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  1. Article ; Online: Single-cell transcriptomics identifies pathogenic T-helper 17.1 cells and pro-inflammatory monocytes in immune checkpoint inhibitor-related pneumonitis.

    Franken, Amelie / Van Mol, Pierre / Vanmassenhove, Sam / Donders, Elena / Schepers, Rogier / Van Brussel, Thomas / Dooms, Christophe / Yserbyt, Jonas / De Crem, Nico / Testelmans, Dries / De Wever, Walter / Nackaerts, Kristiaan / Vansteenkiste, Johan / Vos, Robin / Humblet-Baron, Stéphanie / Lambrechts, Diether / Wauters, Els

    Journal for immunotherapy of cancer

    2022  Volume 10, Issue 9

    Abstract: Background: Immune checkpoint inhibitor (ICI)-related pneumonitis is the most frequent fatal immune-related adverse event associated with programmed cell death protein-1/programmed death ligand-1 blockade. The pathophysiology however remains largely ... ...

    Abstract Background: Immune checkpoint inhibitor (ICI)-related pneumonitis is the most frequent fatal immune-related adverse event associated with programmed cell death protein-1/programmed death ligand-1 blockade. The pathophysiology however remains largely unknown, owing to limited and contradictory findings in existing literature pointing at either T-helper 1 or T-helper 17-mediated autoimmunity. In this study, we aimed to gain novel insights into the mechanisms of ICI-related pneumonitis, thereby identifying potential therapeutic targets.
    Methods: In this prospective observational study, single-cell RNA and T-cell receptor sequencing was performed on bronchoalveolar lavage fluid of 11 patients with ICI-related pneumonitis and 6 demographically-matched patients with cancer without ICI-related pneumonitis. Single-cell transcriptomic immunophenotyping and cell fate mapping coupled to T-cell receptor repertoire analyses were performed.
    Results: We observed enrichment of both CD4+ and CD8+ T cells in ICI-pneumonitis bronchoalveolar lavage fluid. The CD4+ T-cell compartment showed an increase of pathogenic T-helper 17.1 cells, characterized by high co-expression of
    Conclusions: Using single-cell transcriptomics, we identified accumulation of pathogenic T-helper 17.1 cells in ICI-pneumonitis bronchoalveolar lavage fluid-a phenotype explaining previous divergent findings on T-helper 1 versus T-helper 17 involvement in ICI-pneumonitis-,putatively engaging in detrimental crosstalk with pro-inflammatory 'M1-like' monocytes. This finding yields several novel potential therapeutic targets for the treatment of ICI-pneumonitis. Most notably repurposing anti-IL-23 merits further research as a potential efficacious and safe treatment for ICI-pneumonitis.
    MeSH term(s) Anti-Inflammatory Agents ; Apoptosis Regulatory Proteins ; Granulocyte-Macrophage Colony-Stimulating Factor ; Humans ; Immune Checkpoint Inhibitors/adverse effects ; Interleukin-17 ; Interleukin-6 ; Monocytes ; Nuclear Receptor Subfamily 1, Group F, Member 3 ; Pneumonia ; RNA ; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor ; Transcriptome
    Chemical Substances Anti-Inflammatory Agents ; Apoptosis Regulatory Proteins ; Immune Checkpoint Inhibitors ; Interleukin-17 ; Interleukin-6 ; Nuclear Receptor Subfamily 1, Group F, Member 3 ; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor ; RNA (63231-63-0) ; Granulocyte-Macrophage Colony-Stimulating Factor (83869-56-1)
    Language English
    Publishing date 2022-09-28
    Publishing country England
    Document type Journal Article ; Observational Study ; Research Support, Non-U.S. Gov't
    ZDB-ID 2719863-7
    ISSN 2051-1426 ; 2051-1426
    ISSN (online) 2051-1426
    ISSN 2051-1426
    DOI 10.1136/jitc-2022-005323
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Lower respiratory tract single-cell RNA sequencing and neutrophil extracellular trap profiling of COVID-19-associated pulmonary aspergillosis: a single centre, retrospective, observational study.

