkers recommended to make a diagnosis in individuals with inconclusive sweat test and genetics and a clinical suspicion for cystic fibrosis (CF) or CFTR-related disorder (CFTR-RD).

Methods: NPD and ICM were measured according to standard operating procedures of the European Cystic Fibrosis Society Diagnostic Network Working Group.

Results: We assessed 219 individuals by NPD or ICM who had been referred to our laboratory due to clinical symptoms suggestive of CF, but inconclusive sweat test and genetics (median age: 16.3 years, range 0.4 to 76 years). CF or CFTR-related disorder was diagnosed in 22 of 29 patients (76%) with a genotype of unknown or variable clinical significance and in 51 of 190 carriers (27%) of one (35/42) or no (16/148) identified mutation. If two sequence variants had been identified, the outcome of NPD and ICM was consistent with the classification of the CFTR2 database. Moreover, a suspected false-positive diagnosis of CF was confirmed in seven and withdrawn in eight patients. Of 26 individuals assessed by both NPD and ICM, eleven individuals exhibited discordant tracings of ICM and NPD, with one measurement being in the CF range and the other in the normal range.

Conclusion: The majority of patients whom we diagnosed with CF or CFTR-RD by extended electrophysiology are carriers of the wild-type coding sequence on at least one of their CF alleles. The disease-causing genetic lesions should reside in the non-coding region of or elsewhere in the genome, affecting the regulation of CFTR expression in a tissue-depending fashion which may explain the large within-group variability of CFTR activity in the respiratory and intestinal epithelium seen in this group.
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http://dx.doi.org/10.1136/bmjresp-2020-000736DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537139PMC
October 2020

Dupilumab Improves Asthma Control and Lung Function in Patients with Insufficient Outcome During Previous Antibody Therapy.

J Allergy Clin Immunol Pract 2020 Sep 24. Epub 2020 Sep 24.

Department of Internal Medicine V, Ludwig-Maximilians-University of Munich (LMU), Munich, Germany; Comprehensive Pneumology Center (CPC-M), Helmholtz Center Munich, Member of the German Center for Lung Research (DZL), Munich, Germany. Electronic address:

Background: Biological treatments directed against IgE and IL-5 have largely improved outcomes for patients with severe type 2-high asthma. However, a fraction of patients with severe asthma show insufficient treatment outcome under anti-IgE and anti-IL-5/IL-5 receptor α antibodies.

Objective: To evaluate whether switching to dupilumab was of benefit in patients with insufficient outcome under previous anti-IgE or anti-IL-5/IL-5 receptor α therapy.

Methods: We retrospectively analyzed 38 patients who were switched to dupilumab from a previous anti-IgE or anti-IL-5/IL-5 receptor α medication because of insufficient outcome. We defined response criteria after 3 to 6 months as an improvement in at least 1 of the following criteria without deterioration in the other criteria, comparing values under dupilumab with values under previous antibody therapy: (1) increase of 3 or more in Asthma Control Test score, (2) 50% or more reduction in oral corticosteroid dose, and (3) FEV improvement greater than or equal to 150 mL, and classified patients as responders and nonresponders.

Results: Switch to dupilumab led to a response in 76% of patients. In the total cohort, Asthma Control Test score increased by a mean of 2.9 (P < .0001), whereas exacerbations decreased significantly (P < .0001) and number of oral corticosteroid-dependent patients decreased from 15 to 12. Mean FEV improved by 305 mL (P < .0001). Median fractional exhaled nitric oxide decreased by -30 ppb (P < .0001), whereas eosinophil counts increased by 0.17 G/L (P < .01). There were no significant differences in clinical characteristics between responders and nonresponders to dupilumab. However, patients with increased fractional exhaled nitric oxide (≥25 ppb) during previous antibody therapy were more often responders than patients with low fractional exhaled nitric oxide (<25 ppb) (P < .05).

Conclusions: Altogether, we show that a switch to dupilumab in patients with insufficient outcome under previous biological therapy was effective in most patients.
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http://dx.doi.org/10.1016/j.jaip.2020.09.014DOI Listing
September 2020

Benefits of pulmonary rehabilitation in patients with advanced lymphangioleiomyomatosis (LAM) compared with COPD - a retrospective analysis.

