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1. IgM N-glycosylation correlates with COVID-19 severity and rate of complement deposition

Author

Ozonoff, Al, Ehrlich, Lauren IR, Melamed, Esther, Sesma, Ana Fernandez, Simon, Viviana, Pulendran, Bali, Nadeau, Kari C, Davis, Mark M, McCoey, Grace A, Sekaly, Rafick, Baden, Lindsey R, Levy, Ofer, Schaenman, Joanna, Reed, Elaine F, Shaw, Albert C, Hafler, David A, Montgomery, Ruth R, Kleinstein, Steven H, Becker, Patrice M, Augustine, Alison D, Calfee, Carolyn S, Erle, David J, DeBakey, Michael E, Corry, David B, Kheradmand, Farrah, Atkinson, Mark A, Brakenridge, Scott C, Higuita, Nelson I Agudelo, Metcalf, Jordan P, Hough, Catherine L, Messer, William B, Kraft, Monica, Bime, Chris, Peters, Bjoern, Milliren, Carly E, Syphurs, Caitlin, McEnaney, Kerry, Barton, Brenda, Lentucci, Claudia, Saluvan, Mehmet, Chang, Ana C, Hoch, Annmarie, Albert, Marisa, Shaheen, Tanzia, Kho, Alvin T, Liu, Shanshan, Thomas, Sanya, Chen, Jing, Murphy, Maimouna D, Cooney, Mitchell, Hayati, Arash Nemati, Bryant, Robert, Abraham, James, Jayavelu, Naresh Doni, Presnell, Scott, Jancsyk, Tomasz, Maguire, Cole, Qi, Jingjing, Lee, Brian, Fourati, Slim, Esserman, Denise A, Guan, Leying, Gygi, Jeremy, Pawar, Shrikant, Brito, Anderson, Fragiadakis, Gabriela K, Patel, Ravi, Overton, James A, Vita, Randi, Westendorf, Kerstin, Shannon, Casey P, Tebbutt, Scott J, Thyagarajan, Rama V, Rousseau, Justin F, Wylie, Dennis, Triplett, Todd A, Kojic, Erna, Chinthrajah, Sharon, Ahuja, Neera, Rogers, Angela J, Artandi, Maja, Geng, Linda, Yendewa, George, Powell, Debra L, Kim, James N, Simmons, Brent, Goonewardene, I Michael, Smith, Cecilia M, Martens, Mark, Sherman, Amy C, Walsh, Stephen R, Issa, Nicolas C, Salehi-Rad, Ramin, Dela Cruz, Charles, Farhadian, Shelli, Iwasaki, Akiko, Ko, Albert I, Anderson, Evan J, Mehta, Aneesh K, and Sevransky, Jonathan E

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Immunology, Infectious Diseases, Coronaviruses, Lung, Emerging Infectious Diseases, Inflammatory and immune system, Good Health and Well Being, Humans, COVID-19, Glycosylation, SARS-CoV-2, Glycosyltransferases, Complement System Proteins, Immunoglobulin M, IMPACC Network
Abstract

The glycosylation of IgG plays a critical role during human severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, activating immune cells and inducing cytokine production. However, the role of IgM N-glycosylation has not been studied during human acute viral infection. The analysis of IgM N-glycosylation from healthy controls and hospitalized coronavirus disease 2019 (COVID-19) patients reveals increased high-mannose and sialylation that correlates with COVID-19 severity. These trends are confirmed within SARS-CoV-2-specific immunoglobulin N-glycan profiles. Moreover, the degree of total IgM mannosylation and sialylation correlate significantly with markers of disease severity. We link the changes of IgM N-glycosylation with the expression of Golgi glycosyltransferases. Lastly, we observe antigen-specific IgM antibody-dependent complement deposition is elevated in severe COVID-19 patients and modulated by exoglycosidase digestion. Taken together, this work links the IgM N-glycosylation with COVID-19 severity and highlights the need to understand IgM glycosylation and downstream immune function during human disease.

Published
2024

2. Features of acute COVID-19 associated with post-acute sequelae of SARS-CoV-2 phenotypes: results from the IMPACC study

Author

Ozonoff, Al, Jayavelu, Naresh Doni, Liu, Shanshan, Melamed, Esther, Milliren, Carly E., Qi, Jingjing, Geng, Linda N., McComsey, Grace A., Cairns, Charles B., Baden, Lindsey R., Schaenman, Joanna, Shaw, Albert C., Samaha, Hady, Seyfert-Margolis, Vicki, Krammer, Florian, Rosen, Lindsey B., Steen, Hanno, Syphurs, Caitlin, Dandekar, Ravi, Shannon, Casey P., Sekaly, Rafick P., Ehrlich, Lauren I. R., Corry, David B., Kheradmand, Farrah, Atkinson, Mark A., Brakenridge, Scott C., Higuita, Nelson I. Agudelo, Metcalf, Jordan P., Hough, Catherine L., Messer, William B., Pulendran, Bali, Nadeau, Kari C., Davis, Mark M., Sesma, Ana Fernandez, Simon, Viviana, van Bakel, Harm, Kim-Schulze, Seunghee, Hafler, David A., Levy, Ofer, Kraft, Monica, Bime, Chris, Haddad, Elias K., Calfee, Carolyn S., Erle, David J., Langelier, Charles R., Eckalbar, Walter, Bosinger, Steven E., Peters, Bjoern, Kleinstein, Steven H., Reed, Elaine F., Augustine, Alison D., Diray-Arce, Joann, Maecker, Holden T., Altman, Matthew C., Montgomery, Ruth R., Becker, Patrice M., and Rouphael, Nadine