    Feys, Simon / Vanmassenhove, Sam / Kraisin, Sirima / Yu, Karen / Jacobs, Cato / Boeckx, Bram / Cambier, Seppe / Cunha, Cristina / Debaveye, Yves / Gonçalves, Samuel M / Hermans, Greet / Humblet-Baron, Stephanie / Jansen, Sander / Lagrou, Katrien / Meersseman, Philippe / Neyts, Johan / Peetermans, Marijke / Rocha-Pereira, Joana / Schepers, Rogier /
    Spalart, Valérie / Starick, Marick R / Thevissen, Karin / Van Brussel, Thomas / Van Buyten, Tina / Van Mol, Pierre / Vandenbriele, Christophe / Vanderbeke, Lore / Wauters, Els / Wilmer, Alexander / Van Weyenbergh, Johan / Van De Veerdonk, Frank L / Carvalho, Agostinho / Proost, Paul / Martinod, Kimberly / Lambrechts, Diether / Wauters, Joost

    The Lancet. Microbe

    2024  Volume 5, Issue 3, Page(s) e247–e260

    Abstract: Background: COVID-19-associated pulmonary aspergillosis (CAPA) is a severe superinfection with the fungus Aspergillus affecting patients who are critically ill with COVID-19. The pathophysiology and the role of neutrophil extracellular traps (NETs) in ... ...

    Abstract Background: COVID-19-associated pulmonary aspergillosis (CAPA) is a severe superinfection with the fungus Aspergillus affecting patients who are critically ill with COVID-19. The pathophysiology and the role of neutrophil extracellular traps (NETs) in this infection are largely unknown. We aimed to characterise the immune profile, with a focus on neutrophils and NET concentrations, of critically ill patients with COVID-19, with or without CAPA.
    Methods: We conducted a single-centre, retrospective, observational study in two patient cohorts, both recruited at University Hospitals Leuven, Belgium. We included adults aged 18 years or older who were admitted to the intensive care unit because of COVID-19 between March 31, 2020, and May 18, 2021, and who were included in the previous Contagious trial (NCT04327570). We investigated the immune cellular landscape of CAPA versus COVID-19 only by performing single-cell RNA sequencing (scRNA-seq) on bronchoalveolar lavage fluid. Bronchoalveolar lavage immune cell fractions were compared between patients with CAPA and patients with COVID-19 only. Additionally, we determined lower respiratory tract NET concentrations using biochemical assays in patients aged 18 years and older who were admitted to the intensive care unit because of severe COVID-19 between March 15, 2020, and Dec 31, 2021, for whom bronchoalveolar lavage was available in the hospital biobank. Bronchoalveolar lavage NET concentrations were compared between patients with CAPA and patients with COVID-19 only and integrated with existing data on immune mediators in bronchoalveolar lavage and 90-day mortality.
    Findings: We performed scRNA-seq of bronchoalveolar lavage on 43 samples from 39 patients, of whom 36 patients (30 male and six female; 14 with CAPA) were included in downstream analyses. We performed bronchoalveolar lavage NET analyses in 59 patients (46 male and 13 female), of whom 26 had CAPA. By scRNA-seq, patients with CAPA had significantly lower neutrophil fractions than patients with COVID-19 only (16% vs 33%; p=0·0020). The remaining neutrophils in patients with CAPA preferentially followed a hybrid maturation trajectory characterised by expression of genes linked to antigen presentation, with enhanced transcription of antifungal effector pathways. Patients with CAPA also showed depletion of mucosal-associated invariant T cells, reduced T helper 1 and T helper 17 differentiation, and transcriptional defects in specific aspects of antifungal immunity in macrophages and monocytes. We observed increased formation of NETs in patients with CAPA compared with patients with COVID-19 only (DNA complexed with citrullinated histone H3 median 15 898 ng/mL [IQR 4588-86 419] vs 7062 ng/mL [775-14 088]; p=0·042), thereby explaining decreased neutrophil fractions by scRNA-seq. Low bronchoalveolar lavage NET concentrations were associated with increased 90-day mortality in patients with CAPA.
    Interpretation: Qualitative and quantitative disturbances in monocyte, macrophage, B-cell, and T-cell populations could predispose patients with severe COVID-19 to develop CAPA. Hybrid neutrophils form a specialised response to CAPA, and an adequate neutrophil response to CAPA is a major determinant for survival in these patients. Therefore, measuring bronchoalveolar lavage NETs could have diagnostic and prognostic value in patients with CAPA. Clinicians should be wary of aspergillosis when using immunomodulatory therapy that might inhibit NETosis to treat patients with severe COVID-19.
    Funding: Research Foundation Flanders, KU Leuven, UZ Leuven, VIB, the Fundação para a Ciência e a Tecnologia, the European Regional Development Fund, la Caixa Foundation, the Flemish Government, and Horizon 2020.
    MeSH term(s) Adult ; Humans ; Female ; Male ; Extracellular Traps ; Retrospective Studies ; Antifungal Agents ; Critical Illness ; COVID-19/complications ; Pulmonary Aspergillosis ; Respiratory System ; Sequence Analysis, RNA
    Chemical Substances Antifungal Agents
    Language English
    Publishing date 2024-01-24
    Publishing country England
    Document type Observational Study ; Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 2666-5247
    ISSN (online) 2666-5247
    DOI 10.1016/S2666-5247(23)00368-3
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Lung epithelial and myeloid innate immunity in influenza-associated or COVID-19-associated pulmonary aspergillosis: an observational study.

