Publications by authors named "Felix Herth"

433 Publications

ERS/EAACI statement on adherence to international adult asthma guidelines.

Eur Respir Rev 2021 Sep 15;30(161). Epub 2021 Sep 15.

Dept of Medical Science, Respiratory, Allergy and Sleep Research, Uppsala University and University Hospital, Uppsala, Sweden.

Guidelines aim to standardise and optimise asthma diagnosis and management. Nevertheless, adherence to guidelines is suboptimal and may vary across different healthcare professional (HCP) groups.Further to these concerns, this European Respiratory Society (ERS)/European Academy of Allergy and Clinical Immunology (EAACI) statement aims to: 1) evaluate the understanding of and adherence to international asthma guidelines by HCPs of different specialties an international online survey; and 2) assess strategies focused at improving implementation of guideline-recommended interventions, and compare process and clinical outcomes in patients managed by HCPs of different specialties systematic reviews.The online survey identified discrepancies between HCPs of different specialties which may be due to poor dissemination or lack of knowledge of the guidelines but also a reflection of the adaptations made in different clinical settings, based on available resources. The systematic reviews demonstrated that multifaceted quality improvement initiatives addressing multiple challenges to guidelines adherence are most effective in improving guidelines adherence. Differences in outcomes between patients managed by generalists or specialists should be further evaluated.Guidelines need to consider the heterogeneity of real-life settings for asthma management and tailor their recommendations accordingly. Continuous, multifaceted quality improvement processes are required to optimise and maintain guidelines adherence. Validated referral pathways for uncontrolled asthma or uncertain diagnosis are needed.
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http://dx.doi.org/10.1183/16000617.0132-2021DOI Listing
September 2021

Mediastinal Nodular Lymphocyte Predominant Hodgkin Lymphoma Achieved by Endoscopic Transesophageal Cryobiopsy.

Respiration 2021 Sep 1:1-5. Epub 2021 Sep 1.

Department of Respiratory Disease, Xinqiao Hospital, Third Military Medical University, Chongqing, China.

Guidelines have recommended endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and endoscopic ultrasound-guided fine-needle aspiration biopsy as initial sampling approaches of mediastinal lymph nodes for lung cancer staging. However, the small sample volume might restrict the diagnostic utility of needle aspiration in certain mediastinal diseases. We have recently shown that transbronchial mediastinal cryobiopsy, which is capable of providing larger amounts of intact tissue, improves diagnostic yield in rare tumors and benign diseases compared to EBUS-TBNA. Here, we present a case of mediastinal nodular lymphocyte predominant Hodgkin lymphoma successfully diagnosed by endoscopic transesophageal cryobiopsy.
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http://dx.doi.org/10.1159/000518598DOI Listing
September 2021

Impact of the COVID-19 pandemic on the behaviour and health status of patients with COPD: results from the German COPD cohort COSYCONET.

ERJ Open Res 2021 Jul 23;7(3). Epub 2021 Aug 23.

Dept of Pneumology and Critical Care Medicine, Thoraxklinik University of Heidelberg, Translational Lung Research Center Heidelberg (TLRC-H), DZL, Heidelberg, Germany.

Background: Infection control measures for coronavirus disease 2019 (COVID-19) might have affected management and clinical state of patients with COPD. We analysed to which extent this common notion is fact-based.

Methods: Patients of the COSYCONET cohort were contacted with three recurring surveys (COVID1, 2 and 3 at 0, 3 and 6 months, respectively). The questionnaires comprised behaviour, clinical and functional state, and medical treatment. The responses to the questionnaires were compared amongst themselves and with pre-COVID information from the last visit of COSYCONET.

Results: Overall, 594 patients were contacted and 375 patients (58% males, forced expiratory volume in 1 s (FEV) 61±22% predicted) provided valid data in COVID1 and COVID2. Five patients reported infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Most patients - except for patients with higher education - reported compliance with recommended protective measures, whereby compliance to hygiene, contact and access to physicians slightly improved between COVID1 and COVID2. Also, patients obtained more information from physicians than from public media. In the majority of cases, the personal physician could not be substituted by remote consultation. Over time, symptoms slightly increased and self-assessed physical capacity decreased. Results of COVID3 were similar. Women and patients with more exacerbations and dyspnoea avoided medical consultations, whereas Global Initiative for Chronic Obstructive Lung Disease (GOLD) D patients were more amenable to tele-consultation.

Conclusion: In well-characterised COPD patients, we observed on average slight deteriorations of clinical state during the period of COVID-19 restrictions, with high and partially increasing adherence to protective measures. The data suggest that in particular, women and GOLD D patients should be actively contacted by physicians to identify deteriorations.
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http://dx.doi.org/10.1183/23120541.00242-2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8287574PMC
July 2021

Real-world implementation of sequential targeted therapies for EGFR-mutated lung cancer.

Ther Adv Med Oncol 2021 24;13:1758835921996509. Epub 2021 Mar 24.

Department of Thoracic Oncology, Thoraxklinik at Heidelberg University Hospital, Röntgenstraße 1, Heidelberg, Baden-Württemberg 69126, Germany.

Background: Epidermal growth factor receptor-mutated (EGFR) non-small-cell lung cancer (NSCLC) patients failing tyrosine kinase inhibitors (TKI) can benefit from next-line targeted therapies, but implementation is challenging.

Methods: EGFR NSCLC patients treated with first/second-generation (1G/2G) TKI at our institution with a last follow-up after osimertinib approval (February 2016), were analyzed retrospectively, and the results compared with published data under osimertinib.