Published
2024
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3. Phenotypes of disease severity in a cohort of hospitalized COVID-19 patients: Results from the IMPACC study

Author

Ozonoff, Al, Schaenman, Joanna, Jayavelu, Naresh Doni, Milliren, Carly E, Calfee, Carolyn S, Cairns, Charles B, Kraft, Monica, Baden, Lindsey R, Shaw, Albert C, Krammer, Florian, van Bakel, Harm, Esserman, Denise A, Liu, Shanshan, Sesma, Ana Fernandez, Simon, Viviana, Hafler, David A, Montgomery, Ruth R, Kleinstein, Steven H, Levy, Ofer, Bime, Christian, Haddad, Elias K, Erle, David J, Pulendran, Bali, Nadeau, Kari C, Davis, Mark M, Hough, Catherine L, Messer, William B, Higuita, Nelson I Agudelo, Metcalf, Jordan P, Atkinson, Mark A, Brakenridge, Scott C, Corry, David, Kheradmand, Farrah, Ehrlich, Lauren IR, Melamed, Esther, McComsey, Grace A, Sekaly, Rafick, Diray-Arce, Joann, Peters, Bjoern, Augustine, Alison D, Reed, Elaine F, Altman, Matthew C, Becker, Patrice M, Rouphael, Nadine, Bime, Chris, McEnaney, Kerry, Barton, Brenda, Lentucci, Claudia, Saluvan, Mehmet, Chang, Ana C, Hoch, Annmarie, Albert, Marisa, Shaheen, Tanzia, Kho, Alvin T, Thomas, Sanya, Chen, Jing, Murphy, Maimouna D, Cooney, Mitchell, Presnell, Scott, and Fragiadakis, Gabriela K

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Genetics, Clinical Research, Infectious Diseases, Lung, Emerging Infectious Diseases, Prevention, Coronaviruses, Good Health and Well Being, COVID-19, Creatinine, Female, Hospitalization, Humans, Male, Phenotype, Prospective Studies, RNA, Viral, SARS-CoV-2, Severity of Illness Index, Troponin, Post-Acute COVID-19 Syndrome, Viral load, Antibody, IMPACC study group members, Public Health and Health Services, Clinical sciences, Epidemiology
Abstract

BackgroundBetter 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.MethodsImmunophenotyping 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.FindingsThe 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.InterpretationIntegration 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.FundingNIH.

Published
2022

4. Immunophenotyping assessment in a COVID-19 cohort (IMPACC): A prospective longitudinal study

Author

Rouphael, Nadine, Maecker, Holden, Montgomery, Ruth R, Diray-Arce, Joann, Kleinstein, Steven H, Altman, Matthew C, Bosinger, Steven E, Eckalbar, Walter, Guan, Leying, Hough, Catherine L, Krammer, Florian, Langelier, Charles, Levy, Ofer, McEnaney, Kerry, Peters, Bjoern, Rahman, Adeeb, Rajan, Jayant V, Sigelman, Steven, Steen, Hanno, van Bakel, Harm, Ward, Alyssa, Wilson, Michael R, Woodruff, Prescott, Zamecnik, Colin R, Augustine, Alison D, Ozonoff, Al, Reed, Elaine F, Becker, Patrice M, Higuita, Nelson Agudelo, Atkinson, Mark A, Baden, Lindsey R, Bime, Christian, Brakenridge, Scott C, Calfee, Carolyn S, Cairns, Charles B, Corry, David, Davis, Mark M, Ehrlich, Lauren IR, Haddad, Elias K, Erle, David J, Fernandez-Sesma, Ana, Hafler, David A, Kheradmand, Farrah, Kraft, Monica, McComsey, Grace A, Melamed, Esther, Messer, William, Metcalf, Jordan, Nadeau, Kari C, Pulendran, Bali, Sarwal, Minnie, Schaenman, Joanna, Sekaly, Rafick, Shaw, Albert C, and Simon, Viviana

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Clinical Research, Biomarkers, COVID-19, Computational Biology, Data Analysis, Gene Expression Profiling, Hospitalization, Humans, Immunophenotyping, Longitudinal Studies, Molecular Diagnostic Techniques, Prospective Studies, Proteomics, SARS-CoV-2, United States, IMPACC Manuscript Writing Team, IMPACC Network Steering Committee, Clinical sciences, Immunology
Abstract

The IMmunoPhenotyping Assessment in a COVID-19 Cohort (IMPACC) is a prospective longitudinal study designed to enroll 1000 hospitalized patients with COVID-19 (NCT04378777). IMPACC collects detailed clinical, laboratory and radiographic data along with longitudinal biologic sampling of blood and respiratory secretions for in depth testing. Clinical and lab data are integrated to identify immunologic, virologic, proteomic, metabolomic and genomic features of COVID-19-related susceptibility, severity and disease progression. The goals of IMPACC are to better understand the contributions of pathogen dynamics and host immune responses to the severity and course of COVID-19 and to generate hypotheses for identification of biomarkers and effective therapeutics, including optimal timing of such interventions. In this report we summarize the IMPACC study design and protocols including clinical criteria and recruitment, multi-site standardized sample collection and processing, virologic and immunologic assays, harmonization of assay protocols, high-level analyses and the data sharing plans.