    Feys, Simon / Gonçalves, Samuel M / Khan, Mona / Choi, Sumin / Boeckx, Bram / Chatelain, Denis / Cunha, Cristina / Debaveye, Yves / Hermans, Greet / Hertoghs, Marjan / Humblet-Baron, Stephanie / Jacobs, Cato / Lagrou, Katrien / Marcelis, Lukas / Maizel, Julien / Meersseman, Philippe / Nyga, Rémy / Seldeslachts, Laura / Starick, Marick Rodrigues /
    Thevissen, Karin / Vandenbriele, Christophe / Vanderbeke, Lore / Vande Velde, Greetje / Van Regenmortel, Niels / Vanstapel, Arno / Vanmassenhove, Sam / Wilmer, Alexander / Van De Veerdonk, Frank L / De Hertogh, Gert / Mombaerts, Peter / Lambrechts, Diether / Carvalho, Agostinho / Van Weyenbergh, Johan / Wauters, Joost

    The Lancet. Respiratory medicine

    2022  Volume 10, Issue 12, Page(s) 1147–1159

    Abstract: Background: Influenza-associated pulmonary aspergillosis (IAPA) and COVID-19-associated pulmonary aspergillosis (CAPA) affect about 15% of critically ill patients with influenza or COVID-19, respectively. These viral-fungal coinfections are difficult to ...

