Publications by authors named "Timm Greulich"

61 Publications

Standardisation of Clinical Assessment, Management and Follow-Up of Acute Hospitalised Exacerbation of COPD: A Europe-Wide Consensus.

Int J Chron Obstruct Pulmon Dis 2021 16;16:321-332. Epub 2021 Feb 16.

Respiratory Medicine Unit, Nuffield Department of Medicine - Experimental Medicine, University of Oxford, Oxford, UK.

Background: Despite hospitalization for exacerbation being a high-risk event for morbidity and mortality, there is little consensus globally regarding the assessment and management of hospitalised exacerbations of COPD. We aimed to establish a consensus list of symptoms, physiological measures, clinical scores, patient questionnaires and investigations to be obtained at time of hospitalised COPD exacerbation and follow-up.

Methods: A modified Delphi online survey with pre-defined consensus of importance, feasibility and frequency of measures at hospitalisation and follow-up of a COPD exacerbation was undertaken.

Findings: A total of 25 COPD experts from 18 countries contributed to all 3 rounds of the survey. Experts agreed that a detailed history and examination were needed. Experts also agreed on which treatments are needed and how soon these should be delivered. Experts recommended that a full blood count, renal function, C-reactive protein and cardiac blood biomarkers (BNP and troponin) should be measured within 4 hours of admission and that the modified Medical Research Council dyspnoea scale (mMRC) and COPD assessment test (CAT) should be performed at time of exacerbation and follow-up. Experts encouraged COPD clinicians to strongly consider discussing palliative care, if indicated, at time of hospitalisation.

Interpretation: This Europe-wide consensus document is the first attempt to standardise the assessment and care of patients hospitalised for COPD exacerbations. This should be regarded as the starting point to build knowledge and evidence on patients hospitalised for COPD exacerbations.
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http://dx.doi.org/10.2147/COPD.S287705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7896731PMC
February 2021

Research priorities in α-antitrypsin deficiency: results of a patients' and healthcare providers' international survey from the EARCO Clinical Research Collaboration.

ERJ Open Res 2020 Oct 21;6(4). Epub 2020 Dec 21.

Pulmonology Dept, Centro Hospitalar do Porto, Porto, Portugal.

α-antitrypsin deficiency (AATD) is a rare and under-recognised genetic condition. Owing to its low prevalence, international initiatives are key for conducting high-quality research in the field. From July 2018 to December 2019, the European Alpha-1 Research Collaboration (EARCO) developed and conducted two surveys, one for healthcare providers and one for patients and caregivers, aiming to identify research priorities and barriers in access to treatment for AATD. A survey on 164 research questions was electronically sent to 230 AATD experts in Europe, and 94 completed surveys from 24 countries were received. The top research areas identified by healthcare providers were causes of variable progression and poor outcomes, improvement in diagnosis, initiation and optimal dosing of augmentation therapy and effectiveness of self-management interventions. During the same period, 438 surveys were completed by patients and caregivers from 26 countries. The top research areas identified were improving knowledge about AATD, in particular among general practitioners, access to AATD specialised centres and access to reliable, easy to understand information about living with AATD. Regarding barriers to treatment, participants from countries where augmentation therapy was reimbursed prioritised improving knowledge in AATD, while respondents in non-reimbursed countries regarded access to AATD augmentation therapy and to specialised centres as the most relevant. The main research and management priorities identified by healthcare providers and patients included understanding the natural history of AATD, improving information to physicians, improving access to specialised reference centres, personalising treatment and having equal opportunities for access to existing therapies.
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http://dx.doi.org/10.1183/23120541.00523-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792815PMC
October 2020

The Distribution of Alpha-1 Antitrypsin Genotypes Between Patients with COPD/Emphysema, Asthma and Bronchiectasis.

Int J Chron Obstruct Pulmon Dis 2020 6;15:2827-2836. Epub 2020 Nov 6.

Department of Medicine, Pulmonary and Critical Care Medicine, University Medical Center Giessen and Marburg, Member of the German Center for Lung Research, Marburg, Germany.

Purpose: Alpha-1-antitrypsin deficiency (AATD) is a rare hereditary condition characterized by low circulating levels of alpha-1antitrypsin (AAT). While the association between AATD and COPD/emphysema is undisputed, the association between AATD and asthma or bronchiectasis is still a matter of debate.

Aims And Objectives: Our study aimed to investigate the distribution of AAT genotypes between patients with COPD/emphysema, asthma and bronchiectasis. To back up the diagnostic labels, we described symptoms associated with the diagnosis.

Methods: Between September 2003 and March 2020, 29,465 testing kits (AlphaKit®) were analyzed in the AAT laboratory, University of Marburg, Germany. The diagnosis of AATD has been made based on the measurements of AAT serum levels, followed by genotyping, phenotyping or whole gene sequencing depending on the availability and/or the need for more detailed interpretation of the results. The respiratory symptoms were recorded as well.

Results: Regarding the distribution of the wild type allele M and the most frequent mutations S (E264V) and Z (E342K), no significant differences could be found between COPD/emphysema [Pi*MM (58.24%); Pi*SZ (2.49%); Pi*ZZ (9.12%)] and bronchiectasis [Pi*MM (59.30%) Pi*SZ (2.81%); Pi*ZZ (7.02%)]. When COPD/emphysema and bronchiectasis were recorded in the same patient, the rate of Pi* ZZ (14.78%) mutations was even higher. Asthma patients exhibited significantly less deficient genotypes [Pi*MM (54.81%); Pi*SZ (2%); Pi*ZZ (2.77%)] than two other groups. Associated respiratory symptoms confirmed the diagnosis.

