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Mark Kuehnel

Bio: Mark Kuehnel is an academic researcher from Hannover Medical School. The author has contributed to research in topics: Medicine & Lung. The author has an hindex of 7, co-authored 19 publications receiving 2671 citations. Previous affiliations of Mark Kuehnel include Hochschule Hannover & University of Mainz.

Papers
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Journal ArticleDOI
TL;DR: In this small series, vascular angiogenesis distinguished the pulmonary pathobiology of Covid-19 from that of equally severe influenza virus infection.
Abstract: Background Progressive respiratory failure is the primary cause of death in the coronavirus disease 2019 (Covid-19) pandemic. Despite widespread interest in the pathophysiology of the dise...

4,134 citations

Journal ArticleDOI
TL;DR: Three distinct manifestations of neoangiogenesis are identified as drivers of pulmonary remodelling in human ILDs, modulated by bone marrow-derived monocytes.
Abstract: The pathogenetic role of angiogenesis in interstitial lung diseases (ILDs) is controversial. This study represents the first investigation of the spatial complexity and molecular motifs of microvascular architecture in important subsets of human ILD. The aim of our study was to identify specific variants of neoangiogenesis in three common pulmonary injury patterns in human ILD.We performed comprehensive and compartment-specific analysis of 24 human lung explants with usual intersitial pneumonia (UIP), nonspecific interstitial pneumonia (NSIP) and alveolar fibroelastosis (AFE) using histopathology, microvascular corrosion casting, micro-comupted tomography based volumetry and gene expression analysis using Nanostring as well as immunohistochemistry to assess remodelling-associated angiogenesis.Morphometrical assessment of vessel diameters and intervascular distances showed significant differences in neoangiogenesis in characteristically remodelled areas of UIP, NSIP and AFE lungs. Likewise, gene expression analysis revealed distinct and specific angiogenic profiles in UIP, NSIP and AFE lungs.Whereas UIP lungs showed a higher density of upstream vascularity and lower density in perifocal blood vessels, NSIP and AFE lungs revealed densely packed alveolar septal blood vessels. Vascular remodelling in NSIP and AFE is characterised by a prominent intussusceptive neoangiogenesis, in contrast to UIP, in which sprouting of new vessels into the fibrotic areas is characteristic. The molecular analyses of the gene expression provide a foundation for understanding these fundamental differences between AFE and UIP and give insight into the cellular functions involved.

53 citations

Journal ArticleDOI
01 Jan 2017
TL;DR: An evolutionary model for the AFE pattern is described: a non‐specific fibrin‐rich reaction to injury pattern triggers a misguided resolution attempt and eventual progression towards manifest AFE.
Abstract: Chronic lung allograft dysfunction (CLAD) remains the major obstacle to long-term survival following lung transplantation (LuTx). Morphologically CLAD is defined by obliterative remodelling of the small airways (bronchiolitis obliterans, BO) as well as a more recently described collagenous obliteration of alveoli with elastosis summarized as alveolar fibroelastosis (AFE). Both patterns are not restricted to pulmonary allografts, but have also been reported following haematopoietic stem cell transplantation (HSCT) and radio chemotherapy (RC). In this study we performed compartment-specific morphological and molecular analysis of BO and AFE lesions in human CLAD (n=22), HSCT (n=29) and RC (n=6) lung explants, utilizing conventional histopathology, laser-microdissection, PCR techniques and immunohistochemistry to assess fibrosis-associated gene and protein expression. Three key results emerged from our analysis of fibrosis-associated genes: i) generally speaking, “BO is BO”. Despite the varying clinical backgrounds, the molecular characteristics of BO lesions were found to be alike in all groups. ii) “AFE is AFE”. In all groups of patients suffering from restrictive changes to lung physiology due to AFE there were largely – but not absolutely - identical gene expression patterns. iii) BO concomitant to AFE after LuTx is characterized by an AFE-like molecular microenvironment, representing the only exception to i). Additionally, we describe an evolutionary model for the AFE pattern: a non-specific fibrin-rich reaction to injury pattern triggers a misguided resolution attempt and eventual progression towards manifest AFE. Our data point towards an absence of classical fibrinolytic enzymes and an alternative fibrin degrading mechanism via macrophages, resulting in fibrous remodelling and restrictive functional changes. These data may serve as diagnostic adjuncts and help to predict the clinical course of respiratory dysfunction in LuTx and HSCT patients. Moreover, analysis of the mechanism of fibrinolysis and fibrogenesis may unveil potential therapeutic targets to alter the course of the eventually fatal lung remodelling. This article is protected by copyright. All rights reserved.

37 citations

Journal ArticleDOI
TL;DR: “Tissue remains the (main) issue,” as the authors are still limited in their knowledge about the actual triggers and specific mechanisms of all late forms of posttransplant graft failure, a shortcoming that needs to be addressed in order to further improve the outcome of lung transplant recipients.