Results: A total of 207 patients received erlotinib (37%), gefitinib (16%) or afatinib (47%). The median age was 66 years, with a predominance of female (70%), never/light-smokers (69%). T790M testing was performed in 174/202 progressive cases (86%), positive in 93/174 (53%), and followed by osimertinib in 87/93 (94%). Among the 135 deceased patients, 94 (70%) received subsequent systemic treatment (43% chemotherapy, 39% osimertinib), while 30% died without, either before (4%) or after progression, due to rapid clinical deterioration (22%), patient refusal of further therapy (2%), or severe competing illness (2%). Lack of subsequent treatment was significantly (4.5x,  < 0.001) associated with lack of T790M testing, whose most frequent cause (in approximately 50% of cases) was also rapid clinical decline. Among the 127 consecutive patients with failure of 1G/2G TKI started after November 2015, 47 (37%) received osimertinib, with a median overall survival of 36 months 24 and 21 months for patients with alternative and no subsequent therapies ( = 0.003).

Conclusion: Osimertinib after 1G/2G TKI failure prolongs survival, but approximately 15% and 30% of patients forego molecular retesting and subsequent treatment, respectively, mainly due to rapid clinical deterioration. This is an important remediable obstacle to sequential TKI treatment for EGFR NSCLC. It pertains also to other actionable resistance mechanisms emerging under 1G/2G inhibitors or osimertinib, whose rate for lack of next-line therapy is similar (approximately 35% in the FLAURA/AURA3 trials), and highlights the need for closer monitoring alongside broader profiling of TKI-treated EGFR NSCLC in the future.
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http://dx.doi.org/10.1177/1758835921996509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8366107PMC
March 2021

Controversies in EUS: Do we need miniprobes?

Endosc Ultrasound 2021 Jul-Aug;10(4):246-269

Department of Allgemeine Innere Medizin, Kliniken Hirslanden, Beau Site, Salem und Permanence, Bern, Switzerland; Department of Medical Ultrasound, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China.

This is the fifth in a series of papers entitled "Controversies in EUS." In the current paper, we deal with high-resolution catheter probes, otherwise known as EUS miniprobes (EUS-MPs). The application of miniprobes for early carcinomas in the entire intestinal tract, for subepithelial lesions, and for findings in the bile duct and pancreatic duct as well as endobronchial use is critically discussed. Submucous lesions, especially in the colon, but also early carcinomas in special cases are considered the most important indications. The argument is illustrated by numerous examples.
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http://dx.doi.org/10.4103/EUS-D-20-00252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8411553PMC
August 2021

Endobronchial Valve (Zephyr) Treatment in Homogeneous Emphysema: One-Year Results from the IMPACT Randomized Clinical Trial.

Respiration 2021 Jul 23:1-12. Epub 2021 Jul 23.

Department of Respiratory and Critical Care Medicine, Otto-Wagner-Spital, Wien, Austria.

Rationale: The long-term safety and effectiveness of bronchoscopic lung volume reduction with Zephyr endobronchial valves in subjects with severe homogeneous emphysema with little to no collateral ventilation beyond 3 months have yet to be established.

Methods: Ninety-three subjects were randomized to either bronchoscopic lung volume reduction with Zephyr valves or standard of care (SoC) (1:1). Zephyr valve subjects were assessed at 3, 6, and 12 months. SoC subjects were assessed at 3 and 6 months; they were then offered crossover to Zephyr valve treatment.

Results: The mean group difference (Zephyr valve - SoC) for change in FEV1 from baseline to 6 months was 16.3 ± 22.1% (mean ± SD; p < 0.001). Secondary outcomes showed the mean between-group difference for the six-minute walk distance of +28.3 ± 55.3 m (p = 0.016); St. George's Respiratory Questionnaire, -7.51 ± 9.56 points (p < 0.001); modified Medical Research Council, -0.42 ± 0.81 points (p = 0.019); BODE index, -0.85 ± 1.39 points (p = 0.006); and residual volume of -430 ± 830 mL (p = 0.011) in favor of the Zephyr valve group. At 6 months, there were significantly more responders based on the minimal clinically important difference for these same measures in the Zephyr valve versus the SoC group. The clinical benefits were persistent at 12 months. The percentage of subjects with respiratory serious adverse events was higher in the Zephyr valve group compared to SoC during the first 30 days post-procedure but not statistically different for the Zephyr valve and SoC groups from 31 days to 6 months, and stable in the Zephyr valve group out to 12 months. There were 2 deaths in the SoC group in the 31-day to 6-month period and none in the Zephyr valve group out to 12 months.

Conclusions: Bronchoscopic lung volume reduction with Zephyr valves in subjects with severe homogeneous emphysema and little to no collateral ventilation provides clinically meaningful change from baseline in lung function, quality of life, exercise capacity, dyspnea, and the BODE index at 6 months, with benefits maintained out to 12 months.
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http://dx.doi.org/10.1159/000517034DOI Listing
July 2021

Gender-specific differences in COPD symptoms and their impact for the diagnosis of cardiac comorbidities.

Clin Res Cardiol 2021 Jul 31. Epub 2021 Jul 31.

Department of Internal Medicine V, Comprehensive Pneumology Center (CPC-M), German Center for Lung Research (DZL), University Hospital, Ludwig-Maximilians University (LMU), Munich, Germany.

Background: In chronic obstructive pulmonary disease (COPD), gender-specific differences in the prevalence of symptoms and comorbidity are known.

Research Question: We studied whether the relationship between these characteristics depended on gender and carried diagnostic information regarding cardiac comorbidities.

Study Design And Methods: The analysis was based on 2046 patients (GOLD grades 1-4, 795 women; 38.8%) from the COSYCONET COPD cohort. Assessments comprised the determination of clinical history, comorbidities, lung function, COPD Assessment Test (CAT) and modified Medical Research Council dyspnea scale (mMRC). Using multivariate regression analyses, gender-specific differences in the relationship between symptoms, single CAT items, comorbidities and functional alterations were determined. To reveal the relationship to cardiac disease (myocardial infarction, or heart failure, or coronary artery disease) logistic regression analysis was performed separately in men and women.