Conclusion: COPD/emphysema and bronchiectasis, but not asthma patients, exhibit higher frequency of AATD genotypes. Our data suggest that AATD testing should be offered to patients with COPD/emphysema and bronchiectasis.
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http://dx.doi.org/10.2147/COPD.S271810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654539PMC
November 2020

Disease control in patients with asthma and respiratory symptoms (wheezing, cough) during sleep.

Asthma Res Pract 2020 23;6. Epub 2020 Sep 23.

Department of Internal Medicine, Division of Pneumology, Intensive Care and Sleep Medicine, Hospital of the University of Marburg, Baldingerstrasse 1, 35033 Marburg, Germany.

Introduction: The GINA)-defined criteria for asthma control include questions about daytime symptoms, limitation of activity, nocturnal symptoms, need for reliever treatment and patients' satisfaction. Patients with nocturnal symptoms like wheezing and cough often suffer from lower sleep quality and impaired daytime performance. The lack of an appropriate method for standardized and objective monitoring of respiratory symptoms leads to difficulties in asthma management. The aim of this study is to present a new method for automated wheeze and cough detection during sleep and to assess the actual level of asthma control by the Asthma Control Test (ACT).

Methods: Respiratory symptoms like wheezing and cough were recorded with the LEOSound-Monitor for one night in 55 asthmatic patients in their individual domestic setting. Patients were asked to assess their level of asthma subjectively with the ACT. The study consisted of 37 women and 18 men, with a mean age of 41 years, and a mean BMI of 27 kg/m. Most of the patients had been taking an ICS/LABA combination and would resort to a SABA as their rescue medication.

Results: 60% of the participants were classed as having controlled, and 40% were classed as having partially- or uncontrolled asthma. During sleep wheezing was found in 8 of the 55 asthma patients (14.5%) and coughing was found in 30 patients (54.5%). The median ACT score in wheezing-patients was 14, while in non-wheezing patients it was 21. Uncontrolled asthma was found in 6 of the 8 wheezing-patients. Coughing versus non-coughing patients did not show a significant difference in the ACT-score (20, 22 respectively).

Conclusion: Wheezing is a sign of uncontrolled asthma. The ACT-score in wheezing patients is worse compared to patients without wheezing. LEOSound proofed to be a useful tool in providing an objective evaluation of respiratory symptoms, like coughing and wheezing. In clinical practice, this may allow an improvement in asthma therapy.
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http://dx.doi.org/10.1186/s40733-020-00062-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7513478PMC
September 2020

Effects of Vibration Training in Interstitial Lung Diseases: A Randomized Controlled Trial.

Respiration 2020;99(8):658-666. Epub 2020 Aug 19.

Center for Interstitial and Rare Lung Diseases, Pneumology, Thoraxklinik University of Heidelberg, Heidelberg, Germany.

Background: Numerous studies have reported positive effects of exercise training in patients with interstitial lung disease (ILD) on physical capacity and quality of life. However, evidence is rare on the effects of specific forms of training and further pathophysiological mechanisms in these patients.

Objectives: In this multicenter study we aimed to explore the clinical effects of whole-body vibration training (WBVT) in patients with ILD on various outcome measures, including proinflammatory cytokines and myostatin.

Methods: We randomly assigned 26 patients with different forms of multidisciplinary confirmed fibrotic ILDs either to the WBVT group (n = 11; 55% male, 61 ± 14 years old, forced vital capacity 83.2 ± 29.3% predicted, 6-min walking distance [6MWD] 478 ± 79 m) performing 3 months of a standardized training (3 times per week), or to a control training group (CTG, n = 15; 60% male, 63 ± 9 years old, FVC 74.6 ± 20.5% predicted, 6MWD 455 ± 85 m) performing sham WBV training. Training in the two groups was performed on a GalileoTM vibration plate (6-20 vs. 5 Hz). The functional assessments before and after the intervention period included pulmonary function, 6MWD test, chair rise test, ultrasonographic measurement of quadriceps muscle thickness (cross-sectional area), quality of life questionnaires, and serum samples.

Results: We observed a significant increase in 6MWD (∆Training = 30 m [12-67], p = 0.024) and a decrease of myostatin (∆Training = -465 pg/mL [-713 to -166], p = 0.008) in the WBVT group. In contrast, no significant differences were observed in the CTG.

Conclusions: The present study demonstrates that WBVT is able to significantly increase 6MWD and decrease myostatin in patients with fibrotic ILDs. Therefore, WBVT seems to be a beneficial and feasible training modality in ILD patients. Clinical Trial Registry: German Clinical Trials Registry (DRKS00012930).
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http://dx.doi.org/10.1159/000508977DOI Listing
August 2020

High eosinophil blood counts are associated with a shorter length of hospital stay in exacerbated COPD patients - a retrospective analysis.

Respir Res 2020 May 6;21(1):106. Epub 2020 May 6.

Department of Medicine, Pulmonary and Critical Care Medicine, University Medical Centre Giessen and Marburg, Philipps-University, Centre for Lung Research (DZL), 35043, Marburg, Germany.

Background: In COPD, the course of the disease including morbidity and mortality is strongly associated with severe exacerbations. The current GOLD recommendations emphasize blood eosinophil counts as a marker for responsiveness to inhaled corticosteroids (ICS). Retrospective analyses from randomized clinical trials indicate a favorable response to systemic corticosteroids in exacerbated COPD patients with blood eosinophils > 2%, however data outside clinical trials are scarce.

Patients And Methods: We retrospectively evaluated data from 1007 cases of patients who were admitted to the University Medical Center Marburg between 01/2013 and 12/2018. All patients had been diagnosed with an acute exacerbation of COPD (ICD-10 J44.0/J44.1). Our analysis was based on a subgroup of 417 patients in whom a full blood cell count was obtained at the day of admission. Patients were predominantly male (63.3%), had a median age of 74 years (IQR 65 years - 83 years) and a median FEV1 of 1.03 l (42.6% predicted). We compared the hospital length of stay and other outcome parameters using established thresholds for the eosinophil blood cell count (100 and 300 eosinophils/μl and 2%).