23 citations

Journal ArticleDOI
TL;DR: The current state of the literature on chronic lung allograft dysfunction is reviewed and light is shed on classification systems, corresponding clinical and morphological changes, key cellular players and underlying molecular pathways, as well as on emerging diagnostic and therapeutic approaches.
Abstract: Following lung transplantation, fibrotic remodelling of the small airways has been recognized for almost 5 decades as the main correlate of chronic graft failure and a major obstacle to long-term survival. Mainly due to airway fibrosis, pulmonary allografts currently show the highest attrition rate of all solid organ transplants, with a 5-year survival rate of 58 % on a worldwide scale. The observation that these morphological changes are not just the hallmark of chronic rejection but rather represent a manifestation of a multitude of alloimmune-dependent and -independent injuries was made more recently, as was the discovery that chronic lung allograft dysfunction manifests in different clinical phenotypes of respiratory impairment and corresponding morphological subentities. Although recent years have seen considerable advances in identifying and categorizing these subgroups on the basis of clinical, functional and histomorphological changes, as well as susceptibility to medicinal treatment, this process is far from over. Since the actual pathophysiological mechanisms governing airway remodelling are still only poorly understood, diagnosis and therapy of chronic lung allograft dysfunction presents a major challenge to clinicians, radiologists and pathologists alike. Here, we review and discuss the current state of the literature on chronic lung allograft dysfunction and shed light on classification systems, corresponding clinical and morphological changes, key cellular players and underlying molecular pathways, as well as on emerging diagnostic and therapeutic approaches.

14 citations


Cited by
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Journal ArticleDOI
TL;DR: In this small series, vascular angiogenesis distinguished the pulmonary pathobiology of Covid-19 from that of equally severe influenza virus infection.
Abstract: Background Progressive respiratory failure is the primary cause of death in the coronavirus disease 2019 (Covid-19) pandemic. Despite widespread interest in the pathophysiology of the dise...

4,134 citations

Journal ArticleDOI
TL;DR: A comprehensive review of the current literature on post-acute COVID-19, its pathophysiology and its organ-specific sequelae is provided in this paper, where the authors discuss relevant considerations for the multidisciplinary care of COPD survivors and propose a framework for the identification of those at high risk for COPD and their coordinated management through dedicated COPD clinics.
Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the pathogen responsible for the coronavirus disease 2019 (COVID-19) pandemic, which has resulted in global healthcare crises and strained health resources. As the population of patients recovering from COVID-19 grows, it is paramount to establish an understanding of the healthcare issues surrounding them. COVID-19 is now recognized as a multi-organ disease with a broad spectrum of manifestations. Similarly to post-acute viral syndromes described in survivors of other virulent coronavirus epidemics, there are increasing reports of persistent and prolonged effects after acute COVID-19. Patient advocacy groups, many members of which identify themselves as long haulers, have helped contribute to the recognition of post-acute COVID-19, a syndrome characterized by persistent symptoms and/or delayed or long-term complications beyond 4 weeks from the onset of symptoms. Here, we provide a comprehensive review of the current literature on post-acute COVID-19, its pathophysiology and its organ-specific sequelae. Finally, we discuss relevant considerations for the multidisciplinary care of COVID-19 survivors and propose a framework for the identification of those at high risk for post-acute COVID-19 and their coordinated management through dedicated COVID-19 clinics.