Results: Most functional parameters and comorbidities, as well as CAT items 1 (cough), 2 (phlegm) and 5 (activities), differed significantly (p < 0.05) between men and women. Beyond this, the relationship between functional parameters and comorbidities versus symptoms showed gender-specific differences, especially for single CAT items. In men, item 8 (energy), mMRC, smoking status, BMI, age and spirometric lung function was related to cardiac disease, while in women primarily age was predictive.

Interpretation: Gender-specific differences in COPD not only comprised differences in symptoms, comorbidities and functional alterations, but also differences in their mutual relationships. This was reflected in different determinants linked to cardiac disease, thereby indicating that simple diagnostic information might be used differently in men and women.

Clinical Trial Registration: The cohort study is registered on ClinicalTrials.gov with identifier NCT01245933 and on GermanCTR.de with identifier DRKS00000284, date of registration November 23, 2010. Further information can be obtained on the website http://www.asconet.net .
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http://dx.doi.org/10.1007/s00392-021-01915-xDOI Listing
July 2021

Description and analysis of representative COVID-19 cases-A retrospective cohort study.

PLoS One 2021 30;16(7):e0255513. Epub 2021 Jul 30.

Heidelberg Institute of Global Health, Heidelberg University Hospital, Heidelberg, Germany.

Background: Most data on COVID-19 was collected in hospitalized cases. Much less is known about the spectrum of disease in entire populations. In this study, we examine a representative cohort of primarily symptomatic cases in an administrative district in Southern Germany.

Methods: We contacted all confirmed SARS-CoV-2 cases in the administrative district. Consenting participants answered a retrospective survey either via a telephone, electronically or via mail. Clinical and sociodemographic features were compared between hospitalized and non-hospitalized patients. Additionally, we assessed potential risk factors for hospitalization and time to hospitalization in a series of regression models.

Results: We included 897 participants in our study, 69% out of 1,305 total cases in the district with a mean age of 47 years (range 2-97), 51% of which were female and 47% had a pre-existing illness. The percentage of asymptomatic, mild, moderate (leading to hospital admission) and critical illness (requiring mechanical ventilation) was 54 patients (6%), 713 (79%), 97 (11%) and 16 (2%), respectively. Seventeen patients (2%) died. The most prevalent symptoms were fatigue (65%), cough (62%) and dysgeusia (60%). The risk factors for hospitalization included older age (OR 1.05 per year increase; 95% CI 1.04-1.07) preexisting lung conditions (OR 3.09; 95% CI 1.62-5.88). Female sex was a protective factor (OR 0.51; 95% CI 0.33-0.77).

Conclusion: This representative analysis of primarily symptomatic COVID-19 cases confirms age, male sex and preexisting lung conditions but not cardiovascular disease as risk factors for severe illness. Almost 80% of infection take a mild course, whereas 13% of patients suffer moderate to severe illness.

Trial Registration: German Clinical Trials Register, DRKS00022926. URL: https://www.drks.de/drks_web/setLocale_EN.do.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0255513PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8323911PMC
August 2021

Risk of complications rise with coronary artery disease and diabetes mellitus after endobronchial valve placement in severe heterogeneous emphysema.

Clin Respir J 2021 Jul 23. Epub 2021 Jul 23.

Department of Pulmonology and Respiratory Care Medicine, Thoraxklinik at the University of Heidelberg, Heidelberg, Germany.

Background: Patients with chronic obstructive pulmonary disease (COPD) commonly have comorbidities which may impact both symptoms and prognosis. Endoscopic lung volume reduction (ELVR) with endobronchial valves (EBV) is an innovative, effective and safe treatment for patients with severe emphysema who remain symptomatic despite optimal medical therapy.

Objectives: To evaluate medical comorbidities associated with increased risk of complications after EBV procedure.

Method: This was a retrospective cohort review of patients with severe, heterogeneous emphysema who underwent Zephyr® EBV installation for ELVR. Demographics, baseline comorbidities, dyspnea scores, data regarding procedure, pulmonary function test, minimal clinically important difference and post-EBV complications were recorded.

Results: Of a total 82 participants, 24 were identified as having a post procedure complication. There was a significant difference in the incidence of type 2 diabetes mellitus (T2DM) at baseline (25%) in complication group compared with non-complication group (5.1%) (p value = 0.01). There was also a significant difference between baseline coronary artery disease (CAD) in those with (58.3%) or without (29.3%) complication (p = 0.01). Multivariate analysis of other covariables, identified associations of both CAD and T2DM with a heightened risk of complication (adjusted OR 4.19 CI: 1.23-14.2, p value = 0.02 and adjusted OR of 6.1 CI: 1.3-26.1, p value = 0.02 respectively).

Conclusions: Our study found that patients with severe, heterogeneous emphysema who undergo ELVR utilizing Zephyr® EBV and suffer complications during post-procedure period are more likely to have CAD or T2DM as baseline comorbidity. These data suggest that baseline CAD and T2DM might be predictive of increased risk of complications following ELVR with EBV.
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http://dx.doi.org/10.1111/crj.13426DOI Listing
July 2021

Reply to: "Digging mediastinal holes in vigor: a word of caution".

Eur Respir J 2021 Jun 17. Epub 2021 Jun 17.

Department of Respiratory Disease, Xinqiao Hospital, Third Military Medical University, Chongqing, China.

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http://dx.doi.org/10.1183/13993003.01528-2021DOI Listing
June 2021

Deciphering the immunosuppressive tumor microenvironment in ALK- and EGFR-positive lung adenocarcinoma.

Cancer Immunol Immunother 2021 Jun 14. Epub 2021 Jun 14.

Institute of Pathology, Heidelberg University Hospital, Im Neuenheimer Feld 224, Heidelberg, Germany.

Introduction: The advent of immune checkpoint blockade (ICB) has led to significantly improved disease outcome in lung adenocarcinoma (ADC), but response of ALK/EGFR-positive tumors to immune therapy is limited. The underlying immune biology is incompletely understood.

Methods: We performed comparative mRNA expression profiling of 31 ALK-positive, 40 EGFR-positive and 43 ALK/EGFR-negative lung ADC focused on immune gene expression. The presence and levels of tumor infiltration lymphocytes (TILs) as well as fourteen specific immune cell populations were estimated from the gene expression profiles.