Orphanet J Rare Dis 2020 09 22;15(1):255. Epub 2020 Sep 22.

Department of Pulmonary Rehabilitation, Philipps - University of Marburg, German Center for Lung Research (DZL), Marburg, Germany.

Lymphangioleiomyomatosis (LAM) is a rare and progressive cystic lung disease with limited therapeutic options. We retrospectively analyzed the effects of a comprehensive 4-week inpatient pulmonary rehabilitation (PR) program in 58 patients with advanced LAM (FEV1: 45 ± 34%predicted, 6-min walk distance (6MWD): 338 ± 167 m). Exercise performance (6MWD: + 49 ± 50 m; p < 0.001) and quality of life (SF-36 physical component: + 2.4 ± 7.8 points; p = 0.049 and mental component: + 5.2 ± 12.1 points; p < 0.001) increased significantly after PR comparable to an COPD cohort. There were no clinical parameters that predicted changes in outcomes following PR. PR seems to be an effective therapeutic option even in patients with advanced LAM. TRIAL REGISTRATION: Clinical-Trials registration number: NCT04184193 ; date of registration: December 3, 2019.
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http://dx.doi.org/10.1186/s13023-020-01540-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7507679PMC
September 2020

Generation of two hiPSC clones (MHHi019-A, MHHi019-B) from a primary ciliary dyskinesia patient carrying a homozygous deletion in the NME5 gene (c.415delA (p.Ile139Tyrfs*8)).

Stem Cell Res 2020 10 7;48:101988. Epub 2020 Sep 7.

Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, 30625 Hannover, Germany; REBIRTH - Research Center for Translational Regenerative Medicine, Hannover Medical School, 30625 Hannover, Germany; Biomedical Research in Endstage and Obstructive Lung Disease (BREATH), Member of the German Center for Lung Research (DZL), Germany. Electronic address:

Primary ciliary dyskinesia (PCD) is a genetic disorder characterized by defects in motile cilia and is known to occur in about 1 in 20,000 live births (Horani and Ferkol, 2018). Among the many genes associated with PCD, NME5, a gene encoding a protein involved in ciliary function, was recently reported to be involved in PCD (Anderegg et al., 2019; Cho et al., 2020). We have established two human induced pluripotent stem cell clones from a PCD patient carrying a deletion in the NME5 gene (c.415delA (p.Ile139Tyrfs*8)).
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http://dx.doi.org/10.1016/j.scr.2020.101988DOI Listing
October 2020

How are rapid diagnostic tests for infectious diseases used in clinical practice: a global survey by the International Society of Antimicrobial Chemotherapy (ISAC).

Eur J Clin Microbiol Infect Dis 2021 Feb 9;40(2):429-434. Epub 2020 Sep 9.

School of Medicine, University of Southampton, Southampton, UK.

Novel rapid diagnostic tests (RDTs) offer huge potential to optimise clinical care and improve patient outcomes. In this study, we aim to assess the current patterns of use around the world, identify issues for successful implementation and suggest best practice advice on how to introduce new tests. An electronic survey was devised by the International Society of Antimicrobial Chemotherapy (ISAC) Rapid Diagnostics and Biomarkers working group focussing on the availability, structure and impact of RDTs around the world. It was circulated to ISAC members in December 2019. Results were collated according to the UN human development index (HDI). 81 responses were gathered from 31 different countries. 84% of institutions reported the availability of any test 24/7. In more developed countries, this was more for respiratory viruses, whereas in high and medium/low developed countries, it was for HIV and viral hepatitis. Only 37% of those carrying out rapid tests measured the impact. There is no 'one-size fits all' solution to RDTs: the requirements must be tailored to the healthcare setting in which they are deployed and there are many factors that should be considered prior to this.
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http://dx.doi.org/10.1007/s10096-020-04031-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7478941PMC
February 2021

Invasive and Non-Invasive Ventilation in Patients With COVID-19.