Published
2021

5. Multi-omic longitudinal study reveals immune correlates of clinical course among hospitalized COVID-19 patients

Author

Abraham, James, Adkisson, Michael, Albert, Marisa, Altamirano, Luz Torres, Alvarenga, Bonny, Anderson, Matthew L., Anderson, Evan J., Arnett, Azlann, Asashima, Hiromitsu, Atkinson, Mark A., Baden, Lindsey R., Barton, Brenda, Beach, Katherine, Beagle, Elizabeth, Becker, Patrice M., Bell, Matthew R., Bernui, Mariana, Bime, Christian, Boddapati, Arun Kumar, Booth, J. Leland, Borresen, Brittney, Brakenridge, Scott C., Bristow, Laurel, Bryant, Robert, Calfee, Carolyn S., Carreño, Juan Manuel, Carrillo, Sidney, Chak, Suzanna, Chang, Iris, Connors, Jennifer, Conway, Michelle, Corry, David B., Cowan, David, Croen, Brett, Dela Cruz, Charles S., Cusimano, Gina, Eaker, Lily, Edwards, Carolyn, Ehrlich, Lauren I.R., Elashoff, David, Erickson, Heidi, Erle, David J., Farhadian, Shelli, Farrugia, Keith, Fatou, Benoit, Fernandes, Andrea, Fernandez-Sesma, Ana, Fragiadakis, Gabriela K., Furukawa, Sara, Geltman, Janelle N., Ghale, Rajani, Bermúdez González, Maria Carolina, Goonewardene, I. Michael, Guerrero, Estella Sanchez, Guirgis, Faheem W., Hafler, David A., Hamilton, Sydney, Harris, Paul, Hayati, Arash Nemati, Hendrickson, Carolyn M., Agudelo Higuita, Nelson I., Hodder, Thomas, Holland, Steven M., Hough, Catherine L., Huerta, Christopher, Hurley, Kerin C., Hutton, Scott R., Iwasaki, Akiko, Jauregui, Alejandra, Jha, Meenakshi, Johnson, Brandi, Joyner, David, Kangelaris, Kirsten N., Kelly, Geoffrey, Khalil, Zain, Khan, Zenab, Kheradmand, Farrah, Kim, James N., Kimura, Hiroki, Ko, Albert I., Kohr, Bernard, Kraft, Monica, Krummel, Matthew, Kutzler, Michele A., Lasky-Su, Jessica, Lee, Serena, Lee, Deanna, Leipold, Michael, Lentucci, Claudia, Leroux, Carolyn, Lin, Edward, Liu, Shanshan, Love, Christina, Lu, Zhengchun, Maliskova, Lenka, Manning, Brittany Roth, Manohar, Monali, Martens, Mark, McComsey, Grace A., McEnaney, Kerry, McLin, Renee, Melamed, Esther, Melnyk, Nataliya, Mendez, Kevin, Messer, William B., Metcalf, Jordan P., Michelotti, Gregory, Mick, Eran, Mohanty, Subhasis, Mosier, Jarrod, Mulder, Lubbertus C.F., Murphy, Maimouna, Nadeau, Kari R.C., Nelson, Ebony, Nelson, Allison, Nguyen, Viet, Oberhaus, Jordan, Panganiban, Bernadine, Pellegrini, Kathryn L., Pickering, Harry C., Powell, Debra L., Presnell, Scott, Pulendran, Bali, Rahman, Adeeb H., Rashid, Ahmad Sadeed, Raskin, Ariel, Reed, Elaine F., Ribeiro, Susan Pereira, Rivera, Adreanne M., Rogers, Jacob E., Rogers, Angela, Rogowski, Brandon, Rooks, Rebecca, Rosenberg-Hasson, Yael, Rothman, Jessica, Rousseau, Justin F., Salehi-Rad, Ramin, Saluvan, Mehmet, Samaha, Hady, Schaenman, Joanna, Schunk, Ron, Semenza, Nicholas C., Sen, Subha, Sevransky, Jonathan, Seyfert-Margolis, Vicki, Shaheen, Tanzia, Shaw, Albert C., Sieg, Scott, Siegel, Sarah A.R., Sigal, Natalia, Siles, Nadia, Simmons, Brent, Simon, Viviana, Singh, Gagandeep, Sinko, Lauren, Smith, Cecilia M., Smolen, Kinga K., Song, Li-Zhen, Srivastava, Komal, Sullivan, Peter, Syphurs, Caitlin, Tcheou, Johnstone, Tegos, George P., Tharp, Greg K., Tong, Alexandra, Tsitsiklis, Alexandra, Ungaro, Ricardo F., Vaysman, Tatyana, Viode, Arthur, Vita, Randi, Wang, Xiaomei, Ward, Alyssa, Ward, Dawn C., Willmore, Andrew, Woloszczuk, Kyra, Wong, Kari, Woodruff, Prescott G., Xu, Leqi, van Haren, Simon, van de Guchte, Adriana, Zhao, Yujiao, Diray-Arce, Joann, Fourati, Slim, Doni Jayavelu, Naresh, Patel, Ravi, Maguire, Cole, Chang, Ana C., Dandekar, Ravi, Qi, Jingjing, Lee, Brian H., van Zalm, Patrick, Schroeder, Andrew, Chen, Ernie, Konstorum, Anna, Brito, Anderson, Gygi, Jeremy P., Kho, Alvin, Chen, Jing, Pawar, Shrikant, Gonzalez-Reiche, Ana Silvia, Hoch, Annmarie, Milliren, Carly E., Overton, James A., Westendorf, Kerstin, Cairns, Charles B., Rouphael, Nadine, Bosinger, Steven E., Kim-Schulze, Seunghee, Krammer, Florian, Rosen, Lindsey, Grubaugh, Nathan D., van Bakel, Harm, Wilson, Michael, Rajan, Jayant, Steen, Hanno, Eckalbar, Walter, Cotsapas, Chris, Langelier, Charles R., Levy, Ofer, Altman, Matthew C., Maecker, Holden, Montgomery, Ruth R., Haddad, Elias K., Sekaly, Rafick P., Esserman, Denise, Ozonoff, Al, Augustine, Alison D., Guan, Leying, Peters, Bjoern, and Kleinstein, Steven H.