Results: Patients with low eosinophils (< 2%, <100 cells/μl) had a longer median time in hospital (length of hospital stay - LOS) as compared to patients with high eosinophils (< 2%: 9.31 vs. ≥2%:7 days, and < 100/μl: 10 vs. 100-300/μl: 8 vs. > 300/μl: 7 days). The median CRP was higher in patients with low eosinophils as compared to the other groups (< 2%: 22.7 vs. ≥2%: 9 mg/dl and < 100: 25 vs. 100-300: 13.5 vs. > 300: 7.1 mg/dl). Time to re-hospitalization or time to death did not differ between strata of eosinophils. Sensitivity analysis in a subgroup of patients in which pneumonia was excluded by chest x-ray did not significantly alter the results.

Conclusion: The results support the hypothesis that patients with severe COPD exacerbations and elevated blood eosinophil counts respond better to systemic corticosteroid treatment than patients with a non-eosinophilic exacerbation.
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http://dx.doi.org/10.1186/s12931-020-01365-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7204070PMC
May 2020

Protocol for the EARCO Registry: a pan-European observational study in patients with α-antitrypsin deficiency.

ERJ Open Res 2020 Jan 2;6(1). Epub 2020 Mar 2.

Pneumology Dept, Hospital Universitari Vall d'Hebron/Vall d'Hebron Research Institute (VHIR), CIBER de Enfermedades Respiratorias (CIBERES), Barcelona, Spain.

Rationale And Objectives: Alpha-1 antitrypsin deficiency (AATD) is a genetic condition that leads to an increased risk of emphysema and liver disease. Despite extensive investigation, there remain unanswered questions concerning the natural history, pathophysiology, genetics and the prognosis of the lung disease in association with AATD. The European Alpha-1 Clinical Research Collaboration (EARCO) is designed to bring together researchers from European countries and to create a standardised database for the follow-up of patients with AATD.

Study Design And Population: The EARCO Registry is a non-interventional, multicentre, pan-European, longitudinal observational cohort study enrolling patients with AATD. Data will be collected prospectively without interference/modification of patient's management by the study team. The major inclusion criterion is diagnosed severe AATD, defined by an AAT serum level <11 µM (50 mg·dL) and/or a proteinase inhibitor genotype ZZ, SZ or compound heterozygotes or homozygotes of other rare deficient variants. Assessments at baseline and during the yearly follow-up visits include lung function testing (spirometry, body plethysmography and diffusing capacity of the lung), exercise capacity, blood tests and questionnaires (symptoms, quality of life and physical activity). To ensure correct data collection, there will be designated investigator staff to document the data in the case report form. All data will be reviewed by the EARCO database manager.

Summary: The EARCO Registry aims to understand the natural history and prognosis of AATD better with the goal to create and validate prognostic tools to support medical decision-making.
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http://dx.doi.org/10.1183/23120541.00181-2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049712PMC
January 2020

New Patient-Centric Approaches to the Management of Alpha-1 Antitrypsin Deficiency.

Int J Chron Obstruct Pulmon Dis 2020 12;15:345-355. Epub 2020 Feb 12.

Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, University of Miami School of Medicine, Miami, FL, USA.

Alpha-1 antitrypsin deficiency (AATD) is a rare and underdiagnosed genetic predisposition for COPD and emphysema and other conditions, including liver disease. Although there have been improvements in terms of awareness of AATD and understanding of its treatment in recent years, current challenges center on optimizing detection and management of patients with AATD, and improving access to intravenous (IV) AAT therapy - the only available pharmacological intervention that can slow disease progression. However, as an orphan disease with geographically dispersed patients, international cooperation is essential to address these issues. To achieve this, new European initiatives in the form of the European Reference Network for Rare Lung Diseases (ERN-LUNG) and the European Alpha-1 Research Collaboration (EARCO) have been established. These organizations are striving to address the current challenges in AATD, and provide a new platform for future research efforts in AATD. The first objectives of ERN-LUNG are to establish a quality control program for European AATD laboratories and create a disease management program for AATD, following the success of such programs in the United States. The main purpose of EARCO is to create a pan-European registry, with the aim of understanding the natural history of the disease and supporting the development of new treatment modalities in AATD and access to AAT therapy. Going further, other patient-centric initiatives involve improving the convenience of intravenous AAT therapy infusions through extended-interval dosing and self-administration. The present review will discuss the implementation of these initiatives and their potential contribution to the optimization of patient care in AATD.
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http://dx.doi.org/10.2147/COPD.S234646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7024807PMC
February 2021

Caspase-11 promotes allergic airway inflammation.

Nat Commun 2020 02 26;11(1):1055. Epub 2020 Feb 26.

School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute (TBSI)Trinity College Dublin, Dublin, Ireland.

Activated caspase-1 and caspase-11 induce inflammatory cell death in a process termed pyroptosis. Here we show that Prostaglandin E (PGE) inhibits caspase-11-dependent pyroptosis in murine and human macrophages. PGE suppreses caspase-11 expression in murine and human macrophages and in the airways of mice with allergic inflammation. Remarkably, caspase-11-deficient mice are strongly resistant to developing experimental allergic airway inflammation, where PGE is known to be protective. Expression of caspase-11 is elevated in the lung of wild type mice with allergic airway inflammation. Blocking PGE production with indomethacin enhances, whereas the prostaglandin E analog misoprostol inhibits lung caspase-11 expression. Finally, alveolar macrophages from asthma patients exhibit increased expression of caspase-4, a human homologue of caspase-11. Our findings identify PGE as a negative regulator of caspase-11-driven pyroptosis and implicate caspase-4/11 as a critical contributor to allergic airway inflammation, with implications for pathophysiology of asthma.
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http://dx.doi.org/10.1038/s41467-020-14945-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7044193PMC
February 2020

Transcriptional analysis identifies potential biomarkers and molecular regulators in pneumonia and COPD exacerbation.