Dtsch Arztebl Int 2020 08;117(31-32):528-533

Department of Respiratory Medicine, Kliniken der Stadt Köln gGmbH, University of Witten/Herdecke; Surgical Intensive Care, Department of Anesthesiology, Charité University Medical Center, Berlin; Department of Intensive Care, University Medical Center Hamburg-Eppendorf; Department of Anesthesiology, University Medical Center Aachen, RWTH Aachen University; Director of Patient Care at MHH, The German Center for Lung Research, University Medical School Hanover (MHH), Hanover.

Background: The reported high mortality of COVID-19 patients in intensive care has given rise to a debate over whether patients with this disease are being intubated too soon and might instead benefit from more non-invasive ventilation.

Methods: This review is based on articles published up to 12 June 2020 that were retrieved by a selective literature search on the topic of invasive and non-invasive ventilation for respiratory failure in COVID-19. Guideline recommendations and study data on patients with respiratory failure in settings other than COVID-19 are also considered, as are the current figures of the intensive care registry of the German Interdisciplinary Association for Intensive Care and Emergency Medicine (Deutsche Interdisziplinäre Vereinigung für Intensiv- und Notfallmedizin).

Results: The high mortality figures among patients receiving invasive ventilation that have been reported in studies from abroad cannot be uncritically applied to the current situation in Germany. Study data on ventilation specifically in COVID-19 patients would be needed to do justice to the special pathophysiology of this disease, but such data are lacking. Being intubated too early is evidently associated with risks for the patient, but being intubated too late is as well. A particularly im - portant consideration is the potential harm associated with prolonged spontaneous breathing, with or without non-invasive assistance, as any increase in respiratory work can seriously worsen respiratory failure. On the other hand, it is clearly unacceptable to intubate patients too early merely out of concern that the medical staff might become infected with COVID-19 if they were ventilated non-invasively.

Conclusion: Nasal high flow, non-invasive ventilation, and invasive ventilation with intubation should be carried out in a stepwise treatment strategy, under appropriate intensive-care monitoring and with the observance of all relevant anti-infectious precautions. Germany is better prepared that other countries to provide COVID-19 patients with appropriate respiratory care, in view of the high per capita density of intensive-care beds and the availability of a nationwide, interdisciplinary intensive care registry for the guidance and coordination of intensive care in patients who need it.
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http://dx.doi.org/10.3238/arztebl.2020.0528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658682PMC
August 2020

Recurrent Life-threatening Pneumonitis in a 37-Year-Old Woman.

Chest 2020 Sep;158(3):e127-e132

Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany; Member of the German Center for Lung Research (DZL BREATH), Hannover, Germany.

Case Presentation: A 37-year-old previously healthy and athletic woman presented to the ED in October 2018 with acute-onset high fever, dyspnea, and productive cough. Chest radiograph showed bilateral infiltrates that correlated with multifocal ground glass opacities in a thoracic CT scan (Fig 1). The patient was severely hypoxemic and required intensive care and oxygen administration via a high-flow nasal cannula. On admission, leucocyte counts were 23.3 k/μL; platelet counts were 518 k/μL; hemoglobin level was 12 g/dL; C-reactive protein was 83 mg/L, and procalcitonin was 0.7 μg/L. An auto-antibody panel that included antinuclear antibodies, extractable nuclear antigen (including anti-centromere-antibodies), antineutrophil cytoplasmic antibodies, and myositis- and granulocyte macrophage colony-stimulating factor-antibodies was negative, as was the rheumatoid factor. Immunoglobulins that included IgG1-4 and IgA and renal function were normal. Sicca symptoms like xerophthalmia and xerostomia were negated. The patient fully recovered after empiric administration of antibiotics and glucocorticoids (initially 500 mg methylprednisolone daily over 3 days with consecutive tapering).
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http://dx.doi.org/10.1016/j.chest.2020.03.066DOI Listing
September 2020

Relationship between clinical and radiological signs of bronchiectasis in COPD patients: Results from COSYCONET.

Respir Med 2020 10 22;172:106117. Epub 2020 Aug 22.

Department of Pneumology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.