Results: While total TILs were not lower in ALK-positive and EGFR-positive tumors compared to ALK/EGFR-negative tumors, specific immunosuppressive characteristics were detected in both subgroups: In ALK-positive tumors, regulatory T cells were significantly higher compared to EGFR-positive (fold change: FC = 1.9, p = 0.0013) and ALK/EGFR-negative tumors (FC = 2.1, p = 0.00047). In EGFR-positive tumors, cytotoxic cells were significantly lower compared to ALK-positive (FC =  - 1.7, p = 0.016) and to ALK/EGFR-negative tumors (FC =  - 2.1, p = 2.0E-05). A total number of 289 genes, 40 part of cytokine-cytokine receptor signaling, were differentially expressed between the three subgroups. Among the latter, five genes were differently expressed in both ALK-positive and EGFR-positive tumors, while twelve genes showed differential expression solely in ALK-positive tumors and eleven genes solely in EGFR-positive tumors.

Conclusion: Targeted gene expression profiling is a promising tool to read out tumor microenvironment characteristics from routine diagnostic lung cancer biopsies. Significant immune reactivity including specific immunosuppressive characteristics in ALK- and EGFR-positive lung ADC, but not a total absence of immune infiltration supports further clinical evaluation of immune-modulators as partners of ICB in such tumors.
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http://dx.doi.org/10.1007/s00262-021-02981-wDOI Listing
June 2021

[Lung cancer reduction strategies].

Authors:
Felix J F Herth

MMW Fortschr Med 2021 06;163(11):46-47

Thoraxklinik Universitätsklinikum Heidelberg, Röntgenstr. 1, 69126, Heidelberg, Deutschland.

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http://dx.doi.org/10.1007/s15006-021-9958-8DOI Listing
June 2021

Expert Statement: Pneumothorax Associated with One-Way Valve Therapy for Emphysema: 2020 Update.

Respiration 2021 Jun 1:1-10. Epub 2021 Jun 1.

Department of Pulmonary Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

For selected patients with advanced emphysema, bronchoscopic lung volume reduction with one-way valves can lead to clinically relevant improvements of airflow obstruction, hyperinflation, exercise capacity, and quality of life. The most common complication of this procedure is pneumothorax with a prevalence of up to ±34% of the treated patients. Patients who develop a pneumothorax also experience meaningful clinical benefits once the pneumothorax is resolved. Timely resolution of a post-valve treatment pneumothorax requires skilled and adequate pneumothorax management. This expert panel statement is an updated recommendation of the 2014 statement developed to help guide pneumothorax management after valve placement. Additionally, mechanisms for pneumothorax development, risk assessment, prevention of pneumothorax, and outcomes after pneumothorax are addressed. This recommendation is based on a combination of the current scientific literature and expert opinion, which was obtained through a modified Delphi method.
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http://dx.doi.org/10.1159/000516326DOI Listing
June 2021

Echo Time-Dependent Observed Lung T in Patients With Chronic Obstructive Pulmonary Disease in Correlation With Quantitative Imaging and Clinical Indices.

J Magn Reson Imaging 2021 May 28. Epub 2021 May 28.

Department of Diagnostic and Interventional Radiology, University of Heidelberg, Heidelberg, Germany.

Background: There is a clinical need for imaging-derived biomarkers for the management of chronic obstructive pulmonary disease (COPD). Observed pulmonary T (T (TE)) depends on the echo-time (TE) and reflects regional pulmonary function.

Purpose: To investigate the potential diagnostic value of T (TE) for the assessment of lung disease in COPD patients by determining correlations with clinical parameters and quantitative CT.

Study Type: Prospective non-randomized diagnostic study.

Population: Thirty COPD patients (67.7 ± 6.6 years). Data from a previous study (15 healthy volunteers [26.2 ± 3.9 years) were used as reference.

Field Strength/sequence: Study participants were examined at 1.5 T using dynamic contrast-enhanced three-dimensional gradient echo keyhole perfusion sequence and a multi-echo inversion recovery two-dimensional UTE (ultra-short TE) sequence for T (TE) mapping at TE  = 70 μsec, 500 μsec, 1200 μsec, 1650 μsec, and 2300 μsec.

Assessment: Perfusion images were scored by three radiologists. T (TE) was automatically quantified. Computed tomography (CT) images were quantified in software (qCT). Clinical parameters including pulmonary function testing were also acquired.

Statistical Tests: Spearman rank correlation coefficients (ρ) were calculated between T (TE) and perfusion scores, clinical parameters and qCT. A P-value <0.05 was considered statistically significant.

Results: Median values were T (TE ) = 644 ± 78 msec, 835 ± 92 msec, 835 ± 87 msec, 831 ± 131 msec, 893 ± 220 msec, all significantly shorter than previously reported in healthy subjects. A significant increase of T was observed from TE to TE , with no changes from TE to TE (P = 0.48), TE to TE (P = 0.94) or TE to TE (P = 0.02) which demonstrates an increase at shorter TEs than in healthy subjects. Moderate to strong Spearman's correlations between T and parameters including the predicted diffusing capacity for carbon monoxide (DLCO, ρ < 0.70), mean lung density (MLD, ρ < 0.72) and the perfusion score (ρ > -0.69) were found. Overall, correlations were strongest at TE , weaker at TE and rarely significant at TE -TE .

Data Conclusion: In COPD patients, the increase of T (TE) with TE occurred at shorter TEs than previously found in healthy subjects. Together with the lack of correlation between T and clinical parameters of disease at longer TEs, this suggests that T (TE) quantification in COPD patients requires shorter TEs. The TE-dependence of correlations implies that T (TE) mapping might be developed further to provide diagnostic information beyond T at a single TE.