Sci Rep 2020 01 14;10(1):241. Epub 2020 Jan 14.

Institute for Lung Research, Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Marburg, Germany.

Lower respiratory infections, such as community-acquired pneumonia (CAP), and chronic obstructive pulmonary disease (COPD) rank among the most frequent causes of death worldwide. Improved diagnostics and profound pathophysiological insights are urgent clinical needs. In our cohort, we analysed transcriptional networks of peripheral blood mononuclear cells (PBMCs) to identify central regulators and potential biomarkers. We investigated the mRNA- and miRNA-transcriptome of PBMCs of healthy subjects and patients suffering from CAP or AECOPD by microarray and Taqman Low Density Array. Genes that correlated with PBMC composition were eliminated, and remaining differentially expressed genes were grouped into modules. One selected module (120 genes) was particularly suitable to discriminate AECOPD and CAP and most notably contained a subset of five biologically relevant mRNAs that differentiated between CAP and AECOPD with an AUC of 86.1%. Likewise, we identified several microRNAs, e.g. miR-545-3p and miR-519c-3p, which separated AECOPD and CAP. We furthermore retrieved an integrated network of differentially regulated mRNAs and microRNAs and identified HNF4A, MCC and MUC1 as central network regulators or most important discriminatory markers. In summary, transcriptional analysis retrieved potential biomarkers and central molecular features of CAP and AECOPD.
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http://dx.doi.org/10.1038/s41598-019-57108-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6959367PMC
January 2020

High degree of polyclonality hinders somatic mutation calling in lung brush samples of COPD cases and controls.

Sci Rep 2019 12 27;9(1):20158. Epub 2019 Dec 27.

CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.

Chronic obstructive pulmonary disease (COPD) is induced by cigarette smoking and characterized by inflammation of airway tissue. Since smokers with COPD have a higher risk of developing lung cancer than those without, we hypothesized that they carry more mutations in affected tissue. We called somatic mutations in airway brush samples from medium-coverage whole genome sequencing data from healthy never and ex-smokers (n = 8), as well as from ex-smokers with variable degrees of COPD (n = 4). Owing to the limited concordance of resulting calls between the applied tools we built a consensus, a strategy that was validated with high accuracy for cancer data. However, consensus calls showed little promise of representing true positives due to low mappability of corresponding sequence reads and high overlap with positions harbouring known genetic polymorphisms. A targeted re-sequencing approach suggested that only few mutations would survive stringent verification testing and that our data did not allow the inference of any difference in the mutational load of bronchial brush samples between former smoking COPD cases and controls. High polyclonality in airway brush samples renders medium-depth sequencing insufficient to provide the resolution to detect somatic mutations. Deep sequencing data of airway biopsies are needed to tackle the question.
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http://dx.doi.org/10.1038/s41598-019-56618-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934450PMC
December 2019

Diagnosing Alpha-1-Antitrypsin Deficiency Using A PCR/Luminescence-Based Technology.

Int J Chron Obstruct Pulmon Dis 2019 18;14:2535-2542. Epub 2019 Nov 18.

Department of Medicine, Pulmonary and Critical Care Medicine, Member of the German Center for Lung Research Marburg, University Medical Center Giessen And Marburg, Germany.

Purpose: Alpha-1-antitrypsin deficiency (AATD) is a rare hereditary condition resulting from the mutations in the SERPINA1 (serine protease inhibitor) gene and is characterized by low circulating levels of the alpha-1 antitrypsin (AAT) protein. The traditional algorithm for laboratory testing of AATD involves the analysis of AAT concentrations (nephelometry), phenotyping (isoelectric focusing, IEF), and genotyping (polymerase chain reaction, PCR); in selected cases, full sequencing of the SERPINA1 gene can be undertaken. New technologies arise that may make diagnosis easier and faster.

Methods: We developed and evaluated a new diagnostic algorithm based on Luminex xMAP (multi-analyte profiling) technology using Progenika A1AT Genotyping Test. In an initial learning phase, 1979 samples from individuals suspected of having AATD were examined by both, a traditional and a "new" algorithm. In a second phase, 1133 samples were analyzed with the Luminex xMAP only.

Results: By introducing a Luminex xMAP based algorithm, we were able to simultaneously identify 14 mutations in SERPINA1 gene (instead of two- S and Z-by using our old algorithm). Although the quantity of IEF assays remained unchanged, the nephelometric measurements and sequencing were reduced by 79% and 63.4%, respectively.

Conclusion: The new method is convenient, fast and user-friendly. The application of the Luminex xMAP technology can simplify and shorten the diagnostic workup of patients with suspected AATD.
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http://dx.doi.org/10.2147/COPD.S224221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6873957PMC
April 2020

Surface Proteome of Plasma Extracellular Vesicles as Biomarkers for Pneumonia and Acute Exacerbation of Chronic Obstructive Pulmonary Disease.

J Infect Dis 2020 01;221(2):325-335

Institute for Lung Research, Universities of Giessen and Marburg Lung Center, Philipps-University Marburg, Member of the German Center for Lung Research, Marburg, Germany.

Background: Community-acquired pneumonia (CAP) and acute exacerbation of chronic obstructive pulmonary disease (AECOPD) represent a major burden of disease and death and their differential diagnosis is critical. A potential source of relevant accessible biomarkers are blood-borne small extracellular vesicles (sEVs).

Methods: We performed an extracellular vesicle array to find proteins on plasma sEVs that are differentially expressed and possibly allow the differential diagnosis between CAP and AECOPD. Plasma samples were analyzed from 21 healthy controls, 24 patients with CAP, and 10 with AECOPD . The array contained 40 antibodies to capture sEVs, which were then visualized with a cocktail of biotin-conjugated CD9, CD63, and CD81 antibodies.

