Citations 2
Immune checkpoint dysregulation in COVID-19 pathogenesis and disease severity.
Villalba, Julian A. , Shih, Angela , Alba, George A. , Loyola-Rodríguez, Georgina, Alcántara, Ismael Ramírez, Ferreira, Luíz Carlos de Lima , Stigliano, Egidio, Hirschbühl, Klaus , Argueta, Allan , Ackermann, Maximillian , Werlein, Christopher , Uribe‐Uribe, Norma , Vázquez-Benítez, Greissy, Tzankov, Alexandar , Stalder, Anna K. , Francesqui, Joel , Osborn, Michael , Hanley, Brian , Johnston, Robert, Lacy, J. Matthew , Marshall, Desiree A. , Schwensen, Hanna Ferløv , Okudela, Koji , Flikweert, Antine, Iles, Linda , d’Amati, Giulia , Träger, Lene Hoffmann , Çınar, Hüseyin, Aguiar, Diego , Dolhnokoff, Marisa, Chilosi, Marco , Salmon, I, Colville‐Ebeling, Bonnie, Poissy, Julien , Haahr, Martha Kirstine , Reyes, Fabiola, Parry, Blair A. , Garlin, Michelle, Hilburn, Caroline F., ELLIOTT, G. A., Rosas, Iván O. , Sade-Feldman, Moshe , Hacohen, Nir , Baden, Lindsey R. , Li, Jonathan Z. , Schaller, Tina , Gigli, L, Macciò, Umberto , Yick, David C.Y., Bruni, Barbara, Pernazza, Angelina , Mauad, Thaís , Dubini, Alessandra, Hartmann, Arndt, Remmelink, Myriam , Aviles, Alexis J., Barth, Jamie L., Boyraz, Bariş , Araujo-Medina, Milagros, Mendez-Pena, Javier E., Chebib, Ivan , Hung, Yin P. , Rosales, Ivy A. , Smith, Rex-Neal, Hung, Yin P , Tzankov, Alexandar , Li, Yijia , Poli, Sergio , Kunitoki, Keiko , Mehta, Arnav , Santana, Monique Freire , Lacerda, Marcus , Dell’Aquila, Marco , Arena, Vincenzo , Calabrese, Fiorella , Pezzuto, Federica , Märkl, Bruno , Lozano, Maria, Jonigk, Danny David , Pomara, Cristoforo , Salerno, Monica , Salas, Clara , Martínez, Daniel, Parra-Medina, Rafael Santiago , Bradley, Benjamin T. , Chen, Sonja , Varga, Zsuzsanna , Steinestel, Konrad , Harper, Holly , Aiolfi, Alberto , Scendoni, Roberto , Fabro, Alexandre Todorovic , Doglioni, Claudio , Rossi, Giulio , Poletti, Venerino , Herrmann, Martin , Pugh, Matthew , Yan, Lei , Gentili, Matteo , Garlin, Michelle A., Lo, Ying‐Chun , Elliott, Grant, Martínez, Leonardo , Stone, James R. , Colvin, Robert B. , Goldberg, Marcia B. , Filbin, Michael R. , Mino-Kenudson, Mari A. , Kröncke, Thomas J. , Gigli, Laura Álvarez, Sessa, Francesco , Caltabiano, Rosario , Menter, Thomas , Sellarés, Jacobo , Storgaard, Merete , Hamilton‐Dutoit, Stephen , Dannheim, Katelyn , Witte, Hanno Maximilian , Bona, Davide , Leth, Peter Mygind , Banner, Jytte , Batah, Sabrina Setembre , Silva, Luiz Fernando Ferraz da , Duarte‐Neto, Amaro Nunes , Saldiva, Paulo Hilário Nascimento , Munoz, Luis Enrique , Jensen, T. , Brøchner, Christian Beltoft , Gibier, Jean‐Baptiste , Gilbert, Andrea , Madrigal, Emilio , Ly, Amy , Hariri, Lida P. , Caldwell, Nicholas J
No container title available | October 2, 2024 | Volume: No volume available | Issue: No issue available | Pages: No page available
Abstract Accumulating evidence suggests dysregulated immune checkpoint (IC) signaling can exacerbate COVID-19 severity, but the role of these molecules in the pathogenesis of fatal COVID-19-related diffuse alveolar damage (DAD) remains elusive. Understanding how IC proteins influence acute lung injury due to COVID-19 can provide insights into potential therapeutic strategies to modulate immune responses and improve patient outcomes. Here, in a single-center autopsy cohort, we determined the cellular localization of ICs in lung tissue from cases of fatal COVID-19, DAD-comparators, and non-fibrotic controls by using immunohistochemistry, and investigated their association with clinical outcomes. We expanded our findings by performing analyses of publicly available single-cell RNA sequencing datasets from patients with fatal COVID-19 and non-fibrotic controls. We demonstrated the presence of protein-protein interaction networks of ICs in the lung cellular niche by performing transcriptomic profiling of lung tissue-derived RNA counts from patients with fatal COVID-19. Further, we leveraged data from the largest international, multi-center COVID-19 autopsy cohort and validated that, among patients with fatal COVID-19, those with higher PD-L1/CD274 expression in lung endothelial cells had more rapid clinical deterioration. Lastly, in a cohort of individuals with early COVID-19, IC plasma protein levels were elevated in those with persistent SARS-CoV-2 RNAemia and adverse clinical outcomes. Collectively, our data provide unique pathological insights into the role of IC dysregulation and differential disease severity in COVID-19.
