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1. Longitudinal multicompartment characterization of host-microbiota interactions in patients with acute respiratory failure

Author

Georgios D. Kitsios, Khaled Sayed, Adam Fitch, Haopu Yang, Noel Britton, Faraaz Shah, William Bain, John W. Evankovich, Shulin Qin, Xiaohong Wang, Kelvin Li, Asha Patel, Yingze Zhang, Josiah Radder, Charles Dela Cruz, Daniel A. Okin, Ching‐Ying Huang, Daria Van Tyne, Panayiotis V. Benos, Barbara Methé, Peggy Lai, Alison Morris, and Bryan J. McVerry

Subjects
Science
Abstract

Abstract Critical illness can significantly alter the composition and function of the human microbiome, but few studies have examined these changes over time. Here, we conduct a comprehensive analysis of the oral, lung, and gut microbiota in 479 mechanically ventilated patients (223 females, 256 males) with acute respiratory failure. We use advanced DNA sequencing technologies, including Illumina amplicon sequencing (utilizing 16S and ITS rRNA genes for bacteria and fungi, respectively, in all sample types) and Nanopore metagenomics for lung microbiota. Our results reveal a progressive dysbiosis in all three body compartments, characterized by a reduction in microbial diversity, a decrease in beneficial anaerobes, and an increase in pathogens. We find that clinical factors, such as chronic obstructive pulmonary disease, immunosuppression, and antibiotic exposure, are associated with specific patterns of dysbiosis. Interestingly, unsupervised clustering of lung microbiota diversity and composition by 16S independently predicted survival and performed better than traditional clinical and host-response predictors. These observations are validated in two separate cohorts of COVID-19 patients, highlighting the potential of lung microbiota as valuable prognostic biomarkers in critical care. Understanding these microbiome changes during critical illness points to new opportunities for microbiota-targeted precision medicine interventions.

Published
2024
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2. MicroRNA-1 protects the endothelium in acute lung injury

Author

Asawari Korde, Maria Haslip, Prachi Pednekar, Alamzeb Khan, Maurizio Chioccioli, Sameet Mehta, Francesc Lopez-Giraldez, Santos Bermejo, Mauricio Rojas, Charles Dela Cruz, Michael A. Matthay, Jordan S. Pober, Richard W. Pierce, and Shervin S. Takyar

Subjects
Pulmonology, Vascular biology, Medicine
Abstract

Acute lung injury (ALI) and its most severe form, acute respiratory distress syndrome (ARDS), cause severe endothelial dysfunction in the lung, and vascular endothelial growth factor (VEGF) is elevated in ARDS. We found that the levels of a VEGF-regulated microRNA, microRNA-1 (miR-1), were reduced in the lung endothelium after acute injury. Pulmonary endothelial cell–specific (EC-specific) overexpression of miR-1 protected the lung against cell death and barrier dysfunction in both murine and human models and increased the survival of mice after pneumonia-induced ALI. miR-1 had an intrinsic protective effect in pulmonary and other types of ECs; it inhibited apoptosis and necroptosis pathways and decreased capillary leak by protecting adherens and tight junctions. Comparative gene expression analysis and RISC recruitment assays identified miR-1 targets in the context of injury, including phosphodiesterase 5A (PDE5A), angiopoietin-2 (ANGPT2), CNKSR family member 3 (CNKSR3), and TNF-α–induced protein 2 (TNFAIP2). We validated miR-1–mediated regulation of ANGPT2 in both mouse and human ECs and found that in a 119-patient pneumonia cohort, miR-1 correlated inversely with ANGPT2. These findings illustrate a previously unknown role of miR-1 as a cytoprotective orchestrator of endothelial responses to acute injury with prognostic and therapeutic potential.

Published
2023
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4. Beneficial and Detrimental Effects of Cytokines during Influenza and COVID-19

Author

De Chang, Charles Dela Cruz, and Lokesh Sharma

Subjects
Influenza, COVID-19, SARS-CoV-2, Cytokines, Microbiology, QR1-502
Abstract

Cytokines are signaling molecules that play a role in myriad processes, including those occurring during diseases and homeostasis. Their homeostatic function begins during embryogenesis and persists throughout life, including appropriate signaling for the cell and organism death. During viral infections, antiviral cytokines such as interferons and inflammatory cytokines are upregulated. Despite the well-known benefits of these cytokines, their levels often correlate with disease severity, linking them to unfavorable outcomes. In this review, we discuss both the beneficial and pathological functions of cytokines and the potential challenges in separating these two roles. Further, we discuss challenges in targeting these cytokines during disease and propose a new method for quantifying the cytokine effect to limit the pathological consequences while preserving their beneficial effects.

Published
2024
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5. Management of nontuberculous mycobacteria in lung transplant cases: an international Delphi study

Author

Huda Asif, Franck F. Rahaghi, Akihiro Ohsumi, Julie Philley, Amir Emtiazjoo, Takashi Hirama, Arthur W. Baker, Chin-Chung Shu, Fernanda Silveira, Vincent Poulin, Pete Rizzuto, Miki Nagao, Pierre-Régis Burgel, Steve Hays, Timothy Aksamit, Takeshi Kawasaki, Charles Dela Cruz, Stefano Aliberti, Takahiro Nakajima, Stephen Ruoss, Theodore K. Marras, Gregory I. Snell, Kevin Winthrop, and Mehdi Mirsaeidi

Subjects
Medicine
Abstract

Rationale Nontuberculous mycobacterial (NTM) diseases are difficult-to-treat infections, especially in lung transplant (LTx) candidates. Currently, there is a paucity of recommendations on the management of NTM infections in LTx, focusing on Mycobacterium avium complex (MAC), M. abscessus and M. kansasii. Methods Pulmonologists, infectious disease specialists, LTx surgeons and Delphi experts with expertise in NTM were recruited. A patient representative was also invited. Three questionnaires comprising questions with multiple response statements were distributed to panellists. Delphi methodology with a Likert scale of 11 points (5 to −5) was applied to define the agreement between experts. Responses from the first two questionnaires were collated to develop a final questionnaire. The consensus was described as a median rating >4 or

Published
2023
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6. Colchicine and high-intensity rosuvastatin in the treatment of non-critically ill patients hospitalised with COVID-19: a randomised clinical trial

Author

Jing Lu, Christopher Song, Prashant Patel, Christopher Howes, Michael Cleman, Alexandra Lansky, Tayyab Shah, Marianne McCarthy, Irem Nasir, Herb Archer, Elio Ragheb, Jonathan Kluger, Nitu Kashyap, Carlos Paredes, Prakash Kandel, Mustafa Khan, Haocheng Huang, Faheem Ul Haq, Rami Ahmad, Brian Cambi, Gilead Lancaster, Charles Dela Cruz, and Helen Parise

Subjects
Medicine
Abstract

Objective To evaluate the effect of colchicine and high-intensity rosuvastatin in addition to standard of care on the progression of COVID-19 disease in hospitalised patients.Design A pragmatic, open-label, multicentre, randomised controlled trial conducted from October 2020 to September 2021. Follow-up was conducted at 30 and 60 days. The electronic medical record was used at all stages of the trial including screening, enrolment, randomisation, event ascertainment and follow-up.Setting Four centres in the Yale New Haven Health System.Participants Non-critically ill hospitalised patients with COVID-19.Interventions Patients were randomised 1:1 to either colchicine plus high-intensity rosuvastatin in addition to standard of care versus standard of care alone. Assigned treatment was continued for the duration of index hospitalisation or 30 days, whichever was shorter.Primary and secondary outcome measures The prespecified primary endpoint was progression to severe COVID-19 disease (new high-flow or non-invasive ventilation, mechanical ventilation, need for vasopressors, renal replacement therapy or extracorporeal membrane oxygenation, or death) or arterial/venous thromboembolic events (ischaemic stroke, myocardial infarction, deep venous thrombosis or pulmonary embolism) evaluated at 30 days.Results Among the 250 patients randomised in this trial (125 to each arm), the median age was 61 years, 44% were women, 15% were Black and 26% were Hispanic/Latino. As part of the standard of care, patients received remdesivir (87%), dexamethasone (92%), tocilizumab (18%), baricitinib (2%), prophylactic/therapeutic anticoagulation (98%) and aspirin (91%). The trial was terminated early by the data and safety monitoring board for futility. No patients were lost to follow-up due to electronic medical record follow-up. There was no significant difference in the primary endpoint at 30 days between the active arm and standard of care arm (15.2% vs 8.8%, respectively, p=0.17).Conclusions In this small, open-label, randomised trial of non-critically ill hospitalised patients with COVID-19, the combination of colchicine and rosuvastatin in addition to standard of care did not appear to reduce the risk of progression of COVID-19 disease or thromboembolic events, although the trial was underpowered due to a lower-than-expected event rate. The trial leveraged the power of electronic medical records for efficiency and improved follow-up and demonstrates the utility of incorporating electronic medical records into future trials.Trial registration NCT04472611.

Published
2023
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7. Phenotypes of disease severity in a cohort of hospitalized COVID-19 patients: Results from the IMPACC study