2,307 citations

20 Mar 2020
TL;DR: The effects of the epidemic caused by the new CoV has yet to emerge as the situation is quickly evolving, and world governments are at work to establish countermeasures to stem possible devastating effects.
Abstract: According to the World Health Organization (WHO), viral diseases continue to emerge and represent a serious issue to public health In the last twenty years, several viral epidemics such as the severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002 to 2003, and H1N1 influenza in 2009, have been recorded Most recently, the Middle East respiratory syndrome coronavirus (MERS-CoV) was first identified in Saudi Arabia in 2012 In a timeline that reaches the present day, an epidemic of cases with unexplained low respiratory infections detected in Wuhan, the largest metropolitan area in China's Hubei province, was first reported to the WHO Country Office in China, on December 31, 2019 Published literature can trace the beginning of symptomatic individuals back to the beginning of December 2019 As they were unable to identify the causative agent, these first cases were classified as "pneumonia of unknown etiology " The Chinese Center for Disease Control and Prevention (CDC) and local CDCs organized an intensive outbreak investigation program The etiology of this illness is now attributed to a novel virus belonging to the coronavirus (CoV) family, COVID-19 On February 11, 2020, the WHO Director-General, Dr Tedros Adhanom Ghebreyesus, announced that the disease caused by this new CoV was a "COVID-19," which is the acronym of "coronavirus disease 2019" In the past twenty years, two additional coronavirus epidemics have occurred SARS-CoV provoked a large-scale epidemic beginning in China and involving two dozen countries with approximately 8000 cases and 800 deaths, and the MERS-CoV that began in Saudi Arabia and has approximately 2,500 cases and 800 deaths and still causes as sporadic cases This new virus seems to be very contagious and has quickly spread globally In a meeting on January 30, 2020, per the International Health Regulations (IHR, 2005), the outbreak was declared by the WHO a Public Health Emergency of International Concern (PHEIC) as it had spread to 18 countries with four countries reporting human-to-human transmission An additional landmark occurred on February 26, 2020, as the first case of the disease, not imported from China, was recorded in the United States Initially, the new virus was called 2019-nCoV Subsequently, the task of experts of the International Committee on Taxonomy of Viruses (ICTV) termed it the SARS-CoV-2 virus as it is very similar to the one that caused the SARS outbreak (SARS-CoVs) The CoVs have become the major pathogens of emerging respiratory disease outbreaks They are a large family of single-stranded RNA viruses (+ssRNA) that can be isolated in different animal species For reasons yet to be explained, these viruses can cross species barriers and can cause, in humans, illness ranging from the common cold to more severe diseases such as MERS and SARS Interestingly, these latter viruses have probably originated from bats and then moving into other mammalian hosts — the Himalayan palm civet for SARS-CoV, and the dromedary camel for MERS-CoV — before jumping to humans The dynamics of SARS-Cov-2 are currently unknown, but there is speculation that it also has an animal origin The potential for these viruses to grow to become a pandemic worldwide seems to be a serious public health risk Concerning COVID-19, the WHO raised the threat to the CoV epidemic to the "very high" level, on February 28, 2020 Probably, the effects of the epidemic caused by the new CoV has yet to emerge as the situation is quickly evolving World governments are at work to establish countermeasures to stem possible devastating effects Health organizations coordinate information flows and issues directives and guidelines to best mitigate the impact of the threat At the same time, scientists around the world work tirelessly, and information about the transmission mechanisms, the clinical spectrum of disease, new diagnostics, and prevention and therapeutic strategies are rapidly developing Many uncertainties remain with regard to both the virus-host interac ion and the evolution of the epidemic, with specific reference to the times when the epidemic will reach its peak At the moment, the therapeutic strategies to deal with the infection are only supportive, and prevention aimed at reducing transmission in the community is our best weapon Aggressive isolation measures in China have led to a progressive reduction of cases in the last few days In Italy, in geographic regions of the north of the peninsula, political and health authorities are making incredible efforts to contain a shock wave that is severely testing the health system In the midst of the crisis, the authors have chosen to use the "Statpearls" platform because, within the PubMed scenario, it represents a unique tool that may allow them to make updates in real-time The aim, therefore, is to collect information and scientific evidence and to provide an overview of the topic that will be continuously updated

2,161 citations

Journal ArticleDOI
TL;DR: The extrapulmonary organ-specific pathophysiology, presentations and management considerations for patients with COVID-19 are reviewed to aid clinicians and scientists in recognizing and monitoring the spectrum of manifestations, and in developing research priorities and therapeutic strategies for all organ systems involved.
Abstract: Although COVID-19 is most well known for causing substantial respiratory pathology, it can also result in several extrapulmonary manifestations. These conditions include thrombotic complications, myocardial dysfunction and arrhythmia, acute coronary syndromes, acute kidney injury, gastrointestinal symptoms, hepatocellular injury, hyperglycemia and ketosis, neurologic illnesses, ocular symptoms, and dermatologic complications. Given that ACE2, the entry receptor for the causative coronavirus SARS-CoV-2, is expressed in multiple extrapulmonary tissues, direct viral tissue damage is a plausible mechanism of injury. In addition, endothelial damage and thromboinflammation, dysregulation of immune responses, and maladaptation of ACE2-related pathways might all contribute to these extrapulmonary manifestations of COVID-19. Here we review the extrapulmonary organ-specific pathophysiology, presentations and management considerations for patients with COVID-19 to aid clinicians and scientists in recognizing and monitoring the spectrum of manifestations, and in developing research priorities and therapeutic strategies for all organ systems involved.