Results: We detected significant differences in the protein decoration of sEVs between healthy controls and patients with CAP or AECOPD. We found CD45 and CD28 to be the best discrimination markers between CAP and AECOPD in receiver operating characteristic analyses, with an area under the curve >0.92. Additional ensemble feature selection revealed the possibility to distinguish between CAP and AECOPD even if the patient with CAP had COPD, with a panel of CD45, CD28, CTLA4 (cytotoxic T-lymphocyte-associated protein 4), tumor necrosis factor-R-II, and CD16.

Conclusion: The discrimination of sEV-associated proteins is a minimally invasive method with potential to discriminate between CAP and AECOPD.
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http://dx.doi.org/10.1093/infdis/jiz460DOI Listing
January 2020

Blood eosinophil count and airway epithelial transcriptome relationships in COPD versus asthma.

Allergy 2020 02 10;75(2):370-380. Epub 2019 Sep 10.

Institute for Lung Health, Leicester NIHR Biomedical Research Centre, University of Leicester, Leicester, UK.

Background: Whether the clinical or pathophysiologic significance of the "treatable trait" high blood eosinophil count in COPD is the same as for asthma remains controversial. We sought to determine the relationship between the blood eosinophil count, clinical characteristics and gene expression from bronchial brushings in COPD and asthma.

Methods: Subjects were recruited into a COPD (emphysema versus airway disease [EvA]) or asthma cohort (Unbiased BIOmarkers in PREDiction of respiratory disease outcomes, U-BIOPRED). We determined gene expression using RNAseq in EvA (n = 283) and Affymetrix microarrays in U-BIOPRED (n = 85). We ran linear regression analysis of the bronchial brushings transcriptional signal versus blood eosinophil counts as well as differential expression using a blood eosinophil > 200 cells/μL as a cut-off. The false discovery rate was controlled at 1% (with continuous values) and 5% (with dichotomized values).

Results: There were no differences in age, gender, lung function, exercise capacity and quantitative computed tomography between eosinophilic versus noneosinophilic COPD cases. Total serum IgE was increased in eosinophilic asthma and COPD. In EvA, there were 12 genes with a statistically significant positive association with the linear blood eosinophil count, whereas in U-BIOPRED, 1197 genes showed significant associations (266 positive and 931 negative). The transcriptome showed little overlap between genes and pathways associated with blood eosinophil counts in asthma versus COPD. Only CST1 was common to eosinophilic asthma and COPD and was replicated in independent cohorts.

Conclusion: Despite shared "treatable traits" between asthma and COPD, the molecular mechanisms underlying these clinical entities are predominately different.
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http://dx.doi.org/10.1111/all.14016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7064968PMC
February 2020

Anti-interleukin-5 therapy (mepolizumab) in life-threatening asthma attack: A case-based discussion.

Respir Med Case Rep 2019 22;28:100927. Epub 2019 Aug 22.

Department of Medicine, Pulmonary and Critical Care Medicine, University Medical Center Giessen and Marburg, Philipps-University Marburg, Germany.

We report about a case of a compassionate off-label use of the anti-interleukin-5-agent mepolizumab in a ventilated patient with life-threatening asthma attack in eosinophilic asthma. The patient suffered from severe eosinophilic asthma and was transmitted to our hospital with an asthma attack and a life-threatening respiratory state under ventilation. Since high dose steroids had not yielded a sufficient respiratory improvement mepolizumab was administered subcutaneously. After administration of mepolizumab respiratory state and ventilation parameter improved significantly. Two days after administration the patient was weaned could be extubated 8 days later and recovered completely from the asthma attack. The presented clinical case is suggestive of future clinical trials or registry studies to evaluate potential clinical benefits of anti-interleukin-5 treatment in patients with severe exacerbations of eosinophilic asthma.
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http://dx.doi.org/10.1016/j.rmcr.2019.100927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6715903PMC
August 2019

Treatment response in COPD: does FEV say it all? A analysis of the CRYSTAL study.

ERJ Open Res 2019 Feb 25;5(1). Epub 2019 Feb 25.

Dept of Medicine, Pulmonary and Critical Care Medicine, University Medical Center Giessen and Marburg, Philipps-Universität Marburg, Member of the German Center for Lung Research (DZL), Giessen, Germany.

The association between clinically relevant changes in patient-reported outcomes (PROs) and forced expiratory volume in 1 s (FEV) in patients with chronic obstructive pulmonary disease (COPD) has rarely been investigated. Using CRYSTAL, a 12-week open-label study in symptomatic, nonfrequently exacerbating patients with moderate COPD, we assessed at baseline the correlations between several PROs (Baseline Dyspnoea Index, modified Medical Research Council dyspnoea scale, COPD Assessment Test (CAT) and Clinical COPD Questionnaire (CCQ)), and between FEV and PROs. Associations between clinically relevant responses in FEV, CAT, CCQ and Transition Dyspnoea Index (TDI) at week 12 were also assessed. Using data from 4324 patients, a strong correlation was observed between CAT and CCQ (r=0.793) at baseline, with moderate or weak correlations between other PROs, and no correlation between FEV and any PRO. At week 12, 2774 (64.2%) patients were responders regarding TDI, CAT or CCQ, with 583 (13.5%) responding using all three measures. In comparison, 3235 (74.8%) were responders regarding FEV, TDI, CAT or CCQ, with 307 (7.1%) responding concerning all four parameters. Increases in lung function were accompanied by clinically relevant improvements of PROs in a minority of patients. Our results also suggest that PROs are not interchangeable. Thus, the observed treatment success in a clinical trial may depend on the selected parameters.
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http://dx.doi.org/10.1183/23120541.00243-2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6387992PMC
February 2019

The European Alpha-1 Research Collaboration (EARCO): a new ERS Clinical Research Collaboration to promote research in alpha-1 antitrypsin deficiency.