Vasculopathy and Increased Vascular Congestion in Fatal COVID-19 and Acute Respiratory Distress Syndrome
Villalba, Julian A. , Hilburn, Caroline F., Garlin, Michelle A., Elliott, Grant A., Li, Yijia , Kunitoki, Keiko , Poli, Sergio , Alba, George A. , Taso, Manuel , Price, Melissa C. , Aviles, Alexis J., Araujo-Medina, Milagros, Bonanno, Liana, Boyraz, Bariş , Champion, Samantha N. , Harris, Cynthia K. , Helland, T. Leif , Hutchison, Bailey , Jobbagy, Soma , Shepherd, Daniel , Barth, Jaimie L., Hung, Yin P. , Ly, Amy , Turbett, Sarah E. , Pierce, Virginia , Branda, John A. , Rosenberg, Eric , Mendez-Pena, Javier E., Chebib, Ivan , Rosales, Ivy A. , Smith, R. Neal , Miller, Miles A. , Rosas, Iván O. , Hardin, C. Corey , Baden, Lindsey R. , Stone, James R. , Shih, Angela , Politis, Michelle Garlin , Little, Brent P. , Hung, Yin P , Miller, Miles A , Garlin Politis, Michelle , Madrigal, Emilio , Marshall, Michael S. , Hariri, Lida P. , Medoff, Benjamin D. , Colvin, Robert B. , Mino-Kenudson, Mari A. , Shih, Angela
American Journal of Respiratory and Critical Care Medicine | June 7, 2022 | Volume: 206 | Issue: 7 | Pages: 857-873
Abstract Rationale The leading cause of death in coronavirus disease 2019 (COVID-19) is severe pneumonia, with many patients developing acute respiratory distress syndrome (ARDS) and diffuse alveolar damage (DAD). Whether DAD in fatal COVID-19 is distinct from other causes of DAD remains unknown. Objective To compare lung parenchymal and vascular alterations between patients with fatal COVID-19 pneumonia and other DAD-causing etiologies using a multidimensional approach. Methods This autopsy cohort consisted of consecutive patients with COVID-19 pneumonia (n = 20) and with respiratory failure and histologic DAD (n = 21; non–COVID-19 viral and nonviral etiologies). Premortem chest computed tomography (CT) scans were evaluated for vascular changes. Postmortem lung tissues were compared using histopathological and computational analyses. Machine-learning-derived morphometric analysis of the microvasculature was performed, with a random forest classifier quantifying vascular congestion (CVasc) in different microscopic compartments. Respiratory mechanics and gas-exchange parameters were evaluated longitudinally in patients with ARDS. Measurements and Main Results In premortem CT, patients with COVID-19 showed more dilated vasculature when all lung segments were evaluated (P = 0.001) compared with controls with DAD. Histopathology revealed vasculopathic changes, including hemangiomatosis-like changes (P = 0.043), thromboemboli (P = 0.0038), pulmonary infarcts (P = 0.047), and perivascular inflammation (P < 0.001). Generalized estimating equations revealed significant regional differences in the lung microarchitecture among all DAD-causing entities. COVID-19 showed a larger overall CVasc range (P = 0.002). Alveolar-septal congestion was associated with a significantly shorter time to death from symptom onset (P = 0.03), length of hospital stay (P = 0.02), and increased ventilatory ratio [an estimate for pulmonary dead space fraction (Vd); p = 0.043] in all cases of ARDS. Conclusions Severe COVID-19 pneumonia is characterized by significant vasculopathy and aberrant alveolar-septal congestion. Our findings also highlight the role that vascular alterations may play in Vd and clinical outcomes in ARDS in general.