    Abstract Background: Influenza-associated pulmonary aspergillosis (IAPA) and COVID-19-associated pulmonary aspergillosis (CAPA) affect about 15% of critically ill patients with influenza or COVID-19, respectively. These viral-fungal coinfections are difficult to diagnose and are associated with increased mortality, but data on their pathophysiology are scarce. We aimed to explore the role of lung epithelial and myeloid innate immunity in patients with IAPA or CAPA.
    Methods: In this observational study, we retrospectively recruited patients who had been admitted to the intensive care unit (ICU) of University Hospitals Leuven, Belgium, requiring non-invasive or invasive ventilation because of severe influenza or COVID-19, with or without aspergillosis, between Jan 1, 2011, and March 31, 2021, whose bronchoalveolar lavage samples were available at the hospital biobank. Additionally, biobanked in vivo tracheobronchial biopsy samples from patients with IAPA or CAPA and invasive Aspergillus tracheobronchitis admitted to ICUs requiring invasive ventilation between the same dates were collected from University Hospitals Leuven, Hospital Network Antwerp (Belgium), and Amiens-Picardie University Hospital (France). We did nCounter gene expression analysis of 755 genes linked to myeloid innate immunity and protein analysis of 47 cytokines, chemokines, and growth factors on the bronchoalveolar lavage samples. Gene expression data were used to infer cell fractions by use of CIBERSORTx, to perform hypergeometric enrichment pathway analysis and gene set enrichment analysis, and to calculate pathway module scores for the IL-1β, TNF-α, type I IFN, and type II IFN (IFNγ) pathways. We did RNAScope targeting influenza virus or SARS-CoV-2 RNA and GeoMx spatial transcriptomics on the tracheobronchial biopsy samples.
    Findings: Biobanked bronchoalveolar lavage samples were retrieved from 166 eligible patients, of whom 40 had IAPA, 52 had influenza without aspergillosis, 33 had CAPA, and 41 had COVID-19 without aspergillosis. We did nCounter gene expression analysis on bronchoalveolar lavage samples from 134 patients, protein analysis on samples from 162 patients, and both types of analysis on samples from 130 patients. We performed RNAScope and spatial transcriptomics on the tracheobronchial biopsy samples from two patients with IAPA plus invasive Aspergillus tracheobronchitis and two patients with CAPA plus invasive Aspergillus tracheobronchitis. We observed a downregulation of genes associated with antifungal effector functions in patients with IAPA and, to a lesser extent, in patients with CAPA. We found a downregulated expression of several genes encoding proteins with functions in the opsonisation, recognition, and killing of conidia in patients with IAPA versus influenza only and in patients with CAPA versus COVID-19 only. Several genes related to LC3-associated phagocytosis, autophagy, or both were differentially expressed. Patients with CAPA had significantly lower neutrophil cell fractions than did patients with COVID-19 only. Patients with IAPA or CAPA had downregulated IFNγ signalling compared with patients with influenza only or COVID-19 only, respectively. The concentrations of several fibrosis-related growth factors were significantly elevated in the bronchoalveolar lavage fluid from patients with IAPA versus influenza only and from patients with CAPA versus COVID-19 only. In one patient with CAPA, we visualised an active or very recent SARS-CoV-2 infection disrupting the epithelial barrier, facilitating tissue-invasive aspergillosis.
    Interpretation: Our results reveal a three-level breach in antifungal immunity in IAPA and CAPA, affecting the integrity of the epithelial barrier, the capacity to phagocytise and kill Aspergillus spores, and the ability to destroy Aspergillus hyphae, which is mainly mediated by neutrophils. The potential of adjuvant IFNγ in the treatment of IAPA and CAPA should be investigated.
    Funding: Research Foundation Flanders, Coronafonds, the Max Planck Society, the Fundação para a Ciência e a Tecnologia, the European Regional Development Fund, "la Caixa" Foundation, and Horizon 2020.
    MeSH term(s) Humans ; COVID-19/complications ; Influenza, Human/complications ; Influenza, Human/drug therapy ; SARS-CoV-2 ; Antifungal Agents/therapeutic use ; Retrospective Studies ; RNA, Viral ; Pulmonary Aspergillosis/complications ; Lung/pathology ; Aspergillosis ; Immunity, Innate ; Invasive Pulmonary Aspergillosis/complications
    Chemical Substances Antifungal Agents ; RNA, Viral
    Language English
    Publishing date 2022-08-24
    Publishing country England
    Document type Observational Study ; Journal Article
    ZDB-ID 2686754-0
    ISSN 2213-2619 ; 2213-2600
    ISSN (online) 2213-2619
    ISSN 2213-2600
    DOI 10.1016/S2213-2600(22)00259-4
    Database MEDical Literature Analysis and Retrieval System OnLINE

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