Author

Al Ozonoff, Joanna Schaenman, Naresh Doni Jayavelu, Carly E. Milliren, Carolyn S. Calfee, Charles B. Cairns, Monica Kraft, Lindsey R. Baden, Albert C. Shaw, Florian Krammer, Harm van Bakel, Denise A. Esserman, Shanshan Liu, Ana Fernandez Sesma, Viviana Simon, David A. Hafler, Ruth R. Montgomery, Steven H. Kleinstein, Ofer Levy, Christian Bime, Elias K. Haddad, David J. Erle, Bali Pulendran, Kari C. Nadeau, Mark M. Davis, Catherine L. Hough, William B. Messer, Nelson I. Agudelo Higuita, Jordan P. Metcalf, Mark A. Atkinson, Scott C. Brakenridge, David Corry, Farrah Kheradmand, Lauren I.R. Ehrlich, Esther Melamed, Grace A. McComsey, Rafick Sekaly, Joann Diray-Arce, Bjoern Peters, Alison D. Augustine, Elaine F. Reed, Matthew C. Altman, Patrice M. Becker, Nadine Rouphael, Chris Bime, Mark M Davis, Kerry McEnaney, Brenda Barton, Claudia Lentucci, Mehmet Saluvan, Ana C. Chang, Annmarie Hoch, Marisa Albert, Tanzia Shaheen, Alvin T. Kho, Sanya Thomas, Jing Chen, Maimouna D. Murphy, Mitchell Cooney, Scott Presnell, Gabriela K. Fragiadakis, Ravi Patel, Leying Guan, Jeremy Gygi, Shrikant Pawar, Anderson Brito, Zain Khalil, Cole Maguire, Slim Fourati, James A. Overton, Randi Vita, Kerstin Westendorf, Ramin Salehi-Rad, Aleksandra Leligdowicz, Michael A. Matthay, Jonathan P. Singer, Kirsten N. Kangelaris, Carolyn M. Hendrickson, Matthew F. Krummel, Charles R. Langelier, Prescott G. Woodruff, Debra L. Powell, James N. Kim, Brent Simmons, I. Michael Goonewardene, Cecilia M. Smith, Mark Martens, Jarrod Mosier, Hiroki Kimura, Amy C. Sherman, Stephen R. Walsh, Nicolas C. Issa, Charles Dela Cruz, Shelli Farhadian, Akiko Iwasaki, Albert I. Ko, Sharon Chinthrajah, Neera Ahuja, Angela J. Rogers, Maja Artandi, Sarah A.R. Siegel, Zhengchun Lu, Douglas A. Drevets, Brent R. Brown, Matthew L. Anderson, Faheem W. Guirgis, Rama V. Thyagarajan, Justin F. Rousseau, Dennis Wylie, Johanna Busch, Saurin Gandhi, Todd A. Triplett, George Yendewa, Olivia Giddings, Evan J. Anderson, Aneesh K. Mehta, Jonathan E. Sevransky, Bernard Khor, Adeeb Rahman, Daniel Stadlbauer, Jayeeta Dutta, Hui Xie, Seunghee Kim-Schulze, Ana Silvia Gonzalez-Reiche, Adriana van de Guchte, Keith Farrugia, Zenab Khan, Holden T. Maecker, David Elashoff, Jenny Brook, Estefania Ramires-Sanchez, Megan Llamas, Adreanne Rivera, Claudia Perdomo, Dawn C. Ward, Clara E. Magyar, Jennifer A. Fulcher, Yumiko Abe-Jones, Saurabh Asthana, Alexander Beagle, Sharvari Bhide, Sidney A. Carrillo, Suzanna Chak, Rajani Ghale, Ana Gonzalez, Alejandra Jauregui, Norman Jones, Tasha Lea, Deanna Lee, Raphael Lota, Jeff Milush, Viet Nguyen, Logan Pierce, Priya A. Prasad, Arjun Rao, Bushra Samad, Cole Shaw, Austin Sigman, Pratik Sinha, Alyssa Ward, Andrew Willmore, Jenny Zhan, Sadeed Rashid, Nicklaus Rodriguez, Kevin Tang, Luz Torres Altamirano, Legna Betancourt, Cindy Curiel, Nicole Sutter, Maria Tercero Paz, Gayelan Tietje-Ulrich, Carolyn Leroux, Jennifer Connors, Mariana Bernui, Michel A. Kutzler, Carolyn Edwards, Edward Lee, Edward Lin, Brett Croen, Nicholas C. Semenza, Brandon Rogowski, Nataliya Melnyk, Kyra Woloszczuk, Gina Cusimano, Mathew R. Bell, Sara Furukawa, Renee McLin, Pamela Marrero, Julie Sheidy, George P. Tegos, Crystal Nagle, Nathan Mege, Kristen Ulring, Vicki Seyfert-Margolis, Michelle Conway, Dave Francisco, Allyson Molzahn, Heidi Erickson, Connie Cathleen Wilson, Ron Schunk, Bianca Sierra, Trina Hughes, Kinga Smolen, Michael Desjardins, Simon van Haren, Xhoi Mitre, Jessica Cauley, Xiaofang Li, Alexandra Tong, Bethany Evans, Christina Montesano, Jose Humberto Licona, Jonathan Krauss, Jun Bai Park Chang, Natalie Izaguirre, Omkar Chaudhary, Andreas Coppi, John Fournier, Subhasis Mohanty, M. Catherine Muenker, Allison Nelson, Khadir Raddassi, Michael Rainone, William E. Ruff, Syim Salahuddin, Wade L. Schulz, Pavithra Vijayakumar, Haowei Wang, Elsio Wunder Jr., H. Patrick Young, Yujiao Zhao, Miti Saksena, Deena Altman, Erna Kojic, Komal Srivastava, Lily Q. Eaker, Maria C. Bermúdez-González, Katherine F. Beach, Levy A. Sominsky, Arman R. Azad, Juan Manuel Carreño, Gagandeep Singh, Ariel Raskin, Johnstone Tcheou, Dominika Bielak, Hisaaki Kawabata, Lubbertus CF Mulder, Giulio Kleiner, Alexandra S. Lee, Evan Do Do, Andrea Fernandes, Monali Manohar, Thomas Hagan, Catherine A. Blish, Hena Naz Din, Jonasel Roque, Samuel Yang, Amanda Brunton, Peter E. Sullivan, Matthew Strnad, Zoe L. Lyski, Felicity J. Coulter, J. Leland Booth, Lauren A. Sinko, Lyle L. Moldawer, Brittany Borresen, Brittney Roth-Manning, Li-Zhen Song, Ebony Nelson, Megan Lewis-Smith, Jacob Smith, Pablo Guaman Tipan, Nadia Siles, Sam Bazzi, Janelle Geltman, Kerin Hurley, Gio Gabriele, Scott Sieg, Tatyana Vaysman, Laurel Bristow, Laila Hussaini, Kieffer Hellmeister, Hady Samaha, Andrew Cheng, Christine Spainhour, Erin M. Scherer, Brandi Johnson, Amer Bechnak, Caroline R. Ciric, Lauren Hewitt, Erin Carter, Nina Mcnair, Bernadine Panganiban, Christopher Huerta, Jacob Usher, and Susan Pereira Ribeiro

Subjects
COVID-19, SARS-CoV-2, Viral load, Antibody, Medicine, Medicine (General), R5-920
Abstract

Summary: Background: Better understanding of the association between characteristics of patients hospitalized with coronavirus disease 2019 (COVID-19) and outcome is needed to further improve upon patient management. Methods: Immunophenotyping Assessment in a COVID-19 Cohort (IMPACC) is a prospective, observational study of 1164 patients from 20 hospitals across the United States. Disease severity was assessed using a 7-point ordinal scale based on degree of respiratory illness. Patients were prospectively surveyed for 1 year after discharge for post-acute sequalae of COVID-19 (PASC) through quarterly surveys. Demographics, comorbidities, radiographic findings, clinical laboratory values, SARS-CoV-2 PCR and serology were captured over a 28-day period. Multivariable logistic regression was performed. Findings: The median age was 59 years (interquartile range [IQR] 20); 711 (61%) were men; overall mortality was 14%, and 228 (20%) required invasive mechanical ventilation. Unsupervised clustering of ordinal score over time revealed distinct disease course trajectories. Risk factors associated with prolonged hospitalization or death by day 28 included age ≥ 65 years (odds ratio [OR], 2.01; 95% CI 1.28–3.17), Hispanic ethnicity (OR, 1.71; 95% CI 1.13–2.57), elevated baseline creatinine (OR 2.80; 95% CI 1.63– 4.80) or troponin (OR 1.89; 95% 1.03–3.47), baseline lymphopenia (OR 2.19; 95% CI 1.61–2.97), presence of infiltrate by chest imaging (OR 3.16; 95% CI 1.96–5.10), and high SARS-CoV2 viral load (OR 1.53; 95% CI 1.17–2.00). Fatal cases had the lowest ratio of SARS-CoV-2 antibody to viral load levels compared to other trajectories over time (p=0.001). 589 survivors (51%) completed at least one survey at follow-up with 305 (52%) having at least one symptom consistent with PASC, most commonly dyspnea (56% among symptomatic patients). Female sex was the only associated risk factor for PASC. Interpretation: Integration of PCR cycle threshold, and antibody values with demographics, comorbidities, and laboratory/radiographic findings identified risk factors for 28-day outcome severity, though only female sex was associated with PASC. Longitudinal clinical phenotyping offers important insights, and provides a framework for immunophenotyping for acute and long COVID-19. Funding: NIH.

Published
2022
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8. A practical treatment for COVID‐19 and the next pandemic

Author

Jahar Bhattacharya, Robert Booy, Arturo Casadevall, Charles Dela Cruz, David S. Fedson, Joe G. N. Garcia, Gary Grohmann, Ivan F. N. Hung, Jeffrey R. Jacobson, Lance C. Jennings, Lester Kobzik, Aleksandra Leligdowicz, James K. Liao, Jennifer H. Martin, Daniel M. Musher, Charles N. Serhan, and Masato Tashiro

Subjects
ACE inhibitors, ARBs, COVID‐19, generic drugs, next pandemic, statins, Therapeutics. Pharmacology, RM1-950
Published
2022
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9. No evidence of fetal defects or anti-syncytin-1 antibody induction following COVID-19 mRNA vaccination

Author

Alice Lu-Culligan, Alexandra Tabachnikova, Eddy Pérez-Then, Maria Tokuyama, Hannah J. Lee, Carolina Lucas, Valter Silva Monteiro, Marija Miric, Vivian Brache, Leila Cochon, M. Catherine Muenker, Subhasis Mohanty, Jiefang Huang, Insoo Kang, Charles Dela Cruz, Shelli Farhadian, Melissa Campbell, Inci Yildirim, Albert C. Shaw, Shuangge Ma, Sten H. Vermund, Albert I. Ko, Saad B. Omer, and Akiko Iwasaki

Subjects
Biology (General), QH301-705.5
Abstract

The impact of Coronavirus Disease 2019 (COVID-19) mRNA vaccination on pregnancy and fertility has become a major topic of public interest. We investigated 2 of the most widely propagated claims to determine (1) whether COVID-19 mRNA vaccination of mice during early pregnancy is associated with an increased incidence of birth defects or growth abnormalities; and (2) whether COVID-19 mRNA-vaccinated human volunteers exhibit elevated levels of antibodies to the human placental protein syncytin-1. Using a mouse model, we found that intramuscular COVID-19 mRNA vaccination during early pregnancy at gestational age E7.5 did not lead to differences in fetal size by crown-rump length or weight at term, nor did we observe any gross birth defects. In contrast, injection of the TLR3 agonist and double-stranded RNA mimic polyinosinic-polycytidylic acid, or poly(I:C), impacted growth in utero leading to reduced fetal size. No overt maternal illness following either vaccination or poly(I:C) exposure was observed. We also found that term fetuses from these murine pregnancies vaccinated prior to the formation of the definitive placenta exhibit high circulating levels of anti-spike and anti-receptor-binding domain (anti-RBD) antibodies to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) consistent with maternal antibody status, indicating transplacental transfer in the later stages of pregnancy after early immunization. Finally, we did not detect increased levels of circulating anti-syncytin-1 antibodies in a cohort of COVID-19 vaccinated adults compared to unvaccinated adults by ELISA. Our findings contradict popular claims associating COVID-19 mRNA vaccination with infertility and adverse neonatal outcomes. The impact of COVID-19 mRNA vaccination on pregnancy and fertility has become a major topic of public interest. This study shows that after inoculation of pregnant mice with COVID mRNA vaccines, no birth defects or growth restrictions were found, and no induction of anti-syncytin-1 antibodies was detected in a longitudinal human cohort compared to unvaccinated volunteers.