Level Of Evidence: 2 TECHNICAL EFFICACY: Stage 1.
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http://dx.doi.org/10.1002/jmri.27746DOI Listing
May 2021

Conventional and semi-automatic histopathological analysis of tumor cell content for multigene sequencing of lung adenocarcinoma.

Transl Lung Cancer Res 2021 Apr;10(4):1666-1678

Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.

Background: Targeted genetic profiling of tissue samples is paramount to detect druggable genetic aberrations in patients with non-squamous non-small cell lung cancer (NSCLC). Accurate upfront estimation of tumor cell content (TCC) is a crucial pre-analytical step for reliable testing and to avoid false-negative results. As of now, TCC is usually estimated on hematoxylin-eosin (H&E) stained tissue sections by a pathologist, a methodology that may be prone to substantial intra- and interobserver variability. Here we the investigate suitability of digital pathology for TCC estimation in a clinical setting by evaluating the concordance between semi-automatic and conventional TCC quantification.

Methods: TCC was analyzed in 120 H&E and thyroid transcription factor 1 (TTF-1) stained high-resolution images by 19 participants with different levels of pathological expertise as well as by applying two semi-automatic digital pathology image analysis tools (HALO and QuPath).

Results: Agreement of TCC estimations [intra-class correlation coefficients (ICC)] between the two software tools (H&E: 0.87; TTF-1: 0.93) was higher compared to that between conventional observers (0.48; 0.47). Digital TCC estimations were in good agreement with the average of human TCC estimations (0.78; 0.96). Conventional TCC estimators tended to overestimate TCC, especially in H&E stainings, in tumors with solid patterns and in tumors with an actual TCC close to 50%.

Conclusions: Our results determine factors that influence TCC estimation. Computer-assisted analysis can improve the accuracy of TCC estimates prior to molecular diagnostic workflows. In addition, we provide a free web application to support self-training and quality improvement initiatives at other institutions.
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http://dx.doi.org/10.21037/tlcr-20-1168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107748PMC
April 2021

Safety and Performance of Transbronchial Cryobiopsy for Parenchymal Lung Lesions.

Chest 2021 May 7. Epub 2021 May 7.

Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University, Baltimore, MD. Electronic address:

Background: Despite advances in technology, the bronchoscopic diagnosis of parenchymal pulmonary lesions (PPLs) remains difficult to achieve. Transbronchial lung cryobiopsy (TLCB) offers the potential for larger samples with improved diagnostic yield; however, a paucity of data exists describing its safety and usefulness for the diagnosis of PPL.

Research Question: What is the safety profile of TLCB for PPL?

Study Design And Methods: An observational, retrospective, multicenter cohort study enrolled patients without endobronchial disease undergoing TLCB of PPL from 2015 through 2019. All procedures were performed using both rigid and flexible bronchoscopy with a flexible cryoprobe. Complication rates, including bleeding and pneumothorax rates, were collected. Bleeding was graded on a scale from 0 (trace) to 4 (requiring surgical intervention) with a grade of ≥ 3 considered clinically significant. Pneumothorax, tube thoracostomy placement, diagnostic yield, and need for subsequent interventions were recorded.

Results: One thousand twenty-four patients underwent TLCB. One hundred eighty-eight patients (18%) experienced bleeding; in 36 patients (3.5%), the bleeding was clinically significant. Sixty-eight patients (6.6%) demonstrated a pneumothorax and 64 patients (6.3%) required drainage with tube thoracostomy. All chest drains were removed within 4 days, and no cases of prolonged air leak occurred. A definitive diagnosis was achieved in 932 patients (91%). Adenocarcinoma (46%) and metastatic disease (21%) were the most common diagnoses.

Interpretation: TLCB showed an acceptable safety profile and diagnostic yield for the evaluation of PPL in this large retrospective cohort. Prospective clinical trials are underway to validate these findings further.
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http://dx.doi.org/10.1016/j.chest.2021.04.063DOI Listing
May 2021

Endobronchial Coil System versus Standard-of-Care Medical Management in the Treatment of Subjects with Severe Emphysema.

Respiration 2021;100(8):804-810. Epub 2021 May 7.

Department of Pulmonary Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Background: Bronchoscopic lung volume reduction using endobronchial coils is a new treatment for patients with severe emphysema. To date, the benefits have been modest and have been suggested to be much larger in patients with severe hyperinflation and nonmulti-comorbidity.

Objective: We aimed to evaluate the efficacy and safety of endobronchial coil treatment in a randomized multicenter clinical trial using optimized patient selection.

Method: Patients with severe emphysema on HRCT scan with severe hyperinflation (residual volume [RV] ≥200% predicted and RV/total lung capacity [TLC] >55%) were randomized to coil treatment or control. Primary outcome measures were differences in the forced expiratory volume in 1 s (FEV1) and St George's Respiratory Questionnaire (SGRQ) total score at 6 months.

Results: Due to premature study termination, a total of 120 patients (age 63 ± 7 years, FEV1 29 ± 7% predicted, RV 251 ± 41% predicted, RV/TLC 67 ± 6%, and SGRQ 58 ± 13 points), instead of 210 patients, were randomized. At study termination, 91 patients (57 coil and 34 control) had 6-month results available. Analyses showed significantly greater improvements in favor of the coil group. The increase in FEV1 was greater in the coil group than that in the control group by + 10.3 [+4.7 to +16.0] % and in SGRQ by -10.6 [-15.9 to -5.4] points. At study termination, there were 5 (6.8%) deaths in the coil cohort reported.

Conclusion: Despite early study termination, coil treatment compared to control results in a significant improvement in the lung function and quality of life benefits for up to 6 months in patients with emphysema and severe hyperinflation. These improvements were of clinical importance but were associated with a higher likelihood of serious adverse events.
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http://dx.doi.org/10.1159/000515744DOI Listing
May 2021

[Patient self-inflicted lung injury (P-SILI) : From pathophysiology to clinical evaluation with differentiated management].

Med Klin Intensivmed Notfmed 2021 May 7. Epub 2021 May 7.