Eur Respir J 2019 02 14;53(2). Epub 2019 Feb 14.

Dept of Medicine, Pulmonary and Critical Care Medicine, University Medical Centre Giessen and Marburg, Philipps-University, Member of the German Centre for Lung Research (DZL), Marburg, Germany.

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http://dx.doi.org/10.1183/13993003.00138-2019DOI Listing
February 2019

[The stepwise approach of COPD therapy].

Dtsch Med Wochenschr 2019 01 2;144(1):15-20. Epub 2019 Jan 2.

The goal of pharmacologic therapy of stable chronic obstructive pulmonary disease (COPD) is to reduce symptoms, improve exercise intolerance and health-related quality of life, and to reduce exacerbations. Inhaled long-acting β2-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) are equally effective for the symptomatic management of COPD. However, LAMAs are more effective than LABAs in the reduction of exacerbations. In patients with symptomatic COPD pharmacologic therapy is usually escalated using the fixed combination of LAMAs and LABAs (dual bronchodilation), which is also superior to LAMA monotherapy in the prevention of exacerbations. Adding inhaled corticosteroids (ICS) to LABA and LAMA (triple therapy) for a prevention of exacerbations results in a further reduction of exacerbations, especially in those patients with higher blood eosinophil counts. Non-pharmacologic management of COPD patients includes smoking cessation programs, vaccination, pulmonary rehabilitation, and strategies to improve or maintain their physical activity.
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http://dx.doi.org/10.1055/a-0570-3595DOI Listing
January 2019

Longitudinal stability of blood eosinophil count strata in the COPD COSYCONET cohort.

Int J Chron Obstruct Pulmon Dis 2018 28;13:2999-3002. Epub 2018 Sep 28.

Pulmonary Research Institute at Lungen Clinic Grosshansdorf, Airway Research Center North (ARCN), Member of the German Centre for Lung Research (DZL), Grosshansdorf, Germany.

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http://dx.doi.org/10.2147/COPD.S165909DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6168004PMC
March 2019

Proviral MicroRNAs Detected in Extracellular Vesicles From Bronchoalveolar Lavage Fluid of Patients With Influenza Virus-Induced Acute Respiratory Distress Syndrome.

J Infect Dis 2019 01;219(4):540-543

Institute for Lung Research, Universities of Giessen and Marburg Lung Center.

Influenza A virus (IAV) causes severe respiratory infections and alveolar epithelial damage resulting in acute respiratory distress syndrome (ARDS). Extracellular vesicles (EVs) have been shown to mediate cellular crosstalk in inflammation by transfer of microRNAs (miRNAs). In this study, we found significant changes in the miRNA composition of EVs in the bronchoalveolar lavage fluid from patients with IAV-induced ARDS. Among the 9 significantly deregulated microRNAs, miR-17-5p was upregulated in patients' BALF and in EVs of IAV-infected lung epithelial cells (A549). In these cells, transfer of miR-17-5p strongly downregulated expression of the antiviral factor Mx1 and significantly enhanced IAV replication.
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http://dx.doi.org/10.1093/infdis/jiy554DOI Listing
January 2019

Safety of biweekly α-antitrypsin treatment in the RAPID programme.

Eur Respir J 2018 11 29;52(5). Epub 2018 Nov 29.

Irish Centre for Genetic Lung disease, Beaumont Hospital, Royal College of Surgeons in Ireland, Dublin, Ireland.

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http://dx.doi.org/10.1183/13993003.00897-2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6557539PMC
November 2018

Real world evaluation of a novel lateral flow assay (AlphaKit® QuickScreen) for the detection of alpha-1-antitrypsin deficiency.

Respir Res 2018 Aug 13;19(1):151. Epub 2018 Aug 13.

Pneumology Department, Hospital Universitari Vall d'Hebron, CIBER de Enfermedades Respiratorias (CIBERES), Barcelona, Spain.

Background: Alpha-1-Antitrypsin (AAT) deficiency (AATD) is a hereditary disorder that manifests primarily as pulmonary emphysema and liver cirrhosis. The clinically most relevant mutation causing AATD is a single nucleotide polymorphism Glu342Lys (Z-mutation). Despite the recommendation to test every COPD patient, the condition remains severely underdiagnosed with a delay of several years between first symptoms and diagnosis. The Grifols' AlphaKit® QuickScreen is a novel qualitative point-of-care (POC) in vitro screening test developed for the detection of the Z AAT protein in capillary whole blood. The objective of this prospective, international, multi-center, diagnostic, interventional real-world study was to assess the performance of this device for the detection of AATD in test-naïve COPD patients.

Methods: 1044 test-naïve COPD patients were recruited from 9 centers in Spain and 10 centers in Germany, ranging from primary to tertiary care. To evaluate the performance of the test, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated compared with the gold standard (genotyping).

Results: Genotyping and phenotyping of all 1019 evaluable samples revealed 4.12% of patients as carriers of at least one Z-allele, while 0.29% carried the homozygous genotype Pi*ZZ. The evaluation of the test's ability to detect the PiZ protein yielded the following results: specificity 97.8%, sensitivity 73.8%, negative predictive value 98.9%, and positive predictive value 58.5%. All false negatives (n = 11) were heterozygote Pi*MZ samples.

Conclusions: The tested device can be used as an appropriate tool to exclude AATD in primary care and in the overall COPD population, except in patients with a high a-priori- probability of AATD.
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http://dx.doi.org/10.1186/s12931-018-0826-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6090649PMC
August 2018

An Unusual Case of Noncatamenial Recurrent Pneumothorax.

Thorac Cardiovasc Surg Rep 2018 Jan 9;7(1):e36-e38. Epub 2018 Aug 9.