Published
2023
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6. Host-microbe multiomic profiling reveals age-dependent immune dysregulation associated with COVID-19 immunopathology.

Author

Phan, Hoang Van, Tsitsiklis, Alexandra, Maguire, Cole P., Haddad, Elias K., Becker, Patrice M., Kim-Schulze, Seunghee, Lee, Brian, Chen, Jing, Hoch, Annmarie, Pickering, Harry, van Zalm, Patrick, Altman, Matthew C., Augustine, Alison D., Calfee, Carolyn S., Bosinger, Steve, Cairns, Charles B., Eckalbar, Walter, Guan, Leying, Jayavelu, Naresh Doni, and Kleinstein, Steven H.

Abstract

Age is a major risk factor for severe coronavirus disease 2019 (COVID-19), yet the mechanisms behind this relationship have remained incompletely understood. To address this, we evaluated the impact of aging on host immune response in the blood and the upper airway, as well as the nasal microbiome in a prospective, multicenter cohort of 1031 vaccine-naïve patients hospitalized for COVID-19 between 18 and 96 years old. We performed mass cytometry, serum protein profiling, anti–severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody assays, and blood and nasal transcriptomics. We found that older age correlated with increased SARS-CoV-2 viral abundance upon hospital admission, delayed viral clearance, and increased type I interferon gene expression in both the blood and upper airway. We also observed age-dependent up-regulation of innate immune signaling pathways and down-regulation of adaptive immune signaling pathways. Older adults had lower naïve T and B cell populations and higher monocyte populations. Over time, older adults demonstrated a sustained induction of pro-inflammatory genes and serum chemokines compared with younger individuals, suggesting an age-dependent impairment in inflammation resolution. Transcriptional and protein biomarkers of disease severity differed with age, with the oldest adults exhibiting greater expression of pro-inflammatory genes and proteins in severe disease. Together, our study finds that aging is associated with impaired viral clearance, dysregulated immune signaling, and persistent and potentially pathologic activation of pro-inflammatory genes and proteins. Editor's summary: It is well-established that older adults are at increased risk of severe and fatal COVID-19, but the mechanisms underlying this susceptibility are not entirely clear. To better understand features associated with age and COVID-19 severity, Phan et al. comprehensively studied the immune response to SARS-CoV-2 in a large longitudinal clinical cohort. By integrating mass cytometry, serum proteomics, antibody assays, and transcriptional analysis, the authors found that age was associated with increased viral load, delayed viral clearance, and alterations to immune cell frequencies. Markers of disease severity, such as interleukin-6, were the most extreme in the oldest patients. Together, these data provide insight into why age is a major risk factor for severe COVID-19. —Courtney Malo [ABSTRACT FROM AUTHOR]

Published
2024
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7. Corrigendum to “Phenotypes of disease severity in a cohort of hospitalized COVID-19 patients: results from the IMPACC study” [eBioMedicine 83 (2022) 104208]

Author

Ozonoff, Al, primary, Schaenman, Joanna, additional, Jayavelu, Naresh Doni, additional, Milliren, Carly E., additional, Calfee, Carolyn S., additional, Cairns, Charles B., additional, Kraft, Monica, additional, Baden, Lindsey R., additional, Shaw, Albert C., additional, Krammer, Florian, additional, van Bakel, Harm, additional, Esserman, Denise A., additional, Liu, Shanshan, additional, Sesma, Ana Fernandez, additional, Simon, Viviana, additional, Hafler, David A., additional, Montgomery, Ruth R., additional, Kleinstein, Steven H., additional, Levy, Ofer, additional, Bime, Chris, additional, Haddad, Elias K., additional, Erle, David J., additional, Pulendran, Bali, additional, Nadeau, Kari C., additional, Davis, Mark M., additional, Hough, Catherine L., additional, Messer, William B., additional, Agudelo Higuita, Nelson I., additional, Metcalf, Jordan P., additional, Atkinson, Mark A., additional, Brakenridge, Scott C., additional, Corry, David, additional, Kheradmand, Farrah, additional, Ehrlich, Lauren I.R., additional, Melamed, Esther, additional, McComsey, Grace A., additional, Sekaly, Rafick, additional, Diray-Arce, Joann, additional, Peters, Bjoern, additional, Augustine, Alison D., additional, Reed, Elaine F., additional, Altman, Matthew C., additional, Becker, Patrice M., additional, and Rouphael, Nadine, additional

Published
2023
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8. Integrated longitudinal multi-omics study identifies immune programs associated with COVID-19 severity and mortality in 1152 hospitalized participants

