{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T14:01:51Z","timestamp":1760623311274,"version":"build-2065373602"},"reference-count":35,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2023,9,8]],"date-time":"2023-09-08T00:00:00Z","timestamp":1694131200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Royal Free Charity","award":["Trust Fund 35"],"award-info":[{"award-number":["Trust Fund 35"]}]},{"name":"Boehringer Ingelheim","award":["Trust Fund 35"],"award-info":[{"award-number":["Trust Fund 35"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Acute lung injury in COVID-19 results in diffuse alveolar damage with disruption of the alveolar-capillary barrier, coagulation activation, alveolar fibrin deposition and pulmonary capillary thrombi. Nebulized recombinant tissue plasminogen activator (rt-PA) has the potential to facilitate localized thrombolysis in the alveolar compartment and improve oxygenation. In this proof-of-concept safety study, adults with COVID-19-induced respiratory failure and a &lt;300 mmHg PaO2\/FiO2 (P\/F) ratio requiring invasive mechanical ventilation (IMV) or non-invasive respiratory support (NIRS) received nebulized rt-PA in two cohorts (C1 and C2), alongside standard of care, between 23 April\u201330 July 2020 and 21 January\u201319 February 2021, respectively. Matched historical controls (MHC; n = 18) were used in C1 to explore efficacy. Safety co-primary endpoints were treatment-related bleeds and &lt;1.0\u20131.5 g\/L fibrinogen reduction. A variable dosing strategy with clinical efficacy endpoint and minimal safety concerns was determined in C1 for use in C2; patients were stratified by ventilation type to receive 40\u201360 mg rt-PA daily for \u226414 days. Nine patients in C1 (IMV, 6\/9; NIRS, 3\/9) and 26 in C2 (IMV, 12\/26; NIRS, 14\/26) received nebulized rt-PA for a mean (SD) of 6.7 (4.6) and 9.1(4.6) days, respectively. Four bleeds (one severe, three mild) in three patients were considered treatment related. There were no significant fibrinogen reductions. Greater improvements in mean P\/F ratio from baseline to study end were observed in C1 compared with MHC (C1; 154 to 299 vs. MHC; 154 to 212). In C2, there was no difference in the baseline P\/F ratio of NIRS and IMV patients. However, a larger improvement in the P\/F ratio occurred in NIRS patients (NIRS; 126 to 240 vs. IMV; 120 to 188) and fewer treatment days were required (NIRS; 7.86 vs. IMV; 10.5). Nebulized rt-PA appears to be well-tolerated, with a trend towards improved oxygenation, particularly in the NIRS group. Randomized clinical trials are required to demonstrate the clinical effect significance and magnitude.<\/jats:p>","DOI":"10.3390\/jcm12185848","type":"journal-article","created":{"date-parts":[[2023,9,8]],"date-time":"2023-09-08T07:57:17Z","timestamp":1694159837000},"page":"5848","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Nebulized Recombinant Tissue Plasminogen Activator (rt-PA) for Acute COVID-19-Induced Respiratory Failure: An Exploratory Proof-of-Concept Trial"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6690-8586","authenticated-orcid":false,"given":"Pratima","family":"Chowdary","sequence":"first","affiliation":[{"name":"Katharine Dormandy Haemophilia and Thrombosis Centre, Royal Free London NHS Foundation Trust, London NW3 2QG, UK"},{"name":"Cancer Institute, University College London, London WC1E 6DD, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5508-2590","authenticated-orcid":false,"given":"Banwari","family":"Agarwal","sequence":"additional","affiliation":[{"name":"Department of Intensive Care and Anaesthesia, Royal Free London NHS Foundation Trust, London NW3 2QG, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Rita","family":"Peralta","sequence":"additional","affiliation":[{"name":"Katharine Dormandy Haemophilia and Thrombosis Centre, Royal Free London NHS Foundation Trust, London NW3 2QG, UK"},{"name":"Cancer Institute, University College London, London WC1E 6DD, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sanjay","family":"Bhagani","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Royal Free London NHS Foundation Trust, London NW3 2QG, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simon","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Royal Free London NHS Foundation Trust, London NW3 2QG, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James","family":"Goldring","sequence":"additional","affiliation":[{"name":"Respiratory Medicine, Royal Free London NHS Foundation Trust, London NW1 2BU, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marc","family":"Lipman","sequence":"additional","affiliation":[{"name":"Respiratory Medicine, Royal Free London NHS Foundation Trust, London NW1 2BU, UK"},{"name":"UCL Respiratory, University College London, London WC1E 6JF, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emal","family":"Waqif","sequence":"additional","affiliation":[{"name":"Katharine Dormandy Haemophilia and Thrombosis Centre, Royal Free London NHS