Bronchiectasis (BE) might be frequently present in COPD but masked by COPD symptoms. We studied the relationship of clinical signs of bronchiectasis to the presence and extent of its radiological signs in patients of different COPD severity. Visit 4 data (GOLD grades 1-4) of the COSYCONET cohort was used. Chest CT scans were evaluated for bronchiectasis in 6 lobes using a 3-point scale (0: absence, 1: ≤50%, 2: >50% BE-involvement for each lobe). 1176 patients were included (61%male, age 67.3y), among them 38 (3.2%) with reported physicians' diagnosis of bronchiectasis and 76 (6.5%) with alpha1-antitrypsin deficiency (AA1D). CT scans were obtained in 429 patients. Within this group, any signs of bronchiectasis were found in 46.6% of patients, whereby ≤50% BE occurred in 18.6% in ≤2 lobes, in 10.0% in 3-4 lobes, in 15.9% in 5-6 lobes; >50% bronchiectasis in at least 1 lobe was observed in 2.1%. Scores ≥4 correlated with an elevated ratio FRC/RV. The clinical diagnosis of bronchiectasis correlated with phlegm and cough and with radiological scores of at least 3, optimally ≥5. In COPD patients, clinical diagnosis and radiological signs of BE showed only weak correlations. Correlations became significant with increasing BE-severity implying radiological alterations in several lobes. This indicates the importance of reporting both presence and extent of bronchiectasis on CT. Further research is warranted to refine the criteria for CT scoring of bronchiectasis and to determine the relevance of radiologically but not clinically detectible bronchiectasis and their possible implications for therapy in COPD patients.
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http://dx.doi.org/10.1016/j.rmed.2020.106117DOI Listing
October 2020

International Perspective on the New 2019 American Thoracic Society/Infectious Diseases Society of America Community-Acquired Pneumonia Guideline: A Critical Appraisal by a Global Expert Panel.

Chest 2020 Nov 25;158(5):1912-1918. Epub 2020 Aug 25.

Respiratory Unit, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.

In 2019, the American Thoracic Society (ATS) and Infectious Diseases Society of America (IDSA) issued a substantial revision of the 2007 guideline on community-acquired pneumonia (CAP). Despite the fact that generalization of infectious disease guidelines is limited because of substantial geographic differences in microbiologic etiology and antimicrobial resistance, the ATS/IDSA guideline is frequently applied outside the United States. Therefore, this project aimed to give a perspective on the ATS/IDSA CAP recommendations related to the management of CAP outside the United States. For this, an expert panel composed of 14 international key opinion leaders in the field of CAP from 10 countries across five continents, who were not involved in producing the 2019 guideline, was asked to subjectively name the five most useful changes, the recommendation viewed most critically, and the recommendation that cannot be applied to their respective region. There was no formal consensus process, and the article reflects different opinions. Recommendations welcomed by most of the international pneumonia experts included the abandonment of the concept of "health-care-associated pneumonia," the more restrictive indication for empiric macrolide treatment in outpatients, the increased emphasis on microbiologic diagnostics, and addressing the use of corticosteroids. Main criticisms included the somewhat arbitrary choice of a 25% resistance threshold for outpatient macrolide monotherapy. Experts from areas with elevated mycobacterial prevalence particularly opposed the recommendation of fluoroquinolones, even as an alternative.
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http://dx.doi.org/10.1016/j.chest.2020.07.089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7445464PMC
November 2020

Clinical Molecular Imaging of Pulmonary CXCR4 Expression to Predict Outcome of Pirfenidone Treatment in Idiopathic Pulmonary Fibrosis.

Chest 2020 Aug 19. Epub 2020 Aug 19.

Department of Pulmonology, Hannover Medical School, Hannover, Germany; Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany; DZL-BREATH, Hannover, Germany. Electronic address:

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive disease for which two antifibrotic drugs recently were approved. However, an unmet need exists to predict responses to antifibrotic treatment, such as pirfenidone. Recent data suggest that upregulated expression of CXCR4 is indicative of outcomes in IPF.

Research Question: Can quantitative, molecular imaging of pulmonary CXCR4 expression as a biomarker for disease activity predict response to the targeted treatment pirfenidone and prognosis in patients with IPF?

