TY - JOUR
T1 - Longitudinal analyses reveal immunological misfiring in severe COVID-19
AU - Yale IMPACT Team
AU - Lucas, Carolina
AU - Wong, Patrick
AU - Klein, Jon
AU - Castro, Tiago B.R.
AU - Silva, Julio
AU - Sundaram, Maria
AU - Ellingson, Mallory K.
AU - Mao, Tianyang
AU - Oh, Ji Eun
AU - Israelow, Benjamin
AU - Takahashi, Takehiro
AU - Tokuyama, Maria
AU - Lu, Peiwen
AU - Venkataraman, Arvind
AU - Park, Annsea
AU - Mohanty, Subhasis
AU - Wang, Haowei
AU - Wyllie, Anne L.
AU - Vogels, Chantal B.F.
AU - Earnest, Rebecca
AU - Lapidus, Sarah
AU - Ott, Isabel M.
AU - Moore, Adam J.
AU - Muenker, M. Catherine
AU - Fournier, John B.
AU - Campbell, Melissa
AU - Odio, Camila D.
AU - Casanovas-Massana, Arnau
AU - Obaid, Abeer
AU - Lu-Culligan, Alice
AU - Nelson, Allison
AU - Brito, Anderson
AU - Nunez, Angela
AU - Martin, Anjelica
AU - Watkins, Annie
AU - Geng, Bertie
AU - Kalinich, Chaney
AU - Harden, Christina
AU - Todeasa, Codruta
AU - Jensen, Cole
AU - Kim, Daniel
AU - McDonald, David
AU - Shepard, Denise
AU - Courchaine, Edward
AU - White, Elizabeth B.
AU - Song, Eric
AU - Silva, Erin
AU - Kudo, Eriko
AU - DeIuliis, Giuseppe
AU - Fauver, Joseph
N1 - Funding Information:
Acknowledgements We thank M. Linehan for technical and logistical assistance, and A. Wang, A. Ring, C. Wilen and D. Mucida for discussions. This work was supported by the Women’s Health Research at Yale Pilot Project Program (A.I.), Fast Grant from Emergent Ventures at the Mercatus Center, Mathers Foundation, and the Ludwig Family Foundation, the Department of Internal Medicine at the Yale School of Medicine, Yale School of Public Health and the Beatrice Kleinberg Neuwirth Fund. IMPACT received support from the Yale COVID-19 Research Resource Fund. A.I. is an Investigator of the Howard Hughes Medical Institute. C.L. is a Pew Latin American Fellow. P.W. is supported by Gruber Foundation and the NSF. B.I. is supported by NIAID 2T32AI007517-16. C.B.F.V. is supported by NOW Rubicon 019.181EN.004.
Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2020/8/20
Y1 - 2020/8/20
N2 - 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.
AB - 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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U2 - 10.1038/s41586-020-2588-y
DO - 10.1038/s41586-020-2588-y
M3 - Article
C2 - 32717743
AN - SCOPUS:85088583601
SN - 0028-0836
VL - 584
SP - 463
EP - 469
JO - Nature
JF - Nature
IS - 7821
ER -