Thoraxklinik am Universitätsklinikum Heidelberg, Pneumologie und Beatmungsmedizin, Translational Lung Research Center Heidelberg (TLRC), Röntgenstraße 1, 69126, Heidelberg, Deutschland.

The establishment of assisted spontaneous breathing is a phase of ventilation therapy that is generally considered to be beneficial and not dangerous. However, recent findings regarding potential damage from vigorous spontaneous breathing effort should be noticed in patients with acute injured lungs. This syndrome is called patient self-inflicted lung injury. Physicians, nurses and respiratory therapists should be aware of this issue. Parameters that can be determined using esophageal pressure measurement or simple maneuvers on the respirator are helpful when deciding to implement and to monitor assisted spontaneous breathing, even in the acute phases of lung damage. In addition to monitoring, there are therapeutic options for dealing with high respiratory drive or increased breathing effort.
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http://dx.doi.org/10.1007/s00063-021-00823-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8103432PMC
May 2021

Transbronchial mediastinal cryobiopsy in the diagnosis of mediastinal lesions: a randomised trial.

Eur Respir J 2021 May 6. Epub 2021 May 6.

Department of Respiratory Disease, Xinqiao Hospital, Third Military Medical University, Chongqing, China.

Background: Guidelines recommend endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) as an initial investigation technique for mediastinal nodal staging in lung cancer. However, EBUS-TBNA can be limited by the inadequacy of intact tissues, which might restrict its diagnostic yield in mediastinal lesions of certain etiologies. We have previously shown that EBUS-guided transbronchial mediastinal cryobiopsy can provide intact samples with greater volume.

Methods: This randomised study determined the diagnostic yield and safety of transbronchial mediastinal cryobiopsy monitored by endosonography for the diagnosis of mediastinal lesions. Patients with mediastinal lesion of 1 cm or more in the short axis were recruited. Following identification of the mediastinal lesion by linear EBUS, fine-needle aspiration and cryobiopsy were sequently performed in a randomised order. Primary endpoints were diagnostic yield defined as the percentage of patients for whom mediastinal biopsy provided a definite diagnosis, and procedure-related adverse events.

Results: One hundred and ninety-seven patients were enrolled and randomly allocated. The overall diagnostic yield was 79.9% and 91.8% for TBNA and transbronchial mediastinal cryobiopsy, respectively (p=0.001). Diagnostic yields were similar for metastatic lymphadenopathy (94.1% 95.6%, p=0.58), while cryobiopsy was more sensitive than TBNA in uncommon tumors (91.7% 25.0%, p=0.001) and benign disorders (80.9% 53.2%, p=0.004). No significant differences in diagnostic yield were detected between TBNA first and cryobiopsy first groups. We observed 2 cases of pneumothorax and 1 case of pneumomediastinum.

Conclusions: Transbronchial cryobiopsy performed under EBUS guidance is a safe and useful approach that offers diagnostic histological samples of mediastinal lesions.
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http://dx.doi.org/10.1183/13993003.00055-2021DOI Listing
May 2021

Role of Synaptophysin, Chromogranin and CD56 in adenocarcinoma and squamous cell carcinoma of the lung lacking morphological features of neuroendocrine differentiation: a retrospective large-scale study on 1170 tissue samples.

BMC Cancer 2021 May 1;21(1):486. Epub 2021 May 1.

Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, Heidelberg, Germany.

Background: Synaptophysin, chromogranin and CD56 are recommended markers to identify pulmonary tumors with neuroendocrine differentiation. Whether the expression of these markers in pulmonary adenocarcinoma and pulmonary squamous cell carcinoma is a prognostic factor has been a matter of debate. Therefore, we investigated retrospectively a large cohort to expand the data on the role of synaptophysin, chromogranin and CD56 in non-small cell lung cancer lacking morphological features of neuroendocrine differentiation.

Methods: A cohort of 627 pulmonary adenocarcinomas (ADC) and 543 squamous cell carcinomas (SqCC) lacking morphological features of neuroendocrine differentiation was assembled and a tissue microarray was constructed. All cases were stained with synaptophysin, chromogranin and CD56. Positivity was defined as > 1% positive tumor cells. Data was correlated with clinico-pathological features including overall and disease free survival.

Results: 110 (18%) ADC and 80 (15%) SqCC were positive for either synaptophysin, chromogranin, CD56 or a combination. The most commonly positive single marker was synaptophysin. The least common positive marker was chromogranin. A combination of ≤2 neuroendocrine markers was positive in 2-3% of ADC and 0-1% of SqCC. There was no significant difference in overall survival in tumors with positivity for neuroendocrine markers neither in ADC (univariate: P = 0.4; hazard ratio [HR] = 0.867; multivariate: P = 0.5; HR = 0.876) nor in SqCC (univariate: P = 0.1; HR = 0.694; multivariate: P = 0.1, HR = 0.697). Likewise, there was no significant difference in disease free survival.

Conclusions: We report on a cohort of 1170 cases that synaptophysin, chromogranin and CD56 are commonly expressed in ADC and SqCC and that their expression has no impact on survival, supporting the current best practice guidelines.
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http://dx.doi.org/10.1186/s12885-021-08140-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088012PMC
May 2021

Management of Significant Airway Bleeding during Robotic Assisted Bronchoscopy: A Tailored Approach.

Respiration 2021;100(6):547-550. Epub 2021 Mar 26.

Division of General Thoracic Surgery/Mayo Clinic, Rochester, Minnesota, USA.

Robotic assisted bronchoscopy represents a major turning point in bronchoscopic history. The management strategies to address significant airway bleeding in this "robotic era" are not well documented, and further guidance is required. We present a case report that exemplifies our approach and management strategy using a combined and simultaneous flexible/robotic bronchoscopy if this complication is encountered.
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http://dx.doi.org/10.1159/000514830DOI Listing
March 2021

Targeting rare and non-canonical driver variants in NSCLC - An uncharted clinical field.

