Nature - USA (2020-08-20)

Nature | Vol 584 | 20 August 2020 | 465

in patients with severe disease than in those with moderate disease. By
contrast, IL-4 levels were not significantly different. However, IL-4, simi-
lar to IL-5 and IL-13, showed an upward trend over the course of disease

in patients with severe COVID-19 (Fig. 2e). The type 2 antibody isotype

IgE was also higher in patients with severe diasease and continued to

increase during the disease course (Fig. 2e).

Uninfected

(108HCWs)

Moderate

(80patients)

Severe

(33patients)

Clinical score

6

0

1

4

5

3

2

>6 l min−1

>2 or >3 l min−1

1–3 l min−1

None

SARS-CoV-2 negative

(qPCRandserologynegative)

Low O 2 supplement

ModerateO 2

supplement

ICU

MV

D

Hospital admission

Yale IMPACT Study

Supplemental O 2

d

Moderate

Sever

e

–1.0 –0.8 –0.6 –0.4 –0.2 0 0.2 0.4 0.6 0.8 1.0

VEGF

A

PDGFAA

PDGF

AB/B

IL-7IL-8

Eotaxin2CXCL^5

TP O

SDF1

a/B

LIF

IL-18IgE

CCL22TR AIL

IL-1RACCL2

CCL1TNFα

MCSFIL-10

CCL21

IL-12p

40

IL-17AIL-1b

IL-4IL-2

GMCSFTNFβ

CCL7

EotaxinIFNα^2

FL T3LIL-27

IL-23IL-21

CCL3

EGF

sCD40LCXCL1

CCL4TGFα

CCL17IL-17F

IL-33IL-20

IFNL2CCL5

CCL27

CXCL13CCL15

CXCL9IL-6

CX3CL1IL-15

CCL8

CXCL10GCSF

IL-1a

FGF2IL-22

IL-17E

/IL-25

IL-12p

70

IL-13IFNγ

CCL13

Eotaxin3IL-3

IL-5

TSLPIL-16

IL-9SCF

P = 0.81P = 0.14

P = 0.082

0

1

2

3

IL-1b

P = 2.1× 10 –6

P = 1.8×P 10 = –70.028

0

2

4

IL-18

P = P0.042 = 6.9×^10

P = –50.041

0

1

2

3

4

5

IFNγ

HCW Moderate Severe HCW Moderate Severe

HCW Moderate Severe

P = 0.51P = 0.038

P = 0.048

0

3

IL-17A

1

2

HCW Moderate Severe

P = 0.0089

P = 0.016P = 0.42

0

2

4

IL-1a

P < 2.22× 10 –16

P = 3.4P× 10 = 1.1–15×^10

–7

0

2

4

IL-6

log

pg ml 10

–1

log

pg ml 10

–1

log

pg ml 10

–1

log

pg ml 10

–1

P = 0.0014P = 0.00021

P = 0.13

1

2

3

4

IFNα

PP = = 4.17.1× 10 ×^10 –9

P = 0.012–10

0

1

2

CCL1

e

fg

c T cells

Cells per ml (

×^10

6 )

Per cent of live cells

Monocytes

P< 2.22 P< 2.22 × 10 −16×^10

P = 1.9 −16× 10 −5

0

10

20

30

P = 5.1 × 10 −10

P = 4.9 P× 10 = 0.064−9

0.0

0.1

0.2

0.3

HCWModerateSevere

Neutrophils

P = 1.2 P = 2.3 × 10 −10×^10

P = 0.09−11

0.0

2.5

5.0

7.5

10.0

P = 5.4 P = 4.2 × 10 −5×^10

P = 0.016−9

0.000

0.025

0.050

0.075

0.100

HCWModerateSevere

Eosinophils

P = 3.7 × 10 −10

P = 9 P = 0.41× 10 −8

0.0

0.5

1.0

1.5

2.0

0

P = 6.3 P < ×2.22 10 −16×^10

P = 2.4 −16× 10 −6

25

50

75

100

HCWModerateSevere

0

P = 2.4 P× = 1 10 −10×^10

P = 0.0037−11

20

40

60

HCWModerateSevere

P = 0.057

P = 0.0023P = 0.058

0.0

0.5

1.0

1.5

2.0

Z-score of

cell frequency:

–4

–2

0

2

4

Severe

Moderate

HCW

b

Eoso Neut

ncMonocMonoointMonoB cells

DC2DC1pDCT-CD8T-CD4NKTNK

a Immune cell subsets in PBMC

Fig. 1 | Overview of immunological features in patients with COVID-19.
a, Overview of cohort, including healthy donors (HCWs) and patients with
moderate or severe COVID-19. Ordinal scores assigned according to clinical
severity scale as described in Methods. D, deceased; ICU, intensive care
unit; MV, mechanical ventilation. b, Heat map comparison of the major immune
cell populations within PBMCs in patients with moderate (n = 121) or severe
(n = 43) COVID-19, or HCSs (n = 43). n values represent a separate time point per
subject Subjects are arranged across rows, with each coloured unit indicating
the relative distribution of an immune cell population normalized against the
same population across all subjects. K-means clustering was used to arrange
patients and measurements. Eoso, eosinophil; ncMono, non-classical
monocyte; neut, neutrophil; cMono, classical monocyte; intMono,
intermediate monocyte; DC2 and DC1, type 2 and 1 dendritic cells, respectively;
pDC, plasmacytoid dendritic cell; T-CD8 and T-CD4, CD8+ and CD4+ T cells,

respectively; NKT, natural killer T cell; NK, natural killer cell. c, Immune cell

subsets plotted as a concentration of millions of cells per millilitre of blood or

as a percentage of live single cells. Each dot represents a separate time point

per subject (HCW, n = 50; moderate, n = 117; severe, n = 40). d, Correlation

matrices across all time points of 71 cytokines from patient blood, comparing

patients with moderate and severe disease. Only significant correlations

(<0.05) are represented as dots. Pearson’s correlation coefficients from

comparisons of cytokine measurements within the same patients are

visualized by colour intensity. e–g, Quantification of prominent inf lammatory

cytokines (e), interferons type I and II (f), and CCL1 and IL-17 (g) presented as

log 10 -transformed concentrations. Each dot represents a separate time point

per subject (HCW, n = 50; moderate, n = 117; severe, n = 40). Centre, median; box

limits, first and third percentiles; whiskers, 1.5× interquartile range (IQR).

Significance determined by two-sided, Wilcoxon rank-sum test.