Journal Article Randomized Controlled Trial Epublish
PubMed: 40559541 DOI: 10.3390/pathogens14060533
Pathophysiology of COVID-19: A Post Hoc Analysis of the ICAT-COVID Clinical Trial of the Bradykinin Antagonist Icatibant.
Pathogens 14(6)
Authors: Pierre Malchair, Jordi Giol, Javier Jacob, Jesús Villoria, Thiago Carnaval, Sebastián Videla
Affiliations
- Emergency Department, Bellvitge University Hospital, University of Barcelona, Carrer de la Feixa Llarga, s/n, L'Hospitalet de Llobregat, 08907 Barcelona, Spain.
- Design and Biometrics Department, Medicxact, Plaza Ermita 4, Alpedrete, 28430 Madrid, Spain.
- Neuropharmacology & Pain Group, Neuroscience Program, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet de Llobregat, 08907 Barcelona, Spain.
- Clinical Research Support Area, Clinical Pharmacology Department, Germans Trias i Pujol University Hospital, Carretera de Canyet, s/n, Badalona, 08916 Barcelona, Spain.
- Fight Infectious Diseases Foundation, Badalona, 08916 Barcelona, Spain.
Abstract
We used the data from a successful therapeutic assay that used icatibant in patients with hypoxemic COVID-19 pneumonia (the ICAT·COVID trial) to explore pathophysiological mechanisms. We performed concurrent-type, criterion-related validity analyses to assess the discriminative ability of a panel of nine potential serum markers (interleukin 6, ferritin, lactate dehydrogenase, C reactive protein, fibrin fragment D (D-dimer), complement 1 esterase inhibitor (antigenic and functional), complement 4 factor, and lymphocyte count) to predict the clinical milestones. Consistent with previous research, we evidenced a significant relationship between interleukin 6, lactate dehydrogenase and the lymphocyte count, and the clinical events. Furthermore, exposure to icatibant, a bradykinin B2 receptor antagonist (which improved pneumonia and mortality in the aforementioned randomised trial), attenuated this relationship, although this effect faded over time. The results reinforce the key role that the angiotensin-converting enzyme 2 has on COVID-19 pathophysiology as a point of convergence between the renin-angiotensin and kallikrein-kinin systems. This was shown clinically by the successful blocking of inflammatory pathways by icatibant at the bradykinin effector loop level early during the acute hyperinflammatory stage of the disease.
MeSH
Lymphocyte Count, Oxidoreductases, Lymphocytes, Interleukin-6, Kinins, Bradykinin Receptor Antagonists, Angiotensins, Covid-19, Pneumonia, Bradykinin, Coronavirus Infections, Pandemics, Complement System Proteins, L-Lactate Dehydrogenase