Longitudinal analyses reveal immunological misfiring in severe COVID-19
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Abstract
Recent studies have provided insights into the pathogenesis of coronavirus disease 2019 (COVID-19)1-4. However, the longitudinal immunological correlates of disease outcome remain unclear. Here we serially analysed immune responses in 113 patients with moderate or severe COVID-19. Immune profiling revealed an overall increase in innate cell lineages, with a concomitant reduction in T cell number. An early elevation in cytokine levels was associated with worse disease outcomes. Following an early increase in cytokines, patients with moderate COVID-19 displayed a progressive reduction in type 1 (antiviral) and type 3 (antifungal) responses. By contrast, patients with severe COVID-19 maintained these elevated responses throughout the course of the disease. Moreover, severe COVID-19 was accompanied by an increase in multiple type 2 (anti-helminths) effectors, including interleukin-5 (IL-5), IL-13, immunoglobulin E and eosinophils. Unsupervised clustering analysis identified four immune signatures, representing growth factors (A), type-2/3 cytokines (B), mixed type-1/2/3 cytokines (C), and chemokines (D) that correlated with three distinct disease trajectories. The immune profiles of patients who recovered from moderate COVID-19 were enriched in tissue reparative growth factor signature A, whereas the profiles of those with who developed severe disease had elevated levels of all four signatures. Thus, we have identified a maladapted immune response profile associated with severe COVID-19 and poor clinical outcome, as well as early immune signatures that correlate with divergent disease trajectories.
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A longitudinal analysis confirmed an early peak with subsequent decline of IFNα and IFNλ in mild-to-moderate COVID-19, whereas levels further increased particularly during the second week in severe patients.
“A longitudinal analysis confirmed an early peak with subsequent decline of IFNα and IFNλ in mild-to-moderate COVID-19, whereas levels further increased particularly during the second week in severe patients (Lucas et al., 2020).”
From COVID-19 and the human innate immune system (2021) · cites this paper as Lucas et al., 2020
A current model holds that SARS-CoV-2 enters type II pneumocytes via ACE2, causing rapid replication and a proinflammatory state with elevated IL-1, IL-6, CXCL8, and TNF.
“SARS-CoV-2 enters type II pneumocytes via ACE2 in the respiratory system leading to rapid virus replication as well as concomitantly to a proinflammatory state with elevated levels of cytokines such as IL-1, IL-6, CXCL8, and TNF”
From COVID-19 and the human innate immune system (2021) · cites this paper as Lucas et al., 2020
Other classifiers that incorporated immune mediators were created to forecast death or recovery.
“Several other classifiers, including immune mediators, (Lucas et al., 2020) were developed for predicting fatality or convalescence”
From COVID-19 and the human innate immune system (2021) · cites this paper as Lucas et al., 2020
pDCs are reduced and functionally impaired in COVID-19, suggesting the lung is a source of elevated plasma type I IFNs early in infection.
“suggesting the lung as a source for the elevated plasma levels of type I IFNs early on infection”
From COVID-19 and the human innate immune system (2021) · cites this paper as Lucas et al., 2020
Single-cell transcriptomics of circulating innate immune cells supports a general IFN response in all COVID-19 patients with a strong temporal component.
“Single-cell transcriptomics of circulating innate immune cells strongly support a general IFN response in all COVID-19 patients with a strong temporal component”
From COVID-19 and the human innate immune system (2021) · cites this paper as Lucas et al., 2020
Sustained increases in neutrophils and monocytes in the blood are associated with severe COVID-19.
“studies have shown that the sustained presence of increased neutrophils and monocytes in the blood are associated with severe COVID-19 disease89,90.”
From SARS-CoV-2, COVID-19 and the aging immune system (2021) · cites this paper as [90]
SARS-CoV-2 infection induces a broad inflammatory response well beyond the typical type-1 immune response seen with other respiratory viral infections.
“SARS-CoV-2 infection induces a broad inflammatory response—well beyond the typical type-1 immune response seen with other respiratory viral infections (Lucas et al., 2020).”
From Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation (2022) · cites this paper as Lucas et al., 2020
The particularly immunogenic nature of SARS-CoV-2, the persistence of the neuroinflammatory changes observed here, and the magnitude of the population infected during this pandemic contribute to the emerging crisis of lasting cognitive impairment associated with COVID.
“The particularly immunogenic nature of SARS-CoV-2 (Lucas et al., 2020) and the persistence of the neuroinflammatory changes observed here, together with the magnitude of the population infected during this pandemic, contribute to the emerging crisis of lasting cognitive impairment associated with COVID.”
From Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation (2022) · cites this paper as Lucas et al., 2020
Patient plasma was collected with informed consent and IRB approval.
“Patient plasma was collected with informed consent and IRB approval as previously described (Lucas et al., 2020).”
From Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation (2022) · cites this paper as Lucas et al., 2020
The correlation between nasopharyngeal viral load and cytokine levels, as well as a declining viral load in moderate but not severe cases, suggests that the immune response is positively associated with viral burden.