Author

Gygi, Jeremy P., primary, Maguire, Cole, additional, Patel, Ravi K., additional, Shinde, Pramod, additional, Konstorum, Anna, additional, Shannon, Casey P., additional, Xu, Leqi, additional, Hoch, Annmarie, additional, Jayavelu, Naresh Doni, additional, Network, IMPACC, additional, Haddad, Elias K., additional, Reed, Elaine F., additional, Kraft, Monica, additional, McComsey, Grace A., additional, Metcalf, Jordan, additional, Ozonoff, Al, additional, Esserman, Denise, additional, Cairns, Charles B., additional, Rouphael, Nadine, additional, Bosinger, Steven E., additional, Kim-Schulze, Seunghee, additional, Krammer, Florian, additional, Rosen, Lindsey B., additional, van Bakel, Harm, additional, Wilson, Michael, additional, Eckalbar, Walter, additional, Maecker, Holden, additional, Langelier, Charles R., additional, Steen, Hanno, additional, Altman, Matthew C., additional, Montgomery, Ruth R., additional, Levy, Ofer, additional, Melamed, Esther, additional, Pulendran, Bali, additional, Diray-Arce, Joann, additional, Smolen, Kinga K., additional, Fragiadakis, Gabriela K., additional, Becker, Patrice M., additional, Augustine, Alison D., additional, Sekaly, Rafick P., additional, Ehrlich, Lauren I. R., additional, Fourati, Slim, additional, Peters, Bjoern, additional, Kleinstein, Steven H., additional, and Guan, Leying, additional

Published
2023
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9. Multi-omic longitudinal study reveals immune correlates of clinical course among hospitalized COVID-19 patients

Author

Diray-Arce, Joann, primary, Fourati, Slim, additional, Jayavelu, Naresh Doni, additional, Patel, Ravi, additional, Maguire, Cole, additional, Chang, Ana C., additional, Dandekar, Ravi, additional, Qi, Jingjing, additional, Lee, Brian, additional, van Zalm, Patrick, additional, Schroeder, Andrew, additional, Chen, Ernie, additional, Konstorum, Anna, additional, Brito, Anderson, additional, Gygi, Jeremy P., additional, Kho, Alvin, additional, Chen, Jing, additional, Pawar, Shrikant, additional, Gonzalez-Reiche, Ana Silvia, additional, Hoch, Annmarie, additional, Milliren, Carly E., additional, Overton, James A., additional, Westendorf, Kerstin, additional, Cairns, Charles B., additional, Rouphael, Nadine, additional, Bosinger, Steven, additional, Kim-Schulze, Seunghee, additional, Krammer, Florian, additional, Rosen, Lindsey, additional, Grubaugh, Nathan, additional, van Bakel, Harm, additional, Wilson, Michael, additional, Rajan, Jayant, additional, Steen, Hanno, additional, Eckalbar, Walter, additional, Cotsapas, Chris, additional, Langelier, Charles R., additional, Levy, Ofer, additional, Altman, Matthew C., additional, Maecker, Holden, additional, Montgomery, Ruth R., additional, Haddad, Elias K., additional, Sekaly, Rafick P., additional, Esserman, Denise, additional, Ozonoff, Al, additional, Becker, Patrice M., additional, Augustine, Alison D., additional, Guan, Leying, additional, Peters, Bjoern, additional, and Kleinstein, Steven H., additional

Published
2023
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10. Multi-omic longitudinal study reveals immune correlates of clinical course among hospitalized COVID-19 patients.

Author

Diray-Arce, Joann, Diray-Arce, Joann, Fourati, Slim, Doni Jayavelu, Naresh, Patel, Ravi, Maguire, Cole, Chang, Ana C, Dandekar, Ravi, Qi, Jingjing, Lee, Brian H, van Zalm, Patrick, Schroeder, Andrew, Chen, Ernie, Konstorum, Anna, Brito, Anderson, Gygi, Jeremy P, Kho, Alvin, Chen, Jing, Pawar, Shrikant, Gonzalez-Reiche, Ana Silvia, Hoch, Annmarie, Milliren, Carly E, Overton, James A, Westendorf, Kerstin, IMPACC Network, Cairns, Charles B, Rouphael, Nadine, Bosinger, Steven E, Kim-Schulze, Seunghee, Krammer, Florian, Rosen, Lindsey, Grubaugh, Nathan D, van Bakel, Harm, Wilson, Michael, Rajan, Jayant, Steen, Hanno, Eckalbar, Walter, Cotsapas, Chris, Langelier, Charles R, Levy, Ofer, Altman, Matthew C, Maecker, Holden, Montgomery, Ruth R, Haddad, Elias K, Sekaly, Rafick P, Esserman, Denise, Ozonoff, Al, Becker, Patrice M, Augustine, Alison D, Guan, Leying, Peters, Bjoern, Kleinstein, Steven H, Diray-Arce, Joann, Diray-Arce, Joann, Fourati, Slim, Doni Jayavelu, Naresh, Patel, Ravi, Maguire, Cole, Chang, Ana C, Dandekar, Ravi, Qi, Jingjing, Lee, Brian H, van Zalm, Patrick, Schroeder, Andrew, Chen, Ernie, Konstorum, Anna, Brito, Anderson, Gygi, Jeremy P, Kho, Alvin, Chen, Jing, Pawar, Shrikant, Gonzalez-Reiche, Ana Silvia, Hoch, Annmarie, Milliren, Carly E, Overton, James A, Westendorf, Kerstin, IMPACC Network, Cairns, Charles B, Rouphael, Nadine, Bosinger, Steven E, Kim-Schulze, Seunghee, Krammer, Florian, Rosen, Lindsey, Grubaugh, Nathan D, van Bakel, Harm, Wilson, Michael, Rajan, Jayant, Steen, Hanno, Eckalbar, Walter, Cotsapas, Chris, Langelier, Charles R, Levy, Ofer, Altman, Matthew C, Maecker, Holden, Montgomery, Ruth R, Haddad, Elias K, Sekaly, Rafick P, Esserman, Denise, Ozonoff, Al, Becker, Patrice M, Augustine, Alison D, Guan, Leying, Peters, Bjoern, and Kleinstein, Steven H