Department of Surgery, University Hospital Marburg, Marburg, Germany.

In a 28-year-old female, seven recurrent pneumothoraces occurred during a period of 2 years despite multiple thoracic interventions, all on the left thoracic side. Despite profound differential diagnostic analysis, the underlying cause remains unclear. An accumulation of conditions in this patient affecting only the left half of the body is remarkable: sinistral glaucoma as an infant, a sinistral pigmentation disorder, and a sinistral Bochdalek hernia.
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http://dx.doi.org/10.1055/s-0038-1667318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6085136PMC
January 2018

The Multifaceted Effects of Alpha1-Antitrypsin on Neutrophil Functions.

Front Pharmacol 2018 17;9:341. Epub 2018 Apr 17.

Department of Genetics and Clinical Immunology, National Institute of Tuberculosis and Lung Diseases, Warsaw, Poland.

Neutrophils are the predominant immune cells in human blood possessing heterogeneity, plasticity and functional diversity. The activation and recruitment of neutrophils into inflamed tissue in response to stimuli are tightly regulated processes. Alpha1-Antitrypsin (AAT), an acute phase protein, is one of the potent regulators of neutrophil activation via both -protease inhibitory and non-inhibitory functions. This review summarizes our current understanding of the effects of AAT on neutrophils, illustrating the interplay between AAT and the key effector functions of neutrophils.
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http://dx.doi.org/10.3389/fphar.2018.00341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5914301PMC
April 2018

Indacaterol/glycopyrronium reduces the risk of clinically important deterioration after direct switch from baseline therapies in patients with moderate COPD: a post hoc analysis of the CRYSTAL study.

Int J Chron Obstruct Pulmon Dis 2018;13:1229-1237. Epub 2018 Apr 16.

Novartis Pharma AG, Basel, Switzerland.

Purpose: COPD is a progressive disease characterized by exacerbations and a decline in health status and lung function. Clinically important deterioration (CID) is a composite endpoint used to evaluate treatment efficacy. This analysis evaluated the impact of a direct switch to once-daily indacaterol/glycopyrronium 110/50 µg (IND/GLY) from previous monotherapy with a long-acting β-agonist (LABA) or long-acting muscarinic antagonist (LAMA) or with an LABA and an inhaled corticosteroid (LABA + ICS) on reducing CID.

Methods: CRYSTAL was a 12-week, prospective, multicenter, randomized, open-label study conducted in clinical practice settings. Three definitions of CID (D1-D3) were used, including: 1) ≥100 mL decrease in trough forced expiratory volume in 1 second (FEV), 2) ≥1 point decrease in transition dyspnea index (TDI) and/or ≥0.4 points increase in clinical COPD questionnaire score (CCQ), or 3) an acute moderate/severe exacerbation (AECOPD). In D1 and D2, either TDI or CCQ was evaluated along with FEV and AECOPD, whereas in D3, all 4 parameters were included. ClinicalTrials.gov number: NCT01985334.

Results: Of the 2,159 patients analyzed, 1,622 switched to IND/GLY and 537 continued their baseline treatments. The percentage of patients with a CID was significantly lower after a direct switch to IND/GLY versus LABA or LAMA using all 3 CID definitions (D1: odds ratio [OR] 0.41 [95% CI: 0.30-0.55]; D2: OR 0.41 [95% CI: 0.31-0.55]; D3: OR 0.39 [95% CI: 0.29-0.52]). Compared with LABA + ICS, IND/GLY also reduced the risk of CID (D1: OR 0.76 [95% CI: 0.56-1.02]; D2: OR 0.75 [95% CI: 0.56-1.00]; D3: OR 0.67 [95% CI: 0.51-0.89]).

Conclusion: In this analysis, IND/GLY reduced the risk of a CID in moderate COPD patients after direct switch from LABA + ICS or LABA or LAMA in real-life clinical practice.
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http://dx.doi.org/10.2147/COPD.S159732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5909796PMC
October 2018

Blood eosinophils as a marker of eosinophilic exacerbations in COPD.

Lancet Respir Med 2018 05 5;6(5):e17. Epub 2018 Apr 5.

Department of Medicine, Pulmonary and Critical Care Medicine, University Hospital of Giessen and Marburg, University of Marburg, 35043 Marburg, Germany.

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http://dx.doi.org/10.1016/S2213-2600(18)30095-XDOI Listing
May 2018

A GATA3-specific DNAzyme attenuates sputum eosinophilia in eosinophilic COPD patients: a feasibility randomized clinical trial.

Respir Res 2018 04 4;19(1):55. Epub 2018 Apr 4.

Pulmonary Research Institute at LungenClinic Grosshansdorf, Airway Research Center North (ARCN), Member of the German Centre for Lung Research (DZL), Grosshansdorf, Germany.

Background: A subset of COPD-patients presents with eosinophilic airway inflammation. While treatment of asthmatic patients with the GATA3-specific DNAzyme SB010 attenuated sputum eosinophilia after allergen challenge, this specific treatment has not been evaluated in patients with COPD. Our objective was to evaluate the feasibility and safety of inhaled SB010 in COPD patients with sputum eosinophilia.

Methods: We conducted a randomized, double-blind, placebo-controlled, multicentre clinical trial in COPD-patients with sputum eosinophilia (≥2.5% non-squamous cells). Patients inhaled 10 mg SB010 bid or matching placebo via the controlled inhalation system AKITA2 APIXNEB for 28 days. Endpoints included the feasibility of the study (primary), patient's safety, sputum eosinophils, FNO, lung function, symptoms, and biomarkers. The study was registered in the German Clinical Trials Register: DRKS00006087.