Published
2022

10. Neurologic Manifestations of Severe Acute Respiratory Syndrome Coronavirus 2 Infection in Hospitalized Patients During the First Year of the COVID-19 Pandemic

Author

Anna M. Cervantes-Arslanian, MD, Chakradhar Venkata, MD, Pria Anand, MD, Joseph D. Burns, MD, Charlene J. Ong, MD, Allison M. LeMahieu, MS, Phillip J. Schulte, PhD, Tarun D. Singh, MD, Alejandro A. Rabinstein, MD, Neha Deo, BS, Vikas Bansal, MBBS, MPH, Karen Boman, BS, Juan Pablo Domecq Garces, MD, Donna Lee Armaignac, PhD, APRN, Amy B. Christie, MD, Roman R. Melamed, MD, Yasir Tarabichi, MD, MSCR, Sreekanth R. Cheruku, MD, MPH, Ashish K. Khanna, MD, FCCP, FCCM, FASA, Joshua L. Denson, MD, MS, Valerie M. Banner-Goodspeed, MPH, Harry L. Anderson, III, MD, FACS, FICS, FCCM, FCCP, FAIM, Ognjen Gajic, MD, MS, Vishakha K. Kumar, MD, MBA, Allan Walkey, MD, Rahul Kashyap, MD, MBA, on behalf of the Society of Critical Care Medicine Discovery Viral Infection and Respiratory Illness Universal Study (VIRUS): COVID-19 Registry Investigator Group, Jean-Baptiste Mesland, Pierre Henin, Hélène Petre, Isabelle Buelens, Anne-Catherine Gerard, Philippe Clevenbergh, Rolando Claure-Del Granado, Jose A. Mercado, Esdenka Vega-Terrazas, Maria F. Iturricha-Caceres, Ruben Garza, Eric Chu, Victoria Chan, Oscar Y Gavidia, Felipe Pachon, Yeimy A Sanchez, Danijel knežević, Mohamed El Kassas, Mohamed Badr, Ahmed Tawheed, Hend Yahia, Dimitrios Kantas, Vasileios Koulouras, Estela Pineda, Gabina María Reyes Guillen, Helin Archaga Soto, Ana Karen Vallecillo Lizardo, Csaba Kopitkó, Ágnes Bencze, István Méhész, Zsófia Gerendai,, Girish Vadgaonkar, Rekha Ediga, Shilpa Basety, Shwetha Dammareddy, Phani Sreeharsha Kasumalla, Smitha S. Segu, Tuhin Chakraborty, Epcebha Joyce, Sridhar Papani, Mahesh Kamuram, Mradul Kumar Daga, Munisha Agarwal, Ishan Rohtagi, Anusha Cherian, Sreejith Parameswaran, Magesh Parthiban, Phaneendra Doddaga, Neethi Chandra, Puneet Rijhwani, Ashish Jain, Aviral Gupta, Ram Mohan Jaiswal, Ambika Tyagi, Nimish Mathur, Madhav Prabhu, Vishal Jakati, Mukur Petrolwala, Bharat Ladva, Surapaneni Krishna Mohan, Ekambaram Jyothisree, Umamaheswara Raju, Janaki Manduva, Naresh Kolakani, Shreeja Sripathi, Sheetal Chaitanya, Kamlesh Kumar Agrawal, Vijendra Baghel, Kirti Kumar Patel, Nooshin Dalili, Mohsen Nafa, Wataru Matsuda, Reina Suzuki, Michihito Kyo, Shu Tahara, Mineji Hayakawa, Kunihiko Maekawa, Masamitsu Sanui, Sho Horikita, Yuki Itagaki, Akira Kodate, Yuki Takahashi, Koyo Moriki, Takuya Shiga, Yudai Iwasaki, Hidenobu Shigemitsu, Yuka Mishima, Nobuyuki Nosaka, Michio Nagashima, Abdulrahman Al-Fares, Rene Rodriguez-Gutierrez, Jose Gerardo Gonzalez-Gonzalez, Alejandro Salcido-Montenegro, Adrian Camacho-Ortiz, Mariana Janeth Hermosillo Ulloa, Fatimah Hassan-Hanga, Hadiza Galadanci, Abubakar Shehu Gezawa, Halima M. S. Kabara, Taiwo Gboluwaga Amole, Halima Kabir, Dalha Gwarzo Haliru, Abdullahi S Ibrahim, Muhammad Sohaib Asghar, Mashaal Syed, Syed Anosh Ali Naqvi, Igor Borisovich Zabolotskikh,, Konstantin Dmitrievich Zybin, Sergey Vasilevich Sinkov, Tatiana Sergeevna Musaeva, Razan K Alamoudi, Hassan M. AlSharif, Sarah A. Almazwaghi, Mohammed S Elsakran, Mohamed A Aid, Mouaz A Darwich, Omnia M Hagag, Salah A Ali, Alona rocacorba, Kathrine Supeña, Efren Ray Juane, Jenalyn Medina, Jowany Baduria, Marwa Ridha Amer, Mohammed Abdullah, Bawazeer, Talal I. Dahhan, Eiad Kseibi, Abid Shahzad Butt, Syed Moazzum Khurshid, Muath Rabee, Mohammed Abujazar, Razan Alghunaim, Maal Abualkhair, Abeer Turki AlFirm, Yaseen M Arabi, Sheryl Ann Abdukahil, Mohammed A Almazyad, Mohammed I Alarifi, Jara M Macarambon, Ahmad Abdullah Bukhari, Hussain A. Albahrani, Kazi N Asfina, Kaltham M Aldossary, Marija Zdravkovic, Zoran Todorovic, Viseslav Popadic, Slobodan Klasnja, Ana Andrijevic, Srdjan Gavrilovic, Vladimir Carapic, Bojan Kovacevic, Jovana Bojicic, Stevanovic Predrag, Dejan S Stojakov, Duska K Ignjatovic, Suzana C Bojic, Marina M Bobos, Irina B Nenadic, Milica S Zaric, Marko D Djuric, Vladimir R Djukic, Santiago Y. Teruel, Belen C. Martin, Uluhan Sili, Huseyin Bilgin, Pinar Ay, Varsha P Gharpure, Usman Raheemi, Kenneth W. Dodd, Nicholas Goodmanson, Kathleen Hesse, Paige Bird, Chauncey Weinert, Nathan Schoenrade, Abdulrahman Altaher, Esmael Mayar, Matthew Aronson, Tyler Cooper, Monica Logan, Brianna Miner, Gisele Papo, Eric M. Siegal, Phyllis Runningen, Suzanne Barry, Christopher Woll, Gregory Wu, Erin Carrole, Kathryn Burke, Mustafa Mohammed, Roman R. Melamed, David M. Tierney, Love A. Patel, Vino S. Raj, Barite U. Dawud, Narayana Mazumder, Abbey Sidebottom, Alena M. Guenther, Benjamin D. Krehbiel, Nova J. Schmitz, Stacy L. Jepsen, Lynn Sipsey, Anna Schulte, Whitney Wunderlich, Cecely Hoyt, Abhijit A Raval, Andrea Franks, Katherine Irby, Ronald C. Sanders, Jr., Glenda Hefley, Jennifer M. Jarvis, Anmol Kharbanda, Sunil Jhajhria, Zachary Fyffe, Stephen Capizzi, Bethany Alicie, Martha Green, Lori Crockarell, Amelia Drennan, Kathleen Dubuque, Tonya Fambrough, Nikole Gasaway, Briana Krantz, Peiman Nebi, Jan Orga, Margaret Serfass, Alina Simion, Kimberly Warren, Cassie Wheeler, CJ Woolman, Amy B. Christie, Dennis W. Ashley, Rajani Adiga, Andrew S. Moyer, George M. Verghese, Andrea Sikora Newsome, Christy C. Forehand, Rebecca Bruning, Timothy W. Jones, Moldovan Sabov, Fatema Zaidi, Fiona Tissavirasingham, Dhatri Malipeddi, Jarrod M Mosier, Karen Lutrick, Beth Salvagio Campbell, Cathleen Wilson, Patrick Rivers, Jonathan Brinks, Mokenge Ndiva Mongoh, Boris Gilson, Donna Lee Armaignac, Don Parris, Maria Pilar Zuniga, Ilea Vargas, Viviana Boronat, Anneka Hutton, Navneet Kaur, Prashank Neupane, Nohemi Sadule-Rios, Lourdes M. Rojas, Aashish Neupane, Priscilla Rivera, Carlos Valle Carlos, Gregory Vincent, Mahesh Amin, Mary E Schelle, Amanda Steadham, Christopher M Howard, Cameron McBride, Jocelyn Abraham, Orlando Garner, Katherine Richards, Keegan Collins, Preethi Antony, Sindhu Mathew, Valerie C. Danesh, Gueorgui Dubrocq, Amber L. Davis, Marissa J Hammers, ill M. McGahey, Amanda C. Farris, Elisa Priest, Robyn Korsmo, Lorie Fares, Kathy Skiles, Susan M. Shor, Kenya Burns, Corrie A Dowell, Gabriela “Hope” Gonzales, Melody Flores, Lindsay Newman, Debora A Wilk, Jason Ettlinger, Jaccallene Bomar, Himani Darji, Alejandro Arroliga, Alejandro C Arroliga, Corrie A. Dowell, Gabriela Hope Conzales, Debora A. Wilk, Paras B. Khandhar, Elizabeth Kring, Valerie M. Banner-Goodspeed, Somnath Bose, Lauren E. Kelly, Melisa Joseph, Marie McGourty, Krystal Capers, Benjamin Hoenig, Maria C. Karamourtopoulos, Anica C. Law, Elias N. Baedorf Kassis, Allan J. Walkey, Sushrut S. Waikar, Michael A. Garcia, Mia Colona, Zoe Kibbelaar, Michael Leong, Daniel Wallman, Kanupriya Soni, Jennifer Maccarone, Joshua Gilman, Ycar Devis, Joseph Chung, Munizay Paracha, David N. Lumelsky, Madeline DiLorenzo, Najla Abdurrahman, Shelsey Johnson, Maj Andrew M. Hersh, CPT Stephanie L Wachs, Brittany S. Swigger, Stephanie L Wachs, Capt Lauren A. Sattler, Capt Michael N. Moulton, Kimberly Zammit, Patrick, J McGrath, William Loeffler, Maya, R. Chilbert, Aaron S. Miller, Edwin L. Anderson, Rosemary Nagy, Ravali R. Inja, Pooja A. Nawathe, Isabel Pedraza, Jennifer Tsing, Karen Carr, Anila Chaudhary, Kathleen Guglielmino, Raghavendra Tirupathi, Alymer Tang, Arshad Safi, Cindy Green, Jackie Newell, Rayan E. Ihle, Shelda A. Martin, Elaine A. Davis, Katja M. Gist, Imran A Sayed, John Brinton, Larisa Strom, Kathleen Chiotos, Allison M. Blatz, Giyoung Lee, Ryan H. Burnett, Guy I. Sydney, Danielle M. Traynor, Karissa Nauert, Annika Gonzalez, Mariel Bagley, Anita Santpurkar, Salim Surani, Joshua White, Aftab Khan, Rahul Dhahwal, Sreekanth Cheruku, Farzin Ahmed, Christopher Deonarine, Ashley Jones, Mohammad-Ali Shaikh, David Preston, Jeanette Chin, Vidula Vachharajani, Abhijit Duggal, Prabalini Rajendram, Omar Mehkri, Siddharth Dugar, Michelle Biehl, Gretchen Sacha, Stuart Houltham, Alexander King, Kiran Ashok, Bryan Poynter, Mary Beukemann, Richard Rice, Susan Gole, Valerie Shaner, Adarsh Conjeevaram, Michelle Ferrari, Narendrakumar Alappan, Steven Minear, Jaime Hernandez-Montfort, Syed Sohaib Nasim, Ravi Sunderkrishnan, Debasis Sahoo, Patrick S. Milligan, Sandeep K. Gupta, Joy M. Koglin, Regina Gibson, Lana Johnson, Felicia Preston, Crimson Scott, Bethany Nungester, Dana D Byrne, Christa A Schorr, Katie Grant, Katherine L Doktor, Maura C Porto, Olga Kaplan, James E. Siegler, III, Brian Schonewald, Ashley Woodford, Alan Tsai, Savina