Abstract

The IMPACC cohort, composed of >1,000 hospitalized COVID-19 participants, contains five illness trajectory groups (TGs) during acute infection (first 28 days), ranging from milder (TG1-3) to more severe disease course (TG4) and death (TG5). Here, we report deep immunophenotyping, profiling of >15,000 longitudinal blood and nasal samples from 540 participants of the IMPACC cohort, using 14 distinct assays. These unbiased analyses identify cellular and molecular signatures present within 72 h of hospital admission that distinguish moderate from severe and fatal COVID-19 disease. Importantly, cellular and molecular states also distinguish participants with more severe disease that recover or stabilize within 28 days from those that progress to fatal outcomes (TG4 vs. TG5). Furthermore, our longitudinal design reveals that these biologic states display distinct temporal patterns associated with clinical outcomes. Characterizing host immune responses in relation to heterogeneity in disease course may inform clinical prognosis and opportunities for intervention.

Published
2023

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

Author

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

Published
2022
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12. NIAID Workshop on Flavivirus Immunity

Author

Augustine, Alison D., primary, Cassetti, M. Cristina, additional, Ennis, Francis A., additional, Harris, Eva, additional, Hildebrand, William H., additional, and Repik, Patricia M., additional

Published
2010
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13. Immunophenotyping assessment in a COVID-19 cohort (IMPACC): A prospective longitudinal study

Author

Rouphael, Nadine, Maecker, Holden, Montgomery, Ruth R., Diray-Arce, Joann, Kleinstein, Steven H., Altman, Matthew C., Bosinger, Steven E., Eckalbar, Walter, Guan, Leying, Hough, Catherine L., Krammer, Florian, Langelier, Charles, Levy, Ofer, McEnaney, Kerry, Peters, Bjoern, Rahman, Adeeb, Rajan, Jayant V., Sigelman, Steven, Steen, Hanno, van Bakel, Harm, Ward, Alyssa, Wilson, Michael R., Woodruff, Prescott, Zamecnik, Colin R., Augustine, Alison D., Ozonoff, Al, Reed, Elaine F., Becker, Patrice M., Higuita, Nelson Agudelo, Atkinson, Mark A., Baden, Lindsey R., Bime, Christian, Brakenridge, Scott C., Calfee, Carolyn S., Cairns, Charles B., Corry, David, Davis, Mark M., Ehrlich, Lauren I. R., Haddad, Elias K., Erle, David J., Fernandez-Sesma, Ana, Hafler, David A., Kheradmand, Farrah, Kraft, Monica, McComsey, Grace A., Melamed, Esther, Messer, William, Metcalf, Jordan, Nadeau, Kari C., Pulendran, Bali, Sarwal, Minnie, Schaenman, Joanna, Sekaly, Rafick, Shaw, Albert C., and Simon, Viviana

Subjects
Oncology, Data Analysis, Proteomics, medicine.medical_specialty, Longitudinal study, Immunology, Psychological intervention, MEDLINE, Immunophenotyping, Clinical Research, Internal medicine, Research Resources, medicine, Research Resource, Humans, Sampling (medicine), Longitudinal Studies, Prospective Studies, Prospective cohort study, SciImmunol r-resources, business.industry, SARS-CoV-2, Systems Biology, Gene Expression Profiling, COVID-19, Computational Biology, General Medicine, United States, Coronavirus, Hospitalization, Molecular Diagnostic Techniques, Cohort, Sample collection, business, Biomarkers
Abstract

Description, IMPACC is a multicenter longitudinal study assessing clinical and immunologic manifestations of COVID-19 in hospitalized patients., The Immunophenotyping Assessment in a COVID-19 Cohort (IMPACC) is a prospective longitudinal study designed to enroll 1000 hospitalized patients with COVID-19 (NCT04378777). IMPACC collects detailed clinical, laboratory, and radiographic data along with longitudinal biologic sampling of blood and respiratory secretions for in-depth testing. Clinical and laboratory data are integrated to identify immunologic, virologic, proteomic, metabolomic, and genomic features of COVID-19–related susceptibility, severity, and disease progression. The goals of IMPACC are to better understand the contributions of pathogen dynamics and host immune responses to the severity and course of COVID-19 and to generate hypotheses for identification of biomarkers and effective therapeutics, including optimal timing of such interventions. In this report, we summarize the IMPACC study design and protocols including clinical criteria and recruitment, multisite standardized sample collection and processing, virologic and immunologic assays, harmonization of assay protocols, high-level analyses, and the data sharing plans.