Lung Cancer 2021 04 19;154:131-141. Epub 2021 Feb 19.

Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany; Translational Lung Research Center Heidelberg (TLRC-H), Heidelberg, Member of the German Center for Lung Research (DZL), Germany; German Cancer Consortium (DKTK), Berlin, Munich and Heidelberg Partner Sites, Germany. Electronic address:

Objectives: Implementation of tyrosine kinase inhibitors (TKI) and other targeted therapies was a main advance in thoracic oncology with survival gains ranging from several months to years for non-small-cell lung cancer (NSCLC) patients. High-throughput comprehensive molecular profiling is of key importance to identify patients that can potentially benefit from these novel treatments.

Material And Methods: Next-generation sequencing (NGS) was performed on 4500 consecutive formalin-fixed, paraffin-embedded specimens of advanced NSCLC (n = 4172 patients) after automated extraction of DNA and RNA for parallel detection of mutations and gene fusions, respectively.

Results And Conclusion: Besides the 24.9 % (n = 1040) of cases eligible for approved targeted therapies based on the presence of canonical alterations in EGFR exons 18-21, BRAF, ROS1, ALK, NTRK, and RET, an additional n = 1260 patients (30.2 %) displayed rare or non-canonical mutations in EGFR (n = 748), BRAF (n = 135), ERBB2 (n = 30), KIT (n = 32), PIK3CA (n = 221), and CTNNB1 (n = 94), for which targeted therapies could also be potentially effective. A systematic literature search in conjunction with in silico evaluation identified n = 232 (5.5 %) patients, for which a trial of targeted treatment would be warranted according to available evidence (NCT level 1, i.e. published data showing efficacy in the same tumor entity). In conclusion, a sizeable fraction of NSCLC patients harbors rare or non-canonical alterations that may be associated with clinical benefit from currently available targeted drugs. Systematic identification and individualized management of these cases can expand applicability of precision oncology in NSCLC and extend clinical gain from established molecular targets. These results can also inform clinical trials.
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http://dx.doi.org/10.1016/j.lungcan.2021.02.022DOI Listing
April 2021

Diagnosis and staging of lung cancer with the use of one single echoendoscope in both the trachea and the esophagus: A practical guide.

Endosc Ultrasound 2021 Mar 2. Epub 2021 Mar 2.

Department Allgemeine Innere Medizin (DAIM), Kliniken Hirslanden Beau Site, Salem und Permanence, Bern, Switzerland.

Accurate staging of non-small cell lung cancer (NSCLC) is crucial for allocation to surgical, medical or multimodal treatment. EUS and endobronchial ultrasound (EBUS) have gained ground in the diagnosis and staging of lung cancer in addition to radiological imaging (e.g., computed tomography, fluoroscopy, and magnetic resonance imaging), nuclear medicine techniques (e.g. positron emission tomography, PET), combined techniques (e.g., fluorodesoxyglucosepositron emission tomography scanning), and sonographic imaging including conventional transcutaneous mediastinal and lung ultrasound. By using one single echoendoscope in both the trachea and the esophagus, surgical staging procedures (e.g. mediastinoscopy and video assisted thoracoscopy) can be avoided in a considerable proportion of patients with NSCLC.
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http://dx.doi.org/10.4103/EUS-D-20-00139DOI Listing
March 2021

Versatile workflow for cell type-resolved transcriptional and epigenetic profiles from cryopreserved human lung.

JCI Insight 2021 03 22;6(6). Epub 2021 Mar 22.

BioMed X Institute, Heidelberg, Germany.

Complexity of lung microenvironment and changes in cellular composition during disease make it exceptionally hard to understand molecular mechanisms driving development of chronic lung diseases. Although recent advances in cell type-resolved approaches hold great promise for studying complex diseases, their implementation relies on local access to fresh tissue, as traditional tissue storage methods do not allow viable cell isolation. To overcome these hurdles, we developed a versatile workflow that allows storage of lung tissue with high viability, permits thorough sample quality check before cell isolation, and befits sequencing-based profiling. We demonstrate that cryopreservation enables isolation of multiple cell types from both healthy and diseased lungs. Basal cells from cryopreserved airways retain their differentiation ability, indicating that cellular identity is not altered by cryopreservation. Importantly, using RNA sequencing and EPIC Array, we show that gene expression and DNA methylation signatures are preserved upon cryopreservation, emphasizing the suitability of our workflow for omics profiling of lung cells. Moreover, we obtained high-quality single-cell RNA-sequencing data of cells from cryopreserved human lungs, demonstrating that cryopreservation empowers single-cell approaches. Overall, thanks to its simplicity, our workflow is well suited for prospective tissue collection by academic collaborators and biobanks, opening worldwide access to viable human tissue.
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http://dx.doi.org/10.1172/jci.insight.140443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026197PMC
March 2021

Multiple breath washout (MBW) testing using sulfur hexafluoride: reference values and influence of anthropometric parameters.

Thorax 2021 04 16;76(4):380-386. Epub 2021 Feb 16.

Department of Biomedical Informatics, Centre for Preventive Medicine & Digital Health Baden-Württemberg, University Medical Centre Mannheim, Mannheim, Germany.

Background: Multiple breath washout (MBW) using sulfur hexafluoride (SF) has the potential to reveal ventilation heterogeneity which is frequent in patients with obstructive lung disease and associated small airway dysfunction. However, reference data are scarce for this technique and mostly restricted to younger cohorts. We therefore set out to evaluate the influence of anthropometric parameters on SF-MBW reference values in pulmonary healthy adults.

Methods: We evaluated cross-sectional data from 100 pulmonary healthy never-smokers and smokers (mean 51 (SD 20), range 20-88 years). Lung clearance index (LCI), acinar (S) and conductive (S) ventilation heterogeneity were derived from triplicate SF-MBW measurements. Global ventilation heterogeneity was calculated for the 2.5% (LCI) and 5% (LCI) stopping points. Upper limit of normal (ULN) was defined as the 95th percentile.