“The correlation between the nasopharyngeal viral load and cytokine levels (e.g., interferon-α, interferon-γ, and TNF), as well as a declining viral load in moderate but not severe cases, suggests that the immune response is positively associated with the viral burden.26”
From Cytokine storm (2020) · cites this paper as [26]
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- Authors
- Lucas, C., Wong, P., Klein, J., Castro, T. B. R., Silva, J., Sundaram, M., Ellingson, M. K., Mao, T., Oh, J. E., Israelow, B., Takahashi, T., Tokuyama, M., Lu, P., Venkataraman, A., Park, A., Mohanty, S., Wang, H., Wyllie, A. L., Vogels, C. B. F., Earnest, R., Lapidus, S., Ott, I. M., Moore, A. J., Muenker, M. C., Fournier, J. B., Campbell, M., Odio, C. D., Casanovas-Massana, A., Yale IMPACT Team, Obaid, A., Lu-Culligan, A., Nelson, A., Brito, A., Nunez, A., Martin, A., Watkins, A., Geng, B., Kalinich, C., Harden, C., Todeasa, C., Jensen, C., Kim, D., McDonald, D., Shepard, D., Courchaine, E., White, E. B., Song, E., Silva, E., Kudo, E., DeIuliis, G., Rahming, H., Park, H.-J., Matos, I., Nouws, J., Valdez, J., Fauver, J., Lim, J., Rose, K.-A., Anastasio, K., Brower, K., Glick, L., Sharma, L., Sewanan, L., Knaggs, L., Minasyan, M., Batsu, M., Petrone, M., Kuang, M., Nakahata, M., Campbell, M., Linehan, M., Askenase, M. H., Simonov, M., Smolgovsky, M., Sonnert, N., Naushad, N., Vijayakumar, P., Martinello, R., Datta, R., Handoko, R., Bermejo, S., Prophet, S., Bickerton, S., Velazquez, S., Alpert, T., Rice, T., Khoury-Hanold, W., Peng, X., Yang, Y., Cao, Y., Strong, Y., Herbst, R., Shaw, A. C., Medzhitov, R., Schulz, W. L., Grubaugh, N. D., Dela Cruz, C., Farhadian, S., Ko, A. I., Omer, S. B., & Iwasaki, A.
- Affiliations
- Yale University (US)
- Rockefeller University (US)
- Yale New Haven Hospital (US)
- Yale Cancer Center (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Iwasaki, Akiko
- ORCID
- Lucas, Carolina
- Wong, Patrick
- Klein, Jon
- Castro, Tiago B. R.
- Sundaram, Maria
- Ellingson, Mallory K.
- Mao, Tianyang
- Oh, Ji Eun
- Israelow, Benjamin
- Takahashi, Takehiro
- Tokuyama, Maria
- Lu, Peiwen
- Venkataraman, Arvind
- Park, Annsea
- Mohanty, Subhasis
- Wang, Haowei
- Wyllie, Anne L.
- Vogels, Chantal B. F.
- Earnest, Rebecca
- Lapidus, Sarah
- Ott, Isabel M.
- Moore, Adam J.
- Muenker, M. Catherine
- Fournier, John B.
- Odio, Camila D.
- Obaid, Abeer
- Lu-Culligan, Alice
- Brito, Anderson
- Martin, Anjelica
- Geng, Bertie
- Kalinich, Chaney
- Harden, Christina
- Kim, Daniel
- White, Elizabeth B.
- Song, Eric
- Silva, Erin
- Kudo, Eriko
- DeIuliis, Giuseppe
- Park, Hong-Jai
- Nouws, Jessica
- Valdez, Jordan
- Fauver, Joseph
- Lim, Joseph
- Rose, Kadi-Ann
- Glick, Laura
- Sharma, Lokesh
- Sewanan, Lorenzo
- Petrone, Mary
- Linehan, Melissa
- Askenase, Michael H.
- Simonov, Michael
- Sonnert, Nicole
- Vijayakumar, Pavithra
- Datta, Rupak
- Handoko, Ryan
- Bermejo, Santos
- Prophet, Sarah
- Bickerton, Sean
- Velazquez, Sofia
- Alpert, Tara
- Rice, Tyler
- Khoury-Hanold, William
- Peng, Xiaohua
- Yang, Yexin
- Cao, Yiyun
- Herbst, Roy
- Shaw, Albert C.
- Medzhitov, Ruslan
- Schulz, Wade L.
- Grubaugh, Nathan D.
- Farhadian, Shelli
- Ko, Albert I.
- Omer, Saad B.
- Iwasaki, Akiko
- Venue
- Nature
- Published
- 2020-07-27
- Volume
- 584
- Issue
- 7821
- Pages
- 463-469
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC7477538
- OpenAlex
- W3043831218
- Cited by
- 2,074
- References
- 30
- Citations by year
- 2026: 109 · 2025: 104 · 2024: 220 · 2023: 367 · 2022: 486 · 2021: 630 · 2020: 155
- FWCI
- 53.92
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Nature (publishedVersion)
- medRxiv (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (1s10od026996-01, UL1TR001863)
- National Institute on Aging (K24AG042489)
- National Institute of General Medical Sciences (T32GM007205)
- National Institute of Allergy and Infectious Diseases (R01AI127429, T32AI007210, T32AI007517)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Health Sciences › Medicine › Neurology › Long-Term Effects of COVID-19
- Keywords
- severe COVID-19, cytokines, type I interferon response, type 2 cytokines, IL-5, IL-13, immunoglobulin E, eosinophils, innate immune cells, T cell depletion, disease trajectories, immune signatures, chemokines, growth factors, tissue repair, disease outcome
- MeSH terms
- COVID-19, Adult, Aged, Aged, 80 and over, Eosinophils, Female, Humans, Immunoglobulin E, Male, Middle Aged, Pneumonia, Viral, T-Lymphocytes, Interleukin-5, Cluster Analysis, Cytokines, Coronavirus Infections, Interleukin-13, Viral Load, Young Adult, Pandemics
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