Reid, Kuntal Bhowmick, Saba Daneshpooy, Cyrus Mowdawalla, Trishna Akshay Dave, Wilhemina Kennedy, Connor Crudeli, Christopher Ferry, Long Nguyen, Sneha Modi, Niharika Padala, Pavan Jitendra Patel, Belle Lin, Lena Chatterjee, Jamie Qiuyun, Fan Mandi Liu, Rasagna Kota, Annesha Banerjee, Steven K. Daugherty, Sam Atkinson, Kelly Shrimpton, Sidney Ontai, Brian Contreras, Uzoma Obinwanko, Nneka Amamasi, Amir Sharafi, Sarah Lee, Zahia Esber, Chetna Jinjvadia, Raquel R Bartz, Vijay Krishnamoorthy, Bryan Kraft, Aaron Pulsipher, Eugene Friedman, Sachin Mehta, Margit Kaufman, Gregg Lobel, Nisha Gandhi, Amr Abdelaty, Elizabeth Shaji, Kiana Lim, Juan Marte, Dani Ashley Sosa, David P. Yamane, Ivy Benjenk, Nivedita Prasanna, Nicholas Perkins, Prera J. Roth, Banu Sivaraj, Haley Fulton, Madison G Herin, Marissa Crum, Morgan E. Fretwell, Emily-Rose Zhou, Christine Waller, Kara Kallies, Jonean Thorsen, Alec Fitzsimmons, Haley Olsen, Heda R. Dapul, Sourabh Verma, Alan Salas, Ariel Daube, Michelle Korn, Michelle Ramirez, Logi Rajagopalan, Laura Santos, Héctor Collazo Santiago, Ricardo Alan Hernandez, Norma Smalls, Asher G Bercow, Mark Shlomovich, Christine Crandall, Sasko Stojanovski, Kristin Johnson, Kelly Michienzi, Steven Q. Davis, Valentina Jovic, Max Masuda, Amanda Hayes, Katharine Nault, Michael Smith, William Snow, Riley Liptak, Hannah Durant, Valerie Pendleton, Alay Nanavati, Risa Mrozowsk, Namrata Nag, Jeff Brauer, Ashwin Dharmadhikari, Sahib Singh, Franco Laghi, Ghania Naeem, Andrew Wang, Kevin Bliden, Amit Rout, Jaime Barnes, Martin Gesheff, Asha Thomas, Melbin Thomas, Alicia R. Liendo, Jovan Milosavljevic, Kenan Abbasi, Nicholas B. Burley, Nicole Rapista, Samuel Amankwah, Sanjay K Poude, Saroj Timilsina, Sauradeep Sarkar, Oluwasayo Akinyosoye, Shashi K. Yalamanchili, Sheena Moorthy, Sonia Sugumar, Jonathan Ford, Martin C. Taylor, Charlotte Dunderdale, Alyssa Henshaw, Mary K. Brunk, Jessica Hagy, Shehryar Masood, Sushrutha Sridhar, Yuk Ming Liu, Sarah Zavala, Esther Shim, Ronald A. Reilkoff, Julia A. Heneghan, Sarah Eichen, Lexie Goertzen, Scott Rajala, Ghislaine Feussom, Ben Tang, Christine C. Junia, Robert Lichtenberg, Hasrat Sidhu, Diana Espinoza, Shelden Rodrigues, Maria Jose Zabala, Daniela Goyes, Ammu Susheela, Buddhi Hatharaliyadda, Naveen Rameshkumar, Amulya Kasireddy, Genessis Maldonado, Lisseth Beltran, Akshata Chaugule, Hassan Khan, Namrata Patil, Ruhi Patil, Rodrigo Cartin-Ceba, Ayan Sen, Fahimeh Talaei, Rahul Kashyap, Juan Pablo Domecq, Ognjen Gajic, Vikas Bansal, Aysun Tekin, Amos Lal, John C. O’Horo, Neha N. Deo, Mayank Sharma, Shahraz Qamar, Romil Singh, Diana J. Valencia Morales, Abigail T. La Nou, Marija Bogojevic, Simon Zec, Devang Sanghavi, Pramod Guru, Pablo Moreno Franco, Karthik Gnanapandithan, Hollie Saunders, Zachary Fleissner, Juan Garcia, Alejandra Yu Lee Mateus, Siva Naga Yarrarapu, Nirmaljot Kaur, Abhisekh Giri, Mohammed Mustafa Hasan, Ashrita Donepudi, Syed Anjum Khan, Nitesh Kumar Jain, Thoyaja Koritala, Alexander Bastidas, Gabriela Orellana, Adriana Briceno Bierwirth, Eliana Milazzo, Juan Guillermo Sierra, Thao Dang, Rahul S Nanchal, Paul A Bergl, Jennifer L Peterson, Jessica Timmer, Kimberly Welker, Travis Yamanaka, Nicholas A. Barreras, Michael Markos, Anita Fareeduddin, Rohan Mehta, Chakradhar Venkata, Miriam Engemann, Annamarie Mantese, Yasir Tarabichi, Adam Perzynski, Christine Wang, Dhatri Kotekal, Adriana C Briceno Bierwirth, Gabriela M Orellana, Gerardo Catalasan, Shohana Ahmed, Carlos F Matute, Ahmad Hamdan, Ivania Salinas, Genesis Del Nogal, Angel Tejada, Anna Eschler, Mary Hejna, Emily Lewandowski, Kristen Kusmierski, Clare Martin, Jen-Ting Chen, Aluko Hope, Zoe Tsagaris, Elise Ruen, Aram Hambardzumyan, Nasar A Siddiqi, Lesly Jurado, Lindsey Tincher, Carolyn Brown, Prithvi Sendi, Meghana Nadiger, Balagangadhar Totapally, Bhagat S. Aulakh, Sandeep Tripathi, Jennifer A. Bandy, Lisa M. Kreps, Dawn R. Bollinger, Neha Gupta, Brent R Brown, Tracy L Jones, Kassidy Malone, Lauren A Sinko, Amy B Harrell, Shonda C Ayers, Lisa M Settle, Taylor J Sears, Roger Scott Stienecker, Andre G. Melendez, Tressa A. Brunner, Sue M Budzon, Jessica L. Heffernan, Janelle M. Souder, Tracy L. Miller, Andrea G. Maisonneuve, Roberta E. Redfern, Jessica Shoemaker, Jennifer Micham, Lynn Kenney, Gabriel Naimy, Victoria Schauf, Sara Utley, Holly Balcer, Kerry P. J. Pulver, Jennifer Yehle, Alicia Weeks, Terra Inman, Majdi Hamarshi, Jeannette Ploetz, Nick Bennett, Kyle Klindworth, Moustafa Younis, Adham Mohamed, Brian L. Delmonaco, Anthony Franklin, Mitchell Heath, Diane Barkas, Antonia L. Vilella, Sara B. Kutner, Kacie Clark, Danielle Moore, Shina Menon, John K McGuire, Deana Rich, Harry L. Anderson, III, Dixy Rajkumar, Ali Abunayla, Jerrilyn Heiter, Howard A. Zaren, Stephanie J. Smith, Grant C. Lewis, Lauren Seames, Cheryl Farlow, Judy Miller, Gloria Broadstreet, John Lin, Cindy Terrill, Brock Montgomery, Sydney Reyes, Summer Reyes, Alex Plattner, Anthony Martinez, Micheal Allison, Aniket Mittal, Rafael Ruiz, Aleta Skaanland, Robert Ross, Umang Patel, Jordesha Hodge, Krunal Kumar Patel, Shivani Dalal, Himanshu Kavani, Sam Joseph, Michael A. Bernstein, Ian K. Goff, Matthew Naftilan, Amal Mathew, Deborah Williams, Sue Murdock, Maryanne Ducey, Kerianne Nelson, Jason Block, James Mitchel, Connor G O’Brien, Sylvan Cox, William Marx, Ioana Amzuta, Asad J. Choudhry, Mohammad T. Azam, Kristina L Carter, Michael A Olmos, Brittany M Parker, Julio Quintanilla, Tara A Craig, Brendon J Clough, Jeffrey T Jameson, Utpal S. Bhalala, Joshua Kuehne, Melinda Garcia, Morgan Beebe, Heather Herrera, Chris Fiack, Stephanie Guo, May Vawer, Beth Blackburn, Caleb Darby, Kristy Page, Amanda Brown, Jessie McAbee, Katherine A. Belden, Michael Baram, Devin M. Weber, Rosalie DePaola, Yuwei Xia, Hudson Carter, Aaron Tolley, Mary Barletta, Mark Steele, Laurie Kemble, Joshua L. Denson, A. Scott Gillet, Margo Brown, Rachael Stevens, Andrew Wetherbie, Kevin Tea, Mathew Moore, Abdurrahman Husain, Atul Malhotra, Qais Zawaydeh, Benjamin J Sines, Thomas J Bice, Emily A. Vail, Susannah Nicholson, Rachelle B. Jonas, AnnaRose E. Dement, William Tang, Mark DeRosa, Robert E. Villarreal, Rajany V. Dy, Alfredo Iardino, Jill Sharma, Richard Czieki, Julia Christopher, Ryan Lacey, Marwan Mashina, Kushal Patel, Erica C. Bjornstad, Nancy M. Tofil, Scott House, Isabella Aldana, Nikhil K. Meena, Jose D. Caceres, Nikhil K Meena, Sarenthia M. Epps, Harmeen Goraya, Kelsey R. Besett, Ryan James, Lana Y. Abusalem, Akash K. Patel, Lana S Hasan, Dina Gomaa, Michael Goodman, Devin Wakefield, Anthony Spuzzillo, John O. Shinn II, Robert MacLaren, Azra Bihorac, Tezcan Ozrazgat Baslanti, George Omalay, Haleh Hashemighouchani, Julie S. Cupka, Matthew M Ruppert, Patrick W. McGonagill, Colette Galet, Janice Hubbard, David Wang, Lauren Allan, Aditya Badheka, Madhuradhar Chegondi, Usman Nazir, Garrett Rampon, Jake Riggle, Nathan Dismang, Vicki Montgomery, Janice Sullivan, Sarah Morris, Jennifer Nason, Ozan Akca, Rainer Lenhardt, Rodrigo S. Cavallazzi, Ann Jerde, Alexa Black, Allison Polidori, Haily Griffey, Justin Winkler, Thomas Brenzel, Roger A. Alvarez, Amarilys Alarcon-Calderon, Marie Anne Sosa, Sunita K. Mahabir, Mausam J. Patel, Pauline Park, Andrew Admon, Sinan Hanna, Rishi Chanderraj, Maria Pliakas, Ann Wolski, Jennifer Cirino, Dima Dandachi, Hariharan Regunath, Maraya N. Camazine, Grant. E. Geiger, Abdoulie O. Njai, Baraa M. Saad, Faraaz Ali Shah, Byron Chuan, Sagar L. Rawal, Manal Piracha, Joseph E. Tonna, Nicholas M. Levin, Kayte Suslavich, Rachel Tsolinas, Zachary T. Fica, Chloe R. Skidmore, Renee D. Stapleton, Anne E. Dixon, Olivia Johnson, Sara S. Ardren, Stephanie Burns, Anna Raymond, Erika Gonyaw, Kevin Hodgdon, Chloe Housenger, Benjamin Lin, Karen McQuesten, Heidi Pecott-Grimm, Julie Sweet, Sebastian Ventrone, Nita Khandelwal, T. Eoin West, Ellen S. Caldwell, Lara Lovelace-Macon, Navya Garimella, Denisse B. Dow, Sreekanth R. Cheruku, Catherine Chen, Murtaza Akhter, Rania Abdul Rahman, Mary Mulrow, Erin M. Wilfong, Kelsi Vela, Ashish K. Khanna, Lynne Harris, Bruce Cusson, Jacob Fowler, David Vaneenenaam, Glen McKinney, Imoh Udoh, Kathleen Johnson, Patrick G. Lyons, Andrew P Michelson, Sara S. Haluf, Lauren M. Lynch, Nguyet M. Nguyen, Aaron Steinberg, Nicholas Braus, Vishwanath Pattan, Jessica Papke, Ismail Jimada, Nida Mhid, Samuel Chakola, Kevin Sheth, Abdalla Ammar, Mahmoud Ammar, Victor Torres Lopez, Charles Dela Cruz,, Akhil Khosla, and Samir Gautam