Results: One hundred thirty patients were screened, 23 patients were randomized (FEV 49.4 ± 11.5%; sputum eosinophils 8.0 ± 8.4%) and 19 patients completed the study (10 placebo, 9 SB010. After 28 days, SB010 decreased the relative sputum eosinophil count (p = 0.004) as compared to no changes in placebo-treated patients. FNO, lung function, and symptoms were not affected significantly. We found an increase in blood IFN-γ (p = 0.02) and a trend to lower IL-5 levels in patients treated with SB010. SB010 was safe and well tolerated. Thirty five AEs (22 SB010, 13 placebo including 1 SAE) were observed with 3 AEs in each group judged to be possibly treatment-related.

Conclusion: In patients with eosinophilic COPD, sputum eosinophils could be reduced by inhalation of SB010. Long-term studies are needed to demonstrate clinical efficacy.
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http://dx.doi.org/10.1186/s12931-018-0751-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5883532PMC
April 2018

Prevalence of comorbidities in COPD patients by disease severity in a German population.

Respir Med 2017 Nov 12;132:132-138. Epub 2017 Oct 12.

Department of Medicine, Pulmonary and Critical Care Medicine, University Medical Centre Giessen and Marburg, Philipps-University, Member of the German Centre for Lung Research (DZL), 35043 Marburg, Germany.

Chronic obstructive pulmonary disease (COPD) is commonly associated with multiple comorbidities. Our objective was to assess the prevalence of comorbidities in patients with COPD and to relate their prevalence to the severity of the disease by using a large German health care database. Based on the retrospective analysis of a two-year (2013-2014) database from the German Statutory Health Insurance system, we obtained a representative sample of 4,075,493 german insurants. This sample included 146,141 patients with COPD (age: ≥35 years). To these patients, we matched 1:1 by age and gender randomly selected non-COPD controls. We assessed the comorbidities and the use of cardiovascular drugs, and examined COPD subgroups according to lung function (ICD-10-coded FEV1) and the treatment with long-acting inhaled bronchodilators. Compared to non-COPD, patients with COPD had a higher prevalence of hypertension, congestive heart failure, diabetes, gastroesophageal reflux disease, chronic kidney disease, osteoporosis, psychiatric disease and lung cancer, and used more cardiovascular-related drugs. However, the prevalence of comorbidities did not correlate to the severity of airflow limitation. The results of this sizeable nationwide survey support the concept that individuals with COPD need careful evaluation regarding comorbidities. This can already be of relevance in patients with mild to moderate airflow limitation.

Take Home Message: Comorbidities in COPD have a complex relationship with disease severity, requiring a comprehensive therapy approach.
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http://dx.doi.org/10.1016/j.rmed.2017.10.007DOI Listing
November 2017

Physician perspectives on the burden and management of asthma in six countries: The Global Asthma Physician Survey (GAPS).

BMC Pulm Med 2017 Nov 23;17(1):153. Epub 2017 Nov 23.

Real World Evidence & Epidemiology, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA, 19426, USA.

Background: Despite recognition of asthma as a growing global issue and development of global guidelines, asthma treatment practices vary between countries. Several studies have reported patients' perspectives on asthma control. This study presents physicians' perspectives and strategies for asthma management.

Methods: Physicians seeing ≥4 adult patients with asthma per month in Australia, Canada, China, France, Germany, and Japan were surveyed (N=1809; ≈300 per country). A standardised questionnaire was developed for this study and administered by telephone, online or face-to-face. Statistics were weighted to account for the sampling scheme.

Results: Physicians estimated that 71% of their adult patients received maintenance medication, with adherence monitored by 76-97% of physicians. Perceived major barriers to patient adherence included: patients taking treatment as needed; acceptance of symptoms; and patients not perceiving treatment benefits. Written action plans (37%) and technology (15%) were seldom employed by physicians to aid patients' asthma management. Physicians rarely (10%) used validated patient-reported questionnaires to monitor asthma control, instead monitoring selected symptoms, exacerbations, and/or lung function measurements. Awareness of single maintenance and reliever therapy (SMART/MART) varied among countries (56-100%); although most physicians (72%) had prescribed SMART/MART, the majority (91%) co-prescribed a short-acting bronchodilator at least some of the time.

Conclusions: These results show that physicians generally do not employ standardised tools to monitor asthma control or to manage its treatment and that despite high awareness of SMART/MART, the strategy appears to be commonly misapplied. Better education for patients and physicians is required to improve asthma management and resulting patient outcomes.
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http://dx.doi.org/10.1186/s12890-017-0492-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5701503PMC
November 2017

Case-finding for alpha1-antitrypsin deficiency in Kazakh patients with COPD.

Multidiscip Respir Med 2017 25;12:23. Epub 2017 Oct 25.

Semey State Medical University, Semey, Kazakhstan.

Background: Alpha-1-antitrypsin deficiency (AATD) is an under-diagnosed condition in patients with chronic obstructive pulmonary disease (COPD). The aim of this study was to screen for AATD in Kazakh patients with COPD using dried blood spot specimens.

Methods: The alpha1-antitrypsin (AAT) concentration was determined by nephelometry, PCR was used to detect PiS and PiZ alleles; and isoelectric focusing was used to confirm questionable genotype results and detect rare AAT variants.

Results: To this aim, 187 Kazakh subjects with COPD were recruited. Blood samples were collected as dried blood spot. Genotyping of 187 samples revealed 3 (1.6%) PI*MZ and 1 (0.53%) PI*MS, Phenotyping identified also two sample (1.1%) with phenotype PiMI. Allelic frequencies of pathological mutations Z, S and I resulted 0.8%, 0.3%, 0.5%, respectively, in COPD Kazakh population.

Conclusion: This study proved that AATD is present in the Kazakh population. These results support the general concept of targeted screening for AAT deficiency in countries like Kazakhstan, with a large population of COPD patients and low awareness among care-givers about this genetic condition.
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http://dx.doi.org/10.1186/s40248-017-0104-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5655868PMC
October 2017