14. Unraveling SARS-CoV-2 Host-Response Heterogeneity through Longitudinal Molecular Subtyping.

Author

Wang K, Nie Y, Maguire C, Syphurs C, Sheen H, Karoly M, Lapp L, Gygi JP, Jayavelu ND, Patel RK, Hoch A, Corry D, Kheradmand F, McComsey GA, Fernandez-Sesma A, Simon V, Metcalf JP, Higuita NIA, Messer WB, Davis MM, Nadeau KC, Kraft M, Bime C, Schaenman J, Erle D, Calfee CS, Atkinson MA, Brackenridge SC, Hafler DA, Shaw A, Rahman A, Hough CL, Geng LN, Ozonoff A, Haddad EK, Reed EF, van Bakel H, Kim-Schultz S, Krammer F, Wilson M, Eckalbar W, Bosinger S, Langelier CR, Sekaly RP, Montgomery RR, Maecker HT, Krumholz H, Melamed E, Steen H, Pulendran B, Augustine AD, Cairns CB, Rouphael N, Becker PM, Fourati S, Shannon CP, Smolen KK, Peters B, Kleinstein SH, Levy O, Altman MC, Iwasaki A, Diray-Arce J, Ehrlich LIR, and Guan L

Abstract

Hospitalized COVID-19 patients exhibit diverse immune responses during acute infection, which are associated with a wide range of clinical outcomes. However, understanding these immune heterogeneities and their links to various clinical complications, especially long COVID, remains a challenge. In this study, we performed unsupervised subtyping of longitudinal multi-omics immunophenotyping in over 1,000 hospitalized patients, identifying two critical subtypes linked to mortality or mechanical ventilation with prolonged hospital stay and three severe subtypes associated with timely acute recovery. We confirmed that unresolved systemic inflammation and T-cell dysfunctions were hallmarks of increased severity and further distinguished patients with similar acute respiratory severity by their distinct immune profiles, which correlated with differences in demographic and clinical complications. Notably, one critical subtype (SubF) was uniquely characterized by early excessive inflammation, insufficient anticoagulation, and fatty acid dysregulation, alongside higher incidences of hematologic, cardiac, and renal complications, and an elevated risk of long COVID. Among the severe subtypes, significant differences in viral clearance and early antiviral responses were observed, with one subtype (SubC) showing strong early T-cell cytotoxicity but a poor humoral response, slower viral clearance, and greater risks of chronic organ dysfunction and long COVID. These findings provide crucial insights into the complex and context-dependent nature of COVID-19 immune responses, highlighting the importance of personalized therapeutic strategies to improve both acute and long-term outcomes.

Published
2024
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15. Chronic Viral Reactivation and Associated Host Immune Response and Clinical Outcomes in Acute COVID-19 and Post-Acute Sequelae of COVID-19.

Author

Maguire C, Chen J, Rouphael N, Pickering H, Phan HV, Glascock A, Chu V, Dandekar R, Corry D, Kheradmand F, Baden LR, Selaky R, McComsey GA, Haddad EK, Cairns CB, Pulendran B, Sesma AF, Simon V, Metcalf JP, Agudelo Higuita NI, Messer WB, David MM, Nadeau KC, Kraft M, Bime C, Schaenman J, Erle D, Calfee CS, Atkinson MA, Brackenridge SC, Ehrlich LIR, Montgomery RR, Shaw AC, Hough CL, Geng LN, Hafler DA, Augustine AD, Becker PM, Peters B, Ozonoff A, Kim-Schulze SH, Krammer F, Bosinger S, Eckalbar W, Altman MC, Wilson M, Guan L, Kleinstein SH, Smolen KK, Reed EF, Levy O, Maecker H, Hunt P, Steen H, Diray-Arce J, Langelier CR, and Melamed E

Abstract

Chronic viral infections are ubiquitous in humans, with individuals harboring multiple latent viruses that can reactivate during acute illnesses. Recent studies have suggested that SARS- CoV-2 infection can lead to reactivation of latent viruses such as Epstein-Barr Virus (EBV) and cytomegalovirus (CMV), yet, the extent and impact of viral reactivation in COVID-19 and its effect on the host immune system remain incompletely understood. Here we present a comprehensive multi-omic analysis of viral reactivation of all known chronically infecting viruses in 1,154 hospitalized COVID-19 patients, from the Immunophenotyping Assessment in a COVID-19 Cohort (IMPACC) study, who were followed prospectively for twelve months. We reveal significant reactivation of Herpesviridae , Enteroviridae , and Anelloviridae families during acute stage of COVID-19 (0-40 days post- hospitalization), each exhibiting distinct temporal dynamics. We also show that viral reactivation correlated with COVID-19 severity, demographic characteristics, and clinical outcomes, including mortality. Integration of cytokine profiling, cellular immunophenotyping, metabolomics, transcriptomics, and proteomics demonstrated virus-specific host responses, including elevated pro-inflammatory cytokines (e.g. IL-6, CXCL10, and TNF), increased activated CD4+ and CD8+ T-cells, and upregulation of cellular replication genes, independent of COVID-19 severity and SARS-CoV-2 viral load. Notably, persistent Anelloviridae reactivation during convalescence (≥3 months post-hospitalization) was associated with Post-Acute Sequelae of COVID-19 (PASC) symptoms, particularly physical function and fatigue. Our findings highlight a remarkable prevalence and potential impact of chronic viral reactivation on host responses and clinical outcomes during acute COVID-19 and long term PASC sequelae. Our data provide novel immune, transcriptomic, and metabolomic biomarkers of viral reactivation that may inform novel approaches to prognosticate, prevent, or treat acute COVID- 19 and PASC.