Subjects
Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Abstract

OBJECTIVES:. To describe the prevalence, associated risk factors, and outcomes of serious neurologic manifestations (encephalopathy, stroke, seizure, and meningitis/encephalitis) among patients hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. DESIGN:. Prospective observational study. SETTING:. One hundred seventy-nine hospitals in 24 countries within the Society of Critical Care Medicine Discovery Viral Infection and Respiratory Illness Universal Study COVID-19 Registry. PATIENTS:. Hospitalized adults with laboratory-confirmed SARS-CoV-2 infection. INTERVENTIONS:. None. RESULTS:. Of 16,225 patients enrolled in the registry with hospital discharge status available, 2,092 (12.9%) developed serious neurologic manifestations including 1,656 (10.2%) with encephalopathy at admission, 331 (2.0%) with stroke, 243 (1.5%) with seizure, and 73 (0.5%) with meningitis/encephalitis at admission or during hospitalization. Patients with serious neurologic manifestations of COVID-19 were older with median (interquartile range) age 72 years (61.0–81.0 yr) versus 61 years (48.0–72.0 yr) and had higher prevalence of chronic medical conditions, including vascular risk factors. Adjusting for age, sex, and time since the onset of the pandemic, serious neurologic manifestations were associated with more severe disease (odds ratio [OR], 1.49; p < 0.001) as defined by the World Health Organization ordinal disease severity scale for COVID-19 infection. Patients with neurologic manifestations were more likely to be admitted to the ICU (OR, 1.45; p < 0.001) and require critical care interventions (extracorporeal membrane oxygenation: OR, 1.78; p = 0.009 and renal replacement therapy: OR, 1.99; p < 0.001). Hospital, ICU, and 28-day mortality for patients with neurologic manifestations was higher (OR, 1.51, 1.37, and 1.58; p < 0.001), and patients had fewer ICU-free, hospital-free, and ventilator-free days (estimated difference in days, –0.84, –1.34, and –0.84; p < 0.001). CONCLUSIONS:. Encephalopathy at admission is common in hospitalized patients with SARS-CoV-2 infection and is associated with worse outcomes. While serious neurologic manifestations including stroke, seizure, and meningitis/encephalitis were less common, all were associated with increased ICU support utilization, more severe disease, and worse outcomes.

Published
2022
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11. Acute encephalopathy with elevated CSF inflammatory markers as the initial presentation of COVID-19

Author

Shelli Farhadian, Laura R. Glick, Chantal B. F. Vogels, Jared Thomas, Jennifer Chiarella, Arnau Casanovas-Massana, Jing Zhou, Camila Odio, Pavithra Vijayakumar, Bertie Geng, John Fournier, Santos Bermejo, Joseph R. Fauver, Tara Alpert, Anne L. Wyllie, Cynthia Turcotte, Matthew Steinle, Patrick Paczkowski, Charles Dela Cruz, Craig Wilen, Albert I. Ko, Sean MacKay, Nathan D. Grubaugh, Serena Spudich, and Lydia Aoun Barakat

Subjects
COVID-19, SARS-CoV-2, Neuroinflammation, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Background COVID-19 is caused by the severe acute respiratory syndrome virus SARS-CoV-2. It is widely recognized as a respiratory pathogen, but neurologic complications can be the presenting manifestation in a subset of infected patients. Case presentation We describe a 78-year old immunocompromised woman who presented with altered mental status after witnessed seizure-like activity at home. She was found to have SARS-CoV-2 infection and associated neuroinflammation. In this case, we undertake the first detailed analysis of cerebrospinal fluid (CSF) cytokines during COVID-19 infection and find a unique pattern of inflammation in CSF, but no evidence of viral neuroinvasion. Conclusion Our findings suggest that neurologic symptoms such as encephalopathy and seizures may be the initial presentation of COVID-19. Central nervous system inflammation may associate with neurologic manifestations of disease.

Published
2020
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12. Variation in Use of Repurposed Medications Among Patients With Coronavirus Disease 2019. From The Society of Critical Care Medicine Discovery Viral Infection and Respiratory Illness Universal Study: Coronavirus Disease 2019 Registry Investigator Group