Study Design And Methods: CXCR4 expression was analyzed by immunohistochemistry examination of lung tissues and reverse-transcriptase polymerase chain reaction analysis of BAL. PET-CT scanning with the specific CXCR4 ligand Ga-pentixafor was performed in 28 IPF patients and compared with baseline clinical characteristics. In 16 patients, a follow-up scan was obtained 6 to 12 weeks after initiation of treatment with pirfenidone. Patients were followed up in our outpatient clinic for ≥ 12 months.

Results: Immunohistochemistry analysis showed high CXCR4 staining of epithelial cells and macrophages in areas with vast fibrotic remodeling. Targeted PET scanning revealed CXCR4 upregulation in fibrotic areas of the lungs, particularly in zones with subpleural honeycombing. Baseline CXCR4 signal demonstrated a significant correlation with Gender Age Physiology stage (r = 0.44; P = .02) and with high-resolution CT scan score (r = 0.38; P = .04). Early changes in CXCR4 signal after initiation of pirfenidone treatment correlated with the long-term course of FVC after 12 months (r = -0.75; P = .0008). Moreover, patients with a high pulmonary CXCR4 signal on follow-up PET scan after 6 weeks into treatment demonstrated a statistically significant worse outcome at 12 months (P = .002). In multiple regression analysis, pulmonary CXCR4 signal on follow-up PET scan emerged as the only independent predictor of long-term outcome (P = .0226).

Interpretation: CXCR4-targeted PET imaging identified disease activity and predicted outcome of IPF patients treated with pirfenidone. It may serve as a future biomarker for personalized guidance of antifibrotic treatment.
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http://dx.doi.org/10.1016/j.chest.2020.08.2043DOI Listing
August 2020

Real-world mepolizumab in the prospective severe asthma REALITI-A study: initial analysis.

Eur Respir J 2020 10 15;56(4). Epub 2020 Oct 15.

Epidemiology, GSK, Upper Providence, PA, USA.

Introduction: Efficacy of mepolizumab, an anti-interleukin-5 monoclonal antibody, was demonstrated in randomised controlled trials; data on its real-world impact in routine clinical practice are starting to emerge. We assessed the effectiveness and safety of mepolizumab prescribed for patients in the real world.

Methods: REALITI-A is a global, prospective, observational cohort study, collecting data from routine healthcare visits from patients with asthma. Patients newly prescribed mepolizumab for severe asthma with 12 months of relevant medical history pre-mepolizumab (collected retrospectively) were enrolled. An initial analysis of data from early initiators who had completed 1 year of follow-up (as of February 28, 2019) was conducted. The primary objective was to compare the rate of clinically significant exacerbations (requiring oral corticosteroids (OCS) and/or hospitalisation and/or emergency department visit) before and after mepolizumab; exacerbations requiring hospitalisation and/or emergency department visit and change in maintenance OCS use were secondary objectives. Treatment-related adverse events were reported.

Results: Overall, 368 mepolizumab-treated patients were included. Rates of clinically significant exacerbations were reduced by 69% from 4.63 per person per year pre-treatment to 1.43 per person per year during follow-up (p<0.001), as were those requiring hospitalisation and/or emergency department visit (from 1.14 to 0.27 per person per year; 77% reduction). In 159 patients with maintenance OCS dose data available during the pre-treatment period, median daily dose decreased from 10.0 (pre-treatment) to 5.0 mg·day by week 21-24 of follow-up, sustained until week 53-56. No new safety signals were reported.

Conclusion: These data demonstrate that the effectiveness of mepolizumab is consistent with clinical trial results under real-world settings, with significant reductions in exacerbations and daily maintenance OCS dose.
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http://dx.doi.org/10.1183/13993003.00151-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7559868PMC
October 2020

World Lung Day: what, why, and where to?

Am J Physiol Lung Cell Mol Physiol 2020 09 12;319(3):L527-L533. Epub 2020 Aug 12.

The Forum of International Respiratory Societies, Lausanne, Switzerland.

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http://dx.doi.org/10.1152/ajplung.00364.2020DOI Listing
September 2020