Published
2024
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16. Host-Microbe Multiomic Profiling Reveals Age-Dependent COVID-19 Immunopathology.

Author

Van Phan H, Tsitsiklis A, Maguire CP, Haddad EK, Becker PM, Kim-Schulze S, Lee B, Chen J, Hoch A, Pickering H, Van Zalm P, Altman MC, Augustine AD, Calfee CS, Bosinger S, Cairns C, Eckalbar W, Guan L, Jayavelu ND, Kleinstein SH, Krammer F, Maecker HT, Ozonoff A, Peters B, Rouphael N, Montgomery RR, Reed E, Schaenman J, Steen H, Levy O, Diray-Arce J, and Langelier CR

Abstract

Age is a major risk factor for severe coronavirus disease-2019 (COVID-19), yet the mechanisms responsible for this relationship have remained incompletely understood. To address this, we evaluated the impact of aging on host and viral dynamics in a prospective, multicenter cohort of 1,031 patients hospitalized for COVID-19, ranging from 18 to 96 years of age. We performed blood transcriptomics and nasal metatranscriptomics, and measured peripheral blood immune cell populations, inflammatory protein expression, anti-SARS-CoV-2 antibodies, and anti-interferon (IFN) autoantibodies. We found that older age correlated with an increased SARS-CoV-2 viral load at the time of admission, and with delayed viral clearance over 28 days. This contributed to an age-dependent increase in type I IFN gene expression in both the respiratory tract and blood. We also observed age-dependent transcriptional increases in peripheral blood IFN-γ, neutrophil degranulation, and Toll like receptor (TLR) signaling pathways, and decreases in T cell receptor (TCR) and B cell receptor signaling pathways. Over time, older adults exhibited a remarkably sustained induction of proinflammatory genes (e.g., CXCL6 ) and serum chemokines (e.g., CXCL9) compared to younger individuals, highlighting a striking age-dependent impairment in inflammation resolution. Augmented inflammatory signaling also involved the upper airway, where aging was associated with upregulation of TLR, IL17, type I IFN and IL1 pathways, and downregulation TCR and PD-1 signaling pathways. Metatranscriptomics revealed that the oldest adults exhibited disproportionate reactivation of herpes simplex virus and cytomegalovirus in the upper airway following hospitalization. Mass cytometry demonstrated that aging correlated with reduced naïve T and B cell populations, and increased monocytes and exhausted natural killer cells. Transcriptional and protein biomarkers of disease severity markedly differed with age, with the oldest adults exhibiting greater expression of TLR and inflammasome signaling genes, as well as proinflammatory proteins (e.g., IL6, CXCL8), in severe COVID-19 compared to mild/moderate disease. Anti-IFN autoantibody prevalence correlated with both age and disease severity. Taken together, this work profiles both host and microbe in the blood and airway to provide fresh insights into aging-related immune changes in a large cohort of vaccine-naïve COVID-19 patients. We observed age-dependent immune dysregulation at the transcriptional, protein and cellular levels, manifesting in an imbalance of inflammatory responses over the course of hospitalization, and suggesting potential new therapeutic targets.

Published
2024
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17. Integrated longitudinal multi-omics study identifies immune programs associated with COVID-19 severity and mortality in 1152 hospitalized participants.

Author

Gygi JP, Maguire C, Patel RK, Shinde P, Konstorum A, Shannon CP, Xu L, Hoch A, Jayavelu ND, Network I, Haddad EK, Reed EF, Kraft M, McComsey GA, Metcalf J, Ozonoff A, Esserman D, Cairns CB, Rouphael N, Bosinger SE, Kim-Schulze S, Krammer F, Rosen LB, van Bakel H, Wilson M, Eckalbar W, Maecker H, Langelier CR, Steen H, Altman MC, Montgomery RR, Levy O, Melamed E, Pulendran B, Diray-Arce J, Smolen KK, Fragiadakis GK, Becker PM, Augustine AD, Sekaly RP, Ehrlich LIR, Fourati S, Peters B, Kleinstein SH, and Guan L

Abstract

Hospitalized COVID-19 patients exhibit diverse clinical outcomes, with some individuals diverging over time even though their initial disease severity appears similar. A systematic evaluation of molecular and cellular profiles over the full disease course can link immune programs and their coordination with progression heterogeneity. In this study, we carried out deep immunophenotyping and conducted longitudinal multi-omics modeling integrating ten distinct assays on a total of 1,152 IMPACC participants and identified several immune cascades that were significant drivers of differential clinical outcomes. Increasing disease severity was driven by a temporal pattern that began with the early upregulation of immunosuppressive metabolites and then elevated levels of inflammatory cytokines, signatures of coagulation, NETosis, and T-cell functional dysregulation. A second immune cascade, predictive of 28-day mortality among critically ill patients, was characterized by reduced total plasma immunoglobulins and B cells, as well as dysregulated IFN responsiveness. We demonstrated that the balance disruption between IFN-stimulated genes and IFN inhibitors is a crucial biomarker of COVID-19 mortality, potentially contributing to the failure of viral clearance in patients with fatal illness. Our longitudinal multi-omics profiling study revealed novel temporal coordination across diverse omics that potentially explain disease progression, providing insights that inform the targeted development of therapies for hospitalized COVID-19 patients, especially those critically ill.

Published
2023
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