Foundation Trust, London NW3 2QG, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark","family":"Phillips","sequence":"additional","affiliation":[{"name":"Katharine Dormandy Haemophilia and Thrombosis Centre, Royal Free London NHS Foundation Trust, London NW3 2QG, UK"},{"name":"Cancer Institute, University College London, London WC1E 6DD, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Helen","family":"Philippou","sequence":"additional","affiliation":[{"name":"Discovery and Translational Science Department, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds LS2 9JT, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan H.","family":"Foley","sequence":"additional","affiliation":[{"name":"Freeline Therapeutics, London SG1 2BP, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7452-0813","authenticated-orcid":false,"given":"Nicola J.","family":"Mutch","sequence":"additional","affiliation":[{"name":"Aberdeen Cardiovascular & Diabetes Centre, School of Medicine, Medical Sciences & Nutrition, Institute of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert A. S.","family":"Ari\u00ebns","sequence":"additional","affiliation":[{"name":"Discovery and Translational Science Department, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds LS2 9JT, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0238-7774","authenticated-orcid":false,"given":"Kathleen A.","family":"Stringer","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, College of Pharmacy University of Michigan, Ann Arbor, MI 48109, USA"},{"name":"Division of Pulmonary and Critical Care Medicine, School of Medicine, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Federico","family":"Ricciardi","sequence":"additional","affiliation":[{"name":"Department of Statistical Science, University College London, London WC1E 6BT, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marie","family":"Watiss\u00e9e","sequence":"additional","affiliation":[{"name":"WStats Limited, Winchester SO23 8GH, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Derralynn","family":"Hughes","sequence":"additional","affiliation":[{"name":"Cancer Institute, University College London, London WC1E 6DD, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amit","family":"Nathwani","sequence":"additional","affiliation":[{"name":"Katharine Dormandy Haemophilia and Thrombosis Centre, Royal Free London NHS Foundation Trust, London NW3 2QG, UK"},{"name":"Cancer Institute, University College London, London WC1E 6DD, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anne","family":"Riddell","sequence":"additional","affiliation":[{"name":"Katharine Dormandy Haemophilia and Thrombosis Centre, Royal Free London NHS Foundation Trust, London NW3 2QG, UK"},{"name":"Haemophilia & Thrombosis Laboratory (Health Services Laboratories), Royal Free Hospital, London WC1H 9AX, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Patch","sequence":"additional","affiliation":[{"name":"Department of Hepatology, Royal Free London NHS Foundation Trust, London NW3 2QG, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jim","family":"Buckley","sequence":"additional","affiliation":[{"name":"Department of Intensive Care and Anaesthesia, Royal Free London NHS Foundation Trust, London NW3 2QG, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark","family":"De Neef","sequence":"additional","affiliation":[{"name":"Department of Intensive Care and Anaesthesia, Royal Free London NHS Foundation Trust, London NW3 2QG, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4207-3411","authenticated-orcid":false,"given":"Rahul","family":"Dimber","sequence":"additional","affiliation":[{"name":"Department of Intensive Care and Anaesthesia, Royal Free London NHS Foundation Trust, London NW3 2QG, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cecilia","family":"Diaz-Garcia","sequence":"additional","affiliation":[{"name":"Katharine Dormandy Haemophilia and Thrombosis Centre, Royal Free London NHS Foundation Trust, London NW3 2QG, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Honey","family":"Patel","sequence":"additional","affiliation":[{"name":"Katharine Dormandy Haemophilia and Thrombosis Centre, Royal Free London NHS Foundation Trust, London NW3 2QG, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aarti","family":"Nandani","sequence":"additional","affiliation":[{"name":"Clinical Trials Pharmacy, Royal Free London NHS Foundation Trust, London NW3 2QG, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Upuli","family":"Dissanayake","sequence":"additional","affiliation":[{"name":"Katharine Dormandy Haemophilia and Thrombosis Centre, Royal Free London NHS Foundation Trust, London NW3 2QG, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nick","family":"Chadwick","sequence":"additional","affiliation":[{"name":"Katharine Dormandy Haemophilia and Thrombosis Centre, Royal Free London NHS Foundation Trust, London NW3 2QG, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ahmed A. 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