Author

Michael A. Garcia, MD, Shelsey W. Johnson, MD, Nicholas A. Bosch, MD, MSc, Emily K. Sisson, MA, Christopher R. Sheldrick, PhD, Vishakha K. Kumar, MD, MBA, Karen Boman, BS, Scott Bolesta, PharmD, Vikas Bansal, MBBS, MPH, Neha Deo, BS, J. P. Domecq, MD, Amos Lal, MD, Amy B. Christie, MD, Valerie M. Banner-Goodspeed, MPH, Devang Sanghavi, MD, MHA, Girish Vadgaonkar, MBBS, Ognjen Gajic, MD, MSc, Rahul Kashyap, MBBS, MBA, Allan J. Walkey, MD, MSc, for the Society of Critical Care Medicine Discovery Viral Infection and Respiratory Illness Universal Study Investigators, Jean-Baptiste Mesland, Pierre Henin, Hélène Petre, Isabelle Buelens, Anne-Catherine Gerard, Philippe Clevenbergh, Dragana Markotić, Ivana Bošnjak, Ruben Garza, Eric Chu, Victoria Chan, Oscar Y Gavidia, Felipe Pachon, Yeimy A Sanchez, Mohamed El Kassas, Mohamed Badr, Ahmed Tawheed, Hend Yahia, Jose Luis Ramos Coello, Guillermo Perez, Ana Karen Vallecillo Lizardo, Gabina María Reyes Guillen, Helin Archaga Soto, Smitha S. Segu, Tuhin Chakraborty, Epcebha Joyce, Girish Vadgaonkar, Rekha Ediga, Shilpa Basety, Shwetha Dammareddy, Phani Sreeharsha Kasumalla, Umamaheswara Raju, Janaki Manduva, Naresh Kolakani, Shreeja Sripathi, Sheetal Chaitanya, Mradul Kumar Daga, Munisha Agarwal, Ishan Rohtagi, Sridhar Papani, Mahesh Kamuram, Kamlesh Kumar Agrawal, Vijendra Baghel, Kirti Kumar Patel, Surapaneni Krishna Mohan, Ekambaram Jyothisree, Wataru Matsuda, Reina Suzuki, Michihito Kyo, Yuki Itagaki, Akira Kodate, Yuki Takahashi, Koyo Moriki, Fatimah Hassan-Hanga, Hadiza Galadanci, Abubakar Shehu Gezawa, Halima M. S. Kabara, Taiwo Gboluwaga Amole, Halima Kabir, Dalha Gwarzo Haliru, Abdullahi S Ibrahim, Muhammad Sohaib Asghar, Mashaal Syed, Syed Anosh Ali Naqvi, Igor Borisovich Zabolotskikh, Konstantin Dmitrievich Zybin, Sergey Vasilevich Sinkov, Tatiana Sergeevna Musaeva, Mohammed A Almazyad, Mohammed I Alarifi, Jara M Macarambon, Ahmad Abdullah Bukhari, Hussain A. Albahrani, Kazi N Asfina, Kaltham M Aldossary, Marija Zdravkovic, Zoran Todorovic, Viseslav Popadic, Slobodan Klasnja, Bojan Kovacevic, Jovana Bojicic, Predrag D Stevanovic, Dejan S Stojakov, Duska K Ignjatovic, Suzana C Bojic, Marina M Bobos, Irina B Nenadic, Milica S Zaric, Marko D Djuric, Vladimir R Djukic, Santiago Y. Teruel, Belen C. Martin, Uluhan Sili, Huseyin Bilgin, Pinar Ay, Abhijit A Raval, Andrea Franks, Anmol Kharbanda, Sunil Jhajhria, Zachary Fyffe, Stephen Capizzi, Bethany Alicie, Martha Green, Lori Crockarell, Amelia Drennan, Kathleen Dubuque, Tonya Fambrough, Nikole Gasaway, Briana Krantz, Peiman Nebi, Jan Orga, Margaret Serfass, Alina Simion, Kimberly Warren, Cassie Wheeler, CJ Woolman, Amy B. Christie, Dennis W. Ashley, Rajani Adiga, Andrew S. Moyer, George M. Verghese, Andrea Sikora Newsome, Christy C. Forehand, Rebecca Bruning, Timothy W. Jones, Moldovan Sabov, Fatema Zaidi, Fiona Tissavirasingham, Dhatri Malipeddi, Donna Lee Armaignac, Don Parris, Maria Pilar Zuniga, Ilea Vargas, Viviana Boronat, Anneka Hutton, Navneet Kaur, Prashank Neupane, Nohemi Sadule-Rios, Lourdes M. Rojas, Aashish Neupane, Priscilla Rivera, Carlos Valle Carlos, Gregory Vincent, Valerie M. Banner-Goodspeed, Somnath Bose, Lauren E. Kelly, Melisa Joseph, Marie McGourty, Krystal Capers, Benjamin Hoenig, Maria C. Karamourtopoulos, Anica C. Law, Elias N. Baedorf Kassis, Allan J. Walkey, Sushrut S. Waikar, Michael A. Garcia, Mia Colona, Zoe Kibbelaar, Michael Leong, Daniel Wallman, Kanupriya Soni, Jennifer Maccarone, Joshua Gilman, Ycar Devis, Joseph Chung, Munizay Paracha, David N. Lumelsky, Madeline DiLorenzo, Najla Abdurrahman, Shelsey Johnson, Kimberly Zammit, Patrick, J McGrath, William Loeffler, Maya, R Chilbert, Raghavendra Tirupathi, Alymer Tang, Arshad Safi, Cindy Green, Jackie Newell, Katja M. Gist, Imran A Sayed, John Brinton, Larisa Strom, Steven K. Daugherty, Sam Atkinson, Kelly Shrimpton, David P. Yamane, Ivy Benjenk, Nivedita Prasanna, Norma Smalls, Michael Smith, William Snow, Riley Liptak, Hannah Durant, Valerie Pendleton, Alay Nanavati, Risa Mrozowsk, Yuk Ming Liu, Sarah Zavala, Esther Shim, Ronald A. Reilkoff, Julia A. Heneghan, Sarah Eichen, Lexie Goertzen, Scott Rajala, Ghislaine Feussom, Ben Tang, Christine C. Junia, Robert Lichtenberg, Hasrat Sidhu, Diana Espinoza, Shelden Rodrigues, Maria Jose Zabala, Daniela Goyes, Ammu Susheela, Buddhi Hatharaliyadda, Naveen Rameshkumar, Amulya Kasireddy, Genessis Maldonado, Lisseth Beltran, Akshata Chaugule, Hassan Khan, Rodrigo Cartin-Ceba, Ayan Sen, Amanda Palacios, Giyth M. Mahdi, Rahul Kashyap, Ognjen Gajic, Vikas Bansal, Aysun Tekin, Amos Lal, John C. O’Horo, Neha N. Deo, Mayank Sharma, Shahraz Qamar, Juan Pablo Domecq, Romil Singh, Alex Niven, Abigail La Nou, Marija Bogojevic, Barbara Mullen, Devang Sanghavi, Pablo Moreno Franco, Pramod Guru, Karthik Gnanapandithan, Hollie Saunders, Zachary Fleissner, Juan Garcia, Alejandra Yu, Lee Mateus, Siva Naga Yarrarapu, Nirmaljot Kaur, Abhisekh Giri, Syed Anjum Khan, Nitesh Kumar Jain, Thoyaja Koritala, Jessica Timmer, Kimberly Welker, Chakradhar Venkata, Miriam Engemann, Annamarie Mantese, Anna Eschler, Mary Hejna, Emily Lewandowski, Kristen Kusmierski, Clare Martin, Bhagat S. Aulakh, Sandeep Tripathi, Jennifer A. Bandy, Lisa M. Kreps, Dawn R. Bollinger, Roger Scott Stienecker, Andre G. Melendez, Tressa A. Brunner, Sue M Budzon, Jessica L. Heffernan, Janelle M. Souder, Tracy L. Miller, Andrea G. Maisonneuve, Brian L. Delmonaco, Anthony Franklin, Mitchell Heath, Antonia L. Vilella, Sara B. Kutner, Kacie Clark, Danielle Moore, Harry L. Anderson, III, Dixy Rajkumar, Ali Abunayla, Jerrilyn Heiter, Howard A. Zaren, Stephanie J. Smith, Grant C. Lewis, Lauren Seames, Cheryl Farlow, Judy Miller, Gloria Broadstreet, Anthony Martinez, Micheal Allison, Aniket Mittal, Rafael Ruiz, Aleta Skaanland, Robert Ross, Paul K Mohabir, Connor G O’Brien, Komal Dasani, Neha Gupta, Tracy L Jones, Shonda C Ayers, Amy B Harrell, Brent R Brown, Megan Edwards, Caleb Darby, Kristy Page, Amanda Brown, Jessie McAbee, Katherine A. Belden, Michael Baram, Devin M. Weber, Rosalie DePaola, Yuwei Xia, Hudson Carter, Aaron Tolley, Mary Barletta, Mary Ferranti, Benjamin J Sines, Thomas J Bice, Patrick W. McGonagill, Colette Galet, Janice Hubbard, David Wang, Lauren Allan, Aditya Badheka, Madhuradhar Chegondi, Usman Nazir, Garrett Rampon, Jake Riggle, Nathan Dismang, Roger A. Alvarez, Amarilys Alarcon-Calderon, Marie Anne Sosa, Sunita K. Mahabir, Mausam J. Patel, Dima Dandachi, Hariharan Regunath, Maraya N. Camazine, Grant. E. Geiger, Abdoulie O. Njai, Baraa M. Saad, Renee D. Stapleton, Anne E. Dixon, Olivia Johnson, Sara S. Ardren, Stephanie Burns, Anna Raymond, Erika Gonyaw, Kevin Hodgdon, Chloe Housenger, Benjamin Lin, Karen McQuesten, Heidi Pecott-Grimm, Julie Sweet, Sebastian Ventrone, Ashish K. Khanna, Lynne Harris, Bruce Cusson, Jacob Fowler, David Vaneenenaam, Glen McKinney, Imoh Udoh, Kathleen Johnson, Vishwanath Pattan, Jessica Papke, Ismail Jimada, Nida Mhid, Samuel Chakola, Kevin Sheth, Abdalla Ammar, Mahmoud Ammar, Victor Torres Lopez, Charles Dela Cruz, Akhil Khosla, and Samir Gautam

Subjects
Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Abstract

IMPORTANCE:. At the start of the coronavirus disease 2019 pandemic, medications repurposed for management of coronavirus disease 2019 were used in the absence of clinical trial evidence. OBJECTIVES:. To describe the variation and evolution in use of repurposed medications for coronavirus disease 2019. DESIGN, SETTING, AND PARTICIPANTS:. Observational cohort study of adults hospitalized with coronavirus disease 2019 between February 15, 2020, and April 12, 2021, across 76 United States and international hospitals within the Society of Critical Care Medicine’s Discovery Viral Infection and Respiratory Illness Universal Study coronavirus disease 2019 registry. MAIN OUTCOMES AND MEASURES:. Hospital variation was quantified using multivariable adjusted random effects logistic regression models and unsupervised clustering. Repurposed medications included antivirals, corticosteroids, hydroxychloroquine, immunomodulators, and therapeutic dose anticoagulants. RESULTS:. Among 7,069 adults hospitalized with coronavirus disease 2019, 1,979 (28%) received antivirals, 2,876 (41%) received corticosteroids, 1,779 (25%) received hydroxychloroquine, 620 (9%) received immunomodulators, and 2,154 (31%) received therapeutic dose anticoagulants. Contribution of hospital site to risk-adjusted variation was 46% for antivirals, 30% for corticosteroids, 48% for hydroxychloroquine, 46% for immunomodulators, and 52% for therapeutic dose anticoagulants. Compared with the early pandemic, the later pandemic practice phenotypes converged with increased use of antivirals (odds ratio, 3.14; 95% CI, 2.40–4.10) and corticosteroids (odds ratio, 5.43; 95% CI, 4.23–6.97), with decreased use of hydroxychloroquine (odds ratio, 0.02; 95% CI, 0.01–0.04) and immunomodulators (odds ratio, 0.49; 95% CI, 0.34–0.70). There was no clinically significant change in the use of therapeutic dose anticoagulants (odds ratio, 1.01; 95% CI, 1.01–1.02). There were no differences in risk-adjusted mortality between hospitals with high rates of repurposed medication use compared with hospitals with low rates of use. CONCLUSIONS AND RELEVANCE:. Hospital variation in the use of repurposed medications varied widely across hospitals early in the pandemic and later converged with the emergence of randomized clinical trials. Platforms developed for rapid activation and enrollment in clinical trials of repurposed medications are needed prior to the next pandemic to expedite effective, evidence-based practice.

Published
2021
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13. IL-13Rα2 uses TMEM219 in chitinase 3-like-1-induced signalling and effector responses

Author

Chang-Min Lee, Chuan Hua He, Adel M. Nour, Yang Zhou, Bing Ma, Jin Wook Park, Kyung Hee Kim, Charles Dela Cruz, Lokesh Sharma, Mahmoud L. Nasr, Yorgo Modis, Chun Geun Lee, and Jack A. Elias

Subjects
Science
Abstract

Chitinase 3-like 1 regulates cell death, inflammation and tissue remodelling via IL-13receptorα2. Here, the authors show that TMEM219 is a IL-13Rα2 co-receptor and modulates oxidant-induced apoptosis and lung injury, melanoma metastasis and TGF-β1 signalling, downstream of Chi3l1-IL-13Rα2.

Published
2016
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14. Correction: Corrigendum: IL-13Rα2 uses TMEM219 in chitinase 3-like-1-induced signalling and effector responses

Author

Chang-Min Lee, Chuan Hua He, Adel M. Nour, Yang Zhou, Bing Ma, Jin Wook Park, Kyung Hee Kim, Charles Dela Cruz, Lokesh Sharma, Mahmoud L. Nasr, Yorgo Modis, Chun Geun Lee, and Jack A. Elias

Subjects
Science
Abstract

Nature Communications 7: Article number: 12752 (2016); Published 15 September 2016; Updated 14 November 2016 The financial support for this Article was not fully acknowledged. The acknowledgements should have included the following: Yorgo Modis, PhD was supported by a senior research fellowship fromthe Wellcome Trust, grant no.