Results: Age was the only meaningful parameter influencing SF-MBW parameters, explaining 47% (CI 33% to 59%) of the variance in LCI, 32% (CI 18% to 47%) in S and 10% (CI 2% to 22%) in S. Mean LCI increases from 6.3 (ULN 7.4) to 8.8 (ULN 9.9) in subjects between 20 and 90 years. Smoking accounted for 2% (CI 0% to 8%) of the variability in LCI, 4% (CI 0% to 13%) in S and 3% (CI 0% to 13%) in S.

Conclusion: SF-MBW outcome parameters showed an age-dependent increase from early adulthood to old age. The effect was most pronounced for global and acinar ventilation heterogeneity and smaller for conductive ventilation heterogeneity. No influence of height, weight and sex was seen. Reference values can now be provided for all important SF-MBW outcome parameters over the whole age range.

Trial Registration Number: NCT04099225.
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http://dx.doi.org/10.1136/thoraxjnl-2020-214717DOI Listing
April 2021

[Mortality of lung cancer].

Internist (Berl) 2021 Apr 10;62(4):458-460. Epub 2021 Feb 10.

, Lippetal, Deutschland.

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http://dx.doi.org/10.1007/s00108-021-00968-4DOI Listing
April 2021

Prognostic Value of Oxygenated Hemoglobin Assessed during Acute Exacerbations of Chronic Pulmonary Disease.

Respiration 2021;100(5):387-394. Epub 2021 Feb 5.

Department of Pneumology and Critical Care Medicine, Thoraxklinik University of Heidelberg, Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany,

Background: Oxygenated hemoglobin(OxyHem) is a simple-to-measure marker of oxygen content capable of predicting all-cause mortality in stable chronic obstructive pulmonary disease (COPD).

Objectives: We aimed to analyze its predictive value during acute exacerbations of COPD (AECOPD).

Methods: In this retrospective study, data from 227 patients discharged after severe AECOPD at RoMed Clinical Center Rosenheim, Germany, between January 2012 and March 2018, was analyzed. OxyHem (hemoglobin concentration [Hb] × fractional SpO2, g/dL) was calculated from oxygen saturation measured by pulse oximetry and hemoglobin assessed within 24 h after admission. The follow-up (1.7 ± 1.5 years) covered all-cause mortality, including readmissions for severe AECOPD.

Results: During the follow-up period, 127 patients died, 56 due to AECOPD and 71 due to other reasons. Survivors and non-survivors showed differences in age, FVC % predicted, C-reactive protein, hemoglobin, Cr, Charlson Comorbidity Index (CCI), and OxyHem (p < 0.05 each). Significant independent predictors of survival were BMI, Cr or CCI, FEV1 % predicted or FVC % predicted, Hb, or OxyHem. The predictive value of OxyHem (p = 0.006) was superior to that of Hb or SpO2 and independent of oxygen supply during blood gas analysis. OxyHem was also predictive when using a cutoff value of 12.1 g/dL identified via receiver operating characteristic curves in analyses including either the CCI (hazard ratio 1.85; 95% CI 1.20, 2.84; p = 0.005) or Cr (2.04; 95% CI 1.35, 3.10; p = 0.001) as covariates.

Conclusion: The concentration of OxyHem provides independent, easy-to-assess information on long-term mortality risk in COPD, even if measured during acute exacerbations. It therefore seems worth to be considered for broader clinical use.
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http://dx.doi.org/10.1159/000513440DOI Listing
February 2021

A gene expression signature associated with B cells predicts benefit from immune checkpoint blockade in lung adenocarcinoma.

Oncoimmunology 2021 01 11;10(1):1860586. Epub 2021 Jan 11.

Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.

Immune checkpoint blockade (ICB) expands the therapeutic options for metastatic lung cancer nowadays representing a standard frontline strategy as monotherapy or combination therapy, as well as an option in oncogene-addicted NSCLC after exhaustion of targeted therapies. Predictive markers are urgently needed, since only a minority of patients benefits from ICB, while serious adverse effects of immunotoxicity may occur. The study cohort included 43 ICB-treated metastatic lung adenocarcinoma showing long-term response (n = 16), rapid progression (n = 21) or intermediate patterns of response (n = 6). Lung biopsies acquired before initiation of ICB were analyzed by targeted mRNA expression profiling of 770 genes. Level and proportions of 14 immune cell types were estimated using characteristic gene expression signatures. Abundance of B cells (HR = 0.66, = .00074), CD45+ cells (HR = 0.61, = .01) and total TILs (HR = 0.62, = .025) was associated with prolonged progression-free survival after ICB treatment. In a ROC analysis, B cells (AUC = 0.77, = .0055) and CD45+ cells (AUC = 0.73, = .019) predicted benefit of ICB, which was not the case for PD-L1 mRNA (AUC = 0.54, = .72) and PD-L1 protein expression (AUC = 0.68, = .082). Clustering of 79 candidate predictive markers identified among 770 investigated genes revealed two distinct predictive clusters which included cytotoxic cell or macrophage markers, respectively. In summary, targeted gene expression profiling was feasible using routine diagnostics biopsies. This study proposes B cells and total TILs as complementary predictors of ICB benefit in NSCLC. While further preferably prospective validation is required, gene expression profiling could be integrated in the routine diagnostic work-up complementing existing NGS protocols.
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http://dx.doi.org/10.1080/2162402X.2020.1860586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808386PMC
January 2021

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

Respiration 2021;100(4):308-317. 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

Residual symptoms and lower lung function in patients recovering from SARS-CoV-2 infection.

Eur Respir J 2021 02 25;57(2). Epub 2021 Feb 25.

Pneumology and Critical Care Medicine, Thoraxklinik at University Hospital Heidelberg, Translational Lung Research Center Heidelberg (TLRC), Member of German Center for Lung Research (DZL), Heidelberg, Germany

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http://dx.doi.org/10.1183/13993003.03002-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821834PMC
February 2021
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