2,113 citations

Journal ArticleDOI
David Ellinghaus1, Frauke Degenhardt1, Luis Bujanda1, Maria Buti1, Agustín Albillos1, Pietro Invernizzi1, J. Fernández1, Daniele Prati1, Guido Baselli1, Rosanna Asselta1, Marit Mæhle Grimsrud1, Chiara Milani1, Fatima Aziz1, Jan Christian Kässens1, Sandra May1, Mareike Wendorff1, Lars Wienbrandt1, Florian Uellendahl-Werth1, Tenghao Zheng1, Xiaoli Yi1, Raúl de Pablo1, Adolfo Garrido Chercoles1, Adriana Palom1, Alba Estela Garcia-Fernandez1, Francisco Rodriguez-Frias1, Alberto Zanella1, Alessandra Bandera1, Alessandro Protti1, Alessio Aghemo1, Ana Lleo1, Andrea Biondi1, Andrea Caballero-Garralda1, Andrea Gori1, Anja Tanck1, Anna Carreras Nolla1, Anna Latiano1, Anna Ludovica Fracanzani1, Anna Peschuck1, Antonio Julià1, Antonio Pesenti1, Antonio Voza1, David Jiménez1, Beatriz Mateos1, Beatriz Nafria Jimenez1, Carmen Quereda1, Cinzia Paccapelo1, Christoph Gassner1, Claudio Angelini1, Cristina Cea1, Aurora Solier1, David Pestana1, Eduardo Muñiz-Diaz1, Elena Sandoval1, Elvezia Maria Paraboschi1, Enrique Navas1, Félix García Sánchez1, Ferruccio Ceriotti1, F. Martinelli-Boneschi1, Flora Peyvandi1, Francesco Blasi1, Luis Téllez1, Albert Blanco-Grau1, Georg Hemmrich-Stanisak1, Giacomo Grasselli1, Giorgio Costantino1, Giulia Cardamone1, Giuseppe Foti1, Serena Aneli1, Hayato Kurihara1, Hesham ElAbd1, Ilaria My1, Iván Galván-Femenía1, Javier Martin1, Jeanette Erdmann1, José Ferrusquía-Acosta1, Koldo Garcia-Etxebarria1, Laura Izquierdo-Sanchez1, Laura Rachele Bettini1, Lauro Sumoy1, Leonardo Terranova1, Leticia Moreira1, Luigi Santoro1, Luigia Scudeller1, Francisco Mesonero1, Luisa Roade1, Malte C. Rühlemann1, Marco Schaefer1, Maria Carrabba1, Mar Riveiro-Barciela1, Maria Eloina Figuera Basso1, Maria Grazia Valsecchi1, María Hernández-Tejero1, Marialbert Acosta-Herrera1, Mariella D'Angiò1, Marina Baldini1, Marina Cazzaniga1, Martin Schulzky1, Maurizio Cecconi1, Michael Wittig1, Michele Ciccarelli1, Miguel Rodríguez-Gandía1, Monica Bocciolone1, Monica Miozzo1, Nicola Montano1, Nicole Braun1, Nicoletta Sacchi1, Nilda Martinez1, Onur Özer1, Orazio Palmieri1, Paola Faverio1, Paoletta Preatoni1, Paolo Bonfanti1, Paolo Omodei1, Paolo Tentorio1, Pedro Castro1, Pedro M. Rodrigues1, Aaron Blandino Ortiz1, Rafael de Cid1, Ricard Ferrer1, Roberta Gualtierotti1, Rosa Nieto1, Siegfried Goerg1, Salvatore Badalamenti1, Sara Marsal1, Giuseppe Matullo1, Serena Pelusi1, Simonas Juzenas1, Stefano Aliberti1, Valter Monzani1, Victor Moreno1, Tanja Wesse1, Tobias L. Lenz1, Tomás Pumarola1, Valeria Rimoldi1, Silvano Bosari1, Wolfgang Albrecht1, Wolfgang Peter1, Manuel Romero-Gómez1, Mauro D'Amato1, Stefano Duga1, Jesus M. Banales1, Johannes R. Hov1, Trine Folseraas1, Luca Valenti1, Andre Franke1, Tom H. Karlsen1 
TL;DR: A 3p21.31 gene cluster is identified as a genetic susceptibility locus in patients with Covid-19 with respiratory failure and a potential involvement of the ABO blood-group system is confirmed.
Abstract: Background There is considerable variation in disease behavior among patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (Covid-19) Genomewide association analysis may allow for the identification of potential genetic factors involved in the development of Covid-19 Methods We conducted a genomewide association study involving 1980 patients with Covid-19 and severe disease (defined as respiratory failure) at seven hospitals in the Italian and Spanish epicenters of the SARS-CoV-2 pandemic in Europe After quality control and the exclusion of population outliers, 835 patients and 1255 control participants from Italy and 775 patients and 950 control participants from Spain were included in the final analysis In total, we analyzed 8,582,968 single-nucleotide polymorphisms and conducted a meta-analysis of the two case-control panels Results We detected cross-replicating associations with rs11385942 at locus 3p2131 and with rs657152 at locus 9q342, which were significant at the genomewide level (P Conclusions We identified a 3p2131 gene cluster as a genetic susceptibility locus in patients with Covid-19 with respiratory failure and confirmed a potential involvement of the ABO blood-group system (Funded by Stein Erik Hagen and others)

1,529 citations