Published
2016
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16. The Stroke Preclinical Assessment Network: Rationale, Design, Feasibility, and Stage 1 Results

Author

Patrick D. Lyden, Francesca Bosetti, Márcio A. Diniz, André Rogatko, James I. Koenig, Jessica Lamb, Karisma A. Nagarkatti, Ryan P. Cabeen, David C. Hess, Pradip K. Kamat, Mohammad B. Khan, Kristofer Wood, Krishnan Dhandapani, Ali S. Arbab, Enrique C. Leira, Anil K. Chauhan, Nirav Dhanesha, Rakesh B. Patel, Mariia Kumskova, Daniel Thedens, Andreia Morais, Takahiko Imai, Tao Qin, Cenk Ayata, Ligia S.B. Boisserand, Alison L. Herman, Hannah E. Beatty, Sofia E. Velazquez, Sebastian Diaz-Perez, Basavaraju G. Sanganahalli, Jelena M. Mihailovic, Fahmeed Hyder, Lauren H. Sansing, Raymond C. Koehler, Steven Lannon, Yanrong Shi, Senthilkumar S. Karuppagounder, Adnan Bibic, Kazi Akhter, Jaroslaw Aronowski, Louise D. McCullough, Anjali Chauhan, Andrew Goh, Shahneela Siddiqui, Kevin Sheth, Charles Matouk, Charles Dela Cruz, Jiangbing Zhou, Valina L. Dawson, Ted M. Dawson, Jian Liang, Peter C.M. van Zijl, Steven R. Zeiler, W. Taylor Kimberly, Taylan Erdogan, Lili Yu, Joseph Mandeville, and Jonah Patrick Weigand Whittier

Subjects
Male, Advanced and Specialized Nursing, Brain, Infarction, Middle Cerebral Artery, Article, Brain Ischemia, Stroke, Mice, Animals, Feasibility Studies, Humans, Neurology (clinical), Cardiology and Cardiovascular Medicine, Aged
Abstract

Cerebral ischemia and reperfusion initiate cellular events in brain that lead to neurological disability. Investigating these cellular events provides ample targets for developing new treatments. Despite considerable work, no such therapy has translated into successful stroke treatment. Among other issues—such as incomplete mechanistic knowledge and faulty clinical trial design—a key contributor to prior translational failures may be insufficient scientific rigor during preclinical assessment: nonblinded outcome assessment; missing randomization; inappropriate sample sizes; and preclinical assessments in young male animals that ignore relevant biological variables, such as age, sex, and relevant comorbid diseases. Promising results are rarely replicated in multiple laboratories. We sought to address some of these issues with rigorous assessment of candidate treatments across 6 independent research laboratories. The Stroke Preclinical Assessment Network (SPAN) implements state-of-the-art experimental design to test the hypothesis that rigorous preclinical assessment can successfully reduce or eliminate common sources of bias in choosing treatments for evaluation in clinical studies. SPAN is a randomized, placebo-controlled, blinded, multilaboratory trial using a multi-arm multi-stage protocol to select one or more putative stroke treatments with an implied high likelihood of success in human clinical stroke trials. The first stage of SPAN implemented procedural standardization and experimental rigor. All participating research laboratories performed middle cerebral artery occlusion surgery adhering to a common protocol and rapidly enrolled 913 mice in the first of 4 planned stages with excellent protocol adherence, remarkable data completion and low rates of subject loss. SPAN stage 1 successfully implemented treatment masking, randomization, prerandomization inclusion/exclusion criteria, and blinded assessment to exclude bias. Our data suggest that a large, multilaboratory, preclinical assessment effort to reduce known sources of bias is feasible and practical. Subsequent SPAN stages will evaluate candidate treatments for potential success in future stroke clinical trials using aged animals and animals with comorbid conditions.

Published
2022

18. A practical treatment for <scp>COVID</scp> ‐19 and the next pandemic

Author

Jahar Bhattacharya, Robert Booy, Arturo Casadevall, Charles Dela Cruz, David S. Fedson, Joe G. N. Garcia, Gary Grohmann, Ivan F. N. Hung, Jeffrey R. Jacobson, Lance C. Jennings, Lester Kobzik, Aleksandra Leligdowicz, James K. Liao, Jennifer H. Martin, Daniel M. Musher, Charles N. Serhan, and Masato Tashiro

Subjects
Angiotensin Receptor Antagonists, Neurology, SARS-CoV-2, COVID-19, Humans, General Pharmacology, Toxicology and Pharmaceutics, Pandemics
Published
2022

19. Abstract TMP112: Stroke-associated Pneumonia Impairs Pulmonary Host Defense While Infection Impairs Stroke Recovery

Author

Ligia Simoes Braga Boisserand, Lokesh Sharma, Tho Tran, Bridget Chen, Jooyoung Kim, Charles Dela Cruz, and Lauren H Sansing

Subjects
Advanced and Specialized Nursing, Neurology (clinical), Cardiology and Cardiovascular Medicine
Abstract

Introduction: Stroke-associated pneumonia (SAP) is a common clinical complication implicated in increased morbidity and mortality after stroke. Dysphagia and stroke-induced immunodepression may contribute to SAP. However, a better understanding of the processes underlying the infection-induced immune response in the recovering brain remains to be unveiled. Methods: Stroke was modeled in mice by tMCAO (1h) followed by reperfusion; at day 3 mice received an oropharyngeal Klebsiella inoculation. To examine how lung infection affects the brain immune response, we compared tMCAo+infection vs tMCAo+vehicle. Functional outcomes and brain leukocyte cytokine expression were analyzed. To investigate how stroke affects the host response to pulmonary infection we compared Sham+infection vs tMCAo+ infection. Bacterial burden in the lung and spleen, tissue injury and immune cell profile in the lungs were evaluated at day 2 post-infection. Results/Conclusions: We detected similar brain leukocyte numbers between the tMCAo infected vs vehicle groups. However, in the tMCAo infected group, cytotoxic T-cells (CD8+) produced less IL-6 and IFNγ and granulocytes/neutrophils produced less INFγ. tMCAo infected animals also exhibited a worse functional recovery (Fig 1a). Klebsiella CFUs were increased in spleen in mice with stroke compared to sham, while lung (BAL) white blood cells counts were reduced in the stroke group, with altered cellular composition (Fig 1b).Our investigation has revealed that lung infection attenuates cytokine production in the brain after stroke. That could have a dual effect, positive for brain injury but detrimental for fighting infection. Stroke affects the response to lung infection by reducing lung leukocyte counts and increasing bacterial dissemination. Advancing our understanding of the mechanisms driving altered immune responses in SAP important for identifying potential treatment targets.

Published
2022

20. Colchicine and high-intensity rosuvastatin in the treatment of non-critically ill patients hospitalised with COVID-19: a randomised clinical trial

Author

Tayyab Shah, Marianne McCarthy, Irem Nasir, Herb Archer, Elio Ragheb, Jonathan Kluger, Nitu Kashyap, Carlos Paredes, Prashant Patel, Jing Lu, Prakash Kandel, Christopher Song, Mustafa Khan, Haocheng Huang, Faheem Ul Haq, Rami Ahmad, Christopher Howes, Brian Cambi, Gilead Lancaster, Michael Cleman, Charles Dela Cruz, Helen Parise, and Alexandra Lansky

Subjects
General Medicine
Abstract

ObjectiveTo evaluate the effect of colchicine and high-intensity rosuvastatin in addition to standard of care on the progression of COVID-19 disease in hospitalised patients.DesignA pragmatic, open-label, multicentre, randomised controlled trial conducted from October 2020 to September 2021. Follow-up was conducted at 30 and 60 days. The electronic medical record was used at all stages of the trial including screening, enrolment, randomisation, event ascertainment and follow-up.SettingFour centres in the Yale New Haven Health System.ParticipantsNon-critically ill hospitalised patients with COVID-19.InterventionsPatients were randomised 1:1 to either colchicine plus high-intensity rosuvastatin in addition to standard of care versus standard of care alone. Assigned treatment was continued for the duration of index hospitalisation or 30 days, whichever was shorter.Primary and secondary outcome measuresThe prespecified primary endpoint was progression to severe COVID-19 disease (new high-flow or non-invasive ventilation, mechanical ventilation, need for vasopressors, renal replacement therapy or extracorporeal membrane oxygenation, or death) or arterial/venous thromboembolic events (ischaemic stroke, myocardial infarction, deep venous thrombosis or pulmonary embolism) evaluated at 30 days.ResultsAmong the 250 patients randomised in this trial (125 to each arm), the median age was 61 years, 44% were women, 15% were Black and 26% were Hispanic/Latino. As part of the standard of care, patients received remdesivir (87%), dexamethasone (92%), tocilizumab (18%), baricitinib (2%), prophylactic/therapeutic anticoagulation (98%) and aspirin (91%). The trial was terminated early by the data and safety monitoring board for futility. No patients were lost to follow-up due to electronic medical record follow-up. There was no significant difference in the primary endpoint at 30 days between the active arm and standard of care arm (15.2% vs 8.8%, respectively, p=0.17).ConclusionsIn this small, open-label, randomised trial of non-critically ill hospitalised patients with COVID-19, the combination of colchicine and rosuvastatin in addition to standard of care did not appear to reduce the risk of progression of COVID-19 disease or thromboembolic events, although the trial was underpowered due to a lower-than-expected event rate. The trial leveraged the power of electronic medical records for efficiency and improved follow-up and demonstrates the utility of incorporating electronic medical records into future trials.Trial registrationNCT04472611.

Published
2023

21. No evidence of fetal defects or anti-syncytin-1 antibody induction following COVID-19 mRNA vaccination

Author

Alice Lu-Culligan, Alexandra Tabachnikova, Maria Tokuyama, Hannah J. Lee, Carolina Lucas, Valter Silva Monteiro, M. Catherine Muenker, Subhasis Mohanty, Jiefang Huang, Insoo Kang, Charles Dela Cruz, Shelli Farhadian, Melissa Campbell, Inci Yildirim, Albert C. Shaw, Albert I. Ko, Saad B. Omer, and Akiko Iwasaki

Abstract

The impact of coronavirus disease 2019 (COVID-19) mRNA vaccination on pregnancy and fertility has become a major topic of public interest. We investigated two of the most widely propagated claims to determine 1) whether COVID-19 mRNA vaccination of mice during early pregnancy is associated with an increased incidence of birth defects or growth abnormalities, and 2) whether COVID-19 mRNA-vaccinated human volunteers exhibit elevated levels of antibodies to the human placental protein syncytin-1. Using a mouse model, we found that intramuscular COVID-19 mRNA vaccination during early pregnancy at gestational age E7.5 did not lead to differences in fetal size by crown-rump length or weight at term, nor did we observe any gross birth defects. In contrast, injection of the TLR3 agonist and double-stranded RNA mimic polyinosinic-polycytidylic acid, or poly(I:C), impacted growth in utero leading to reduced fetal size. No overt maternal illness following either vaccination or poly(I:C) exposure was observed. We also found that term fetuses from vaccinated murine pregnancies exhibit high circulating levels of anti-Spike and anti-RBD antibodies to SARS-CoV-2 consistent with maternal antibody status, indicating transplacental transfer. Finally, we did not detect increased levels of circulating anti-syncytin-1 antibodies in a cohort of COVID-19 vaccinated adults compared to unvaccinated adults by ELISA. Our findings contradict popular claims associating COVID-19 mRNA vaccination with infertility and adverse neonatal outcomes.

Published
2021

22. Diverse functional autoantibodies in patients with COVID-19

Author

Eric Y, Wang, Tianyang, Mao, Jon, Klein, Yile, Dai, John D, Huck, Jillian R, Jaycox, Feimei, Liu, Ting, Zhou, Benjamin, Israelow, Patrick, Wong, Andreas, Coppi, Carolina, Lucas, Julio, Silva, Ji Eun, Oh, Eric, Song, Emily S, Perotti, Neil S, Zheng, Suzanne, Fischer, Melissa, Campbell, John B, Fournier, Anne L, Wyllie, Chantal B F, Vogels, Isabel M, Ott, Chaney C, Kalinich, Mary E, Petrone, Anne E, Watkins, Charles, Dela Cruz, Shelli F, Farhadian, Wade L, Schulz, Shuangge, Ma, Nathan D, Grubaugh, Albert I, Ko, Akiko, Iwasaki, and Yvette, Strong

Subjects
Male, Proteome, COVID-19, Complement System Proteins, Disease Models, Animal, Mice, Organ Specificity, Case-Control Studies, Antigens, Surface, Disease Progression, Animals, Cytokines, Humans, Female, Autoantibodies
Abstract

COVID-19 manifests with a wide spectrum of clinical phenotypes that are characterized by exaggerated and misdirected host immune responses

Published
2020

23. Severe SARS-CoV-2 infection is defined by a shift in the serum lipidome resulting in dysregulation of eicosanoid lipid immune mediators

Author

Benjamin Schwarz, Lokesh Sharma, Lydia Roberts, Xiaohua Peng, Santos Bermejo, Ian Leighton, Arnau Casanovas-Massana, Shelli Farhadian, Albert Ko, Yale IMPACT Team, Charles Dela Cruz, and Catharine Bosio

Subjects
Immune system, Eicosanoid, business.industry, Diabetes mellitus, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Immunology, Pandemic, medicine, Disease, Lipid signaling, Lipidome, medicine.disease, business
Abstract

The COVID-19 pandemic has affected more than 10 million people worldwide with mortality exceeding3 half a million patients. Risk factors associated with severe disease and mortality include advanced age,4 hypertension, diabetes, and obesity.1 Clear mechanistic understanding of how these comorbidities5 converge to enable severe infection is lacking. Notably each of these risk factors pathologically disrupts6 the lipidome and this disruption may be a unifying feature of severe COVID-19.1-7 Here we provide the first in depth interrogation of lipidomic changes, including structural-lipids as well as the eicosanoids and docosanoids lipid mediators (LMs), that mark COVID-19 disease severity. Our data reveal that progression from moderate to severe disease is marked by a loss of specific immune regulatory LMs and increased pro-inflammatory species. Given the important immune regulatory role of LMs, these data provide mechanistic insight into the immune balance in COVID-19 and potential targets for therapy with currently approved pharmaceuticals.8

Published
2020

24. Sex differences in immune responses to SARS-CoV-2 that underlie disease outcomes

Author

Takehiro, Takahashi, Mallory K, Ellingson, Patrick, Wong, Benjamin, Israelow, Carolina, Lucas, Jon, Klein, Julio, Silva, Tianyang, Mao, Ji Eun, Oh, Maria, Tokuyama, Peiwen, Lu, Arvind, Venkataraman, Annsea, Park, Feimei, Liu, Amit, Meir, Jonathan, Sun, Eric Y, Wang, Arnau, Casanovas-Massana, Anne L, Wyllie, Chantal B F, Vogels, Rebecca, Earnest, Sarah, Lapidus, Isabel M, Ott, Adam J, Moore, Albert, Shaw, John B, Fournier, Camila D, Odio, Shelli, Farhadian, Charles, Dela Cruz, Nathan D, Grubaugh, Wade L, Schulz, Aaron M, Ring, Albert I, Ko, Saad B, Omer, and Yexin, Yang

Subjects
Male, Chemokine, T-Lymphocytes, T cell, Disease, Lymphocyte Activation, Monocytes, Article, CCL5, Cohort Studies, Immune system, Humans, Medicine, Sex Characteristics, Innate immune system, biology, SARS-CoV-2, business.industry, Antibody titer, COVID-19, Viral Load, Prognosis, Immunity, Innate, Phenotype, medicine.anatomical_structure, Immunology, Disease Progression, biology.protein, Cytokines, RNA, Viral, Female, Chemokines, business, Viral load
Abstract

A growing body of evidence indicates sex differences in the clinical outcomes of coronavirus disease 2019 (COVID-19)1-4. However, whether immune responses against SARS-CoV-2 differ between sexes, and whether such differences explain male susceptibility to COVID-19, is currently unknown. In this study, we examined sex differences in viral loads, SARS-CoV-2-specific antibody titers, plasma cytokines, as well as blood cell phenotyping in COVID-19 patients. By focusing our analysis on patients with mild to moderate disease who had not received immunomodulatory medications, our results revealed that male patients had higher plasma levels of innate immune cytokines and chemokines including IL-8, IL-18, and CCL5, along with more robust induction of non-classical monocytes. In contrast, female patients mounted significantly more robust T cell activation than male patients during SARS-CoV-2 infection, which was sustained in old age. Importantly, we found that a poor T cell response negatively correlated with patients’ age and was predictive of worse disease outcome in male patients, but not in female patients. Conversely, higher innate immune cytokines in female patients associated with worse disease progression, but not in male patients. These findings reveal a possible explanation underlying observed sex biases in COVID-19, and provide important basis for the development of sex-based approach to the treatment and care of men and women with COVID-19.

Published
2020

25. Prognostic Significance of Urinary Biomarkers in Patients Hospitalized With COVID-19

Author

Steven Menez, Dennis G. Moledina, Heather Thiessen-Philbrook, F. Perry Wilson, Wassim Obeid, Michael Simonov, Yu Yamamoto, Celia P. Corona-Villalobos, Crystal Chang, Brian T. Garibaldi, William Clarke, Shelli Farhadian, Charles Dela Cruz, Steven G. Coca, Chirag R. Parikh, Albert Ko, Akiko Iwasaki, Allison Nelson, Arnau Casanovas-Massana, Elizabeth B. White, Wade Schulz, Andreas Coppi, Patrick Young, Angela Nunez, Denise Shepard, Irene Matos, Yvette Strong, Kelly Anastasio, Kristina Brower, Maxine Kuang, Michael Chiorazzi, Santos Bermejo, Pavithra Vijayakumar, Bertie Geng, John Fournier, Maksym Minasyan, M. Catherine Muenker, Adam J. Moore, and Girish Nadkarni

Subjects
medicine.medical_specialty, medicine.medical_treatment, Original Investigations, chronic kidney disease (CKD), Lower risk, chemistry.chemical_compound, Lipocalin-2, Internal medicine, medicine, Humans, acute kidney injury (AKI), Prospective Studies, Prospective cohort study, Dialysis, Subclinical infection, Creatinine, SARS-CoV-2, business.industry, Acute kidney injury, COVID-19, biomarkers, Acute Kidney Injury, Prognosis, medicine.disease, chemistry, Nephrology, Biomarker (medicine), business, Kidney disease
Abstract

Rationale and Objective Acute kidney injury (AKI) is common in patients with COVID-19 and associated with poor outcomes. Urinary biomarkers have been associated with adverse kidney outcomes in other settings and may provide additional prognostic information in patients with COVID-19. We investigated the association between urinary biomarkers with adverse kidney outcomes among patients hospitalized with COVID-19. Study Design Prospective cohort study. Setting and Participants Patients hospitalized with COVID-19 (n=153) at 2 academic medical centers between April and June 2020. Exposures 19 urinary biomarkers of injury, inflammation, and repair. Outcomes Composite of KDIGO stage 3 AKI, requirement for dialysis, or death within 60 days of hospital admission. We also compared various kidney biomarker levels in the setting of COVID-19 versus other common AKI settings. Analytic Approach Time-varying Cox proportional hazards regression to associate biomarker level with composite outcome. Results Out of 153 patients, 24 (15.7%) experienced the primary outcome. Two-fold higher levels of neutrophil gelatinase-associated lipocalin (NGAL) (HR: 1.34; 95% CI: 1.14-1.57), monocyte chemoattractant protein (MCP-1) (HR: 1.42; 95% CI: 1.09-1.84), and kidney injury molecule-1 (KIM-1) (HR: 2.03; 95% CI: 1.38-2.99) were associated with highest risk of sustaining primary composite outcome. Higher epidermal growth factor (EGF) levels were associated with a lower risk of the primary outcome (HR 0.61; 95% CI: 0.47-0.79). Individual biomarkers provided moderate discrimination and biomarker combinations improved discrimination for the primary outcome. The degree of kidney injury by biomarker level in COVID-19 was comparable to other settings of clinical AKI. There was evidence of subclinical AKI in COVID-19 patients based on elevated injury biomarker level in patients without clinical AKI defined by serum creatinine. Limitations Small sample size with low number of composite outcome events. Conclusion Urinary biomarkers are associated with adverse kidney outcomes in patients hospitalized with COVID-19 and may provide valuable information to monitor kidney disease progression and recovery., Graphical abstract

Published
2022

26. Response

Author

Christina C. Price, Frederick L. Altice, Marwan M. Azar, Dayna McManus, Shana E. Gleeson, Clemente J. Britto, Veronica Azmy, Kelsey Kaman, Matthew Davis, Geoffrey Chupp, Richard Bucala, Naftali Kaminski, Jeffrey E. Topal, Charles Dela Cruz, and Maricar Malinis

Subjects
Pulmonary and Respiratory Medicine, SARS-CoV-2, Correspondence, Humans, Antibodies, Monoclonal, Humanized, Cardiology and Cardiovascular Medicine, Critical Care and Intensive Care Medicine, COVID-19 Drug Treatment
Published
2021

27. Biochemical and biological characterization of a dodecameric CD4-Ig fusion protein: implications for therapeutic and vaccine strategies

Author

James, Arthos, Claudia, Cicala, Tavis D, Steenbeke, Tae-Wook, Chun, Charles, Dela Cruz, Douglas B, Hanback, Prateeti, Khazanie, Daniel, Nam, Peter, Schuck, Sara M, Selig, Donald, Van Ryk, Margery A, Chaikin, and Anthony S, Fauci

Subjects
AIDS Vaccines, CD4-Positive T-Lymphocytes, Antibodies, Monoclonal, HIV Envelope Protein gp120, Virus Replication, Membrane Fusion, Coculture Techniques, Biopolymers, Neutralization Tests, Chromatography, Gel, HIV-1, Humans, CD4 Immunoadhesins, Cells, Cultured
Abstract

Drug toxicities associated with HAART lend urgency to the development of new anti-HIV therapies. Inhibition of viral replication at the entry stage of the viral life cycle is an attractive strategy because it prevents de novo infection. Soluble CD4 (sCD4), the first drug in this class, failed to suppress viral replication in vivo. At least three factors contributed to this failure: sCD4 demonstrated poor neutralizing activity against most primary isolates of HIV in vitro; it demonstrated an intrinsic capacity to enhance viral replication at low concentrations; and it exhibited a relatively short half-life in vivo. Many anti-gp120 monoclonal antibodies, including neutralizing monoclonal antibodies also enhance viral replication at suboptimal concentrations. Advances in our understanding of the events leading up to viral entry suggest strategies by which this activity can be diminished. We hypothesized that by constructing a sCD4-based molecule that is large, binds multiple gp120s simultaneously, and is highly avid toward gp120, we could remove its capacity to enhance viral entry. Here we describe the construction of a polymeric CD4-IgG1 fusion protein. The hydrodynamic radius of this molecule is approximately 12 nm. It can bind at least 10 gp120 subunits with binding kinetics that suggest a highly avid interaction toward virion-associated envelope. This protein does not enhance viral replication at suboptimal concentrations. These observations may aid in the design of new therapeutics and vaccines.

Published
2002

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